Insulin is a principal metabolic hormone. It regulates a plethora of metabolic pathways in peripheral tissues. The highly homologous insulin-like growth factor 1 (IGF-1), on the other hand, is important for development and growth. Recent studies have shown that insulin and IGF-1 signaling plays fundamental roles in the brain. Loss of insulin or IGF-1 receptors in astrocytes leads to altered glucose handling, mitochondrial metabolism, neurovascular coupling, and behavioral abnormalities in mice. Here, we aim to investigate molecular mechanisms by which insulin and IGF-1 signaling regulates astrocyte functions.
IR-flox and IRKO primary astrocytes were treated with 100 nM insulin or IGF-1 for 6 h, and their transcriptomes were analyzed. Astrocytes with either IR deletion, IGF1R deletion or both were used to examine receptor-dependent transcriptional regulations using qPCR. Additional immunoblotting and confocal imaging studies were performed to functionally validate pathways involved in protein homeostasis.
Using next-generation RNA sequencing, we show that insulin significantly regulates the expression of over 1,200 genes involved in multiple functional processes in primary astrocytes. Insulin-like growth factor 1 (IGF-1) triggers a similar robust transcriptional regulation in astrocytes. Thus, over 50% of the differentially expressed genes are regulated by both ligands. As expected, these commonly regulated genes are highly enriched in pathways involved in lipid and cholesterol biosynthesis. Additionally, insulin and IGF-1 induce the expression of genes involved in ribosomal biogenesis, while suppressing the expression of genes involved in autophagy, indicating a common role of insulin and IGF-1 on protein homeostasis in astrocytes. Insulin-dependent suppression of autophagy genes, including p62 , Ulk1/2 , and several Atg genes, is blunted only when both IR and IGF1R are deleted.
In summary, insulin and IGF-1 potently suppress autophagy in astrocytes through transcriptional regulation. Both IR and IGF1R can elicit ligand-dependent transcriptional suppression of autophagy. These results demonstrate an important role of astrocytic insulin/IGF-1 signaling on proteostasis. Impairment of this regulation in insulin resistance and diabetes may contribute to neurological complications related to diabetes.
Background: Esports players, like traditional athletes, practice for long hours and, thus, are vulnerable to the negative health effects of prolonged sitting. There is a lack of research on the physical activity and the health ramifications of prolonged sitting by competitive players. The purpose of this study was to investigate activity levels, body mass index (BMI), and body composition in collegiate esports players as compared to age-matched controls.
Methods: Twenty-four male collegiate esports players and non-esports players between 18 and 25 years of age signed a written consent to participate. Physical activity was examined using daily activity (step count) with a wrist-worn activity tracker. A questionnaire assessing physical activity was also administered. Secondary outcomes included body-fat percentage, lean-body mass, BMI, and bone mineral content measured using dual X-ray absorptiometry.
Results: The step count in the esports players was significantly lower than the age-matched controls (6040.2 ± 3028.6 vs. 12843.8 ± 5661.1; p = 0.004). Esports players exhibited greater body-fat percentage (p = 0.05), less lean body mass (p = 0.003), and less bone mineral content (p = 0.03), despite no difference in BMI between the esports and non-esports players.
Conclusion: As compared to non-esports players, collegiate esports players were significantly less active and had a higher body-fat percentage, with lower lean body mass and bone mineral content. The BMIs showed no difference between the 2 groups. Esports athletes displayed significantly less activity and poor body composition, which are all correlated with potential health issues and risk of injury. BMI did not capture this difference and should not be considered as an accurate measure of health in competitive esports players.
Bidirectional ventricular tachycardia (BD-VT) is an intriguing arrhythmia, characterized by a beat-to-beat alternation of the QRS polarity on electrocardiogram. Currently there is no simple BD-VT animal model.
We report a simple animal model of BD-VT induced by caffeine and dobutamine (C+D) challenge in normal rats in which the arrhythmia can be attenuated by dantrolene (a ryanodine receptor stabilizer) treatment, but not by the pacemaker channel blocker ivabradine treatment.
Adult (4–5 months old) Sprague-Dawley rats (both sexes) were randomized into C+D (n = 8, received caffeine 120 mg/kg intraperitoneally [IP] and dobutamine 60 μg/kg IP, sequentially) and control (n = 8) groups. In addition, a group of 7 rats were pretreated with dantrolene (10 mg/kg, IP) 30 minutes before the C+D challenge and another group of 8 rats were pretreated with ivabradine (5 mg/kg, IP) 30 minutes before the C+D challenge.
C+D challenge induced spontaneous premature ventricular contractions (PVCs) in 7 of 8 rats and BD-VT (lasted 4.3 ± 2.9 minutes, terminated spontaneously) in 6 of 8 (75%) rats. No ventricular arrhythmia was induced in the control group (P < .05 vs C+D group). Dantrolene treatment significantly decreased BD-VT (1 of 7 rats in the Dantrolene+C+D group vs 6 of 8 rats in C+D group, P < .05). Ivabradine treatment did not affect C+D-induced BD-VT (7 of 8 rats in the Ivabradine+C+D group vs 6 of 8 in the C+D group, P > .05).
Caffeine and dobutamine challenge induces BD-VT in a majority of normal rats. Stabilizing cardiac ryanodine receptors with dantrolene treatment can significantly decrease the occurrence of BD-VT, but pacemaker channel blocker ivabradine treatment does not have effect in this animal model.
Introduction: Pregnancy-related trauma is one of the leading causes of morbidity and mortality in pregnant women and fetuses. The fetal response to injury is largely dependent on the timing of fetal presentation and the underlying pathophysiology of the trauma. The optimal management of pregnant patients who have suffered an obstetric emergency depends on clinical assessment and understanding of the placental implantation process, which can be difficult to perform during an emergency. Understanding the mechanisms of traumatic injuries to the fetus is crucial for developing next-generation protective devices.
Methods: This study aimed to investigate the effect of amniotic fluid on mine blast on the uterus, fetus, and placenta via computational analysis. Finite element models were developed to analyze the effects of explosion forces on the uterus, fetus, and placenta, based on cadaveric data obtained from the literature. This study uses computational fluid-structure interaction simulations to study the effect of external loading on the fetus submerged in amniotic fluid inside of the uterus.
Results: Computational fluid-structure interaction simulations are used to study the effect of external loading on the fetus/placenta submerged in amniotic fluid inside the uterus. Cushioning function of the amniotic fluid on the fetus and placenta is demonstrated. The mechanism of traumatic injuries to the fetus/placenta is shown.
Discussion: The intention of this research is to understand the cushioning function of the amniotic fluid on the fetus. Further, it is important to make use of this knowledge in order to ensure the safety of pregnant women and their fetuses.
Keywords: Amniotic fluid; FSI; Fetus; Fluid-structure interaction; Placenta.
Replication stress response is crucial for the maintenance of a stable genome. POLDIP3 (DNA polymerase delta interacting protein 3) was initially identified as one of the DNA polymerase δ (Pol δ) interacting proteins almost 20 years ago. Using a variety of in vitro biochemical assays, we previously established that POLDIP3 is a key regulator of the enzymatic activity of Pol δ. However, the in vivo function of POLDIP3 in DNA replication and DNA damage response has been elusive.
We first generated POLDIP3 knockout (KO) cells using the CRISPR/Cas9 technology. We then investigated its biological functions in vivo using a variety of biochemical and cell biology assays.
We showed that although the POLDIP3-KO cells manifest no pronounced defect in global DNA synthesis under nonstress conditions, they are sensitive to a variety of replication fork blockers. Intriguingly, we found that POLDIP3 plays a crucial role in the activation and maintenance of the DNA damage checkpoint in response to exogenous as well as endogenous replication stress.
Our results indicate that when the DNA replication fork is blocked, POLDIP3 can be recruited to the stalled replication fork and functions to bridge the early DNA damage checkpoint response and the later replication fork repair/restart.
© 2022 The Authors. Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.
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