Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA ...H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep
mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.
46,XY disorders of sex development (DSD) is characterized by incomplete masculinization genitalia, with gonadal dysplasia and with/without the presence of Müllerian structures. At least 30 genes ...related to 46,XY DSD have been found. However, the clinical phenotypes of patients with different gene mutations overlap, and accurate diagnosis relies on gene sequencing technology. Therefore, this study aims to determine the prevalence of pathogenic mutations in a Chinese cohort with 46,XY DSD by the targeted next-generation sequencing (NGS) technology. Eighty-seven 46,XY DSD patients were enrolled from the Peking Union Medical College Hospital (Beijing, China). A total of fifty-four rare variants were identified in 60 patients with 46,XY DSD. The incidence of these rare variants was approximately 69.0% (60/87). Twenty-five novel variants and 29 reported variants were identified. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, thirty-three variants were classified as pathogenic or likely pathogenic variants and 21 variants were assessed as variants of uncertain significance. The overall diagnostic rate was about 42.5% based on the pathogenic and likely pathogenic variants. Androgen receptor (AR), steroid 5-alpha-reductase 2 (SRD5A2) and nuclear receptor subfamily 5 Group A member 1 (NR5A1) gene variants were identified in 21, 13 and 13 patients, respectively. The incidence of these three gene variants was about 78.3% (47/60) in patients with rare variants. It is concluded that targeted NGS is an effective method to detect pathogenic mutations in 46,XY DSD patients and AR, SRD5A2, and NR5A1 genes were the most common pathogenic genes in our cohort.
•Under investigation in this paper is a (2+1)-dimensional Broer-Kaup-Kupershmidt system for the nonlinear and dispersive long gravity waves on two horizontal directions in the shallow water of ...uniform depth. Bilinear forms, Bäcklund transformation and Lax pair are derived based on the Bell polynomials and symbolic computation.•One- and two-soliton solutions with a real function Φ (y) are constructed via the Hirota method, where y is the scaled space coordinate.•Propagation and interaction of the solitons are illustrated graphically: (i)Φ(y) affects the shape of the solitons. (ii) Interaction of the solitons including the elastic and inelastic interactions are discussed. When the solitons’ interaction is elastic, the amplitude, velocity and shape of the soliton remain invariant after the interaction except for a phase shift, and the smaller-amplitude soliton has a larger phase shift. (iii) Height of the water surface above a horizontal bottom can be a bell-shaped soliton or an upside-down bell-shaped soliton under certain conditions, while horizontal velocity of the water wave always keeps bell-shaped.
Under investigation in this paper is a (2+1)-dimensional Broer-Kaup-Kupershmidt system for the nonlinear and dispersive long gravity waves on two horizontal directions in the shallow water of uniform depth. Bilinear forms, Bäcklund transformation and Lax pair are derived based on the Bell polynomials and symbolic computation. One- and two-soliton solutions with a real function ϕ(y) are constructed via the Hirota method, where y is the scaled space coordinate. Propagation and interaction of the solitons are illustrated graphically: (i) ϕ(y) affects the shape of the solitons. (ii) Interaction of the solitons including the elastic and inelastic interactions are discussed. When the solitons’ interaction is elastic, the amplitude, velocity and shape of the soliton remain invariant after the interaction except for a phase shift, and the smaller-amplitude soliton has a larger phase shift. (iii) Height of the water surface above a horizontal bottom can be a bell-shaped soliton or an upside-down bell-shaped soliton under certain conditions, while horizontal velocity of the water wave always keeps bell-shaped.
Partial congenital hypogonadotropic hypogonadism (PCHH) is caused by an insufficiency in, but not a complete lack of, gonadotropin secretion. This leads to reduced testosterone production, mild ...testicular enlargement, and partial pubertal development. No studies have shown the productivity of spermatogenesis in patients with PCHH. We compared the outcomes of gonadotropin-induced spermatogenesis between patients with PCHH and those with complete congenital hypogonadotropic hypogonadism (CCHH). This retrospective study included 587 patients with CHH who were treated in Peking Union Medical College Hospital (Beijing, China) from January 2008 to September 2016. A total of 465 cases were excluded from data analysis for testosterone or gonadotropin-releasing hormone treatment, cryptorchidism, poor compliance, or incomplete medical data. We defined male patients with PCHH as those with a testicular volume of ≥4 ml and patients with a testicular volume of <4 ml as CCHH. A total of 122 compliant, noncryptorchid patients with PCHH or CCHH received combined human chorionic gonadotropin and human menopausal gonadotropin and were monitored for 24 months. Testicular size, serum luteinizing hormone levels, follicle-stimulating hormone levels, serum total testosterone levels, and sperm count were recorded at each visit. After gonadotropin therapy, patients with PCHH had a higher spermatogenesis rate (92.3%) than did patients with CCHH (74.7%). During 24-month combined gonadotropin treatment, the PCHH group took significantly less time to begin producing sperm compared with the CCHH group (median time: 11.7 vs 17.8 months, P < 0.05). In conclusion, after combined gonadotropin treatment, patients with PCHH have a higher spermatogenesis success rate and sperm concentrations and require shorter treatment periods for sperm production.
Background. A disintegrin and metalloproteinase 17 (ADAM17) is a transmembrane protein that is widely expressed in various tissues; it mediates the shedding of many membrane-bound molecules, ...involving cell-cell and cell-matrix interactions. We investigated the role of ADAM17 within mouse cardiac fibroblasts (mCFs) in heart fibrosis. Methods. mCFs were isolated from the hearts of neonatal mice. Effects of ADAM17 on the differentiation of mCFs towards myofibroblasts and their fibrotic behaviors following induction with TGF-β1 were examined. The expression levels of fibrotic proteins, such as collagen I and α-SMA, were assessed by qRT-PCR analysis and western blotting. Cell proliferation and migration were measured using the CCK-8 and wound healing assay. To identify the target gene for ADAM17, the protein levels of the components of endoplasmic reticulum (ER) stress and the PINK1/Parkin pathway were assessed following ADAM17 silencing. The effects of ADAM17 silencing or treatment with thapsigargin, a key stimulator of acute ER stress, on mCFs proliferation, migration, and collagen secretion were also examined. In vivo, we used a mouse model of cardiac fibrosis established by left anterior descending artery ligation; the mice were administered oral gavage with a selective ADAM17 inhibitor (TMI-005) for 4 weeks after the operation. Results. We found that the ADAM17 expression levels were higher in fibrosis heart tissues and TGF-β1-treated mCFs. The ADAM17-specific siRNAs decreased TGF-β1-induced increase in the collagen secretion, proliferation, and migration of mCFs. Knockdown of ADAM17 reduces the activation of mCFs by inhibiting the ATF6 branch of ER stress and further activating mitophagy. Moreover, decreased ADAM17 expression also ameliorated cardiac fibrosis and improved heart function. Conclusions. This study highlights that mCF ADAM17 expression plays a key role in cardiac fibrosis by regulating ER stress and mitophagy, thereby limiting fibrosis and improving heart function. Therefore, ADAM17 downregulation, within the physiological range, could exert protective effects against cardiac fibrosis.
Chronic pancreatitis (CP) is a chronic progressive inflammatory disease of the pancreas, caused by multiple factors and accompanied by irreversible impairment of pancreatic internal and external ...secretory functions. Pathologically, atrophy of the pancreatic acini, tissue fibrosis or calcification, focal edema, inflammation, and necrosis are observed. Clinical manifestations include recurrent or persistent abdominal pain, diarrhea, emaciation, and diabetes. In addition, CP is prone to develop into pancreatic cancer(PC) due to persistent inflammation and fibrosis. The disease course is prolonged and the clinical prognosis is poor. Currently, clinical treatment of CP is still based on symptomatic treatment and there is a lack of effective etiological treatment. Encouragingly, experiments have shown that a variety of active substances have great potential in the etiological treatment of chronic pancreatitis. In this paper, we will review the pathogenesis of CP, as well as the research progress on anti-inflammatory and anti-fibrotic therapies, which will provide new ideas for the development of subsequent clinical studies and formulation of effective treatment programs, and help prevent CP from developing into pancreatic cancer and reduce the prevalence of PC as much as possible.
In this paper, a higher-order (2+1)-dimensional nonlinear Schrödinger-type equation is investigated, which describes the nonlinear spin dynamics of the (2+1)-dimensional Heisenberg ferromagnetic spin ...chain with bilinear and biquadratic interaction. Lax pair and infinite-number conservation laws are constructed, which could prove the existence of the multi-soliton solutions. Via the auxiliary function, bilinear forms and dark-soliton solutions are derived. Properties and interaction patterns for the dark solitons are investigated: (i) Effects on the dark solitons arising from the bilinear interaction, biquadratic interaction and lattice parameter are discussed. (ii) Through the asymptotic analysis, elastic and inelastic interaction between the two solitons is discussed analytically and graphically, respectively. Due to the elastic interaction, amplitudes and velocities of the two dark solitons remain unchanged with the distortion of the interaction area, except for certain phase shifts. However, in virtue of the inelastic interaction, amplitudes of the dark solitons reduce to zero, without the distortion. (iii) Elastic interaction among the three dark solitons is investigated, which implies that the properties of the elastic interaction among the three are similar to that between the two, except for the more complicated distortion. Inelastic–elastic interaction is also investigated, which implies that the interaction between the inelastic region and the dark soliton is elastic. (iv) Linear stability analysis is proposed, which is used to analyze the properties of modulation instability and proves that the dark solitons are modulationally stable.
To compare the pathogenicity of isolates of sequence type 7 (ST-7) Neisseria meningitidis (N. meningitidis) belonging to four different serogroups (A, B, C, and X).
Four ST-7 N. meningitidis isolates ...serogrouped as A, B, C, and X and characterized by different capsule structures, were examined for their adhesion and invasion properties, and their ability to induce cytokine release and apoptosis in the host cell (the A549 cell line).
Among the four ST-7 N. meningitidis isolates, the serogroup A isolate possessed the strongest adhesion and invasion ability. This isolate also induced the release of the highest levels of the proinflammatory mediators interleukin-6, interleukin-1β, and interferon, and the highest apoptosis rate in the host cells. However, there was no significant difference in interleukin-8 and tumor necrosis factor-α secretion between the four isolates. Based on the findings, the serogroup X N. meningitidis isolate had the weakest pathogenicity, whereas there was almost no difference in the pathogenicity of the isolates from serogroups B and C.
The differences in the capsular structure of the four isolates of ST-7 N. meningitidis affected their pathogenic capacities. The findings also imply that the hyperinvasive ST-7 N. meningitidis lineage may include hypoinvasive isolates.
To investigate the effects of sodium danshensu on vessel function in isolated rat aortic ring.
Thoracic aortae from normal rats were isolated and equilibrated in organ bath with Krebs-Henseleit ...buffer and ring tension was recorded. Effects of sodium danshensu on basal tonus of the vessel and its effects on vessel contraction and relaxation with or without endothelium were observed.
In thoracic arteries under basal tonus, sodium danshensu (0.3-3 g/L) produced a dose-dependent transient contraction. In phenylephrine-precontracted thoracic arteries with or without endothelium, low concentration (0.1-0.3 g/L) of sodium danshensu produced a weak contraction, while high concentrations (1-3 g/L) produced a pronounced vasodilator after a transient vasocontraction. Pre-incubation with sodium danshensu could inhibit vessel contraction induced by phenylephrine and potassium chloride in a concentration-dependent way. Sodium danshensu inhibited phenylephrine- and CaCl(2)-induced vasoconstriction in Ca(2+)-free medium. Pre-incubation with tetraethylammonium, a non-selective K(+) channel blocker, and apamin, a small-conductance calcium-activated K(+) channel blocker partially antagonized the relaxation response induced by sodium danshensu. However, iberiotoxin (big-conductance calcium-sensitive K(+) channel blocker), barium chloride (inward rectifier K(+) channel blocker), and glibencalmide (ATP-sensitive K(+) channel blocker) had no influence on the vasodilation effect of sodium danshensu.
Sodium danshensu showed a biphasic effects on vessel tension. While low dosage of sodium danshensu produced small contraction possibly through transient enhancement of Ca(2+) influx, high dosage produced significant vasodilation mainly through promoting the opening of non-selective K(+) channels and small-conductance calcium-sensitive K(+) channels in the vascular smooth muscle cells.
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