Consensus on the pharmacological treatment of acute stress disorder in Chinese pilots: a Delphi study.

BACKGROUND: Appropriate medication is very important for pilots with acute stress disorder. Improper medication can not only affect the physical and mental health of the pilots but can also endanger flight safety. Hence, we aimed to quickly and effectively relieve symptoms and restore cognitive function by forming a consensus of Chinese experts on the pharmacological treatment of acute stress disorder in pilots using the Delphi method. METHODS: Relevant literature was searched to enumerate the current status of pharmacological treatment of acute stress disorder in pilots, followed by two rounds of expert consultation and discussion according to the listed status of the survey using the Delphi method. A descriptive statistical method was used to analyze the basic information, authority coefficients, concentration of opinions, and survey items of the experts to develop a consensus on the pharmacological treatment of acute stress disorder in pilots. RESULTS: A total of 16 experts in psychiatry, pharmacology, and aerospace medicine from different provinces and cities across China were invited for consultation. The recovery rate of the two rounds of consultation was 100%, and the expert authority coefficients were 0.897 and 0.906, respectively. Kendall's coefficient of concordance of indicators at all levels was 0.564-0.594 (p < 0.01). Based on the number of votes received, alprazolam tablets (16), eszopiclone tablets (15), and lorazepam tablets (14) were recommended for the treatment of excitatory psychomotor symptoms of acute stress disorder; paroxetine tablets (15) and sertraline tablets (15) were available for psychomotor depressive symptoms; olanzapine tablets (15), olanzapine orally disintegrating tablets (14), and quetiapine fumarate tablets (14) were selected for psychotic symptoms. CONCLUSIONS: This study formed a consensus on rapid and effective pharmacological treatment for different symptoms of acute stress disorder pilots, which provides a reference for clinical treatment.

Network structure of depression and anxiety symptoms in Chinese female nursing students.

BACKGROUND: Comorbidity between depressive and anxiety disorders is common. From network perspective, mental disorders arise from direct interactions between symptoms and comorbidity is due to direct interactions between depression and anxiety symptoms. The current study investigates the network structure of depression and anxiety symptoms in Chinese female nursing students and identifies the central and bridge symptoms as well as how other symptoms in present network are related to depression symptom "thoughts of death". METHODS: To understand the full spectrum of depression and anxiety, we recruited 776 Chinese female nursing students with symptoms of depression and anxiety that span the full range of normal to abnormal. Depression symptoms were measured by Patient Health Questionnaire-9 while anxiety symptoms were measured by Generalized Anxiety Disorder 7-Item Questionnaire. Network analysis was used to construct networks. Specifically, we computed the predictability, expected influence and bridge expected influence for each symptom and showed a flow network of "thoughts of death". RESULTS: Nine strongest edges existed in network were from the same disorder. Four were between depression symptoms, like "sleep difficulties" and "fatigue", and "anhedonia" and "fatigue". Five were between anxiety symptoms, like "nervousness or anxiety" and "worry too much", and "restlessness" and "afraid something will happen". The symptom "fatigue", "feeling of worthlessness" and "irritable" had the highest expected influence centrality. Results also revealed two bridge symptoms: "depressed or sad mood" and "irritable". As to "thoughts of death", the direct relations between it and "psychomotor agitation/retardation" and "feeling of worthlessness" were the strongest direct relations. CONCLUSIONS: The current study highlighted critical central symptoms "fatigue", "feeling of worthlessness" and "irritable" and critical bridge symptoms "depressed or sad mood" and "irritable". Particularly, "psychomotor agitation/retardation" and "feeling of worthlessness" were identified as key priorities due to their strongest associations with suicide ideation. Implications for clinical prevention and intervention based on these symptoms are discussed.

The relations between different components of intolerance of uncertainty and symptoms of generalized anxiety disorder: a network analysis.

BACKGROUND: Intolerance of uncertainty (IU) is considered as a specific risk factor in the development and maintenance of generalized anxiety disorder (GAD). Yet, researches have investigated the relations between IU and GAD (or worry) using total scores on self-report measures. This ignores that there are different components exist in IU and the heterogeneity of GAD symptoms. In the present study, we explored the relations among different components of IU and symptoms of GAD. METHODS: A dimensional approach which take individual differences into consideration in different components of IU along a full range of normal to abnormal symptom severity levels of GAD were used in this study. Components of IU were measured by 12-item Intolerance of Uncertainty Scale and symptoms of GAD were measured by Generalized Anxiety Disorder 7-Item Questionnaire. Regularized partial-correlation network was estimated using cross-sectional data from 624 university students. RESULTS: Four strongest edges are between components of IU, like "Unforeseen events upset me greatly" and "It frustrates me not having all the information I need". Two strongest edges are between symptoms of GAD, like "Being so restless that it is hard to sit still" and "Feeling afraid as if something awful might happen". Symptom "Worrying too much about different things" and component "It frustrates me not having all the information I need" have the highest expected influences in the present network. In the community of IU, component "It frustrates me not having all the information I need" has the highest bridge expected influence. And in the community of GAD, symptoms "Worrying too much about different things" and "Not being able to stop or control worrying" have the highest bridge expected influence. CONCLUSIONS: This study reveals potential pathways between different components of IU and various symptoms of GAD. Understanding how putative risk factors such as different components of IU are related to symptoms of GAD may provide some references for related preventions and interventions, such as targeting component "It frustrates me not having all the information I need" may be more effective at reducing symptoms of GAD than targeting other components of IU.

The relations among worry, meta-worry, intolerance of uncertainty and attentional bias for threat in men at high risk for generalized anxiety disorder: a network analysis.

BACKGROUND: Improving the psychotherapies for generalized anxiety disorder (GAD) is dependent on a deeper understanding of the relations between GAD and its associated cognitive factors. In the present study, we investigate how the core feature of GAD (i.e., worry) and its associated cognitive factors, such as meta-worry, intolerance of uncertainty, and attention bias towards threat, relate to each other in men at high risk for GAD. METHODS: We used network analysis to explore the relations among these variables in a cross-sectional sample of 122 men at high risk for generalized anxiety disorder. Specifically, we computed the expected influence and predictability of each variable. RESULTS: In the final network, we found that worry and meta-worry had the highest expected influence and predictability. In contrast, attention bias towards threat showed the lowest expected influence and predictability. The estimates of the expected influence of the nodes were stable (correlation stability coefficient = 0.52). CONCLUSIONS: The present study is the first to investigate the relations among worry, meta-worry, intolerance of uncertainty, and attention bias towards threat in men at high risk for generalized anxiety disorder. These findings indicate that worry and meta-worry may play important roles in the present network. The implications for clinical interventions and future studies are discussed.

Ethyl pyruvate inhibits HMGB1 phosphorylation and release by chelating calcium.

Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to have antiinflammatory effects and to confer protective effects in various pathological conditions. Recently, a number of studies have reported EP inhibits high mobility group box 1 (HMGB1) secretion and suggest this might contribute to its antiinflammatory effect. Since EP is used in a calcium-containing balanced salt solution (Ringer solution), we wondered if EP directly chelates Ca(2+) and if it is related to the EP-mediated suppression of HMGB1 release. Calcium imaging assays revealed that EP significantly and dose-dependently suppressed high K(+)-induced transient [Ca(2+)]i surges in primary cortical neurons and, similarly, fluorometric assays showed that EP directly scavenges Ca(2+) as the peak of fluorescence emission intensities of Mag-Fura-2 (a low-affinity Ca(2+) indicator) was shifted in the presence of EP at concentrations of ≥7 mmol/L. Furthermore, EP markedly suppressed the A23187-induced intracellular Ca(2+) surge in BV2 cells and, under this condition, A23187-induced activations of Ca(2+)-mediated kinases (protein kinase Cα and calcium/calmodulin-dependent protein kinase IV), HMGB1 phosphorylation and subsequent secretion of HMGB1 also were suppressed. (A23187 is a calcium ionophore and BV2 cells are a microglia cell line.) Moreover, the above-mentioned EP-mediated effects were obtained independent of cell death or survival, which suggests that they are direct effects of EP. Together, these results indicate that EP directly chelates Ca(2+), and that it is, at least in part, responsible for the suppression of HMGB1 release by EP.

Glycyrrhizin suppresses HMGB1 inductions in the hippocampus and subsequent accumulation in serum of a kainic acid-induced seizure mouse model.

Glycyrrhizin (GL), a triterpene present in the roots and rhizomes of licorice (Glycyrrhiza glabra), has been shown to have anti-inflammatory and anti-viral effects. In our previous reports, we demonstrated the neuroprotective effects of GL in the postischemic brain and in kainic acid (KA)-induced seizure animal model. In this KA-induced seizure model, the systemic administration of GL 30 min before KA administration significantly suppressed neuronal cell death and markedly suppressed gliosis and proinflammatory marker inductions. In the present study, we showed that high-mobility group box 1 (HMGB1), an endogenous danger signal, was induced in hippocampal CA1 and CA3 regions of the same KA-induced model, and peaked at ~3 h and at 6 days post-KA. HMGB1 was transiently induced in neurons and astrocyte at 3 h post-KA, and it was released from dying neurons and accumulated in serum at 12 h post-KA. Furthermore, after ~4 days of almost undetectable levels in the hippocampus, delayed and marked HMGB1 induction was detected at 6 days post-KA, mainly in astrocytes and endothelial cells, in which HMGB1 was localized in nuclei, and not secreted into serum. Interestingly, GL suppressed HMGB1 inductions in hippocampus and also suppressed its release into serum in KA-treated mice. Since we established previously that GL has anti-inflammatory and anti-excitotoxic effects in this KA-induced seizure model, these results indicate that the neuroprotective effect of GL in the KA-injected mouse brain might be attributable to the inhibitions of HMGB1 induction and release, which in turn, mitigates the inflammatory process.

Relationship between parenting style and internet addiction: Interpersonal relationship problem as a mediator and gender as a moderator.

Purpose: This study assessed the moderating effect of gender on the indirect effects of positive and negative parenting styles on Internet addiction through interpersonal relationship problem. Methods: A cross-sectional survey of randomly sampled 1194 college students recruited voluntarily from three universities in China was conducted to assess the variables of positive and negative parenting styles, interpersonal relationship problem, and Internet addiction. Results: Positive parenting style, such as emotional warmth, was a protective factor for the development of Internet addiction, whereas negative parenting style, such as rejection and overprotection, was a potential risk factor for Internet addiction. Furthermore, interpersonal relationship problem completely mediated the association between positive parenting style and Internet addiction but partially mediated the relationship between negative parenting style and Internet addiction. Finally, gender moderated the indirect effect of parenting style on Internet addiction through interpersonal relationship problem. Conclusion: The correlation between positive parenting style and interpersonal relationship problem was considerably weaker among females, whereas the association between interpersonal relationship problem and Internet addiction was much stronger among females. For the prevention and intervention of Internet addiction, it is important to increase positive parenting style for males while enhancing interpersonal skills training for females. Further longitudinal studies should discuss the effects of paternal and maternal parenting styles on Internet addiction.

Effects of intermittent theta-burst transcranial magnetic stimulation on post-traumatic stress disorder symptoms: A randomized controlled trial.

Post-traumatic stress disorder (PTSD) is a prevalent and debilitating illness, which can be alleviated by transcranial magnetic stimulation (TMS). Intermittent theta burst stimulation (iTBS), a newer form of repetitive transcranial magnetic stimulation (rTMS), offers the advantage of shorter treatment sessions compared to the standard 10 Hz rTMS treatment. In order to compare the two forms of TMS, we enrolled 75 participants aged between 18 and 55 years who presented with (PCL-C) scale score of at least 50. Participants were randomly assigned to groups in a ratio of 1:1:1, receiving either 10 Hz rTMS, iTBS, or sham-controlled iTBS. Participants in the two treatment groups underwent 15 therapies which consisted of 1800 pulses and targeted the right dorsolateral prefrontal cortex (DLPFC). The main outcomes included changes in scores on the PCL-C and the Post-Traumatic Growth Inventory (PTGI). After intervention, the PCL-C and PTGI scores in iTBS and rTMS groups were significantly different from those in sham-controlled iTBS group. No significant differences in PCL-C and PTGI were found between the two active treatment groups. ITBS, with a shorter treatment duration, can effectively improve the symptoms of PTSD, with no significant difference in effect from that of rTMS. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of iTBS in PTSD.

Transcutaneous Vagus Nerve Stimulation for Insomnia in People Living in Places or Cities with High Altitudes: A Randomized Controlled Trial.

BACKGROUND: The purpose of this study was to investigate the effectiveness and safety of transcutaneous vagus nerve stimulation (tVNS) to improve insomnia in the special environment of a plateau. METHODS: This study was a single-center, single-blind, randomized controlled trial. A total of 100 patients with insomnia at high altitude were randomized into three groups receiving either transcutaneous vagus nerve stimulation intervention in the left ear tragus (treatment group), pseudo-stimulation intervention (sham group), or cognitive behavioral therapy for insomnia (CBTI group). The primary measure was the Pittsburgh Sleep Quality Index (PSQI) score. In addition, we assessed the patients' objective sleep status with polysomnography and evaluated changes in the Insomnia Severity Index Scale (ISI) and Generalized Anxiety Disorder-7 (GAD-7) scores. We used one-way ANOVA and repeated-measures ANOVA for analysis. RESULTS: Patients' PSQI, ISI, and GAD-7 scale scores significantly decreased after 4 weeks of tVNS treatment and were greater than those of the control group. Polysomnographic data also demonstrated shortened sleep latency and longer deep sleep in the patients. CONCLUSION: tVNS is effective in improving sleep quality and reducing anxiety levels in high-altitude insomnia patients but should be confirmed in future adequate and prolonged trials to guide clinical promotion.

The relationship between obsessive-compulsive symptoms and depressive symptoms in patients with obsessive-compulsive disorder: A network analysis.

Aim: The network model suggests that the comorbidity of obsessive-compulsive disorder (OCD) and depression is due to direct interactions between OCD and depression symptoms. The study investigates the network structure of OCD and depressive symptoms in patients with OCD and explores the pathways that connect the OCD and depression symptoms. Materials and Methods: The items of Yale-Brown Obsessive-Compulsive Symptom (Y-BOCS) Scale and the Depression Self-Rating Scale of 445 patients with OCD were analyzed by network model. Statistical analysis and visualization of the network were conducted using R software. Results: Two bridge edges "uneasiness" and "time consumed by obsessions" and "low spirit" and "distress caused by obsessions" connected the OCD symptoms to depressive symptoms. Two closely related edges were between "interference due to obsessions" and "interference due to compulsions" and between "difficulty resisting obsessions" and "difficulty resisting compulsions." The symptoms "interference due to compulsions," "distress caused by obsessions," "time consumed by compulsions," and "uneasiness" had the highest expected influence centrality. Conclusions: This study highlighted the relationship between "uneasiness" and "time consumed by obsessions" and between "low spirit" and "distress caused by obsessions." In addition, "interference due to compulsions" is found as the core symptom in the network. Targeting these symptoms may help prevent and treat the comorbidity of obsession-compulsion and depression in patients with OCD.

Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion.

High mobility group box 1 (HMGB1) is an endogenous danger signal molecule. In a previous report, we showed that HMGB1 is massively released during NMDA-induced acute damaging process in the postischemic brain and triggers inflammatory processes, like microglial activation. siRNA-mediated HMGB1 knockdown markedly reduced infarct volumes, confirming the crucial role played by HMGB1 in the postischemic brain. In the present study, we showed neuroprotective effects of glycyrrhizin (GL) in the postischemic rat brain after middle cerebral artery occlusion (MCAO). GL, a triterpene present in the roots and rhizomes of licorice, Glycyrrhiza glabra, has been shown to have anti-inflammatory and anti-viral effects. It has been reported that GL binds directly to HMGB1, and inhibits its chemoattractant and mitogenic activities. The administration of GL (10mg/kg) intravenously at 3 or 6h after MCAO reduced infarct volumes to 12.9±4.2% and 46.2±9.9%, respectively, of untreated control. This neuroprotective effect was accompanied by improvements in motor impairment and neurological deficits and suppressions of microglia activation and proinflammatory cytokine induction. Interestingly, GL almost completely blocked HMGB1 secretion in the postischemic brain and in lipopolysaccharide (LPS)-treated microglia cells. Furthermore, HMGB1 phosphorylation, which is the initial step for HMGB1 secretion, and the interaction between HMGB1 and protein kinase C (PKC) or calcium/calmodulin-dependent protein kinase IV (CaMKIV) were suppressed dose-dependently by GL. Here, we hypothesized that the blockage for the putative phosphorylation sites in HMGB1 by GL might be attributed to this suppression. In addition to the anti-inflammatory effects, we found that GL has anti-excitotoxic and anti-oxidative effects in neurons. Together these results indicate that GL has neuroprotective efficacy in the postischemic brain via its anti-inflammatory, anti-excitotoxic, and anti-oxidative effects and in particular, it exerts anti-inflammatory effect, at least in part, by inhibiting HMGB1 secretion.

A Cross-Temporal Meta-Analysis on Marital Satisfaction of Chinese Couples.

Objective: To investigate the changing trend of Chinese couples' marital satisfaction and its relationship with social changes. Methods: A cross-temporal meta-analysis was performed on 118 original studies (n = 31,909) reporting marital satisfaction of Chinese couples from 1994 to 2020, primarily using correlation analysis and regression analysis. Results: (1) Overall, the marital satisfaction of Chinese couples showed a downward trend over time. (2) Men's marital satisfaction displayed almost no change, while women's marital satisfaction had a more obvious downward trend. (3) Changes in macrosocial factors (per capita consumption expenditure, housing prices, old-age dependency ratio, and divorce rate) could significantly predict the downward trend of marital satisfaction, especially for women. Conclusion: In the past 27 years, the overall marital satisfaction level of Chinese couples has shown a downward trend, and there are gendered differences, which may be related to changes in the socioeconomic and cultural environments.

Network structure of PTSD symptoms in Chinese male firefighters.

The network perspective of mental disorder offers a novel way of understanding the psychopathology of post-traumatic stress disorder (PTSD). In this framework, PTSD may arise from direct interactions between its symptoms. In the present study, we used the Post-Traumatic Stress Disorder Checklist-civilian Version (PCL-C) to investigate the network structure of PTSD symptoms in 994 Chinese male firefighters. We also calculated the micro (i.e., edges weight and node expected influence) and middle (i.e., community) indicators of the final network. Nine strongest edges existed in the final network were from the same dimension of PCL-C, like "avoidance of thoughts" and "avoidance of reminders". Symptoms "emotional reactivity", "avoidance of reminders" and "exaggerated startle response" had the highest expected influence. As for the results of community detection, the spinglass and walktrap algorithm detected the same three communities which are slightly different from the original dimensions of PCL-C (i.e., symptoms "avoidance of thoughts", "avoidance of reminders" and "trauma-related amnesia" of avoidance dimension of PCL-C were added to the intrusion dimension of PCL-C). The present study explored the network structure of PTSD symptoms in Chinese male firefighters and provided several implications for clinical prevention and intervention to address the mental health needs in this special group.

Protective effects of tetramethylpyrazine on dysfunction of the locus coeruleus in rats exposed to single prolonged stress by anti-ER stress mechanism.

Post-traumatic stress disorder (PTSD) is a serious stress-related neuropsychiatric disorder caused by major traumatic events. Abnormal activity of the locus coeruleus (LC)-noradrenergic system is related to the development of PTSD-like symptoms. Our previous studies have indicated that endoplasmic reticulum (ER) stress induced neuronal apoptosis of LC in rats with PTSD. The purpose of this study was to further investigate the role of ER stress pathways in LC neuronal dysfunction and elucidate the effect of the bioactive component tetramethylpyrazine (TMP) against ER stress response. We used an acute exposure to single prolonged stress (SPS) to model PTSD in rats. There were higher norepinephrine (NE) levels in the brain, increased tyrosine hydroxylase expression in LC, and enhanced anxiety-like behaviors in rats exposed to SPS, which were observed by enzyme-linked immunosorbent assay, western blot analysis and elevated plus maze test, respectively. In addition, the three major pathways of ER stress were activated by SPS exposure, which may be involved in the dysregulation of the LC-noradrenergic system of rats with PTSD. Furthermore, we found that TMP administration significantly suppressed the increased responsiveness of LC-noradrenergic system, effectively reduced the anxiety response of SPS rats, and selectively attenuated the activation of pro-apoptotic ER stress pathways. The results suggest that TMP was efficient in improving the LC-NE dysfunction induced by excessive ER stress. TMP exhibited a significant neuroprotective effect and potential therapeutics on PTSD-like symptoms.

Shaping the Trans-Scale Properties of Schizophrenia via Cerebral Alterations on Magnetic Resonance Imaging and Single-Nucleotide Polymorphisms of Coding and Non-Coding Regions.

Schizophrenia is a complex mental illness with genetic heterogeneity, which is often accompanied by alterations in brain structure and function. The neurobiological mechanism of schizophrenia associated with heredity remains unknown. Recently, the development of trans-scale and multi-omics methods that integrate gene and imaging information sheds new light on the nature of schizophrenia. In this article, we summarized the results of brain structural and functional changes related to the specific single-nucleotide polymorphisms (SNPs) in the past decade, and the SNPs were divided into non-coding regions and coding regions, respectively. It is hoped that the relationship between SNPs and cerebral alterations can be displayed more clearly and intuitively, so as to provide fresh approaches for the discovery of potential biomarkers and the development of clinical accurate individualized treatment decision-making.

Polystyrene microplastics induce blood-testis barrier disruption regulated by the MAPK-Nrf2 signaling pathway in rats.

As a persistent pollutant, microplastics (MPs) have been reported to induce sperm quantity decrease in mice. However, the related mechanism remains obscure. Therefore, this study is intended to explore the effects of polystyrene microplastics (PS-MPs) on male reproduction and its related mechanism of blood-testis barrier (BTB) impairment. Thirty-two adult male Wistar rats were divided randomly into four groups fed with PS-MPs for 90 days at doses of 0 mg/day (control group), 0.015 mg/day, 0.15 mg/day, and 1.5 mg/day, respectively. The present results have shown that PS-MP exposure led to the damage of seminiferous tubule, resulted in apoptosis of spermatogenic cells, and decreased the motility and concentration of sperm, while the abnormality of sperm was elevated. Meanwhile, PS-MPs could induce oxidative stress and activate the p38 MAPK pathway and thus deplete the nuclear factor erythroid-2 related factor 2 (Nrf2). Noteworthily, PS-MPs led to the BTB-related protein expression decrease. All these results demonstrated that PS-MP exposure may lead to the destruction of BTB integrity and the apoptosis of spermatogenic cells through the activation of the MAPK-Nrf2 pathway. The current study provided novelty evidence for elucidating the effects of PS-MPs on male reproductive toxicity and its potential mechanism.

Proangiogenic functions of osteopontin-derived synthetic peptide RSKSKKFRR in endothelial cells and postischemic brain.

OBJECTIVE: The aim of this study was to investigate the potential therapeutic effects of a newly discovered osteopontin-derived synthetic peptide "RSKKFRR" in a rat model of ischemic stroke. METHODS: A total of 24 male SD rats were randomly divided into three groups. The model of ischemic stroke was made up of the middle cerebral artery occlusion (MACO). The rats were divided into sham operation group (Sham), control group (MACO + PBS) and treatment group (MACO + OPNpt9), eight rats in each group. In the control group and the treatment group, PBS or OPNpt9 was injected into the nasal cavity after MACO once a day, and the area of new blood vessels and the recovery of nerve function were observed 14 days later. Whether the proliferation, migration and tube formation of HUVECs were promoted by OPNpt9 was tested. The expression levels of related proangiogenic factors were also detected. RESULTS: OPNpt9 was found to contribute to cerebral microvascular remodeling and neurological improvement in ischemic rats while promoting endothelial cell migration, proliferation and tube formation in vitro. These effects were mediated by activation of the p-ERK/MMP-9/VEGF pathway. CONCLUSION: In conclusion, OPNpt9 promotes angiogenesis and neurological recovery after ischemic stroke.

Neuroprotective effects of leptin on cerebral ischemia through JAK2/STAT3/PGC-1-mediated mitochondrial function modulation.

Neuroprotective effects of leptin have been shown in mouse model of cerebral ischemia/reperfusion injury and primary cortical neuronal culture with oxygen-glucose deprivation (OGD), while the underlying mechanisms are less understood. In the present study, we investigated whether leptin modulated mitochondrial function through JAK2/STAT3 in vivo mouse model of transient middle cerebral artery occlusion (MCAO) and in OGD-challenged primary neuronal cultures. JAK2/STAT3; mitochondrial biogenesis markers (PGC-1α); and apoptosis-associated proteins (caspase-3, BCL-2, BCL-XL, and cytochrome c) were detected by western blotting and reverse transcription-polymerase chain reaction at 1 h before and after ischemia/reperfusion. P-STAT3 and PGC-1α in neurons and astrocytes were detected. Moreover, mitochondrial morphology of the ischemic ipsilateral penumbra is examined using transmission electron microscopy. Primary cerebral cortical neurons were evaluated for viability, mitochondrial membrane potential (MMP), and apoptosis to assess whether dose-dependent neuroprotective effects of leptin during OGD were mitigated by the JAK2/STAT3 inhibitor AG490. Leptin activated JAK2/STAT3 signaling in neurons and astrocytes distributed in the ischemic ipsilateral penumbra, with peak p-STAT3 levels observed at 1 h after reperfusion. Leptin increased PGC-1α, BCL-2, and BCL-XL protein levels, cell viability, and MMP and decreased apoptosis both in vitro and in vivo; these effects were reversed by AG490 treatment. Our findings suggest that leptin-mediated neuroprotective effects in tMCAO may peak at 1 h to induce the transcription of its target gene PGC-1α, stabilization of MMP, inhibition of mitochondrial permeability transition pore opening, release of cytochrome c, and apoptosis.

Polystyrene microplastics cause cardiac fibrosis by activating Wnt/ß-catenin signaling pathway and promoting cardiomyocyte apoptosis in rats.

Microplastics (MPs) are new persistent organic pollutants derived from the degradation of plastics. They can accumulate along the food chain and enter the human body through oral administration, inhalation and dermal exposure. To identify the impact of Polystyrene (PS) MPs on the cardiovascular system and the underlying toxicological mechanism, 32 male Wister rats were divided into control group and three model groups, which were exposed to 0.5 µm PS MPs at 0.5, 5 and 50 mg/L for 90 days. Our results suggested that PS MPs exposure increased Troponin I and creatine kinase-MB (CK-MB) levels in serum, resulted in structure damage and apoptosis of myocardium, and led to collagen proliferation of heart. Moreover, PS MPs could induce oxidative stress and thus activate fibrosis-related Wnt/ß-catenin signaling pathway. These results suggested that PS MPs could lead to cardiovascular toxicity by inducing cardiac fibrosis via activating Wnt/ß-catenin pathway and myocardium apoptosis triggered by oxidative stress. The present study provided some novelty evidence to elucidate the potential mechanism of cardiovascular toxicity induced by PS MPs.

Combined Administration of Poly-ADP-Ribose Polymerase-1 and Caspase-3 Inhibitors Alleviates Neuronal Apoptosis After Spinal Cord Injury in Rats.

BACKGROUND: Neuronal apoptosis plays a pivotal role in spinal cord injury (SCI)-induced secondary cellular events. Caspase-dependent and -independent pathways are involved in neuronal apoptosis. Caspase-3 is the final effector of caspase-dependent apoptosis, whereas poly-ADP-ribose polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF) are key executors of caspase-independent apoptosis. However, it remains unclear whether simultaneous inhibition of the 2 apoptosis pathways will be more beneficial for neuronal survival. Therefore, this study investigated the ability of coadministration of the PARP-1 inhibitor 3-aminobenzamide (3-AB) and caspase-3 inhibitor z-DEVD-fmk to attenuate apoptosis in a rat SCI model. METHODS: The rats were subjected to moderate contusive SCI. Locomotor function was measured using the Basso, Beattie, and Bresnahan rating scales; neuronal apoptosis was detected using transferase-mediated deoxyuridine triphosphate-biotin nick end labeling; and immunohistochemistry and Western blotting were used to measure protein expression. RESULTS: We found the locomotor function of rats was weakened within 7 days post-SCI. At day 7 post-SCI, neuronal apoptosis dramatically increased and the expression of PARP-1, AIF, and cleaved caspase-3 was significantly upregulated. Further, Bcl-2 expression was significantly downregulated. The highest locomotor function recovery was recorded after the combined administration of 3-AB and z-DEVD-fmk for 7 days post-SCI when compared with 3-AB or z-DEVD-fmk administered alone. In addition, this combination therapy significantly reduced neuronal apoptosis by preventing upregulation of PARP-1 and AIF, inhibiting caspase-3 activation, and elevating Bcl-2 expression. CONCLUSIONS: These results suggest that combination therapy is beneficial for neuronal function recovery in rats with SCI. The underlying mechanism may be associated with cosuppression of caspase-dependent and caspase-independent apoptosis pathways.