Differential expression of components of the CGRP-receptor family in human coronary and human middle meningeal arteries: functional implications.

BACKGROUND: Different responses in human coronary arteries (HCA) and human middle meningeal arteries (HMMA) were observed for some of the novel CGRP receptor antagonists, the gepants, for inhibiting CGRP-induced relaxation. These differences could be explained by the presence of different receptor populations in the two vascular beds. Here, we aim to elucidate which receptors are involved in the relaxation to calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and adrenomedullin 2 (AM2) in HCA and HMMA. METHODS: RNA was isolated from homogenized human arteries (23 HCAs; 12 F, 11 M, age 50 ± 3 years and 26 HMMAs; 14 F, 12 M, age 51 ± 3 years) and qPCR was performed for different receptor subunits. Additionally, relaxation responses to CGRP, AM or AM2 of the human arteries were quantified using a Mulvany myograph system, in the presence or absence of the adrenomedullin 1 receptor antagonist AM22-52 and/or olcegepant. RESULTS: Calcitonin-like receptor (CLR) mRNA was expressed equally in both vascular beds, while calcitonin receptor (CTR) and receptor activity-modifying protein 3 (RAMP3) expression was low and could not be detected in all samples. RAMP1 expression was similar in HCA and HMMA, while RAMP2 expression was higher in HMMA. Moreover, receptor component protein (RCP) expression was higher in HMMA than in HCA. Functional experiments showed that olcegepant inhibits relaxation to all three agonists in both vascular beds. In HCA, antagonist AM22-52 did not inhibit relaxation to any of the agonists, while a trend for blocking relaxation to AM and AM2 could be observed in HMMA. CONCLUSION: Based on the combined results from receptor subunit mRNA expression and the functional responses in both vascular tissues, relaxation of HCA is mainly mediated via the canonical CGRP receptor (CLR-RAMP1), while relaxation of HMMA can be mediated via both the canonical CGRP receptor and the adrenomedullin 1 receptor (CLR-RAMP2). Future research should investigate whether RAMP2 predominance over RAMP1 in the meningeal vasculature results in altered migraine susceptibility or in a different response to anti-migraine medication in these patients. Moreover, the exact role of RCP in CGRP receptor signalling should be elucidated in future research.

The association of plasma asprosin with anthropometric and metabolic parameters in Korean children and adolescents.

Background: This study aimed to determine the correlation of plasma asprosin with anthropometric and metabolic parameters in Korean children and adolescents. Methods: This single-center study included 109 Korean children and adolescents: 62 (56.9%) obese participants with a body mass index (BMI) ≥95th percentile and 47 (43.1%) healthy controls with BMI between the 15th and 85th percentile. Metabolic parameters were measured, including fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride and glucose (TyG) index, and lipid profiles. Results: Plasma asprosin levels were higher in the obese group than in the control group (mean 87.0 vs. 69.3 ng/mL; p = 0.001) and in the IR group than in the non-IR group (mean 98.6 vs. 70.2 ng/mL; p < 0.001). Plasma asprosin levels were not associated with sex or pubertal stage. Plasma asprosin levels were positively correlated with BMI SDS (r = 0.34; p = 0.002), glycated hemoglobin (HbA1c) (r = 0.25; p = 0.02), glucose (r = 0.33; p = 0.002), insulin (r = 0.44; p < 0.001), HOMA-IR (r = 0.47; p < 0.001), triglyceride (TG) (r = 0.33; p = 0.003), high-density lipoprotein (HDL) cholesterol (r = -0.29; p = 0.008), and TyG index (r = 0.38; p < 0.001). Multiple linear regression analysis indicated that plasma asprosin levels were independently associated with HOMA-IR (p < 0.001) and TG/HDL cholesterol ratio (p < 0.001). Conclusions: This study demonstrated an association between plasma asprosin levels and obesity and insulin resistance in Korean children and adolescents.

A systematic scoping review of the multifaceted role of phoenixin in metabolism: insights from in vitro and in vivo studies.

Phoenixin (PNX) is an emerging neuropeptide that plays a significant role in regulating metabolism and reproduction. This comprehensive review examines findings from human, in vivo, and in vitro studies to elucidate the functions of PNX in metabolic processes. PNX has been identified as a key player in essential metabolic pathways, including energy homeostasis, glucose, lipid and electrolyte metabolism, and mitochondrial dynamics. It modulates food and fluid intake, influences glucose and lipid profiles, and affects mitochondrial biogenesis and function. PNX is abundantly expressed in the hypothalamus, where it plays a crucial role in regulating reproductive hormone secretion and maintaining energy balance. Furthermore, PNX is also expressed in peripheral tissues such as the heart, spleen, and pancreas, indicating its involvement in the regulation of metabolism across central and peripheral systems. PNX is a therapeutic peptide that operates through the G protein-coupled receptor 173 (GPR173) at the molecular level. It activates signaling pathways such as cAMP-protein kinase A (PKA) and Epac-ERK, which are crucial for metabolic regulation. Research suggests that PNX may be effective in managing metabolic disorders like obesity and type 2 diabetes, as well as reproductive health issues like infertility. Since metabolic processes are closely linked to reproduction, further understanding of PNX's role in these areas is necessary to develop effective management/treatments. This review aims to highlight PNX's involvement in metabolism and identify gaps in current knowledge regarding its impact on human health. Understanding the mechanisms of PNX's action is crucial for the development of novel therapeutic strategies for the treatment of metabolic disorders and reproductive health issues, which are significant public health concerns globally.

The peptide hormone PjCLE1 stimulates haustorium formation in the parasitic plant Phtheirospermum japonicum.

Phtheirospermum japonicum is a hemiparasitic plant of the Orobanchaceae, the largest family of parasitic plants. It extracts water and nutrients from other plants through haustoria along its roots. Haustoriogenesis, the formation of haustoria, is initiated by host-derived haustorium-inducing factors (HIFs). The first step in haustoriogenesis is the development of parasitically inactive protohaustoria. Here, we report that an endogenous peptide hormone, CLAVATA3/Embryo Surrounding Region 1 (PjCLE1), is sufficient to induce protohaustorium formation. PjCLE1 hyperactivated HIF-responses and caused prolific protohaustoria formation. PjCLE1 expression and activation by the subtilisin-type protease PjSBT1.2.3 occur in fully developed, mature haustoria, suggesting that PjCLE1 acts as an internal signal produced by mature haustoria to stimulate additional protohaustorium formation for effective extraction of resources from hosts. PjCLE1 is similar in sequence to CLEs regulating nodulation in legumes and part of a regulatory system for haustoria formation in parasitic plants.

Role of spexin and DARS2 as potential biomarkers in basal cell carcinoma and cutaneous malignant melanoma diagnosis, and as therapeutic targets.

Basal cell carcinoma (BCC) is a slowly progressive, locally aggressive and rarely metastasizing cancer, and although its mortality is low, its morbidity and cost of disease are high. While BCC is more common, cutaneous malignant melanoma (CMM) is significant due to its higher mortality rate. These patients can be treated, but recurrence, metastasis and mortality may occur in such patients. Various environmental, phenotypic and genotypic factors, especially ultraviolet (UV) radiations, play a role in the etiology of BCC and CMM. Histopathological examination continues to be the "gold standard" in their diagnosis. Spexin (SPX) and DARS2 are newly discovered proteins linked to many diseases, including cancer. These proteins may have an effect on the development and expression of skin cancers such as BCC and CMM. In this study, we evaluated the potential of SPX and DARS2 expressions as immunohistochemical biomarkers in the differential diagnosis of BCC and CMM. This study was conducted retrospectively using samples taken from the pathology laboratory. A total of 180 patient samples were used. The control group consisted of healthy skin tissues of the patients, and the other groups consisted of BCC and CMM tissues of the same patients. Tissue samples of all three groups were evaluated immunohistochemically with SPX and DARS2. The immunoreactivity of SPX was found to be higher in BCC and CMM tissue samples than in healthy skin tissues in the control group. DARS2 immunoreactivity was found to be higher in CMM tissues compared to the other two groups, and statistically significant in BCC tissues when compared with healthy control group tissues. SPX can be used as an immunohistochemical biomarker in the diagnosis of BCC and CMM. Since DARS2 expression is statistically more significant in CMM tissues than in BCC tissues, it can be used in differential diagnosis.

Evaluation of spexin levels in euthyroid patients with Hashimoto thyroiditis and its relation to autoimmunity.

Hashimoto thyroiditis (HT) is chronic lymphocytic thyroiditis. Cytokines and chemokines such as tumor necrosis factor-alpha, interferon-gamma, and interleukin-1 beta originating from immune cells are involved in the etiopathogenesis of HT. Spexin (SPX) is a recently identified novel peptide hormone consisting of 14 amino acids and has been demonstrated in follicle epithelial cells in thyroid tissue. SPX has been shown to affect the inflammatory response and play a role in its regulation in various diseases. There is a need for markers for diagnosis and treatment of HT patients with negative antibody levels. We found that there is no study in the literature that investigates the HT and the role of spexin in this inflammatory process. Forty-five patients aged 18 to 70 years with HT or newly diagnosed HT and 42 healthy subjects as the control group were included in the study. Patients in the HT group were divided into 3 categories according to ultrasound findings. Mild heterogeneity was called grade 1 (G1), moderate heterogeneity was called grade 2 (G2), and high heterogeneity was called grade 3 (G3). Laboratory parameters and anthropometric measurements of all patients participating in the study were performed, and SPX was measured by the ELISA method. There was no significant difference between the HT and control groups in terms of SPX levels (P = .27). In HT subgroup analysis, SPX levels were found to be borderline statistically significantly higher in the G2 group, where antibody levels were higher compared to other groups (P = .061). In our study, we evaluated SPX levels in HT patients, which has never been done before in the literature. We found high SPX levels in HT patients with high antibody levels. Multicenter studies with high case series, especially at the tissue level, are needed to fully explain the role of SPX in HT immunoetiopathogenesis and to understand immune-checkpoint pathways more clearly.

Nesfatin-1 expression and blood plasma concentration in female dogs suffering from cystic endometrial hyperplasia and pyometra and its possible interaction with phoenixin-14.

BACKGROUND: Nesfatin-1 is a neuropeptide that regulates the hypothalamic-pituitary-gonadal axis and may play a role in uterus function. It is co-expressed with other peptides, such as phoenixin, which can influence sex hormone secretion. Our previous research has confirmed that phoenixin-14 is involved in the development of cystic endometrial hyperplasia (CEH) and pyometra in dogs. Therefore, based on the similarities and interactions between these neuropeptides, we hypothesized that nesfatin-1 might also regulate the reproductive system in dogs. This study aimed to determine the expression of nesfatin-1 and its interaction with phoenixin-14 in dogs with CEH or pyometra compared to healthy females, and concerning animals' body condition score (BCS 4-5/9 vs. BCS > 5/9). RESULTS: The analysis of nesfatin-1 in the uterus of bitches consisted of qPCR, western blot and immunofluorescence assays, and ELISAs. The results showed significantly higher nesfatin-1 encoding gene, nucleobindin-2 mRNA (Nucb2) and nesfatin-1 protein expression in overweight females and those suffering from CEH or pyometra compared to healthy animals. The immunoreactivity of nesfatin-1 was elevated in the uteri of bitches with higher BCS > 5/9. Moreover, nesfatin-1 blood concentrations increased in all examined overweight bitches. In the case of phoenixin signals, we found opposite results, regardless of the female body condition score. CONCLUSION: The etiology of CEH and pyometra are not fully known, although we have expanded the level of knowledge with respect to the possible interaction of nesfatin-1 and phoenixin in female dogs' uteri. They interact oppositely. With increasing female body weight, the expression of nesfatin-1 in the uterus and its peripheral blood concentration increased. However, for female dogs affected by CEH and pyometra, a decreased level of phoenixin-14, irrespective of their body condition score is characteristic. This knowledge could be crucial in the development of biomarkers for these conditions, which may lead to earlier recognition.

The Protective Role of Intermedin in Contrast-Induced Acute Kidney Injury: Enhancing Peritubular Capillary Endothelial Cell Adhesion and Integrity Through the cAMP/Rac1 Pathway.

Contrast-induced acute kidney injury (CIAKI) is a common complication with limited treatments. Intermedin (IMD), a peptide belonging to the calcitonin gene-related peptide family, promotes vasodilation and endothelial stability, but its role in mitigating CIAKI remains unexplored. This study investigates the protective effects of IMD in CIAKI, focusing on its mechanisms, particularly the cAMP/Rac1 signaling pathway. Human umbilical vein endothelial cells (HUVECs) were treated with iohexol to simulate kidney injury in vitro. The protective effects of IMD were assessed using CCK8 assay, flow cytometry, ELISA, and Western blotting. A CIAKI rat model was utilized to evaluate renal peritubular capillary endothelial cell injury and renal function through histopathology, immunohistochemistry, immunofluorescence, Western blotting, and transmission electron microscopy. In vitro, IMD significantly enhanced HUVEC viability and mitigated iohexol-induced toxicity by preserving intercellular adhesion junctions and activating the cAMP/Rac1 pathway, with Rac1 inhibition attenuating these protective effects. In vivo, CIAKI caused severe damage to peritubular capillary endothelial cell junctions, impairing renal function. IMD treatment markedly improved renal function, an effect negated by Rac1 inhibition. IMD protects against renal injury in CIAKI by activating the cAMP/Rac1 pathway, preserving peritubular capillary endothelial integrity and alleviating acute renal injury from contrast media. These findings suggest that IMD has therapeutic potential in CIAKI and highlight the cAMP/Rac1 pathway as a promising target for preventing contrast-induced acute kidney injury in at-risk patients, ultimately improving clinical outcomes.

Resolving Sulfation Posttranslational Modifications on a Peptide Hormone using Nanopores.

Peptide hormones are decorated with post-translational modifications (PTMs) that are crucial for receptor recognition. Tyrosine sulfation on plant peptide hormones is, for example, essential for plant growth and development. Measuring the occurrence and position of sulfotyrosine is, however, compromised by major technical challenges during isolation and detection. Nanopores can sensitively detect protein PTMs at the single-molecule level. By translocating PTM variants of the plant pentapeptide hormone phytosulfokine (PSK) through a nanopore, we here demonstrate the accurate identification of sulfation and phosphorylation on the two tyrosine residues of PSK. Sulfation can be clearly detected and distinguished (>90%) from phosphorylation on the same residue. Moreover, the presence or absence of PTMs on the two close-by tyrosine residues can be accurately determined (>96% accuracy). Our findings demonstrate the extraordinary sensitivity of nanopore protein measurements, providing a powerful tool for identifying position-specific sulfation on peptide hormones and promising wider applications to identify protein PTMs.

Investigation of serum spexin concentrations in pregnant women diagnosed with hyperemesis gravidarum.

OBJECTIVE: We aimed to investigate the serum concentration of the spexin, which has been shown to have an anorexic effect in animal models, in pregnant women with hyperemesis gravidarum (HG). METHODS: This case-control study was conducted with 80 pregnant women who applied to the Umraniye Training and Research Hospital Gynecology and Obstetrics Clinic between April 2022 and September 2022. The HG group consisted of 40 pregnant women who were diagnosed with HG in the first 14 weeks of pregnancy, and the control group consisted of 40 healthy pregnant women matched with the HG group in terms of age, BMI, and gestational week. RESULTS: Both groups were similar in terms of demographic characteristics and gestational age at blood sampling for spexin (p > 0.05). While maternal serum spexin concentration was 342.4 pg/ml in the HG group, it was 272.8 pg/ml in the control group (p = 0.003). ROC analysis was performed to determine the value of maternal serum spexin concentration in terms of predicting HG. AUC analysis of maternal serum spexin for HG estimation was 0.693 (p = 0.003, 95% CI =0.577 - 0.809). The optimal cutoff value for maternal serum spexin concentration was determined as 305.90 pg/ml with 65% sensitivity and 65% specificity. CONCLUSIONS: High serum spexin concentration is thought to play a role in the etiopathogenesis of HG, and this should be supported by demonstrating changes in serum spexin concentrations in pregnant women with HG whose symptoms alleviated and weight regain started after treatment.

[Comparison of Serum Spexin Level and its Relationship with Echocardiographic Findings in Prediabetic Patients with and without Hypertension]. / Hipertansiyonu Olan ve Olmayan Prediyabetik Hastalarda Serum Speksin Düzeylerinin Karsilastirilmasi ve Ekokardiyografik Bulgular ile Iliskisinin Degerlendirilmesi.

OBJECTIVE: Prediabetes mellitus, hypertension, and their frequent coexistence are risk factors for macrovascular and cardiovascular complications. In this study we aimed to determine the relationship between spexin levels and echocardiographic findings and hypertension in prediabetic patients. METHODS: This study included 118 adult patients diagnosed with prediabetes mellitus who presented to outpatient clinics between April 2021 and January 2022. The patients were grouped into prediabetic patients with hypertension (n = 58) and those without hypertension (n = 60). The hypertension group was further divided into dipper and non-dipper groups according to the 24-hour ambulatory blood pressure monitoring. Blood samples were collected from all patients and echocardiography was performed. Spexin levels were measured by ELISA. Serum spexin levels, echocardiographic and ambulatory blood pressure monitoring findings were compared between the groups. RESULTS: The hypertension and non-dipper groups had significantly lower spexin levels and higher left atrial volume index, E/Em index, and interventricular septum and posterior wall thicknesses. Spexin levels were negatively correlated with body mass index (r = -0.298, P < 0.001), nighttime systolic blood pressure (r = -0.264, P = 0.006), nighttime diastolic blood pressure (r =-.255, P = 0.005), left atrial volume index (r =-.238, P = 0.009), E/Em (r =-.214,P = 0.020), and low-density lipoprotein cholesterol (r = -.243, P = 0.008). Obesity, overweight and spexin <780 pg/mL were independently associated with hypertension. CONCLUSION: Circulating spexin levels were lower in prediabetic patients with overall hypertension and in non-dipper patients, and were associated with echocardiographic and lipid parameters. The cut-off value of spexin identified in our study may be a useful indicator for hypertension detection and raise clinicians' awareness about evaluating prediabetic patients for hypertension.

Novel hypothalamic pathways for metabolic effects of spexin.

One of the main underlying etiologies of type 2 diabetes (T2DM) is insulin resistance, which is most frequently caused by obesity. Notably, the deregulation of adipokine secretion from visceral adiposity has been identified as a crucial characteristic of type 2 diabetes and obesity. Spexin is an adipokine that is released by many different tissues, including white adipocytes and the glandular stomach, and is negatively connected with the state of energy storage. This peptide acts through GALR2/3 receptors to control a wide range of metabolic processes, including inflammation, browning, lipolysis, energy expenditure, and eating behavior. Specifically, spexin can enter the hypothalamus and regulate the hypothalamic melanocortin system, which in turn balances energy expenditure and food intake. This review examines recent advances and the underlying mechanisms of spexin in obesity and T2DM. In particular, we address a range of topics from basic research to clinical findings, such as an analysis of the possible function of spexin in the hypothalamic melanocortin response, which involves reducing energy intake and increasing energy expenditure while also enhancing insulin sensitivity and glucose tolerance. Gaining more insight into the mechanisms that underlie the spexin system's control over energy metabolism and homeostasis may facilitate the development of innovative treatment approaches that focus on combating obesity and diabetes.

Apelinergic system in acute kidney injury: Mechanistic insights and therapeutic potential.

Acute kidney injury (AKI) has emerged as a global health crisis, surpassing mortality rates associated with several cancers and heart failure. The lack of effective therapies, coupled with challenges in diagnosis and the high cost of kidney transplantation, underscores the urgent need to explore novel therapeutic targets and strategies for AKI. Understanding the intricate pathophysiology of AKI is paramount in this endeavor. The components of the apelinergic system-namely, apelin and elabela/toddler, along with their receptor-are prominently expressed in various kidney cells and have garnered significant attention in renal research. Recent studies have highlighted the renoprotective role of the apelinergic system in AKI. This system exerts its protective effects by modulating several pathophysiological processes, including reducing endoplasmic reticulum (ER) stress, improving mitochondrial dynamics, inhibiting inflammation and apoptosis, promoting diuresis through vasodilation of renal vasculature, and counteracting the effects of reactive oxygen species (ROS). Despite these advancements, the precise involvement of the apelinergic system in the progression of AKI remains unclear. Furthermore, the therapeutic potential of apelin-13 in AKI is not fully understood. This review aims to elucidate the role of the apelinergic system in AKI and its interactions with key pathomechanisms involved in the progression of AKI. Additionally, we discuss the current clinical status of exogenous apelin-13 therapy, providing insights that will guide future research on apelin against AKI.

The determinants of leptin, angiopoietin like 8, and thyroid hormones levels in Saudi females with type 2 diabetes mellitus: A retrospective study.

This study aimed to assess the prevalence of thyroid dysfunction, as measured by hormone levels, in Saudi women with type 2 diabetes mellitus (T2DM). The study will also assess thyroid hormones and leptin, angiopoietin like 8 (ANGPTL8), obesity, and cardiovascular diseases (CVD) in T2D patients. A total of 250 women aged 40 to 60 years with T2DM were retrospectively studied between 2021 and 2022. This research examined medical records for T2DM patients. In this investigation, no T2DM patients had thyroid autoantibodies in their medical records. These patients were chosen for their FT4 and TSH values. All participants were Saudi females with T2DM, aged 54.5 years. Of the 250 participants, 32% had hypothyroidism, 14.8% had hyperthyroidism, and 40.8% (102) had no thyroid disease. Hypothyroidism (7.8 ±â€…0.67 mmol/L) exhibited greater fasting blood glucose (FBG) levels than hyperthyroidism (7.1 ±â€…0.64 mmol/L) (P < .05). Hypothyroid and hyperthyroid females had significant differences in high density lipoprotein-cholestrol (HDL-C), triglycerides, triglyceride glucose (TyG) index, body mass index (BMI), waist circumstance (WC), high-sensitivity C-reactive protein (hs-CRP), leptin, ANGPTL8, insulin resistance (IR), and insulin levels (P < .05). Pearson's correlation test showed that T2DM patients' HDL-C levels were favorably but negatively correlated with leptin and ANGPTL8 levels. In hypothyroidism, thyroid stimulation hormone (TSH) is favorably linked with glycated hemoglobin (HbA1c), triglyscride (TG), TyG index, BMI, WC, leptin, ANGPTL8, hs-CRP, and IR. T2DM is linked to thyroid malfunction, notably hypothyroidism, which correlates positively with TSH. TSH variations due to increasing leptin, ANGPTL8, and TyG index may enhance the risk of insulin resistance diseases, such as obesity and CVD, in Saudi females with T2DM.

Postprandial exercise regulates tissue-specific triglyceride uptake through angiopoietin-like proteins.

Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to fat. While it is well known that exercise mobilizes fat storage from adipose tissues, it remains largely obscure how circulating lipids are distributed tissue-specifically according to distinct energy requirements. Here, we demonstrate that aerobic exercise is linked to nutrient availability to regulate tissue-specific activities of lipoprotein lipase (LPL), the key enzyme catabolizing circulating triglyceride (TG) for tissue uptake, through the differential actions of angiopoietin-like (ANGPTL) proteins. Exercise reduced the tissue binding of ANGPTL3 protein, increasing LPL activity and TG uptake in the heart and skeletal muscle in the postprandial state specifically. Mechanistically, exercise suppressed insulin secretion, attenuating hepatic Angptl8 transcription through the PI3K/mTOR/CEBPα pathway, which is imperative for the tissue binding of its partner ANGPTL3. Constitutive expression of ANGPTL8 hampered lipid utilization and resulted in cardiac dysfunction in response to exercise. Conversely, exercise promoted the expression of ANGPTL4 in white adipose tissues, overriding the regulatory actions of ANGPTL8/ANGPTL3 in suppressing adipose LPL activity, thereby diverting circulating TG away from storage. Collectively, our findings show an overlooked bifurcated ANGPTL-LPL network that orchestrates fuel switching in response to aerobic exercise.

Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system. METHODS: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB-/- mice were generated, and relevant in vivo experiments were performed. RESULTS: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage. CONCLUSION: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.

Impact of Smoking and Obesity on the Selected Peptide Hormones and Metabolic Parameters in the Blood of Women with Polycystic Ovary Syndrome-Preliminary Study.

We investigated the effects of tobacco smoke exposure and abnormal body weight on selected peptide hormones and their association with metabolic and hormonal disorders in women with polycystic ovary syndrome (PCOS). The study group included 88 women with PCOS and 28 women without the disease. In women with PCOS, chemerin, lipocalin, and apelin concentrations were influenced by overweight and obesity status, with the highest concentrations observed in those with a body mass index (BMI) ≥ 30.0. Exposure to tobacco smoke significantly increased only lipocalin-2 concentration. The disease itself did not affect the concentrations of chemerin, lipocalin, and apelin. Additionally, we found a positive correlation between chemerin concentration and fasting glucose, fasting insulin, and triglycerides levels, while a negative correlation was observed with high-density lipoprotein (HDL-C) concentration. In the smoking subgroup, chemerin concentration was positively correlated with free testosterone concentration and the free androgen index and negatively associated with sex hormone-binding globulin concentration. Our findings indicate that abnormal body weight has a stronger impact than tobacco smoke exposure on metabolic and hormonal disorders in women with PCOS, highlighting the important role of weight control in such individuals. However, smoking appears to be an additional factor that intensifies hormonal disorders associated with adipose tissue.

Systemic and tissue-specific spexin response to acute treadmill exercise in rats.

Spexin (SPX) is a 14-amino-acid peptide that plays an important role in the regulation of metabolism and energy homeostasis. It is well known that a variety of bioactive molecules released into the circulation by organs and tissues in response to acute and chronic exercise, known as exerkines, mediate the benefits of exercise by improving metabolic health. However, it is unclear whether acute exercise affects SPX levels in the circulation and peripheral tissues. This study aimed to determine whether acute treadmill exercise induces plasma SPX levels, as well as mRNA expression and immunostaining of SPX in skeletal muscle, adipose tissue, and liver. Male Sprague Dawley rats were divided into sedentary and acute exercise groups. Plasma, soleus (SOL), extensor digitorum longus (EDL), adipose tissue, and liver samples were collected at six time points (0, 1, 3, 6, 12, and 24 h) following 60 min of acute treadmill exercise at a speed of 25 m/min and 0 % grade. Acute exercise increased plasma SPX levels and induced mRNA expression of Spx in the SOL, EDL, and liver. Immunohistochemical analysis demonstrated that acute exercise led to a decrease in SPX immunostaining in the liver. Taken together, these findings suggest that SPX increases in response to acute exercise as a potential exerkine candidate, and the liver may be one of the sources of acute exercise-induced plasma SPX levels in rats. However, a comprehensive analysis is needed to fully elucidate the systemic response of SPX to acute exercise, as well as the tissue from which SPX is secreted.

Spexin inhibits excessive autophagy-induced ferroptosis to alleviate doxorubicin-induced cardiotoxicity by upregulating Beclin 1.

BACKGROUND AND PURPOSE: Doxorubicin is widely used in the treatment of malignant tumours, but doxorubicin-induced cardiotoxicity severely limits its clinical application. Spexin is a neuropeptide that acts as a novel biomarker in cardiovascular disease. However, the effects of spexin on doxorubicin-induced cardiotoxicity is unclear. EXPERIMENTAL APPROACH: We established a model of doxorubicin-induced cardiotoxicity both in vivo and in vitro. Levels of cardiac damage in mice was assessed through cardiac function assessment, determination of serum cardiac troponin T and CKMB levels and histological examination. CCK8 and PI staining were used to assess the doxorubicin-induced toxicity in cultures of cardiomyocytes in vitro. Ferroptosis was assessed using FerroOrange staining, determination of MDA and 4-HNE content and ferroptosis-associated proteins SLC7A11 and GPX4. Mitochondrial membrane potential and lipid peroxidation levels were measured using TMRE and C11-BODIPY 581/591 probes, respectively. Myocardial autophagy was assessed by expression of P62 and Beclin1. KEY RESULTS: Spexin treatment improved heart function of mice with doxorubicin-induced cardiotoxicity, and attenuated doxorubicin-induced cardiotoxicity by decreasing iron accumulation, abnormal lipid metabolism and inhibiting ferroptosis. Interestingly, doxorubicin caused excessive autophagy in cardiomyocyte in culture, which could be alleviated by treatment with spexin. Knockdown of Beclin 1 eliminated the protective effects of spexin in mice with DIC. CONCLUSION AND IMPLICATIONS: Spexin ameliorated doxorubicin-induced cardiotoxicity by inhibiting excessive autophagy-induced ferroptosis, suggesting that spexin could be a drug candidate against doxorubicin-induced cardiotoxicity. Beclin 1 might be critical in mediating the protective effect of spexin against doxorubicin-induced cardiotoxicity.

ANGPTL8 deficiency attenuates lipopolysaccharide-induced liver injury by improving lipid metabolic dysregulation.

Liver injury is closely related to poor outcomes in sepsis patients. Current studies indicate that sepsis is accompanied by metabolic disorders, especially those related to lipid metabolism. It is highly important to explore the mechanism of abnormal liver lipid metabolism during sepsis. As a key regulator of glucose and lipid metabolism, angiopoietin-like 8 (ANGPTL8) is involved in the regulation of multiple chronic metabolic diseases. In the present study, severe liver lipid deposition and lipid peroxidation were observed in the early stages of lipopolysaccharide (LPS) induced liver injury. LPS promotes the expression of ANGPTL8 both in vivo and in vitro. Knockout of Angptl8 reduced hepatic lipid accumulation and lipid peroxidation, improved fatty acid oxidation and liver function, and increased the survival rate of septic mice by activating the PGC1α/PPARα pathway. We also found that the expression of ANGPTL8 induced by LPS depends on TNF-α, and that inhibiting the TNF-α pathway reduces LPS-induced hepatic lipid deposition and lipid peroxidation. However, knocking out Angptl8 improved the survival rate of septic mice better than inhibiting the TNF-α pathway. Taken together, the results of our study suggest that ANGPTL8 functions as a novel cytokine in LPS-induced liver injury by suppressing the PGC1α/PPARα signaling pathway. Therefore, targeting ANGPTL8 to improve liver lipid metabolism represents an attractive strategy for the management of sepsis patients.