A Review of the Associations Between Obstructive Sleep Apnea and Gestational Diabetes Mellitus and Possible Mechanisms of Disease.

Obstructive sleep apnea (OSA) usually leads to the occurrence of diabetes. Gestational diabetes mellitus (GDM) is a common gestational complication associated with adverse maternal and fetal outcomes. Increasing studies suggest that women with OSA during pregnancy may be at a significantly greater risk of developing GDM. It is crucial to explore the association between OSA and GDM and the mechanisms underlying this association. In this review, we presented a comprehensive literature review of the following: the association between OSA and GDM, the possible mechanisms of this association, and the effects of continuous positive airway pressure (CPAP) on OSA with GDM. The results showed that most authors suggested that there was an association between OSA and GDM. The intermittent hypoxemia (IH) and reduction of slow-wave sleep (SWS) may be the key to this association. IH induces the products of oxidative stress and inflammation as well as dysregulation of the hypothalamic-pituitary-adrenal, which lead to diabetes. In addition, SWS reduction in OSA enhances the inflammation by increasing the inflammatory cytokines, increases the sympathetic activation, and causes changes in leptin level, which result in the development of GDM. Additionally, whether CPAP is beneficial to GDM remains still unclear.

Denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women: A randomized, double-blind, placebo-controlled, multicenter phase III study.

Objectives: This study assessed the efficacy, safety, pharmacokinetics (PK), and immunogenicity profiles of a denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women with a high risk of fracture. Methods: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, 448 postmenopausal women aged 50-85 years with osteoporosis were enrolled at 49 centers in China and were randomly assigned (3:1) to receive 60 â€‹mg of the denosumab biosimilar (LY06006) or placebo subcutaneously every 6 months for 1 year. Lumbar spine bone mineral density (BMD) change was the primary endpoint. Results: Of the 448 randomized patients, 409 (LY06006, n â€‹= â€‹311; placebo, n â€‹= â€‹98) completed the study. All 448 (100.0%) subjects were included in the intent-to-treat (ITT) trial, 427 (95.3%) were included in the full analysis set (FAS), 408 (91.1%) were included in the per protocol set (PPS), 446 (99.6%) were included in the safety set (SS), and 336 (75.0%) were included in the pharmacokinetics concentration set (PKCs). For the primary endpoint, a 4.71% (95% CI, 3.81%, 5.60%) treatment difference in percent change in lumbar spine BMD from baseline to month 12 was observed in the LY06006 group compared with the placebo group (P â€‹< â€‹0.0001). For the secondary endpoints, LY06006 was associated with increased lumbar spine BMD levels measured at month 6, BMD levels at the femoral neck, total hip, and trochanter measured at months 6 and 12 and reduced serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 â€‹N-peptide (P1NP) levels at months 1, 6, and 12. Safety analysis was based on the safety analysis set (SS), and 264 (78.6%) subjects in the LY06006 group and 83 (75.5%) in the placebo group experienced adverse events (AEs). Most events were mild or moderate and not related to the study drugs. Conclusion: In postmenopausal women with a high risk of fracture, LY06006 increased the BMD and decreased bone resorption; thus, LY06006 might be an effective treatment for osteoporosis. LY06006 was generally safe and well tolerated without unexpected adverse reactions, similar to the reference drug Prolia®. The characteristics of effectiveness and safety were similar to those reported in previous studies. The translational potential of this article: In this multi-center, randomized, double-blind, placebo-controlled phase 3 study, LY06006 showed substantially efficacy to increase BMD and well tolerance without unexpected adverse reactions, which is comparable to the reference drug Prolia ®. The presented results are encouraging and can offer some valuable evidence for the clinical practice.

Identification and functional characterization of bactericidal permeability/increasing protein (BPI) from frog Nanorana yunnanensis (Paa yunnanensis).

Bactericidal permeability/increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) have been most extensively studied in mammals, but little information is available regarding BPI and LBP in Amphibia. In this study we showed that the cDNA of BPI in the frog N. yunnanensis (P. yunnanensis) encoded a 490-amino-acid-long protein, the predicted tertiary structure appears closely similar to mammalian BPIs in terms of sequence and structure. Like mammalian BPI gene, the frog gene nybpi was widely expressed in various tissues and was inducible by challenge with LPS or Gram-negative bacterium. We also showed that recombinant NyBPI, resembling mammalian BPIs, specifically binds with LPS. In addition, the recombinant NyBPI displayed antibacterial activity against Gram-negative bacteria Vibrio anguillarum in a dose-dependent manner. These results indicate that NyBPI may play an important role in an immune response against bacteria in amphibians.

CHANGES IN MYOPIC MACULOPATHY BASED ON ATN CLASSIFICATION SYSTEM: An Optical Coherence Tomography Angiography Study.

PURPOSE: To assess changes in myopic maculopathy based on the ATN classification system with optical coherence tomography angiography. METHODS: This was a cross-sectional study. The macular choroidal thickness (MCT) and the choriocapillaris flow (CC) were measured with optical coherence tomography angiography. The relationship of MCT and CC with different chorioretinal atrophy (A), myopic foveoschisis (T), and myopic neovascularization (N) grades was investigated. RESULTS: One hundred and fifty-three participates (219 eyes) were included. MCT and CC had no significant correlation with different T grades (P > 0.05). Choriocapillaris flow had a significant decrease in eyes with lacquer cracks compared with those with no neovascular maculopathy (P < 0.05) and showed a significant increase in active choroidal neovascularization compared with those with lacquer cracks (P < 0.05). Macular choroidal thickness and CC had negative correlations with different A grades (P < 0.001). MCT showed the greatest decrease in the early stage of myopic atrophic maculopathy (P < 0.001), and CC showed the most significant reduction in the late stage (P < 0.001). CONCLUSION: Choroidal changes in the highly myopic patients were detected by optical coherence tomography angiography. Progressive ischemia in the macula may play an important role in the development of myopic atrophic maculopathy. Active choroidal neovascularization may have manifested as compensation for the decrease in MCT and CC. On the contrary, myopic traction maculopathy had little correlation with choroidal changes.

14,15-EET involved in the development of diabetic cardiac hypertrophy mediated by PPARs.

Cardiac hypertrophy is a key structural change in diabetic cardiomyopathy, which mechanism is unknown. 14,15-Epoxyeicosatrienoic acid (14,15-EET) generated from arachidonic acid by CYP2J2 has beneficial effects in metabolic syndrome, which also plays vital roles in inflammatory response. Peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor superfamily and have three subtypes of α, ß (or δ) and γ. Studies have found that 14,15-EET can perform various biological functions by activating PPARs, but its role in diabetic cardiac hypertrophy is unknown. This study aimed to investigate the role of 14,15-EET-PPARs signaling pathway in the development of diabetic cardiac hypertrophy. Diabetic cardiac hypertrophy was developed by high-fat diet feeding combined with streptozotocin (40 mg/kg/d for 5 days, i.p.) in mice and was induced by glucose at 25.5 mmol/L (high glucose, HG) in H9c2 cells. The decreased level of 14,15-EET and the down-regulated expression of PPARα, PPARß and PPARγ were found following diabetic cardiac hypertrophy in mice. Similarly, both the level of 14,15-EET and the PPARs expression were also reduced in HG-induced hypertrophic cardiomyocytes. Supplementation with 14,15-EET improved the cardiomyocyte hypertrophy and up-regulated PPARs expression, which were nullified by 14,15-EEZE, a 14,15-EET antagonist. Taken together, we conclude that the decreased 14,15-EET is involved in the development of diabetic cardiac hypertrophy through the down-regulation of PPARs.

Development of a nomogram for predicting the risk of left ventricular diastolic function in subjects with type-2 diabetes mellitus.

Left ventricular diastolic dysfunction (LVDD) can be affected by many factors, including epicardial adipose tissue (EAT), obesity and type-2 diabetes mellitus (T2DM). The aim of this study was to establish and validate an easy-to-use nomogram that predicts the severity of LVDD in patients with T2DM. This is a retrospective study of 84 consecutive subjects with T2DM admitted to the Endocrinology Department, the First People's Hospital of Zunyi City between January 2015 and October 2020. Several echocardiographic characteristics were used to diagnose diastolic dysfunction according to the 2016 diastolic dysfunction ASE guidelines. Anthropometric, demographic, and biochemical parameters were collected. Through a least absolute shrinkage and selection operator (LASSO) regression model, we reduced the dimensionality of the data and determined factors for the nomogram. The mean follow-up was 25.97 months. Cases were divided into two groups, those with LVDD (31) and those without (53). LASSO regression identified total cholesterol (Tol.chol), low-density lipoprotein (LDL), right ventricular anterior wall (RVAW) and epicardial adipose tissue (EAT) were identified as predictive factors in the nomogram. The ROC curve analysis demonstrated that the AUC value for most clinical paramerters was higher than 0.6. The nomogram can be used to promote the individualized prediction of LVDD risk in T2DM patients, and help to prioritize patients diagnosed with echocardiography.

PPARß down-regulation is involved in high glucose-induced endothelial injury via acceleration of nitrative stress.

Endothelial injury plays a vital role in vascular lesions from diabetes mellitus (DM). Therapeutic targets against endothelial damage may provide critical venues for the treatment of diabetic vascular diseases. Peroxisome proliferator-activated receptor ß (PPARß) is a crucial regulator in DM and its complications. However, the molecular signal mediating the roles of PPARß in DM-induced endothelial dysfunction is not fully understood. The impaired endothelium-dependent relaxation and destruction of the endothelium structures appeared in high glucose incubated rat aortic rings. A high glucose level significantly decreased the expression of PPARß and endothelial nitric oxide synthase (eNOS) at the mRNA and protein levels, and reduced the concentration of nitric oxide (NO), which occurred in parallel with an increase in the expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine. The effect of high glucose was inhibited by GW0742, a PPARß agonist. Both GSK0660 (PPARß antagonist) and NG-nitro-l-arginine-methyl ester (NOS inhibitor) could reverse the protective effects of GW0742. These results suggest that the activation of nitrative stress may, at least in part, mediate the down-regulation of PPARß in high glucose-impaired endothelial function in rat aorta. PPARß-nitrative stress may hold potential in treating vascular complications from DM.

Pueribacillus theae gen. nov., sp. nov., isolated from Pu'er tea.

A novel bacterial strain, designated T8T, isolated from ripened Pu'er tea, was investigated by using a polyphasic taxonomic approach. Cells stained Gram-positive and were aerobic, sporogenous and rod-shaped with flagella. Phylogenetic analysis of 16S rRNA gene sequences revealed the strain belonged to the family Bacillaceae in the class Bacilli and represented an independent taxon separated from other genera. Strain T8T shared low levels of 16S rRNA gene sequence similarity (<94 %) to members of other genera in the family Bacillaceae and was most closely related to Bacillus composti SgZ-9T (93.3 % sequence similarity). The DNA G+C content of strain T8T was 40 mol%. The major fatty acids (>10 %) of strain T8T were iso-C15 : 0 and iso-C16 : 0. The strain had a cell-wall type A1γ peptidoglycan with meso-diaminopimelic acid as the diagnostic diamino acid. MK-7 (62 %), MK-6 (31 %) and MK-8 (7 %) were detected as the isoprenoid quinones. The predominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylmethylethanolamine and six unidentified phospholipids. On the basis of the polyphasic evidence presented, strain T8T is considered to represent a novel genus and species in the family Bacillaceae, for which we propose the name Pueribacillus theae gen. nov., sp. nov. The type strain is T8T (=CGMCC 1.15924T=KCTC 333888T).

Activities of Amphioxus GH-Like Protein in Osmoregulation: Insight into Origin of Vertebrate GH Family.

GH is known to play an important role in both growth promotion and osmoregulation in vertebrates. We have shown that amphioxus possesses a single GH-like hormone (GHl) gene encoding a functional protein capable of promoting growth. However, if GHl can mediate osmoregulation remains open. Here, we demonstrated clearly that GHl increased not only the survival rate of amphioxus but also the muscle moisture under high salinity. Moreover, GHl induced the expression of both the ion transporter Na+-K+-ATPase (NKA) and Na+-K+-2Cl- cotransporter (NKCC) in the gill as well as the mediator of GH action IGFl in the hepatic caecum, indicating that GHl fulfills this osmoregulatory activity through the same mechanisms of vertebrate GH. These results together suggest that the osmoregulatory activities of GH had emerged in the basal chordate amphioxus. We also proposed a new model depicting the origin of pituitary hormone family in vertebrates.

Trans-generational enhancement of C-type lysozyme level in eggs of zebrafish by dietary ß-glucan.

ß-glucan has been shown to increase non-specific immunity and resistance against infections or pathogenic bacteria in several fish species, but information regarding its trans-generational immune-enhancing effects is still rather limited. Lysozyme is a maternal immune factor playing an important role in the developing embryos of zebrafish. Here we clearly showe that ß-glucan enhanced the level of C-type lysozyme in eggs of zebrafish, and the embryos derived from ß-glucan-treated zebrafish were more resistant to bacterial challenge than control embryos. Moreover, the transferred lysozyme was apparently linked with the antimicrobial defense of early embryos. In addition, we also showed that ß-glucan induced a significant increase in the synthesis of C-type lysozyme in previtellogenetic oocytes. Therefore, we show for the first time that ß-glucan can enhance the lysozyme level in offspring via both inducing the transfer of the molecule from mothers to eggs and stimulating its endogenous production in oocytes.

Zebrafish phosvitin-derived peptide Pt5 inhibits melanogenesis via cAMP pathway.

Zebrafish phosvitin-derived peptide Pt5, consisting of the C-terminal 55 residues of phosvitin, has been shown to have an antimicrobial-immunomodulatory activity comparable to phosvitin. Here, we showed clearly that Pt5 had the capacity to inhibit tyrosinase (TYR) activity and melanin biosynthesis, and this inhibition was independent of cell proliferation and cytotoxic effects. Incubation of fluorescein isothiocyanate (FITC)-labeled Pt5 with B16F10 melanoma cells revealed that Pt5 was localized in the cytoplasm of the cells. In addition, Pt5 inhibited the expression of TYR, tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2), and microphthalmia-associated transcription factor (MITF) in B16F10 melanoma cells and reduced the intracellular cyclic adenosine monophosphate (cAMP) concentration in the cells, but it did not affect the cellular contents of pERK1/2 and ß-catenin, suggesting that Pt5 regulates melanin biosynthesis via cAMP signaling pathway rather than Wnt and MAPK pathways. Collectively, these data indicate that Pt5 has the potential to be used as a melanogenesis inhibitor in medical and cosmetic industry, a novel role ever reported.

Antibacterial activity and modes of action of phosvitin-derived peptide Pt5e against clinical multi-drug resistance bacteria.

Pt5e, a mutant peptide derived from the C-terminal 55 residues of zebrafish phosvitin, has been suggested to be a novel antibacterial peptide. However, if it is applicable to clinical MDR bacteria remains to be tested. In this study, high-purity Pt5e was first expressed and purified by fusion with cationic elastin-like polypeptide. Pt5e was then shown to be capable of effectively killing all the five clinical MDR bacteria tested. Pt5e kill the MDR bacteria at several levels, including inserting into the bacterial membranes, causing the membrane depolarization and permeabilization, and inducing the intracellular apoptosis/necrosis. All these data suggest that Pt5e is a promising therapeutic potential as an antibiotics against clinical MDR bacteria.

Dietary ß-glucan enhances the contents of complement component 3 and factor B in eggs of zebrafish.

ß-glucan has been shown to increase non-specific immunity and resistance against infections or pathogenic bacteria in several fish species, but no information is available regarding its trans-generational effects to date. Here we clearly demonstrated that ß-glucan enhanced the contents of immune-relevant molecules C3 and Bf in eggs of zebrafish, and the embryos derived from ß-1,3 glucan-treated zebrafish were more resistant to bacterial challenge than control embryos. Moreover, the transferred C3 and Bf were directly associated with the antimicrobial defense of early embryos. In addition, feeding female zebrafish with ß-glucan had little detrimental effects on the number of spawned eggs and their embryonic development. Collectively, these data show for the first time that ß-glucan can be safely used to promote the non-specific immunity in offspring of fishes.

Expression of virus-responsive genes and their response to challenge with poly(I:C) at different stages of the annual fish Nothobranchius guentheri: Implications for an asymmetric decrease in immunity.

Aging deteriorates immunity. However, if aging affects immunity in an asymmetric or symmetric way remains largely unknown. In this study we clearly demonstrate that compared with adult fish, the anti-viral responses of aged annual fish Nothobranchius guentheri, as reflected by the expression levels of virus-responsive genes, including lgp2 and mda5 encoding sensor molecules, ifn-i and viperin encoding the effector molecules and irf1, irf7, stat1 and atf3 encoding the regulation elements, are either reduced remarkably or elevated markedly or show little difference depending upon the different tissues. Moreover, although challenge with poly(I:C) results in a significant decrease in the expression of virus-responsive genes in most tissues of aged N. guentheri, it also causes a considerable increase in the expression of the genes in other tissues of aged fish. Collectively, these data suggest that the anti-viral responses of the annual fish N. guentheri generally reduces with age in an asymmetric way among the most tissues.