Histamine H4 receptor and TRPV1 mediate itch induced by cadaverine, a metabolite of the microbiome.

Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1-/- but not Trpa1-/- mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1-/- mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons.

Decorating Cage-Shaped Cavities with Carboxyl Groups on Two-Dimensional MOF Nanosheet for Trace Uranium(VI) Trapping.

The efficient and complete extraction of uranium from aqueous solutions is crucial for safeguarding human health from potential radiotoxicity and chemotoxicity. Herein, an ultrathin 2D metal-organic framework (MOF) nanosheet with cavity structures was elaborately constructed, based on a calix[4]arene ligand. The large molecular skeleton and cup-shaped feature of the calix[4]arene enabled the as-prepared MOFs with large layer separations, which can be readily delaminated into ultrathin single-layer (∼1.25 nm) nanosheets. The incorporation of permanent cavity structures to the MOF nanosheets can fully utilize their structural features of readily accessible adsorption groups and exposed surface area in uranium removal, reaching ultrafast adsorption kinetics; the functionalized cavity structure endowed MOF nanosheets with the ability to preconcentrate and extract uranium from aqueous solutions with ultrahigh efficiencies, even at extremely low concentrations. As a result, relatively high removal ratios (>95%) can be achieved for uranium within 5 min, even in the ultralow concentration range of 75-250 ppb, and the residual uranium was reduced to below 4.9 ppb. The MOF nanosheets also exhibited extremely high anti-interference ability, which could efficiently remove the low-level uranium (∼150 ppb) from various real samples. The characterizations and density functional theory calculations demonstrated that the synergistic effects of multiple interactions between the carboxylate groups and cage-like cavities with uranyl ions can be responsible for the efficient and selective uranium extraction.

LINC00365 inhibited lung adenocarcinoma progression and glycolysis via sponging miR-429/KCTD12 axis.

This study researched the function of long non-coding RNA LINC00365 in lung adenocarcinoma (LAD) progression. LINC00365, miR-429, and KCTD12 expression in the LAD clinical tissues and cells were detcetd by qRT-PCR and Western blot. LINC00365, miR-429, and KCTD12 effects on H1975 cells malignant phenotype were detected by cell counting kit-8 assay, clone formation experiment, Transwell experiment, and glycolysis. Dual luciferase reporter gene assay and RNA pull-down assay were implemented. LINC00365 effect on H1975 cells in vivo growth was detected. LINC00365 was low expressed in the LAD patients and cells, associating with poor outcome. LINC00365 up-regulation attenuated H1975 cells proliferation, migration, invasion, glycolysis and in vivo growth. LINC00365 inhibited KCTD12 expression by sponging miR-429. miR-429 up-regulation and KCTD12 down-regulation partial reversed LINC00365 inhibition on H1975 cells malignant phenotype. Thus, LINC00365 inhibited LAD progression and glycolysis via targeting miR-429/KCTD12 axis. LINC00365 might be a potential candidate for LAD target treatment clinically.

[Trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy for large-volume benign prostate hyperplasia].

OBJECTIVE: To report the safety and efficacy of trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy (RSS-RASP) in the treatment of large-volume BPH. METHODS: This retrospective study included 24 cases of large-volume (>80 ml) BPH treated by trans-Douglas RSS-RASP from August 2019 to June 2021. The patients ranged in age from 55 to 80 (mean 68.5) years, with an average body mass index of 25.1 (20.5－34.9) kg/m2 , median prostate volume of 132.4 (85.6－235.7) ml, and preoperative tPSA of 10.8 (0.5－37.9) ng/ml, IPSS of 25 (3－35) and quality of life (QOL) score of 5 (3－8). Before surgery, 12 of the patients received catheterization for urinary retention, 1 underwent cystostomy, 2 were complicated with hydronephrosis, 1 had stones and diverticulum in the bladder, and 14 were excluded from the cases of PCa by prostatic biopsy. The operation time, intraoperative blood loss, hemoglobin level on the first day after surgery, blood transfusion, and intra- and postoperative complications were recorded. The patients were followed up for 3 to 21 months postoperatively. Comparisons were made before and after operation in the IPSS, maximum urinary flow rate (Qmax), postvoid residual volume (PVR), QOL score, IIEF score and Male Sexual Health Questionnaire (MSHQ) score. RESULTS: Trans-Douglas RSS-RASP was successfully completed in all the 24 cases, with a mean operation time of 175 (100－285) min, intraoperative blood loss of 200 (50－800) ml, hemoglobin decrease of 25 (4－57) g/L on the first day after surgery, postoperative drainage tube indwelling of 3 (2－7) d, and urinary catheterization of 12 (4－18) d. Six (25%) of the patients received intraoperative blood transfusion, 1 underwent transurethral electrocoagulation hemostasis 1 month after surgery because of postoperative bleeding, and 1 received transurethral resection of the cicatrical adhesive tissue of the bladder neck 12 months after surgery. No other complications occurred postoperatively. The IPSS (3 ［1－7］), Qmax (19.6 ［9.9－32.1］ ml/s), PVR (0 ［0－34.9］ ml) and QOL score (2 ［0－3］) of the patients were significantly improved after surgery (P < 0.05), but no statistically significant differences were observed in the IIEF (20 ［19－24］) and MSHQ scores (14 ［13－14］) as compared with the baseline (P > 0.05). CONCLUSION: Trans-Douglas RSS-RASP is a safe and effective minimally invasive method for the treatment of large-volume (>80 ml) BPH, which can improve the urinary function of the patient after operation.

[Combination of serum PSA assay, multi-parametric MRI and targeted prostate biopsy for prostate cancer screening in Nanjing].

OBJECTIVE: To investigate the exact prevalence of PCa among males in Nanjing and search for a mode of PCa screening suitable for the specific conditions. METHODS: From January to December 2018, we collected serum samples and clinical information from 6 903 men aged ≥50 years taking physical examination in 16 community health service centers in Nanjing. We proposed multi-parametric MRI (mpMRI) for those with serum PSA ≥4 µg/L, transperineal systematic biopsy and MRI/ultrasound fusion targeted prostate biopsy for those who scored ≥3 points on the Prostate Imaging-Reporting and Data System Version 2 (PI-RADS v2), transperineal systematic biopsy only for those with a PI-RADS v2 score of <3 and serum PSA ≥10 µg/L, and follow-up examinations every 6 months for those with a PI-RADS v2 score of <3 and serum PSA <4 µg/L. RESULTS: Among the 6 903 male subjects, 835 (12.1%) were found with serum PSA≥4 µg/L; 229 (77.4%) of the 296 men that received mpMRI scored ≥3 points on PI-RADS v2; and 79 (53.4%) of the 148 males that underwent prostate biopsy were diagnosed with PCa, with a total detection rate of 1.14% in all the subjects. Of the 77 patients with complete pathological data, 73 (94.8%) were found with clinically significant PCa, 30 (39.0%) with localized, 41 (53.2%) with locally advanced and 6 (7.8%) with metastatic malignancy, 6 (7.8%) in stage Ⅰ, 21 (27.3%) in stage Ⅱ, 34 (44.2%) in stage Ⅲ and 16 (20.8%) in stage Ⅳ. There were 47 (66.2%) high-risk, 18 (25.4%) moderate-risk and 6 (8.5%) low-risk cases among those with localized or locally advanced PCa. CONCLUSIONS: The prevalence of PCa in Nanjing deserves considerable attention, and PCa screening is highly necessary in the high-risk population, for which the combination of serum PSA assay, mpMRI and targeted prostate biopsy may be an ideal method.

Association between polymorphisms of the CYP11A1 gene and polycystic ovary syndrome in Chinese women.

The cholesterol side chain cleavage enzyme (CYP11A1) gene plays an important part in the synthesis of sex hormones and has been reported to be involved in the pathogenesis of polycystic ovary syndrome. A case-control study including 314 PCOS patients and 314 controls was conducted to assess the association of the SNPs rs4077582 and rs11632698 in CYP11A1 with PCOS using the polymerase chain reaction-restriction fragment length polymorphism method. Thereafter, 100 DNA samples were re-genotyped by direct sequencing for confirmation. The genotypic distribution of rs4077582 in women with PCOS differed from that in controls (P = 0.002). No such distributional difference was found in rs11632698 (P = 0.912). Data from our previous study of these two SNPs in another population including 290 PCOS patients and 344 controls was combined with the current data. Combined analysis (a total of 1262 participants, including 604 PCOS patients and 658 control women) showed a much more significant difference in the genotypic distribution of rs4077582 between PCOS and controls (P < 0.001). The T allele was more prevalent in PCOS patients (Odds ratio = 1.314; 95 % CI 1.122-1.540). The testosterone levels among the three genotypes for rs4077582 were different in the control group, as were the LH levels and the LH/FSH ratio. Therefore, SNP rs4077582 in CYP11A1 is strongly associated with susceptibility to PCOS and may alter the testosterone levels by the regulation of LH in different genotypes. No association was observed in rs11632698.

Ephrin-B2/Fc promotes proliferation and migration, and suppresses apoptosis in human umbilical vein endothelial cells.

Tumor growth and metastasis are angiogenesis dependent. Angiogenic growth involves endothelial cell proliferation, migration, and invasion. Ephrin-B2 is a ligand for Eph receptor tyrosine kinases and is an important mediator in vascular endothelial growth factor-mediated angiogenesis. However, research offer controversial information regarding effects of ephrin-B2 on vascular endothelial cells. In this paper, proteome analyses showed that ephrin-B2/Fc significantly activates multiple signaling pathways related to cell proliferation, survival, and migration and suppresses apoptosis and cell death. Cytological experiments further confirm that ephrin-B2/Fc stimulates endothelial cell proliferation, triggers dose-dependent migration, and suppresses cell apoptosis. Results demonstrate that soluble dose-dependent ephrinB2 can promote proliferation and migration and inhibit apoptosis of human umbilical vein endothelial cells. These results also suggest that ephrinB2 prevents ischemic disease and can potentially be a new therapeutic target for treating angiogenesis-related diseases and tumors.

Tissue-engineered heart valve on acellular aortic valve scaffold: in-vivo study.

The feasibility of constructing a tissue-engineered heart valve on an acellular porcine aortic valve leaflet was evaluated. A detergent and enzymatic extraction process was developed to remove the cellular components from porcine aortic valves. The acellular valve leaflets were seeded for 7 days in vitro with cells from canine arterial wall and endothelial cells. The constructs were implanted into the lumens of 6 canine abdominal aortas to assess the reconstruction of the valve leaflets. It was found that all cellular components had been removed from the porcine aortic valves. The valve leaflets were completely reconstructed at the end of the 10th week in vivo. Scanning electron microscopy showed that the valve leaflets were partially covered with endothelial cells. It was concluded that porcine aortic valves can be decellularized by the detergent and enzymatic extraction process and it is feasible to construct a tissue-engineered heart valve in vivo on an acellular valve scaffold.

SNP rs2470152 in CYP19 is correlated to aromatase activity in Chinese polycystic ovary syndrome patients.

CYP19 encodes aromatase, a key enzyme essential for estrogen biosynthesis. Single nucleotide polymorphism (SNP) rs2470152 in CYP19 is associated with serum estradiol (E2) level and the E2/T (estradiol/testosterone) ratio. A case­control study including 661 individuals [364 polycystic ovary syndrome (PCOS) patients and 297 controls] was conducted to assess the association of SNP rs2470152 with PCOS. The subjects were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Hormone levels were analyzed among various genotypes. The genotypic distributions of rs2470152 did not differ in PCOS patients when compared to the controls. However, differences in the E2/T ratio were detected, exhibiting a lower ratio in the heterozygous TC genotype in PCOS patients (p=0.01036) and controls (p=0.000). Testosterone levels also differed between the three genotypes of PCOS patients (p=0.00625), with a higher level in the TC genotype. Therefore, rs2470152 in CYP19 was not a major etiological factor for PCOS; however, the heterozygous TC genotype may inhibit aromatase activity, resulting in hyperandrogenism, particularly in PCOS patients.