Axis Dysfunction Research Articles

Senescence and the stress axis: a constraint or a trade-off of reproduction in mammals with fast and slow life histories.

A critical time in the life of a male occurs at reproduction, when his behaviour, physiology and resources must be brought to bear for the central purpose of his life-propagating his genes. We ask whether reproduction results in dysfunction of the stress axis, is linked to life history, and causes senescence. We assessed if deterioration in the axis underlies variation in reproductive lifespan in males of five species of North American ground squirrels whose life history varies from near semelparity to iteroparity. The most stressful and energy-demanding time occurs in spring during the intense 2-3 week breeding competition just after arousal from hibernation. We compared their stress axis functioning before and after the mating period using a hormonal challenge protocol. We found no evidence of stress axis dysfunction after reproduction in any species nor was there a relationship between reproductive lifespan and stress axis functional deterioration. Moreover, there was no consistent relationship between free cortisol levels and downstream measures (energy mobilization, haematology, immunity and body indices of condition). Thus, stress axis function was not traded off to promote reproduction irrespective of life history and lifespan, and we conclude that it is a prerequisite for life. Hence, it functions as a constraint and does not undergo senescence.

Postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement in patients with childhood-onset craniopharyngioma.

Hypothalamic-pituitary axis dysfunction is a common complication in post-operative craniopharyngioma(CP) patients, and it greatly impacts the long-term quality of life of such patients. To better understand the effects of postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement therapy in patients with childhood CP, we assessed approximately 200 patients with childhood-onset CP postoperatively. Clinical details of patients with childhood-onset CP who underwent sellar tumor resection in Beijing Children's Hospital and Beijing Tiantan Hospital from 2018 to 2019 were retrieved retrospectively. The participants were followed up to assess the effects of post-operative long-term hormone replacement therapy and assess the tumor recurrence rate. The median age of admission was 8.1 (1.8, 14.3) years. Headache (45.5%), visual impairment (39.5%), and nausea (33.0%) were the most common clinical manifestations. ACP accounted for 95% of all CP cases. The incidence of central adrenal insufficiency and central hypothyroidism within the first week after surgery was 56.2% and 70.3%, respectively. At the same time 85.5% of the patients required at least one dose of desmopressin to control urine output. Total survival and tumor recurrence rates were 98.6% and 26.1%, respectively, with a median follow-up time of 29.7 (19.0, 40.3) months. During the follow-up period, 28.1% patients met the diagnostic criteria for short stature, while 54.4% fit the criteria for obesity. In addition, 94.4% of the patients were taking at least one kind of hormone substitution, and 74.7% were taking three or more. The prevalence of levothyroxine, glucocorticoid, desmopressin, and growth hormone replacement therapy was 87.3%, 77.5%, 78.9% and 31.0%, respectively. The proportion of patients treated with the substitutive combination of levothyroxine, hydrocortisone, and desmopressin was 54.9%. This study is a large-sample systematic postoperative endocrine function evaluation of patients with childhood-onset CP. Due to the high prevalence of post-operative hypothalamic-pituitary dysfunction, patients with CP usually require long-term multiple hormone substitution therapy. Individualized management and accurate hormone replacement dosage for postoperative childhood-onset CP patients are of great importance.

Impact of the severity of brain injury on secondary adrenal insufficiency in traumatic brain injury patients and the influence of HPA axis dysfunction on prognosis

Objective To investigate secondary adrenal insufficiency post varying traumatic brain injuries’ and its impact on prognosis. Methods 120 traumatic brain injury patients were categorized into mild, moderate and severe groups based on Glasgow Coma Scale. Adrenal function was evaluated through testing. Results Secondary adrenal insufficiency rates were 0% (mild), 22.85% (moderate) and 44.82% (severe). Hypothalamus-pituitary-adrenal axis dysfunction rates were 14.81% (mild), 42.85% (moderate) and 63.79% (severe). Differences among groups were significant (p < .05). Patients with intact hypothalamus-pituitary-adrenal axis had shorter hospital stays and higher Glasgow Coma Scale scores. Receiver operating characteristic analysis of 24-h urinary free cortisol showed an area of 0.846, with a 17.62 μg/24h cutoff, 98.32% sensitivity and 52.37% specificity. In the low-dose adrenocorticotropic hormone test, with an 18 μg/dL cutoff, the receiver operating characteristic area was 0.546, with 46.28% sensitivity and 89.39% specificity. Conclusion As traumatic brain injury severity increases, secondary adrenal insufficiency incidence rises. The low-dose adrenocorticotropic hormone test is promising for hypothalamus-pituitary-adrenal axis evaluation. Patients with hypothalamus-pituitary-adrenal dysfunction experience prolonged hospitalization and worse prognosis.

Stress and Epilepsy: Towards Understanding of Neurobiological Mechanisms for Better Management.

Stress has been identified as a major contributor to human disease and is postulated to play a substantial role in epileptogenesis. In a significant proportion of individuals with epilepsy, sensitivity to stressful events contributes to dynamic symptomatic burden, notably seizure occurrence and frequency, and presence and severity of psychiatric comorbidities [anxiety, depression, posttraumatic stress disorder (PTSD)]. Here, we review this complex relationship between stress and epilepsy using clinical data and highlight key neurobiological mechanisms including the hypothalamic-pituitary-adrenal (HPA) axis dysfunction, altered neuroplasticity within limbic system structures, and alterations in neurochemical pathways such as brain-derived neurotrophic factor (BNDF) linking epilepsy and stress. We discuss current clinical management approaches of stress that help optimize seizure control and prevention, as well as psychiatric comorbidities associated with epilepsy. We propose that various shared mechanisms of stress and epilepsy present multiple avenues for the development of new symptomatic and preventative treatments, including disease modifying therapies aimed at reducing epileptogenesis. This would require close collaborations between clinicians and basic scientists to integrate data across multiple scales, from genetics to systems biology, from clinical observations to fundamental mechanistic insights. In future, advances in machine learning approaches and neuromodulation strategies will enable personalized and targeted interventions to manage and ultimately treat stress-related epileptogenesis.

Bifidobacterium longum subsp. longum BL21 ameliorates alcoholic liver disease in mice through enhancement of the hepatic antioxidant capacity and modulation of the gut microbiota.

Alcoholic liver disease (ALD) is a chronic liver injury caused by excessive alcohol consumption, could be impacted by gut-liver axis dysfunction. The gut microbiota plays a crucial role in the development and progression of ALD. Given the role of gut-liver axis dysfunction in ALD, strategies targeting gut microbiota modulation have gained interest for therapeutic interventions. Bifidobacterium longum subsp. longum BL21 has shown promise in alleviating gut microbiota disturbances and metabolic regulation in high-fat diet-induced obesity and type 2 diabetes mellitus models. Thus, this study aimed to evaluate the therapeutic effect of BL21 on ALD mice and explore the potential mechanism by which the gut microbiota mediates the amelioration of ALD by BL21. A total of 30 mice were randomly assigned to three groups (n=10 mice/group): a healthy control (CTL) group, an ALD group, and a BL21 group. Each group was fed a Lieber-DeCarli liquid diet with (ALD and BL21) or without alcohol (CTL). The intervention period lasted 6 weeks, after which the effects of BL21 intervention (intragastric administration of 1 billion CFU of BL21 daily) on serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, hepatic oxidative stress, serum inflammatory cytokine levels, and gut microbiota composition in ALD mice were investigated. Dietary BL21 reduced the ethanol-induced abnormal elevation of serum AST and ALT levels in ALD mice (P<0.001 for both). BL21 treatment significantly attenuated alcohol-induced hepatic oxidative stress by decreasing malondialdehyde concentration and increasing superoxide dismutase, catalase, and glutathione concentrations in the livers of ALD mice. In addition, the serum levels of tumor necrosis factor-alpha, interleukin-1 beta (IL-1β), and IL-6 were significantly lower (P<0.001 for both), while that of IL-10 was significantly higher (P<0.05), in the BL21 group than in the ALD group. Intestinal microbiota analysis showed an increased relative abundance of Escherichia/Shigella, Enterococcus, and Alistipes in the ALD group compared with the CTL group. BL21 intervention increased the relative abundance of Bifidobacterium and Akkermansia compared with the ALD group. Dietary BL21 ameliorates ALD via enhancement of the hepatic antioxidant capacity and modulation of the gut microbiota and may therefore be a promising strategy to prevent or treat ALD.

The correlation of anxiety and depression with C3 and C4 Levels and systemic lupus erythematosus activity

BackgroundAnxiety and depression are psychosomatic disorders that are frequently observed in chronic conditions such as systemic lupus erythematosus (SLE). Anxiety and depression can be induced by immunological and neurotransmitter dysregulation, which is characterized by hypothalamic–pituitary–adrenal (HPA) axis dysfunction, production of proinflammatory cytokines, and activation of complement in the blood, such as C3 and C4. The causes of anxiety and depression in SLE are complex, ranging from neuropsychiatric involvement to drug adverse effects. Detecting anxiety and depression symptoms in SLE patients is critical to preventing disability from impacting quality of life.ObjectiveTo assess the relationship between anxiety and depression symptomatology, SLE disease activity with levels of C3 and C4 in Cipto Mangunkusumo National Hospital.MethodsThis study used a cross-sectional design. The study included 120 SLE patients from Cipto Mangunkusumo National Hospital, aged 18 to 60 years. All patients were requested to complete a Hospital Anxiety and Depression Scale (HADS) questionnaire to assess their anxiety and depression symptoms. Subjects with anxiety and depression were assessed for disease activity using the Mexican Systemic Lupus Erythematosus Systemic Disease Activity (Mex-SLEDAI), and blood samples were collected to test complement C3 and C4 levels. Spearman's correlation test was used to examine the relationship between HADS scores, Mex-SLEDAI, and C3 and C4 levels.ResultsThe results of the study showed a very weak statistically significant negative correlation between anxiety symptoms based on HADS and C3 levels (r = -0.189; p = 0.038) and a weak correlation between anxiety symptoms and C4 levels (r = -204; p = 0.026). Depressive symptoms based on HADS revealed a very poor connection and no statistical significance with levels of C3 (r = -0.056; p = 0.546) and C4 (r = -0.068; p = 0.461). Anxiety (r = 0.06; p = 0.173) and depression (r = 0.031; p = 0.753) symptoms have a weak and insignificant positive connection with SLE activity.ConclusionC3 and C4 serum levels appeared to decrease when the presence of anxious symptoms increased. There was no significant correlation in SLE disease activity between anxious and depressed patients.

Gut microbiota and autism spectrum disorders: where do we stand?

BackgroundChildren with autism spectrum disorder (ASD) often have digestive problems and microbial imbalances in their guts, suggesting that these conditions may play a role in the development of the disorder. Scopus-based research on the gut microbiota and ASD was examined in this bibliometric analysis to shed light on the current state of research and identify potential hotspots for future work in this area.MethodsWe searched documents from the Scopus database and reference citation analysis to collect published data on the gut microbiota and ASD from 2003 to 2022. The downloaded document records were exported to VOSviewer v.1.6.19 to examine and visualize the collaboration between countries and determine the research hotspots.ResultsThe search yielded 958 articles specifically dedicated to gut microbiota and ASD. The number of publications in this field increased rapidly after 2013, with a peak in 2022. The United States (n = 267; 27.87%) was the most active country, followed by China (n = 171; 17.85%) and Italy (n = 96; 10.02). International collaboration was observed, with the USA playing a central role. University College Cork, Ireland, was the most productive institution (n = 24; 2.51%). The National Natural Science Foundation of China was the most active funding agency (n = 76; 7.93%). Nutrients journal had the highest number of publications (n = 28; 2.92%). The articles related to gut microbiota and ASD were highly cited, with an h-index of 108. The research themes identified focused on the modulation of gut microbiota as a potential therapy for children with ASD and gut-brain axis dysfunction in ASD.ConclusionsIn recent years, the study of gut microbiota and its association with ASD has garnered considerable interest as an emergent field of study. The results of this study substantially enhance our current understanding of the knowledge landscape in this field and illuminate potential avenues for future research. It is essential to emphasize the significance of devoting more resources to the newest and most promising research areas, such as investigating the potential therapeutic benefits of modulating the intestinal microbiota in children with ASD. This research has enormous potential and merits intensified focus and investigation.

Postprandial glucose metabolism in children and adolescents with type 1 diabetes mellitus: potential targets for improvement.

The main goal of therapeutic management of type 1 Diabetes Mellitus (T1DM) is to maintain optimal glycemic control to prevent acute and long-term diabetes complications and to enable a good quality of life. Postprandial glycemia makes a substantial contribution to overall glycemic control and variability in diabetes and, despite technological advancements in insulin treatments, optimal postprandial glycemia is difficult to achieve. Several factors influence postprandial blood glucose levels in children and adolescents with T1DM, including nutritional habits and adjustment of insulin doses according to meal composition. Additionally, hormone secretion, enteroendocrine axis dysfunction, altered gastrointestinal digestion and absorption, and physical activity play important roles. Meal-time routines, intake of appropriate ratios of macronutrients, and correct adjustment of the insulin dose for the meal composition have positive impacts on postprandial glycemic variability and long-term cardiometabolic health of the individual with T1DM. Further knowledge in the field is necessary for management of all these factors to be part of routine pediatric diabetes education and clinical practice. Thus, the aim of this report is to review the main factors that influence postprandial blood glucose levels and metabolism, focusing on macronutrients and other nutritional and lifestyle factors, to suggest potential targets for improving postprandial glycemia in the management of children and adolescents with T1DM.

Associations Between Brain-Gut Axis and Psychological Distress in Fibromyalgia: A Microbiota and Magnetic Resonance Imaging Study

An altered brain-gut axis is suspected to be one of the pathomechanisms in fibromyalgia (FM). This cross-sectional study investigated the associations among altered microbiota, psychological distress, and brain functional connectivity (FC) in FM. We recruited 25 FM patients and 25 healthy people in the present study. Psychological distress was measured using standardized questionnaires. Microbiota analysis was performed on the participants' stools. Functional magnetic resonance imaging data were acquired, and seed-based resting-state FC (rs-FC) analysis was conducted with the salience network nodes as seeds. Linear regression and mediation analyses evaluated microbiota, symptoms, and rs-FCs associations. We found altered microbiota diversity in FM, of which Phascolarctobacterium and Lachnoclostridium taxa increased the most and Faecalibacterium taxon decreased the most compared to controls. The Phascolarctobacterium abundance significantly predicted Beck depression inventory (BDI-II) scores in FM (β = 6.83; P = .033). Rs-FCs from salience network nodes were reduced in FM, of which rs-FCs from the right lateral rostral prefrontal cortex (RPFC) to the lateral occipital cortex, superior division right (RPFC-sLOC) could be predicted by BDI-II scores in patients (β = −.0064; P = .0054). In addition, the BDI-II score was a mediator in the association between Phascolarctobacterium abundance and rs-FCs of RPFC-sLOC (ab = −.06; 95% CI: −.16 to −9.10-3). In conclusion, microbial dysbiosis might be associated with altered neural networks mediated by psychological distress in FM, emphasizing the critical role of the brain-gut axis in FM's non-pain symptoms and supporting further analysis of mechanism-targeted therapies to reduce FM symptoms. PerspectiveOur study suggests microbial dysbiosis might be associated with psychological distress and the altered salience network, supporting the role of brain-gut axis dysfunction in fibromyalgia pathomechanisms. Further targeting therapies for microbial dysbiosis should be investigated to manage fibromyalgia patients in the future.

Clinical characteristics and therapeutic outcomes of acromegalic patients with giant growth hormone-secreting pituitary adenomas: a single-center study of 67 cases.

Acromegalic patients with giant growth hormone-secreting pituitary adenomas (GHPAs) (≥ 40mm) are relatively rare, and their clinical characteristics and treatment outcome data are limited. This study aims to analyze the clinical practice experience of giant GHPAs. Sixty-seven acromegalic patients with giant GHPAs and 67 patients with macro GHPAs (10-39mm), matched for age and gender from the same hospital during the same period, were retrospectively recruited. The clinical characteristics, treatment, and outcomes were analyzed. Enlargement of the extremities and facial features were the most common symptoms in most patients (92.5%). Compared with the macroadenoma group, more frequent visual impairment (86.6% vs. 25.4%, P < 0.001) and gonadal axis dysfunction (49.3% vs. 34.3%, P = 0.008), higher preoperative fasting GH, nadir GH after OGTT and IGF-1 levels, and a higher proportion of extrasellar tumor invasion were seen in the giant adenoma group. As the adenoma size increases, the total resection rate decreases, and postoperative complications and multimodal treatment strategies increase significantly. Fasting and nadir GH levels remained higher at 1week postoperatively, and there were more surgical complications and cases of anterior hypopituitarism in the giant group. After a median follow-up of 36months, 12 patients (36.4%) in the giant GHPA group and 17 (36.2%) in the macro GHPA group achieved biochemical remission. Other factors such as age of onset, age of diagnosis, delayed diagnosis time, metabolic complications, p53 positive rate, and Ki-67 index showed no significant difference between the two groups. With aggressive multimodal therapy, the biochemical remission rate of acromegalic patients with giant GHPAs is comparable to that of patients with macro adenoma. However, postoperative complications and hypopituitarism need to be closely monitored.

FRI441 Antiestrogens To Treat Hypogonadotropic Hypogonadism In Male Users Of Anabolic-androgenic Steroids - A Clinical Pilot Study

Abstract Disclosure: H.C. Henriksen: None. A.P. Jørgensen: None. A. Bjørnebekk: None. S.P. Neupane: None. I.A. Havnes: None. Background: Anabolic-androgenic steroids (AAS) used recreationally in supra-physiological doses is a growing public health concern. The use is associated with cardiovascular, metabolic and endocrine disturbances including AAS induced hypogonadism (ASIH). ASIH is a form of hypogonadotropic hypogonadism caused by AAS’ long-term negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, promoting fatigue, depression and sexual dysfunction. Aims: The primary objective of the study is to explore the safety and efficacy of clomiphene citrate (CC) in treating ASIH. Secondary aims are to detect AAS associated health risks and assess whether these risks are reversed 12 months after cessation. Methods: In this open longitudinal pilot study at Oslo University Hospital in Norway, men with AAS dependence, continuous use and a desire to quit are treated for 16 weeks with an antiestrogen (CC). The CC is given to stimulate endogenous secretion of gonadotropin-releasing hormone (GnRH), gonadotropins (luteinizing hormone (LH)) and testosterone by blocking the estrogenic negative feedback on the HPG-axis. Transdermal testosterone is administered daily during the first four weeks to prevent a sudden drop in androgen levels. If HPG response is subpar, human chorionic gonadotropin (hCG), a synthetic LH analog, is added. The participants are monitored every 4th week during intervention, and at follow-up at 6 and 12 months. Physical health is assessed through clinical examinations, blood and fat tissue sampling, cardiovascular examination, dual-energy x-ray absorptiometry, testicular ultrasound and semen analysis. Results: Preliminary results are available from 11 men that were eligible for endocrine intervention with median age of 33 (range 26-57) and median cumulative lifetime AAS use of 11 years (1-20). Cardiovascular findings were recurrent and included hypertension, myocardial hypertrophy, increased arterial stiffness, reduced flow-mediated dilation and lower carotid artery reactivity. Polycythemia, testicular atrophy and oligozoospermia were other common findings at inclusion. Intervention with CC showed varying HPG response: While some participants responded poorly to treatment, others developed normalized endogenous levels of gonadotropins and testosterone after only 4-8 weeks of therapy. No serious adverse events from CC use were reported. Among the few reported less severe adverse effects were headache, nausea and mood swings. Conclusion: Preliminary results of this ongoing study indicate that treatment with CC and hCG is safe and effective in treating ASIH from long-term continuous AAS use. Insufficient HPG response after 16 weeks of intervention might indicate persisting hypogonadotropic hypogonadism, but further monitoring is needed. Presentation: Friday, June 16, 2023

VWF–ADAMTS13 axis dysfunction in children with sickle cell disease treated with hydroxycarbamide vs blood transfusion

AbstractPrevious studies have reported elevated von Willebrand factor (VWF) levels in patients with sickle cell disease (SCD) and demonstrated a key role for the VWF-ADAMTS13 axis in the pathobiology of SCD vaso-occlusion. Although blood transfusion is the gold standard for stroke prevention in SCD, the biological mechanisms underpinning its improved efficacy compared with hydroxycarbamide are not fully understood. We hypothesized that the improved efficacy of blood transfusion might relate to differences in VWF–ADAMTS13 axis dysfunction. In total, 180 children with a confirmed diagnosis of SCD (hemoglobin SS) on hydroxycarbamide (n = 96) or blood transfusion (n = 84) were included. Despite disease-modifying treatment, plasma VWF and VWF propeptide were elevated in a significant proportion of children with SCD (33% and 47%, respectively). Crucially, all VWF parameters were significantly higher in the hydroxycarbamide compared with the blood transfusion cohort (P < .05). Additionally, increased levels of other Weibel-Palade body–stored proteins, including factor VIII (FVIII), angiopoietin-2, and osteoprotegerin were observed, indicated ongoing endothelial cell activation. Children treated with hydroxycarbamide also had higher FVIII activity and enhanced thrombin generation compared with those in the blood transfusion cohort (P < .001). Finally, hemolysis markers strongly correlated with VWF levels (P < .001) and were significantly reduced in the blood transfusion cohort (P < .001). Cumulatively, to our knowledge, our findings demonstrate for the first time that despite treatment, ongoing dysfunction of the VWF–ADAMTS13 axis is present in a significant subgroup of pediatric patients with SCD, especially those treated with hydroxycarbamide.

Bedside to bench: the outlook for psychedelic research.

There has recently been a resurgence of interest in psychedelic compounds based on studies demonstrating their potential therapeutic applications in treating post-traumatic stress disorder, substance abuse disorders, and treatment-resistant depression. Despite promising efficacy observed in some clinical trials, the full range of biological effects and mechanism(s) of action of these compounds have yet to be fully established. Indeed, most studies to date have focused on assessing the psychological mechanisms of psychedelics, often neglecting the non-psychological modes of action. However, it is important to understand that psychedelics may mediate their therapeutic effects through multi-faceted mechanisms, such as the modulation of brain network activity, neuronal plasticity, neuroendocrine function, glial cell regulation, epigenetic processes, and the gut-brain axis. This review provides a framework supporting the implementation of a multi-faceted approach, incorporating in silico, in vitro and in vivo modeling, to aid in the comprehensive understanding of the physiological effects of psychedelics and their potential for clinical application beyond the treatment of psychiatric disorders. We also provide an overview of the literature supporting the potential utility of psychedelics for the treatment of brain injury (e.g., stroke and traumatic brain injury), neurodegenerative diseases (e.g., Parkinson's and Alzheimer's diseases), and gut-brain axis dysfunction associated with psychiatric disorders (e.g., generalized anxiety disorder and major depressive disorder). To move the field forward, we outline advantageous experimental frameworks to explore these and other novel applications for psychedelics.

바이오피드백을 이용하여 측정한 알코올 사용장애 환자의 정신생리적 특징

Objectives: Previously published studies have shown that hypothalamic-pituitary-adrenal axis axis dysfunction and autonomic arousal are associated with alcohol use disorder. The purpose of this study was to measure the psychophysiological responses in patients with alcohol use disorder using a biofeedback system and compare them with those of healthy subjects.&#x0D; Methods: Fifty-two patients with alcohol use disorder and 149 healthy controls participated in this study. Heart rate (HR), electromyography (EMG), skin conductance (SC), skin temperature, and respiratory rate (RR) were recorded using a biofeedback system during five phases of a stress reactivity test, and average values were calculated. The difference in values between the two groups in each corresponding phase was analyzed with the independent t-test, and the change in values across phases of the stress reactivity test was analyzed with the paired t-test.&#x0D; Results: Compared to the healthy controls, patients with alcohol use disorder had a higher HR and RR in three phases. Change in EMG and SC was higher in patients with alcohol use disorder than the healthy controls from baseline to the stress phase 1.&#x0D; Conclusion: The psychophysiological profiles of patients with alcohol use disorder in a stress reactivity test were different from those of healthy controls. These results suggest that the sympathetic nervous system is more highly activated in patients with alcohol use disorder.

Therapeutic Effects of Baicalin on Diseases Related to Gut-Brain Axis Dysfunctions.

The gut-brain axis is an active area of research. Several representative diseases, including central nervous system disorders (Alzheimer's disease, Parkinson's disease, and depression), metabolic disorders (obesity-related diseases), and intestinal disorders (inflammatory bowel disease and dysbiosis), are associated with the dysfunctional gut-brain axis. Baicalin, a bioactive flavonoid extracted from Scutellaria baicalensis, is reported to exert various pharmacological effects. This narrative review summarizes the molecular mechanisms and potential targets of baicalin in disorders of the gut-brain axis. Baicalin protects the central nervous system through anti-neuroinflammatory and anti-neuronal apoptotic effects, suppresses obesity through anti-inflammatory and antioxidant effects, and alleviates intestinal disorders through regulatory effects on intestinal microorganisms and short-chain fatty acid production. The bioactivities of baicalin are mediated through the gut-brain axis. This review comprehensively summarizes the regulatory role of baicalin in gut-brain axis disorders, laying a foundation for future research, although further confirmatory basic research is required.

Abstract 027: Chronic Unpredictable Stress Affects Mitochondrial Function In The Hypothalamic-Pituitary-Adrenal Axis And Impairs Vascular Reactivity In Male And Female Mice

Chronic stress is associated with hypertension but the underlying mechanisms linking the interplay between the changes in the hypothalamic-pituitary-adrenal axis and vascular dysfunction remain unclear. We hypothesize that chronic unpredictable stress (CUS) induces mitochondrial dysfunction in the HPA axis and in the vasculature, associated with GasderminD pore formation in the mitochondrial membrane. Adult male and female C57Bl6/J mice were exposed to 28 consecutive days of CUS or handling (CTL). Anxiety-like behavior, coping behavior, and systolic blood pressure (SBP) were assessed. Mitochondrial function was assessed using high-resolution respirometry in the hypothalamus, amygdala, and adrenal tissues. The vascular reactivity of mesenteric resistance arteries (MRA), pudendal arteries (PA), and aorta were assessed in response to phenylephrine or acetylcholine. GasderminD protein expression was measured in the MRA. Data are presented as mean ± S.E.M and significance was set at p&lt;0.05. In both sexes, CUS increased SBP by 12.1±4.9%. CUS decreased body weight gain by 53% (p=0.04) and increased anxiety-like behavior (p=0.01) in males (vs CTL) but did not affect females. CUS decreased latency to immobility in the forced swim test by 46% (p=0.0001) in both sexes. Sex-dependent decreases in mitochondrial respiration were observed as follows: in the amygdala of males (20%, p=0.05) and the hypothalamus (20%, p=0.004) and adrenal glands (17%, p=0.06) of females. In the vasculature, CUS led to endothelial dysfunction observed by reduced potency of ACh in the MRA (pEC 50 CUS 6.17±0.09 vs CTL 6.81±0.11; p=0.003) and PA (pEC 50 CUS 6.31 ±0.07 vs CTL 6.65±0.09; p=0.008) of male mice, as well as in the MRA of females (pEC 50 CUS 5.94±0.30 vs CTL 6.98±0.15; p=0.041). Contractile responses to PE were significantly reduced in the aorta of CUS males only (E MAX CTL: 4.70±0.48 mN vs CUS 3.01± 0.23 mN; p=0.007). The expression of gasderminD was increased in the MRA of female mice only. CUS increased SBP in males and females, induced sex-specific changes in the mitochondrial function in key areas of the brain, and caused vascular dysfunction, suggesting that behavioral, brain, and vascular adaptations to CUS are sex-dependent.

GAMBARAN STRES PASIEN GANGREN DIABETIK DI RUMAH SAKIT SANTAELISABETH MEDAN TAHUN 2023

Stress can affect the quality of life of individuals, especially patients suffering from gangrene. The association between stress and diabetes gangrene is the clinical burden of the disease, lifestyle factors and adherence, antidepressant medications, brain structure and function, HPA axis dysfunction, sleep disturbances, inflammation, and environmental factors. Diabetic gangrene is a complication of diabetes mellitus caused by damage to necrosis tissue by embolism of large arteries in parts of the body so that blood supply stops Gangrene disease can cause complications, physical and psychological discomfort. The purpose of this study is to describe the picture of stress in diabetic gangrene patients in April-May 2023. This study uses a quantitative descriptive design with sample of 43 gangrene patients selected by purposive sampling. The instrument used in this study is the Depression Anxiety Stress Scales 21 (DASS-21). The results show that the stress level of gangrene patients is in the category of 43 respondents who have normal stress levels of 2 people (4.7), mild stress are 2 people (4.7), moderate stress are 2 people (4.7), severe stress are 14 people (32.6), and very severe stress 23 people (53.5). The conclusion of this study is that gangrenous patients experienced moderate levels of stress with the emotional dimension being the most influential factor on their stress levels. Further studies are needed to broaden understanding of the factors that can influence stress levels in gangrene patients and efforts that can be made to reduce their impact.

The exploration of neuroinflammatory mechanism by which CRHR2 deficiency induced anxiety disorder

Inflammation stimulates the hypothalamic-pituitary adrenal (HPA) axis and triggers glial neuroinflammatory phenotypes, which reduces monoamine neurotransmitters by activating indoleamine 2,3-dioxygenase enzyme. These changes can induce psychiatric diseases, including anxiety. Corticotropin releasing hormone receptor 2 (CRHR2) in the HPA axis is involved in the etiology of anxiety. Omega(n)-3 polyunsaturated fatty acids (PUFAs) can attenuate anxiety through anti-inflammation and HPA axis modulation. However, the underlying molecular mechanism by CRHR2 modulates anxiety and its correlation with neuroinflammation remain unclear. Here, we first constructed a crhr2 zebrafish mutant line, and evaluated anxiety-like behaviors, gene expression associated with the HPA axis, neuroinflammatory response, neurotransmitters, and PUFAs profile in crhr2+/+ and crhr2−/− zebrafish. The crhr2 deficiency decreased cortisol levels and up-regulated crhr1 and down-regulated crhb, crhbp, ucn3l and proopiomelanocortin a (pomc a) in zebrafish. Interestingly, a significant increase in the neuroinflammatory markers, translocator protein (TSPO) and the activation of microglia M1 phenotype (CD11b) were found in crhr2−/− zebrafish. As a consequence, the expression of granulocyte-macrophage colony-stimulating factor, pro-inflammatory cytokines vascular endothelial growth factor, and astrocyte A1 phenotype c3 were up-regulated. While microglia anti-inflammatory phenotype (CD206), central anti-inflammatory cytokine interleukin-4, arginase-1, and transforming growth factor-β were downregulated. In parallel, crhr2-deficient zebrafish showed an upregulation of vdac1 protein, a TSPO ligand, and its downstream caspase-3. Furthermore, 5-HT/5-HIAA ratio was decreased and n-3 PUFAs deficiency was identified in crhr2−/− zebrafish. In conclusion, anxiety-like behavior displayed by crhr2-deficient zebrafish may be caused by the HPA axis dysfunction and enhanced neuroinflammation, which resulted in n-3 PUFAs and monoamine neurotransmitter reductions.

Investigating the Potential Mechanisms and Therapeutic Targets of Inflammatory Cytokines in Post-stroke Depression.

Post-stroke depression (PSD) affects approximately one-third of stroke survivors, severely impacting general recovery and quality of life. Despite extensive studies, the exact mechanisms underlying PSD remain elusive. However, emerging evidence implicates proinflammatory cytokines, including interleukin-1β, interleukin-6, tumor necrosis factor-alpha, and interleukin-18, play critical roles in PSD development. These cytokines contribute to PSD through various mechanisms, including hypothalamic-pituitary-adrenal (HPA) axis dysfunction, neurotransmitter alterations, neurotrophic factor changes, gut microbiota imbalances, and genetic predispositions. This review is aimed at exploring the role of cytokines in stroke and PSD while identifying their potential as specific therapeutic targets for managing PSD. A more profound understanding of the mechanisms regulating inflammatory cytokine expression and anti-inflammatory cytokines like interleukin-10 in PSD may facilitate the development of innovative interventions to improve outcomes for stroke survivors experiencing depression.

Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis

Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-κB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (H2O2), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium.