Wuhan Youfu Hospital

A rapid increase in the incidence of insulin resistance (IR) induced by long-term olanzapine treatment has been observed; however, there are no more efficient ways to prevent IR. Our study aimed to demonstrate the mechanism underlying olanzapine-induced insulin resistance. In this study, we first analysed the data of 120 schizophrenia patients who had been taking olanzapine for at least 3 months. Eventually, it was found that an increase in circulating tumour necrosis factor-α (TNF-α, p < 0.05). Subsequently, we verified this finding in a rat model. We detected the expression levels of the target genes fatty acid binding protein 4 (FABP4) and the palmitoyltransferase Dhhc7 in both rats and three T3-L1 adipocytes by using Western blotting and polymerase chain reaction (p < 0.05). Exposure to olanzapine increased the expression of FABP4 while decreasing the expression of Dhhc7. Additionally, we demonstrated that it may affect metabolism by inhibiting glucose transporter 4 (GLUT4) membrane transport. Finally, we improved olanzapine-induced insulin resistance by injecting FABP4 adenovirus and elucidating its underlying mechanism. In summary, our study demonstrated that long-term exposure to olanzapine increases circulating plasma levels of TNF-α, thus leading to increased expression of FABP4 protein in white adipose tissue and subsequently inhibiting Dhhc7expression, which correspondingly leads to reduced membrane translocation of GLUT4 and consequent insulin resistance. In conclusion, this study elucidated the signalling pathway through which olanzapine inhibits GLUT4 membrane transport via the TNF-α/FABP4/Dhhc7 axis, thus ultimately leading to insulin resistance.

Background: Suicidal ideation poses a significant risk for suicidal behavior among adolescents globally. While studies have highlighted the association between anxiety and suicidal ideation, little is known regarding these behaviors in the Chinese adolescent population, as well as possible contextual factors that may influence this relationship. This study explores the association between generalized anxiety disorder (GAD) and suicidal ideation in an urban Chinese in-school adolescent population and investigates the contextual influence of primary caregiver mental health, considering comorbid symptoms of depression, anxiety, and insomnia. Methods: Data from the Students' Mental Health Network (SMHN) project in Wuhan, China, involving 7967 adolescents and their primary caregivers, were analyzed. The study assessed adolescents' and primary caregivers' mental health, including depression, insomnia, and GAD. Suicidal ideation was measured using the 9th item of Patient Health Questionnaire-9 (PHQ-9). Multilevel ordinal logistic regression models were used to examine associations between GAD and suicidal ideation, adjusting for covariates. Contextual effects were explored to determine how the mental health of the primary caregiver influences suicidal ideation. Results: The study found that GAD is independently associated with suicidal ideation among adolescents after accounting for other mental health covariates. Specifically, adolescents with more severe GAD symptoms, particularly subtype symptoms of "Restlessness" and "Irritability," had a higher likelihood of experiencing suicidal ideation. There were significant contextual effects on adolescent suicidal ideation at the caregiver mental health level. Adolescents with caregivers experiencing depression and anxiety symptoms had an increased risk of suicidal ideation. Conclusions: This research highlights the importance of recognizing GAD as an independent risk factor for suicidal ideation among Chinese adolescents. It also emphasizes the role of caregiver mental health as a contextual factor. The findings suggest a need for holistic interventions addressing both adolescents' and caregivers' mental well-being, ultimately enhancing suicide prevention efforts.

Alzheimer's disease (AD) is a common neurodegenerative disease associated with deposition of β-amyloid peptide (Aβ). Platycodin D (PLD), a triterpenesaponin, may possess neuro-protective effect. In the current study, we aimed to explore the effects of PLD on Aβ-induced inflammation and oxidative stress in microglial BV-2 cells. Our study showed that PLD treatment improved cell viability in Aβ-induced BV-2 cells. PLD attenuated Aβ-induced inflammation with deceased production of TNF-α, IL-1β and IL-6 in Aβ-induced BV-2 cells. PLD also mitigated the oxidative stress in Aβ-induced BV-2 cells, as evidenced by deceased production of ROS and MDA, and increased SOD activity. Furthermore, the increased expression levels of TLR4 and p-p65 and decreased IκBα expression in the Aβ-stimulated BV-2 cells were attenuated by PLD treatment. Overexpression of TLR4 reversed the anti-inflammatory effect of PLD in Aβ-stimulated BV-2 cells. In addition, PLD treatment enhanced the Aβ-stimulated increase in the expression levels of Nrf2, HO-1, and NQO1 in BV-2 cells. Knockdown of Nrf2 abrogated the anti-oxidative effect of PLD in Aβ-stimulated BV-2 cells. In conclusion, these findings indicated that PLD protected BV-2 cells from Aβ-induced oxidative stress and inflammation via regulating the TLR4/NF-κB and Nrf2/HO-1 signaling pathways. Thus, PLD may be a potential candidate for the treatment of AD.

The presence of multiple comorbidities in patients facing myocardial ischemia-reperfusion (IR) injury is the main obstacle for cardioprotection. This study investigated the effect of melatonin postconditioning combined with sitagliptin pretreatment on cardioprotection in diabetic aged rats by evaluating oxidative stress, apoptosis and involvement of the AMPK/SIRT1 pathway. The type-2 high-fat/streptozotocin experimental model in aged Sprague-Dawley rats (n=78) was used. The animals underwent left coronary occlusion for 30 min, followed by 3 h reperfusion. Diabetic rats were pretreated with sitagliptin (20 mg/kg, i.p.) and received melatonin (10 mg/kg, i.p.) early in reperfusion. Myocardial infarct size, histological changes, oxidative markers, mitochondrial reactive oxygen species (mitoROS) and expression of proteins regulating apoptosis and AMPK/SIRT1 activity were measured. The infarct size-sparing effect of the combination of melatonin plus sitagliptin was greater than that observed in individual treatments (P&lt;0.01). Combination therapy significantly reduced IRinduced elevation of 8-isoprostane, mitoROS and proapoptotic proteins Bax and cleaved caspase-3, and increased IR-induced downregulation of mitochondrial superoxide-dismutase, glutathione, anti-apoptotic protein Bcl2, phosphorylated AMPK and SIRT1 (P&lt;0.01, P&lt;0.001). Inhibition of AMPK via compound-C completely reversed combination-induced cardioprotection. Thus, improving cardiac antioxidative and antiapoptotic responses via upregulation of AMPK/SIRT1 activity may represent a central mechanism through which melatonin plus sitagliptin attenuate myocardial IR injury in diabetic-aged rats.

Traumatic brain injury (TBI) is a public health concern, and causes cognitive dysfunction, emotional disorders, and neurodegeration, as well. The currently available treatments are all symptom-oriented with unsatifying efficacy. It is highly demanded to understand its underlying mechanisms. Controlled cortical impact (CCI) was used to induce TBI in aged female mice subjected to ovariectomy. Brain damages were assessed with neurological severity score, brain infarction and edema. Morris water maze and elevated plus maze were applied to evaluate the levels of anxiety. Apoptosis in the hippocampus was assayed with Fluoro-Jade B staining and TUNEL staining. Western blot was employed to measure the expression of NMDA receptor subunits and phosphorylation of ERK1/2, and biochemical assays were used to estimate oxidative stress. 17beta-Estradiol (E2) was intraperitoneally administered at 10-80 μg/kg once per day for 7 consecutive days before or after CCI. Chronic administration of E2 both before and immediately after CCI conferred neuroprotection, reducing neurological severity score, brain infarction, and edema in TBI mice. Additionally, E2 improved many aspects of deleterious effects of TBI on the hippocampus, including neuronal apoptosis, dysfunction in spatial memory, reduction in NR2B, enhancement of oxidative stress, and activation of ERK1/2 pathway. The present study provides clue for the notion that E2 has therapeutic potential for both prevention and intervention of TBI-induced brain damages.