The aim of this study was to explore the effects and mechanisms of Icarisid II (ICA-II) on enhancing the cellular cGMP in rat corpus cavernosum tissue (RCCT). Diabetes mellitus Wistar rats were induced by streptozotocin, and diabetic ED rats were selected for the RCCT culture by apomorphine. ICA-II was extracted and purified from Icariin (ICA) by enzymatic method. The RCCT was treated with ICA-II, ICA and Sildenafil at different concentrations. cGMP and nitric oxide synthase (NOS) activities were checked respectively by enzyme immunoassay. Meanwhile, nNOS, iNOS and eNOS in RCCT were checked by western blot. ICA-II evaluated the intracellular cGMP to 8.01 ± 1.02 pmol mg(-1) min(-1), which is much weaker than that from Sildenafil (12.4 ± 1.16 pmol mg(-1) min(-1)) (P < 0.05). There is no significant difference between ICA-II and ICA. With the treatment of 10 μm ICA-II for 24 and 48 h, nNOS expression was significantly increased in RCCT (P < 0.05), while the eNOS expression level was very low without any change. Notably, ICA-II increased the intracellular NOS activity significantly in vitro in RCCT. Except the PDE5 inhibitory effect, ICA-II increases the intracellular cGMP through the enhancement of nNOS expression and NOS activity in RCCT in vitro. ICA-II implies a potential compound for neurogenic erectile dysfunction by NO-cGMP pathway.

The abnormality of a single podocyte molecule, caused by a single gene mutation, such as NPHS1, NPHS2, CD2AP, and ACTN4, can lead to the hereditary/congenital nephrotic syndromes (NS). Further studies suggested that more than one podocyte molecule were together involved in acquired or experimental NS. However, we do not know much on the relationship among these podocyte molecules, and the molecular response induced by the change of each podocyte protein to the remaining ones. We respectively knockdown the nephrin, podocin, CD2AP, or alpha-actinin-4 mRNA by using reconstructed RNA interference vector--psiRNA-hH1GFPzeo in mouse podocyte clone. The molecular behavior or response was revealed by the quantitative expression both at mRNA and protein levels with RT-PCR and Western blot, and by the molecular distribution detected with confocal microscopy. With nephrin knockdown, only CD2AP increased, whereas podocin showed no change. Contrarily, with podocin or CD2AP knockdown, nephrin decreased, while CD2AP or podocin increased. Nephrin, podocin, or CD2AP knockdown did not change the expression of alpha-actinin-4, whereas alpha-actinin-4 knockdown begetted the reduction of nephrin, and the increment of podocin and CD2AP. The redistributions of nephrin, podocin, and CD2AP were revealed around a predominant nuclear staining compared with the membrane surface staining in the control podocytes. Our data imply that the response between the four podocyte molecules is very complicated and evidently different. There is not always an interaction between podocyte molecules. The normal localization of podocyte molecules would depend on their normal expression quantity and the molecular reactions between them.

Inferior mesenteric artery lymph node metastasis was an independent predictive factor for high systemic recurrence. Low ligation of the IMA with IMA-LN dissection was not inferior to high ligation.

Diffuse cutaneous mastocytosis (DCM) is an extremely rare disease characterized by massive proliferation of mast cells infiltrating the entire skin. We report a Chinese family with indolent DCM, and detection of a new germline KIT mutation located in the fifth immunoglobulin-like loop of the KIT protein, which probably results in a gain-of-function effect and consequent overactivation of mast cells. Our report expands the knowledge of correlations between the genotype of KIT mutations and the phenotype of DCM.

Background Our study aimed to investigate the prevalence and demographic characteristics of immune checkpoint inhibitor-associated primary adrenal insufficiency (ICI-PAI) and to explore the risk factors of its clinical outcome using data from the US FDA Adverse Event Reporting System (FAERS). Methods This was a retrospective study. All cases of new-onset or newly diagnosed primary adrenal insufficiency associated with FDA-approved ICIs from 1 January 2007 to 31 December 2020 were identified and collected using FAERS. Data on age, sex category, body weight of the participating individuals, the reporting year and the prognosis of cases, and other accompanying endocrinopathies related to ICIs, were analysed. Results The incidence of ICI-PAI was 1.03% (1180/114121). Of the 1180 cases of PAI, 46 were “confirmed PAI”, and 1134 were “suspected PAI”. Combination therapy with anti-CTLA-4 and anti-PD-1 was related to a higher risk of PAI compared with the anti-PD-1-only group (χ2 = 92.88, p < 0.001). Male and elderly individuals showed a higher risk of ICI-PAI (male vs. female, 1.17% vs. 0.94%, χ2 = 12.55, p < 0.001; age < 65 vs. ≥ 65, 1.20 vs. 1.41%, χ2 = 6.89, p = 0.009). The co-occurrence rate of endocrinopathies other than PAI was 24.3%, which showed a higher trend in patients on nivolumab-ipilimumab treatment than in those on PD-1 inhibitors (χ2 = 3.227, p = 0.072). Body weight was negatively associated with the risk of death in the study population [p = 0.033 for the regression model; B = – 0.017, OR 0.984, 95% CI (0.969–0.998), p = 0.029]. Conclusion ICI-associated PAI is a rare but important irAE. Male and elderly patients have a higher risk of ICI-PAI. Awareness among clinicians is critical when patients with a lower body weight develop PAI, which indicates a higher risk of a poor clinical outcome.

The MECP2 mutations occurring in the severe neurological disorder Rett syndrome are predominantly de novo, with rare familial cases. The aims of this study were to provide a precise estimate of the parental origin of MECP2 mutations using a large Chinese sample and to assess whether parental origin varied by mutation type. The parental origin was paternal in 84/88 [95.5%, (95% confidence interval 88.77-98.75)] of sporadic Chinese cases. However, in a pooled sample including data from the literature the spectrum of mutations occurring on maternally and paternally derived chromosomes differed significantly. The excess we found of 'single base pair gains or losses' on maternally derived MECP2 gene alleles suggests that this mutational category is associated with an elevated risk of gonadal mosaicism, which has implications for genetic counseling.

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