Atractylenolide-I Alleviates Hyperglycemia-Induced Heart Developmental Malformations through Direct and Indirect Modulation of the STAT3 Pathway.

BACKGROUND: Gestational diabetes could elevate the risk of congenital heart defects (CHD) in infants, and effective preventive and therapeutic medications are currently lacking. Atractylenolide-I (AT-I) is the active ingredient of Atractylodes Macrocephala Koidz (known as Baizhu in China), which is a traditional pregnancy-supporting Chinese herb. PURPOSE: In this study, we investigated the protective effect of AT-I on the development of CHD in embryos exposed to high glucose (HG). STUDY DESIGN AND METHODS: First, systematic review search results revealed associations between gestational diabetes mellitus (GDM) and cardiovascular malformations. Subsequently, a second systematic review indicated that heart malformations were consistently associated with oxidative stress and cell apoptosis. We assessed the cytotoxic impacts of Atractylenolide compounds (AT-I, AT-II, and AT-III) on H9c2 cells and chick embryos, determining an optimal concentration of AT-I for further investigation. Second, immunofluorescence, western blot, Polymerase Chain Reaction (PCR), and flow cytometry were utilized to delve into the mechanisms through which AT-I mitigates oxidative stress and apoptosis in cardiac cells. Molecular docking was employed to investigate whether AT-I exerts cardioprotective effects via the STAT3 pathway. Then, we developed a streptozotocin-induced diabetes mellitus (PGDM) mouse model to evaluate AT-I's protective efficacy in mammals. Finally, we explored how AT-I protects hyperglycemia-induced abnormal fetal heart development through microbiota analysis and untargeted metabolomics analysis. RESULTS: The study showed the protective effect of AT-I on embryonic development using a chick embryo model which rescued the increase in the reactive oxygen species (ROS) and decrease in cell survival induced by HG. We also provided evidence suggesting that AT-I might directly interact with STAT3, inhibiting its phosphorylation. Further, in the PGDM mouse model, we observed that AT-I not only partially alleviated PGDM-related blood glucose issues and complications but also mitigated hyperglycemia-induced abnormal fetal heart development in pregnant mice. This effect is hypothesized to be mediated through alterations in gut microbiota composition. We proposed that dysregulation in microbiota metabolism could influence the downstream STAT3 signaling pathway via EGFR, consequently impacting cardiac development and formation. CONCLUSIONS: This study marks the first documented instance of AT-I's effectiveness in reducing the risk of early cardiac developmental anomalies in fetuses affected by gestational diabetes. AT-I achieves this by inhibiting the STAT3 pathway activated by ROS during gestational diabetes, significantly reducing the risk of fetal cardiac abnormalities. Notably, AT-I also indirectly safeguards normal fetal cardiac development by influencing the maternal gut microbiota and suppressing the EGFR/STAT3 pathway.

Optimal harvesting of a competitive n-species stochastic model with delayed diffusions.

In this study, we propose an n-species stochastic model which considers the influences of the competitions and delayed diffusions among populations on dynamics of species. We then investigate the stochastic dynamics of the model, such as the persistence in mean of the species, and the asymptotic stability in distribution of the model. Then, by using the Hessian matrix and theory of optimal harvesting, we investigate the optimal harvesting problem, obtaining the optimal harvesting effort and the maximum of expectation of sustainable yield (ESY). Finally, we numerically discuss some examples to illustrate our theoretical findings, and conclude our study by a brief discussion.

Stability and Hopf bifurcation analysis for a Lac operon model with nonlinear degradation rate and time delay.

In this paper, we construct a discrete time delay Lac operon model with nonlinear degradation rate for mRNA, resulting from the interaction among several identical mRNA pieces. By taking a discrete time delay as bifurcation parameter, we investigate the nonlinear dynamical behaviour arising from the model, using mathematical tools such as stability and bifurcation theory. Firstly, we discuss the existence and uniqueness of the equilibrium for this system and investigate the effect of discrete delay on its dynamical behaviour. Absence or limited delay causes the system to have a stable equilibrium, which changes into a Hopf point producing oscillations if time delay is increased. These sustained oscillation are shown to be present only if the nonlinear degradation rate for mRNA satisfies specific conditions. The direction of the Hopf bifurcation giving rise to such oscillations is also determined, via the use of the so-called multiple time scales technique. Finally, numerical simulations are shown to validate and expand the theoretical analysis. Overall, our findings suggest that the degree of nonlinearity of the model can be used as a control parameter for the stabilisation of the system.

Hemodynamic studies on brain CT perfusion imaging with varied injection rates.

OBJECTIVE: This study aimed to determine a contrast medium injection rate that ensures both accuracy for data and safety for operation by comparing hemodynamic parameters of brain CT perfusion imaging with varied injection rates. METHODS: Twenty-four healthy volunteers were divided into three groups based on contrast medium injection rates (4.5, 6.0, and 7.5 ml/s). For all subjects, CT perfusion scanning was started at 4 s after antecubital venous bolus of contrast media injection. A perfusion-analyzing software package was used to produce a time-density curve in the anterior cerebral artery and the superior sagittal sinus and calculate the regional cerebral blood flow (rCBF) in the gray matter and the white matter. The hemodynamic indices were compared among the three groups, and statistical analysis was carried out using the F test. RESULTS: The time for the arterial rise to reach the peak value for the 7.5-ml/s group was only 0.2 s ahead of the initiation time for the rise of the superior sagittal sinus. The differences of rCBF in the gray matter and the white matter among the three groups were statistically significant. rCBF in the gray matter and the white matter for the 7.5-ml/s group was 52.8 ml x min(-1) 100 g(-1) . (+/-3.1) and 21.9 ml x min(-1) . 100 g(-1) (+/-2.4), respectively. CONCLUSIONS: The use of the 7.5-ml/s injection rate can meet the prerequisite of the maximum slope model, and the resulting rCBF can be very close to that measured by positron emission tomography. Therefore, 7.5 ml/s was an ideal contrast medium injection rate.

[Expression of midkine in eutopic and ectopic endometrium of patients with severe endometriosis and its clinical significance].

OBJECTIVE: To investigate the expression of midkine (MK) in eutopic and ectopic endometrium of patients with severe endometriosis and its clinical significance. METHODS: Immunohistochemical streptavidin-biotin peroxidase (SP) method was used to detect MK expression and microvessel density (MVD) in eutopic and ectopic endometrium. Specimens of eutopic and ectopic endometrium were collected from 41 patients with serious endometriosis (study group) and 32 patients with uterine fibroid (control group). RESULTS: The positive rate of MK expression in the eutopic endometrium from study group was 63% (26/41). It was significantly higher than that in the ectopic endometrium from study group was 29% (12/41) and the eutopic endometrium from control group was 22% (7/32, P < 0.05). MK expression was positively correlated to microvessel density (r = 0.637, P < 0.05). CONCLUSION: Over-expression of MK protein is showed in the eutopic endometrium of patients with severe endometriosis and correlated to endometriotic angiogenesis. The change of MK expression in eutopic endometrium may be related to the pathogenesis of severe endometriosis.