ABSTRACT
This study investigated the prevalence and risk factors of urinary incontinence (UI) among perimenopausal women in Wuhan. A cross-sectional survey was performed on 1067 women aged 40-65 years sampled in Wuhan urban area from April to October 2014. Information about demographic characteristics, menstruation, parity and UI symptoms was collected using a questionnaire. The data were evaluated by Chi-square test and multiple Logistic regression analysis. The prevalence rate of UI was 37.2%, with stress UI (32.2%) being more prevalent than urgency UI (21.6%) and mixed UI (16.6%). 31.2% women with UI stated that UI had negative impact on their life. Risk factors for UI included menstrual disorder, menopause, overweight, perineal laceration, atrophic vaginitis, constipation and pelvic organ prolapse. Appropriate investigation apropos the factors associated with UI should be performed to diminish its impact on women's life.
Subject(s)
Perimenopause/physiology , Urinary Incontinence/epidemiology , Adult , Aged , Atrophic Vaginitis/epidemiology , Atrophic Vaginitis/physiopathology , Constipation/epidemiology , Constipation/physiopathology , Female , Humans , Lacerations/epidemiology , Lacerations/physiopathology , Menstrual Cycle/physiology , Middle Aged , Overweight/epidemiology , Overweight/physiopathology , Pelvic Organ Prolapse/epidemiology , Pelvic Organ Prolapse/physiopathology , Pregnancy , Risk Factors , Surveys and Questionnaires , Urinary Incontinence/physiopathologyABSTRACT
The shock-induced serine protease HtrA1 is a potential regulator of human placenta development during pregnancy. The protein contains a functional PDZ domain that has been solved in complex with a phage display-derived heptapeptide: Asp-6 Ser-5 Arg-4 Ile-3 Trp-2 Trp-1 Val0 . In this study, a rationally designed halogen bond was introduced to the domain-peptide complex based on its NMR structure in solution. We computationally compared the stabilization energies and hindrance effects due to the presence of different halogens X (X = F, Cl, Br, or I), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach, and found that the Br atom could considerably promote the peptide binding free energy (ΔΔG = -5.2 kcal/mol). Fluorescence assays confirmed that the peptide affinity to the HtrA1 PDZ domain was improved by approximately sevenfold upon bromination. Structural analysis identified a geometrically perfect halogen bond between the Br atom of the peptide Trp-1 residue and the carbonyl O atom of the HtrA1 Ile385 residue, with a bond length and an interaction energy of d = 3.20 Å and ΔE = -3.7 kcal/mol, respectively.
Subject(s)
Halogens/chemistry , Oligopeptides/chemistry , Placenta/enzymology , Serine Endopeptidases/chemistry , Bromine/chemistry , Female , High-Temperature Requirement A Serine Peptidase 1 , Humans , Ligands , PDZ Domains , Pregnancy , Protein Binding , Quantum Theory , ThermodynamicsABSTRACT
The protein kinase C (PKC) is a family of serine/threonine kinases with a broad range of cellular targets. Members of the PKC family participate at the diverse biological events involved in cellular proliferation, differentiation and survival. The PKC isoform zeta (PKCζ) is an atypical member that has recently been found to play an essential role in promoting human uterine contractility and thus been raised as a new target for treating preterm labour and other tocolytic diseases. In this study, an integrative protocol was described to graft hundreds of inhibitor ligands from their complex crystal structures with cognate kinases into the active pocket of PKCζ and, based on the modeled structures, to evaluate the binding strength of these inhibitors to the non-cognate PKCζ receptor by using a consensus scoring strategy. A total of 32 inhibitors with top score were compiled, and eight out of them were tested for inhibitory potency against PKCζ. Consequently, five compounds, i.e. CDK6 inhibitor fisetin, PIM1 inhibitor myricetin, CDK9 inhibitor flavopiridol and PknB inhibitor mitoxantrone as well as the promiscuous kinase inhibitor staurosporine showed high or moderate inhibitory activity on PKCζ, with IC50 values of 58 ± 9, 1.7 ± 0.4, 108 ± 17, 280 ± 47 and 0.019 ± 0.004 µM, respectively, while other three compounds, including two marketed drugs dasatinib and sunitinib as well as the Rho inhibitor fasudil, have not been detected to possess observable activity. Next, based on the modeled structure data we modified three flavonoid kinase inhibitors, i.e. fisetin, myricetin and flavopiridol, to generate a number of more potential molecular entities, two of which were found to have a moderately improved activity as compared to their parent compounds.