Stress Dysregulation Research Articles

Differentially expressed genes in orbital adipose/connective tissue of thyroid-associated orbitopathy.

Thyroid-associated orbitopathy (TAO) is a disease associated with autoimmune thyroid disorders and it can lead to proptosis, diplopia, and vision-threatening compressive optic neuropathy. To comprehensively understand the molecular mechanisms underlying orbital adipogenesis in TAO, we characterize the intrinsic molecular properties of orbital adipose/connective tissue from patients with TAO and control individuals. RNA sequencing analysis (RNA-seq) was performed to measure the gene expression of orbital adipose/connective tissues of TAO patients. Differentially expressed genes (DEGs) were detected and analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA). The protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified by the Cytoscape plug-in, cytoHubba. We validated several top DEGs through quantitative real-time polymerase chain reaction (qRT-PCR). We identified 183 DEGs in adipose tissue between TAO patients (n=3) and control patients (n=3) through RNA sequencing, including 114 upregulated genes and 69 downregulated genes. The PPI network of these DEGs had 202 nodes and 743 edges. PCR-based validation results of orbital adipose tissue showed multiple top-ranked genes in TAO patients (n=4) are immune and inflammatory response genes compared with the control individual (n=4). They include ceruloplasmin isoform x3 (CP), alkaline tissue-nonspecific isozyme isoform x1 (ALPL), and angiotensinogen (AGT), which were overrepresented by 2.27- to 6.40-fold. Meanwhile, protein mab-21-like 1 (MAB21L1), phosphoinositide 3-kinase gamma-subunit (PIK3C2G), and clavesin-2 (CLVS2) decreased by 2.6% to 32.8%. R-spondin 1 (RSPO1), which is related to oogonia differentiation and developmental angiogenesis, was significantly downregulated in the orbital muscle tissues of patients with TAO compared with the control groups (P=0.024). Our results suggest that there are genetic differences in orbital adipose-connective tissues derived from TAO patients. The upregulation of the inflammatory response in orbital fat of TAO may be consistent with the clinical phenotype like eyelid edema, exophthalmos, and excess tearing. Downregulation of MAB21L1, PIK3C2G, and CLVS2 in TAO tissue demonstrates dysregulation of differentiation, oxidative stress, and developmental pathways.

A guideline of antiphotoaging activity of polysaccharide assay in vitro and in vivo

AbstractPeople have become increasingly concerned about skin beauty and health issues, especially skin photoaging. Previous studies showed that skin photoaging was characterized by skin roughness and dryness. It was caused by UV radiation‐related dysregulation of matrix metalloproteinases (MMPs) and oxidative stress. Therefore, to investigate the antiphotoaging activity of polysaccharides, it is critical to establish the skin photoaging model, including the in vitro cellular model and the in vivo animal model. The in vitro cellular model is judged by cell viability, the MMPs expression, oxidative detection, and the quantities of inflammation cytokines. Moreover, both the damage to the epidermis and dermis of nude mice and the change of collagen content in the skin are indicators of the in vivo animal model. Thus, in this guideline, we tried to summarize the practice of antiphotoaging activity for polysaccharides.

68 The Impact of Pain Catastrophizing on Neuropsychological Performance in Youth with Persistent Post Concussive Symptoms

Objective:Patients with persistent post-concussion symptoms (PPCS) experience prolonged recovery (e.g., headache, fatigue, or dizziness) lasting >2 months post injury. These symptoms are thought to be maintained by several biopsychosocial factors including dysregulated stress responses, such as pain catastrophizing, that may drive behavioral avoidance and contribute to mood symptoms and cognitive difficulties. Conditions with similar symptomatology to PPCS (e.g., anxiety disorders, somatosensory disorders, chronic pain, etc.) also exhibit maladaptive thought patterns like pain catastrophizing as well as decrements in certain aspects of cognitive performance; however little is known about how pain catastrophizing might relate to neuropsychological performance in youth with PPCS. Therefore, the purpose of this study was to examine the relationship between pain catastrophizing and neuropsychological performance in youth participants with PPCS.Participants and Methods:A prospective case-control study design was used to examine 29 participants between the ages of 13 to 23. Participants were divided into two groups: 1) patients with PPCS (2-16 months post-injury; n = 15) and 2) age-matched, non-injured controls (n = 14). Participants completed the Pain Catastrophizing Scale (PCS) to determine degree of catastrophic thinking related to pain experience and the Beck Depression Inventory (BDI). Neuropsychological performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and a modified version of the Paced Auditory Serial Addition Test (PASAT) where performance was evaluated by total correct and error type (i.e., commission and omission) across 5 trials. ANCOVA was used to compare group differences in pain catastrophizing and neuropsychological tests scores while controlling for age and linear regressions examined the relationship between PCS total score and each neuropsychological test score while controlling for level of depression.Results:Overall, the PPCS group reported significantly higher levels of pain catastrophizing on the PCS compared to the control group (p < 0.01). For neuropsychological performance, the PPCS group scored significantly lower than the control group on List Learning (p < 0.01), Semantic Fluency (p < 0.05), and List Recall (p < 0.01) on the RBANS and made significantly higher omission errors (but not commission) on the PASAT(p <.01). Higher pain catastrophizing was also associated with poorer neuropsychological performance on the exact same tasks the PPCS group performed worse than controls. There was no significant interaction by group in the impact of PCS scores on neurocognitive performance.Conclusions:Compared to controls, youth PPCS patients reported higher levels of pain catastrophizing. Additionally, pain catastrophizing was associated with poorer neuropsychological performance. These findings suggest that increased pain catastrophizing after head injury could contribute to poorer cognitive performance in youth. As such, interventions that target maladaptive cognitive coping styles like pain catastrophizing may be especially helpful for patients with PPCS.

Knocking out Selenium Binding Protein 1 Induces Depressive-Like Behavior in Mice.

Selenium binding protein 1 (SELENBP1) is involved in neurologic disorders, such as multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and schizophrenia. However, the role of SELENBP1 in the neurogenesis of depression, which is a neurologic disorder, and the underlying mechanisms of oxidative stress and inflammation in depression remain unknown. In this study, we evaluated the changes in the expression levels of SELENBP1 in the hippocampus of a mouse model of depression and in the serum of human patients with depression using the Gene Expression Omnibus database. These changes were validated using blood samples from human patients with depression and mouse models with chronic unpredictable mild stress (CUMS)-induced depressive-like behavior. We also investigated the effects of SELENBP1 knockout (KO) on inflammation, oxidative stress, and hippocampal neurogenesis in mice with CUMS-induced depression. Our results revealed that SELENBP1 levels was decreased in the blood of human patients with depression and in the hippocampus of mice with CUMS-induced depression. SELENBP1 KO increased CUMS-induced depressive behavior in mice and caused dysregulation of inflammatory cytokines and oxidative stress. This led to a decrease in the numbers of doublecortin- and Ki67-positive cells, which might aggravate CUMS-induced depressive symptoms. These findings suggest that SELENBP1 might be involved in the regulation of neurogenesis in mice with depression and could be served as a potential target for diagnosing and treating depression.

Hydrogen Sulfide: An Emerging Regulator of Oxidative Stress and Cellular Homeostasis-A Comprehensive One-Year Review.

Hydrogen sulfide (H2S), traditionally recognized as a toxic gas, has emerged as a critical regulator in many biological processes, including oxidative stress and cellular homeostasis. This review presents an exhaustive overview of the current understanding of H2S and its multifaceted role in mammalian cellular functioning and oxidative stress management. We delve into the biological sources and function of H2S, mechanisms underlying oxidative stress and cellular homeostasis, and the intricate relationships between these processes. We explore evidence from recent experimental and clinical studies, unraveling the intricate biochemical and molecular mechanisms dictating H2S's roles in modulating oxidative stress responses and maintaining cellular homeostasis. The clinical implications and therapeutic potential of H2S in conditions characterized by oxidative stress dysregulation and disrupted homeostasis are discussed, highlighting the emerging significance of H2S in health and disease. Finally, this review underscores current challenges, controversies, and future directions in the field, emphasizing the need for further research to harness H2S's potential as a therapeutic agent for diseases associated with oxidative stress and homeostatic imbalance. Through this review, we aim to emphasize H2S's pivotal role in cellular function, encouraging further exploration into this burgeoning area of research.

Curcumin alleviates bisphenol AF-induced oxidative stress and apoptosis in caprine endometrial epithelial cells via the Nrf2 signaling pathway.

Bisphenol AF (BPAF), a BPA-substitute, has been widely used in industrial compounds throughout the world. Several studies have shown that BPAF has endocrine interference and reproductive toxicity. However, the toxic effects of BPAF on pregnancy and placenta of goats are still unclear. Therefore, the objective of this study was to reveal the toxic effect of BPAF by using an in vitro culture model of caprine endometrial epithelial cells (EECs) and further attempted to alleviate the toxicity by curcumin pretreatment. The results showed that BPAF induces significant effects on EECs, including decreased cell viability and mitochondrial membrane potential (△ψm), elevating intracellular reactive oxygen species (ROS), promoting cell apoptosis through upregulating the expression of Bax, Cytochrome c, and downregulating the expression of Bcl-2. Meanwhile, BPAF induced dysregulation of oxidative stress by increasing the levels of malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) but decreasing the activities of superoxide dismutase (SOD). However, curcumin pretreatment could significantly attenuate BPAF-induced toxic effects in EECs. Further study revealed that BPAF treatment could activate mitogen-activated protein kinase (MAPK) pathway and nuclear factor-erythroid 2-related factor 2 (Nrf2) expression, but curcumin pretreatment significantly inhibited the activation of MAPK signal pathway and Nrf2 expression induced by BPAF. Overall, this study indicated that curcumin could prevent BPAF-induced EECs cytotoxicity, which provides a potential therapeutic strategy for female infertility associated with BPAF exposure.

Women who pre-game: A study of stress and alcohol use in female collegiate predrinkers

Introduction: This study examined the relationship between stress and pre-gaming (i.e., drinking prior to going out to an event) in female college students. Methods: Thirty-four female college students were grouped as pre-gamers or non-pre-gamers based on self-reported drinking patterns. They completed surveys about alcohol use and mental health and provided a set of salivary cortisol samples upon waking, 30 min later, and at 10am on the same day. Results: Pre-gamers and non-pre-gamers did not differ on demographics or psychosocial variables. Pre-gamers reported riskier drinking overall and had greater endorsement of social, coping, and enhancement drinking motives. Pre-gamers also had lower cortisol levels 30 min after waking and exhibited attenuated CAR. Conclusions: Female collegiate pre-gamers may differ from their peers not only in terms of alcohol consumption and drinking motives, but also on attenuated CAR, a physiological biomarker associated with stress dysregulation and vulnerability to addictive behaviors.

Research Progress of Antioxidants in Oxidative Stress Therapy after Spinal Cord Injury.

Spinal cord injury (SCI) is a serious problem in the central nervous system resulting in high disability and mortality with complex pathophysiological mechanisms. Oxidative stress is one of the main secondary reactions of SCI, and its main pathophysiological marker is the production of excess reactive oxygen species. The overproduction of reactive oxygen species and insufficient antioxidant capacity lead to the occurrence of oxidative stress and neuroinflammation, and the dysregulation of oxidative stress and neuroinflammation leads to further aggravation of damage. Oxidative stress can initiate a variety of inflammatory and apoptotic pathways, and targeted antioxidant therapy can greatly reduce oxidative stress and reduce neuroinflammation, which has a certain positive effect on rehabilitation and prognosis in SCI. This article reviewed the research on different types of antioxidants and related treatments in SCI, focusing on the mechanisms of oxidative stress.

Sex differences in stress responses among underrepresented minority adolescents at risk for substance use disorder

Adolescence is a period of dramatic physiological changes preparing individuals to face future challenges. Prolonged exposure to stressors during childhood can result in dysregulated stress systems which alter normative physiological progression, leading to exacerbated risk for developing psychiatric disorders. Parental substance use disorder (SUD) is considered a significant childhood stressor which increases risk for the offspring to develop SUD. Thus, it is important to understand stress reactivity among adolescents with parental SUD. We used the Trier Social Stress Task (TSST), which includes a public speech presentation, as an acute stressor. Changes in heart-rate (HR) were measured while disadvantaged minority adolescents with and without a family history (FH+/FH-) of SUD performed the TSST. We investigated sex-specific stress response patterns during the TSST. HR peaked during the speech presentation and was overall higher in females than males. Changes in HR measures between baseline and speech showed an interaction between biological sex and FH group. Specifically, FH- females and FH+ males had significantly larger positive HR changes than FH- males. These results suggest that male and female adolescents with parental SUD have atypical, but divergent changes in stress reactivity that could explain their increased risk for developing SUD via different sexually dimorphic mechanisms.

Associations of prenatal and childhood Pb exposure with allostatic load in adolescence: Findings from the ELEMENT cohort study

The biological pathways which link lead (Pb) and long-term outcomes are unclear, though rodent models and a few human studies suggest Pb may alter the body's stress response systems, which over time, can elicit dysregulated stress responses with cumulative impacts. This study examined associations between prenatal and early childhood Pb exposure and adolescent allostatic load, an index of an individual's body burden of stress in multiple biological systems, and further examined sex-based associations. Among 391 (51% male) participants in the ELEMENT birth cohort, we related trimester-specific maternal blood Pb, 1-month postpartum maternal tibia and patella Pb, and child blood Pb at 12–24 months to an allostatic load index in adolescence comprised of biomarkers of cardiovascular, metabolic, neuroendocrine, and immune function. The results were overall mixed, with prenatal exposure, particularly maternal bone Pb, being positively associated with allostatic load, and early childhood Pb showing mixed results for males and females. In adjusted Poisson regression models, 1 mcg/g increase in tibia Pb was associated with a 1% change in expected allostatic load (IRR = 1.01; 95%CI 0.99, 1.02). We found a significant Pb × sex interaction (IRR = 1.05; 95%CI 1.01, 1.10); where males saw an increasing percent change in allostatic load as 12 month Pb levels increased compared to females who saw a decreasing allostatic load. Further examination of allostatic load will facilitate the determination of potential mechanistic pathways between developmental toxicant exposures and later-in-life cardiometabolic outcomes.

Anomic suicides on rise during recently emerging crises: revisiting Durkheim's model.

Suicide is a global public health issue, with behavior differing across genders, age groups, places, and sociopolitical settings. Emile Durkheim characterized anomic suicide as occurring when social standards fail, resulting in purposelessness and directionlessness. Young people who are experiencing social issues are in danger, even if they do not voice suicidal ideas. Prevention interventions should target these people by strengthening resilience, minimizing social dysregulation stress, and fostering the development of life skills, coping resources, and social support. Anomic suicide has important psychological and societal implications, emphasizing the importance of fostering social cohesion and assisting persons experiencing purposelessness or a lack of direction in life.

Oridonin promotes endoplasmic reticulum stress via TP53-repressed TCF4 transactivation in colorectal cancer

BackgroundThe incidence of colorectal cancer and cancer death rate are increasing every year, and the affected population is becoming younger. Traditional Chinese medicine therapy has a unique effect in prolonging survival time and improving the prognosis of patients with colorectal cancer. Oridonin has been reported to have anti-cancer effects in a variety of tumors, but the exact mechanism remains to be investigated.MethodsCell Counting Kit-8 assay (CCK8) and 5-Ethynyl-2'-deoxyuridine (EdU) staining assay, Tranwell, and Wound healing assays were performed to measure cell proliferation, invasion, and migration capacities, respectively. The protein and mRNA expression levels of various molecules were reflected by Western blot and Reverse Transcription quantitative Polymerase Chain Reaction (qRT-PCR). Transcription Factor 4 (TCF4) and its target genes were analyzed by Position Weight Matrices (PWMs) software and the Gene Expression Omnibus (GEO) database. Immunofluorescence (IF) was performed to visualize the expression and position of Endoplasmic Reticulum (ER) stress biomarkers. The morphology of the ER was demonstrated by the ER tracker-red. Reactive Oxygen Species (ROS) levels were measured using a flow cytometer (FCM) or fluorescent staining. Calcium ion (Ca2+) concentration was quantified by Fluo-3 AM staining. Athymic nude mice were modeled with subcutaneous xenografts.ResultsOridonin inhibited the proliferation, invasion, and migration of colorectal cancer, and this effect was weakened in a concentration-dependent manner by ER stress inhibitors. In addition, oridonin-induced colorectal tumor cells showed increased expression of ER stress biomarkers, loose morphology of ER, increased vesicles, and irregular shape. TCF4 was identified as a regulator of ER stress by PWMs software and GEO survival analysis. In vitro and in vivo experiments confirmed that TCF4 inhibited ER stress, reduced ROS production, and maintained Ca2+ homeostasis. In addition, oridonin also activated TP53 and inhibited TCF4 transactivation, further exacerbating the elevated ROS levels and calcium ion release in tumor cells and inhibiting tumorigenesis in colorectal cancer cells in vivo.ConclusionsOridonin upregulated TP53, inhibited TCF4 transactivation, and induced ER stress dysregulation in tumor cells, promoting colorectal cancer cell death. Therefore, TCF4 may be one of the important nodes for tumor cells to regulate ER stress and maintain protein synthesis homeostasis. And the inhibition of the TP53/TCF4 axis plays a key role in the anti-cancer effects of oridonin.

Dysregulation of Inflammation, Oxidative Stress, and Glucose Metabolism-Related Genes and miRNAs in Visceral Adipose Tissue of Women with Type 2 Diabetes Mellitus.

BACKGROUND Human visceral adipose tissue (VAT), now identified as an endocrine organ, plays a significant role in impaired fasting glucose and diabetes through the deregulated metabolism and adipogenesis of visceral adipocytes in obesity. Our study focuses on exploring the link between inflammation, oxidative stress, and glucose metabolism-associated genes with corresponding miRNAs in human visceral adipocytes and VAT from individuals with glucose metabolism disorders. MATERIAL AND METHODS We examined the expression of ATM, NFKB1, SOD2, INSR, and TIGAR, along with their related miRNAs using PCR, in two contexts:1 - During the three-stage visceral adipogenesis under normal glucose levels (5.5 millimoles), intermittent, and chronic hyperglycemia (30 millimoles).2 - In visceral adipose tissue from subjects (34 F, 18 M) with normal glucose metabolism, impaired fasting glucose, and type 2 diabetes mellitus. RESULTS Both chronic and intermittent hyperglycemia similarly influenced ATM, NFKB1, TIGAR, SOD2, INSR gene expression in visceral adipocytes, with corresponding changes in a few tested miRNAs (eg, let-7g-5p, miR-145-5p, miR-21-5p). Anthropometric and biochemical parameters led us to focus on female subjects. Our results showed transactivation of NFKB1, TIGAR, miR-10b-5p, miR-132-3p, miR-20a-5p, miR-21-5p, and miR-26a-5p exclusively in type 2 diabetes mellitus. Upregulated molecules (excluding miR-10b-5p and miR-20a-5p) positively correlated with glucose metabolism markers. CONCLUSIONS The genes studied may undergo miRNA interferences and hyperglycemic memory in visceral adipocytes under hyperglycemic conditions. VAT from women with type 2 diabetes mellitus, but not with impaired fasting glucose, showed transactivated miRNAs and a molecular dysregulation of TIGAR and NFKB1, possibly enhancing inflammation, oxidative stress, and disrupted glucose metabolism. These findings highlight the epigenetic and molecular disturbances in VAT related to glucose metabolism abnormalities. However, additional research is necessary to further understand their biological significance.

The Epigenetic Link of Perinatal BMI to Maternal Phenotype and Fetal Heart Rate

Obesity is a metabolic stressor associated with a suboptimal physiological milieu including an inflammatory state and a dysregulated stress axis. Perinatal maternal BMI impacts pregnancy and birth outcomes along with child metabolic and neurodevelopmental health that are believed to be mediated by epigenetic mechanisms. Our research examines the impacts of pre-pregnancy BMI in a cohort of healthy pregnancies (n=187); first, by characterizing maternal phenotype throughout pregnancy, including her stress physiology (diurnal salivary cortisol), inflammatory status (blood cytokine levels), perinatal depression (EPDS scores), and the underlying epigenetic signature (DNA methylation) in blood that could mediate these effects. Second, we examine the effects of pre-pregnancy BMI on fetal heart rate measurements as an early marker of programming effects of altered autonomic nervous system and the associated placental DNA methylation with a focus on sex-dimorphic effects. Finally, we explore the impact of increasing the allostatic load of high BMI with stress, which was phenotyped in women early in pregnancy driven by data with 27 variables assessing psychological and physical health, on differential placental DNA methylation. To date: regional analysis revealed about 4500 differentially methylated regions (DMR) overall in response to high BMI. Gene ontology enrichment analysis revealed that DM genes annotated to these DMRs were enriched for biological processes involving inflammation in males and RNA silencing in females. This work highlights that the metabolic stress associated with BMI could leave a molecular fingerprint that mediate other maternal physiological and psychological outcomes, which in turn program the fetal neurodevelopmental outcomes.

Relationship between the mechanisms of atherosclerosis and prostate cancer: literature review

Cardiovascular disease and cancer remain the leading causes of hospitalization and death worldwide. Prostate cancer (PC) is one of the most common malignant diseases in men. Epidemiological studies have shown that the majority of patients with PC die not from cancer but from cardiovascular diseases, particularly coronary heart disease. In recent years, several studies have examined the relationship between atherosclerosis and PC, suggesting a stronger relationship than previously thought. Processing characteristics of the development and progression of both diseases include dysregulation of cell proliferation, oxidative stress, genetic changes, and inflammation. Despite conflicting data on the role of high cholesterol levels in the development of PC over the past decade, numerous studies have confirmed its importance in PC development and progression; meanwhile, statins have confirmed their value in reducing the risk of disease development and progression. The presented data confirm the need for a thorough assessment of cardiovascular risk factors, the presence of concomitant cardiovascular diseases in patients with PC, and the use of methods for the prevention and treatment of diseases associated with atherosclerosis to reduce cardiovascular risk and inhibit PC progression.

Transcriptional time course after rotator cuff repair in 6month old female rabbits.

Introduction: Rotator cuff tears are prevalent in the population above the age of 60. The disease progression leads to muscle atrophy, fibrosis, and fatty infiltration, which is not improved upon with surgical repair, highlighting the need to better understand the underlying biology impairing more favorable outcomes. Methods: In this study, we collected supraspinatus muscle tissue from 6month old female rabbits who had undergone unilateral tenotomy for 8weeks at 1, 2, 4, or 8weeks post-repair (n = 4/group). RNA sequencing and enrichment analyses were performed to identify a transcriptional timeline of rotator cuff muscle adaptations and related morphological sequelae. Results: There were differentially expressed (DE) genes at 1 (819 up/210 down), 2 (776/120), and 4 (63/27) weeks post-repair, with none at 8week post-repair. Of the time points with DE genes, there were 1092 unique DE genes and 442 shared genes, highlighting that there are changing processes in the muscle at each time point. Broadly, 1-week post-repair differentially expressed genes were significantly enriched in pathways of metabolism and energetic activity, binding, and regulation. Many were also significantly enriched at 2weeks, with the addition of NIF/NF-kappaB signaling, transcription in response to hypoxia, and mRNA stability alongside many additional pathways. There was also a shift in transcriptional activity at 4weeks post-repair with significantly enriched pathways for lipids, hormones, apoptosis, and cytokine activity, despite an overall decrease in the number of differentially expressed genes. At 8weeks post-repair there were no DE genes when compared to control. These transcriptional profiles were correlated with the histological findings of increased fat, degeneration, and fibrosis. Specifically, correlated gene sets were enriched for fatty acid metabolism, TGF-B-related, and other pathways. Discussion: This study identifies the timeline of transcriptional changes in muscle after RC repair, which by itself, does not induce a growth/regenerative response as desired. Instead, it is predominately related to metabolism/energetics changes at 1week post-repair, unclear or asynchronous transcriptional diversity at 2weeks post-repair, increased adipogenesis at 4weeks post-repair, and a low transcriptional steady state or a dysregulated stress response at 8weeks post-repair.

Curcumin-loaded graphene oxide quantum dots enhance otoprotective effects via blocking cuproptosis.

Background: Cisplatin (CIS) is widely used to treat various cancers but can cause ototoxicity and sensory hair cell loss in the inner ear. Copper induces an excessive production of reactive oxygen species (ROS) in hair cells, leading to the development of various antioxidants. Methods and results: This study aimed to evaluate the potential antioxidant properties of curcumin (CUR) in the inner ear organ of corti-1 cells (OC1) and animal models (zebrafish and guinea pigs). Graphene oxide quantum dots (GOQDs) enabled CUR to penetrate the round window membrane (RWM) and maintain the concentration in the perilymph after inner ear administration. The results showed that CUR/GOQDs had favorable biocompatibility and strongly affected ROS generation induced by CIS in OC1 cells. DCFHDA Green staining demonstrated that CUR/GOQDs successfully reversed the decrease in mitochondrial membrane potential induced by CIS in vitro and rescued cells from early cuproptosis, which was confirmed by FDX1 staining. Additionally, the experiment found that CUR decreased the expression of cuproptosis proteins (FDX1, LIAS, and LIPT1) and increased the expression of the Bcl-2 protein. Conclusion: The results demonstrate that CUR/GOQDs is a promising therapeutic agent that can prevent CIS-induced ototoxicity by blocking the cuproptosis signal pathway.

The Biology of Stress Intolerance in Patients with Chronic Pain-State of the Art and Future Directions.

Stress has been consistently linked to negative impacts on physical and mental health. More specifically, patients with chronic pain experience stress intolerance, which is an exacerbation or occurrence of symptoms in response to any type of stress. The pathophysiological mechanisms underlying this phenomenon remain unsolved. In this state-of-the-art paper, we summarised the role of the autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis, the two major stress response systems in stress intolerance. We provided insights into such mechanisms based on evidence from clinical studies in both patients with chronic pain, showing dysregulated stress systems, and healthy controls supported by preclinical studies, highlighting the link between these systems and symptoms of stress intolerance. Furthermore, we explored the possible regulating role for (epi)genetic mechanisms influencing the ANS and HPA axis. The link between stress and chronic pain has become an important area of research as it has the potential to inform the development of interventions to improve the quality of life for individuals living with chronic pain. As stress has become a prevalent concern in modern society, understanding the connection between stress, HPA axis, ANS, and chronic health conditions such as chronic pain is crucial to improve public health and well-being.

Kaempferia parviflora Extracts Protect Neural Stem Cells from Amyloid Peptide-Mediated Inflammation in Co-Culture Model with Microglia.

The existence of neuroinflammation and oxidative stress surrounding amyloid beta (Aβ) plaques, a hallmark of Alzheimer's disease (AD), has been demonstrated and may result in the activation of neuronal death and inhibition of neurogenesis. Therefore, dysregulation of neuroinflammation and oxidative stress is one possible therapeutic target for AD. Kaempferia parviflora Wall. ex Baker (KP), a member of the Zingiberaceae family, possesses health-promoting benefits including anti-oxidative stress and anti-inflammation in vitro and in vivo with a high level of safety; however, the role of KP in suppressing Aβ-mediated neuroinflammation and neuronal differentiation has not yet been investigated. The neuroprotective effects of KP extract against Aβ42 have been examined in both monoculture and co-culture systems of mouse neuroectodermal (NE-4C) stem cells and BV-2 microglia cells. Our results showed that fractions of KP extract containing 5,7-dimethoxyflavone, 5,7,4'-trimethoxyflavone, and 3,5,7,3',4'-pentamethoxyflavone protected neural stem cells (both undifferentiated and differentiated) and microglia activation from Aβ42-induced neuroinflammation and oxidative stress in both monoculture and co-culture system of microglia and neuronal stem cells. Interestingly, KP extracts also prevented Aβ42-suppressed neurogenesis, possibly due to the contained methoxyflavone derivatives. Our data indicated the promising role of KP in treating AD through the suppression of neuroinflammation and oxidative stress induced by Aβ peptides.

Allopregnanolone Is Associated with a Stress-Induced Reduction of Heart Rate Variability in Premenstrual Dysphoric Disorder

Human survival and wellbeing require appropriate responses to stress, including a highly coordinated and efficient nervous system control of the heart rhythm. During stress, a greater disinhibition of the vagal nerve is reflective of poor stress adaptability, which may be relevant in premenstrual dysphoric disorder (PMDD)-a debilitating affective condition thought to be marked by dysregulated stress processing and sensitivity to allopregnanolone. In the present study, women with PMDD (n = 17) and healthy controls (n = 18), who did not take medication, smoke, or consume illicit drugs, and who were free of other psychiatric conditions, participated in the Trier Social Stress Test, during which we measured the high frequency of the heart rate (HF-HRV) and allopregnanolone using ultra-performance liquid chromatography tandem mass spectrometry. Relative to their baseline, women who have PMDD, but not the healthy controls, experienced a reduction in HF-HRV during stress anticipation (p ≤ 0.05) and stress (p ≤ 0.01). Their recovery from stress was significantly delayed (p ≤ 0.05). Absolute peak HF-HRV change from baseline was significantly predicted by baseline allopregnanolone only in the PMDD group (p ≤ 0.01). The present study shows how an interaction between stress and allopregnanolone-which have both been separately implicated in PMDD-underlies PMDD expression.