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Therapeutic Potential of Sotagliflozin in Animal Models of Non-alcoholic Fatty Liver Disease with and without Diabetes.
Drug Res (Stuttg)
Nitin J Deshmukh, M S Kalshetti, Mohan Patil +2 more
Sotagliflozin, a dual SGLT1/2 inhibitor, enhances glucagon like peptide-1 (GLP-1) levels and GLP-1 receptor agonists are used to manage non-alcoholic fatty liver disease (NAFLD). Study investigates the effects of sotagliflozin on NAFLD, alone and combined with linagliptin, comparing outcomes in normoglycemic and hyperglycemic animal models.Obese fatty liver disease (FLD) model was induced by high-fat diet (HFD) feeding, while a diabetic non-alcoholic steatohepatitis (NASH) model was developed by administering a single dose of streptozotocin to neonatal mice, followed by HFD feeding post-weaning. At termination of the study, parameters including biochemical markers, inflammatory cytokines, hepatic lipid content, and histopathology were assessed.In NASH mice, sotagliflozin and linagliptin reduced hepatic triglycerides by 60% and 44%, respectively, and cholesterol by 46% and 49%. Their combination further decreased triglycerides by 68.5% and cholesterol by 83.9%. In FLD mice, sotagliflozin and linagliptin reduced triglycerides by 33% and 17%, respectively, and cholesterol by 46% and 21%. Combination treatment offered no benefit, reducing triglycerides by 38% and cholesterol by 27%. Both the treatments improved plasma fibroblast growth factor 21, hepatic interlukin-6, glucose tolerance, steatosis and mitigated fat pad weight, but their combination did not show additional benefit. However, combination treatment demonstrated added benefit in modulating NAFLD activity score, liver enzymes, glycogenated hepatic nuclei, plasma glucose and active GLP-1 levels.Study underscores sotagliflozin's potential to mitigate NAFLD and highlights the benefit of combining it with linagliptin in hyperglycemic NASH model, which showed limited efficacy in normoglycemic FLD mice.
Effects of Carnosine Supplementation on Cognitive Outcomes in Prediabetes and Well-Controlled Type 2 Diabetes: A Randomised Placebo-Controlled Clinical Trial.
Pharmaceuticals (Basel)
Rohit Hariharan, Aya Mousa, Kirthi Menon +10 more
Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human studies for improving cognitive function, insulin resistance and T2DM, but its therapeutic effects on cognition remain unclear. The aim of this study is to assess the effects of carnosine on cognitive function in individuals with prediabetes or well-controlled T2DM. Methods: This is a secondary analysis of a double-blind randomised controlled trial (RCT), whereby 49 adults with prediabetes or early-stage well-controlled T2DM were randomised to receive 2 g of carnosine or identical placebo daily for 14 weeks. At baseline and follow-up, cognitive function was assessed as a secondary outcome using the Digit-Symbol Substitution Test, Stroop test, Trail Making Tests A & B, and the Cambridge Automated Neuropsychological Test Battery (CANTAB). Results: In total, 42 adults (23 males and 19 females) completed the trial. There were no differences in participant anthropometry or cognitive functioning between carnosine and placebo groups at baseline (all p > 0.1). After the 14-week supplementation period, there were no differences between carnosine and placebo groups in change and follow-up values for any cognitive measures including Stroop, Digit Symbol Substitution Sest, Trail Making A/B or CANTAB (all p > 0.05). Adjustments for baseline cognitive scores, diabetic status, level of education, age or interaction effects with participants' sex did not change the results. Conclusions: Carnosine supplementation did not improve cognitive measures in individuals with prediabetes or T2DM in this study. While larger trials may provide further insights, alternative factors-such as the relatively young and healthy profile of our cohort-may have contributed to the lack of observed effect. Future research should examine individuals with existing cognitive impairment or those at higher risk of cognitive decline to better define the therapeutic potential of carnosine in this context.
Critical role of PepT1 in promoting colitis-associated cancer and therapeutic benefits of the anti-inflammatory PepT1-mediated tripeptide KPV in a murine model.
Cell Mol Gastroenterol Hepatol
Emilie Viennois, Sarah A Ingersoll, Saravanan Ayyadurai +7 more
The human intestinal peptide transporter 1, hPepT1, is expressed in the small intestine at low levels in the healthy colon and upregulated during inflammatory bowel disease. hPepT1 plays a role in mouse colitis and human studies have demonstrated that chronic intestinal inflammation leads to colorectal cancer (colitis-associated cancer; CAC). Hence, we assessed here the role of PepT1 in CAC.
A nanoparticle platform for combined mucosal healing and immunomodulation in inflammatory bowel disease treatment.
Bioact Mater
Valentina Marotti, Yining Xu, Cécilia Bohns Michalowski +11 more
Current treatments for inflammatory bowel disease (IBD) treatment consist of anti-inflammatory products. In this study, we sought to induce the physiological secretion of glucagon-like peptide 2, a peptide with intestinal growth-promoting activity, via nanoparticles while simultaneously providing with immunomodulation by tailoring the nanoparticle surface. To this end, we developed hybrid lipid hyaluronate-KPV conjugated nanoparticles loaded with teduglutide for combination therapy in IBD. The nanocarriers induced (or did not induce) immunosuppression depending on the presence (or absence) of a hyaluronan-KPV functionalization. This strategy holds promise as a nanoparticle platform for combined mucosal healing and immunomodulation in IBD treatment.
The diagnosis of GH deficiency in adult β-thalassemic patients: are two different stimulation tests necessary to improve specificity?
Pituitary
Daniele Sola, Mirna Solange Barrio Lower Daniele, Leila Danesi +6 more
β-thalassemia major (βTM) frequently leads to endocrinological complications of chronic transfusion-induced iron overload, including growth hormone deficiency (GHD). With contrasting data on GHD in adult βTM populations, our study aimed to reevaluate the diagnosis of GHD using multiple tests and its progression over time.
Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats.
ACS Chem Neurosci
Tori L Schaefer, Curtis E Grace, Matthew R Skelton +4 more
Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown but we hypothesized that it involves perturbations to the serotonergic system as this is the principle mode of action of MDMA in the adult brain. During development 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously showed that MDMA exposure (4×10 mg/kg/day) from P11-20 (analogous to human third trimester exposure) induces ~50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time-points (P12, P16, P21) during the treatment interval (P11-20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug's cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.
The role of Thyrotropin Releasing Hormone in aging and neurodegenerative diseases.
Am J Alzheimers Dis (Columbia)
Caitlin M Daimon, Patrick Chirdon, Stuart Maudsley +1 more
Thyrotropin releasing hormone (TRH) is primarily known as the central regulator of the hypothalamic-pituitary-thyroid (HPT) axis. However, TRH also exerts a variety of central nervous system effects independent from its activity in the HPT axis. With advancing age, decreases in TRH synthesis, expression, and activity have been demonstrated. Associated with this emerging evidence suggests that TRH is implicated in neurodegenerative diseases of aging, including Alzheimer's disease and Parkinson's disease. TRH and its synthetic analogs have been recognized as trophic factors in neurons of the diencephalon and spinal cord, and as neuroprotectants against oxidative stress, glutamate toxicity, caspase-induced cell death, DNA fragmentation, and inflammation. In this review, we will provide an overview of some of the roles of TRH, outside of the HPT axis, associated with pathological aging and neurodegeneration and we shall discuss the potential of TRH and TRH analogs for the treatment of neurodegenerative diseases.
Effects of Hormone Replacement Treatment with Estrogen and Progestins on the Vascular Renin-Angiotensin System of Ovariectomized Rats.
Int J Mol Sci
Laís Almeida Menezes, Patrick Wander Endlich, Deiviany Santana Santos Lima +5 more
The renin-angiotensin system (RAS) is the main endocrine and tissular component responsible for controlling cardiovascular homeostasis, which can be modulated by estrogen levels. This study investigated the effects of hormone treatments with estrogen and progestins on angiotensin-(1-7)-mediated [Ang-(1-7)] vasodilation in ovariectomized rats and the possible mechanisms involving the RAS. Female Wistar rats were divided into the following groups: sham (SHAM), ovariectomized (OVX), OVX and treated with 17β-estradiol (E2) (OE2), OVX and treated with E2 and drospirenone (OE2 + DRSP), and OVX and treated with medroxyprogesterone (MPA). Hormonal treatment was delivered via gavage for 28 days. Vascular responses to Ang-(1-7) were assessed in isolated aortic rings, and a Western blot of the thoracic aorta was used to determine the protein levels of angiotensin II (Ang II) type-1 receptor (AT1R), Ang II type-2 receptor (AT2R), Ang-(1-7) receptor (Mas), angiotensin-converting enzyme 2 (ACE2), and endothelial nitric oxide synthase (eNOS). The results showed impaired vascular reactivity caused by ovariectomy. Ang-(1-7) induced vasodilation in the OE2, OE2 + DRSP, and MPA-treated groups, while the administration of the AT2R antagonist (PD123319) or the selective Mas antagonist (A779) increased the extent of vasorelaxation induced by Ang-(1-7) in the OVX + MPA group. There were no differences in the aortic levels of AT1R or ACE2 between the groups, but the MPA group showed significantly increased levels of AT2R and eNOS. We concluded that ovariectomy induced vascular dysfunction linked to RAS regulation, and both estrogen (E2) and progestins differentially restored these parameters.
GDF11 Alleviates Vascular Calcification in VitD3-Overloaded Mice Through Inhibition of Inflammatory NF-κB Signal.
FASEB J
Jiali Huang, Qingchun Liang, Yuanzhi Ye +4 more
Vascular calcification, an age-associated disorder, is a highly regulated biological process similar to bone formation. Growth differentiation factor 11 (GDF11), a secreted member of the transforming growth factor beta (TGF-β) superfamily, has been shown to act as an anti-aging factor in the brain, heart, skin, and skeletal muscle. Nevertheless, whether GDF11 affects vascular calcification and the underlying mechanisms remain unclear. In the present study, beta-glycerophosphate and calcium chloride-induced calcification of vascular smooth muscle cells (VSMCs) and a VitD3-overloaded mouse model were used to investigate the role of GDF11 in vascular calcification. Our results revealed that the knockdown of GDF11 by siRNA promoted the calcification of rat VSMCs, whereas GDF11 treatment significantly reduced the calcification of human and rat VSMCs in vitro, as detected by alizarin red staining and calcium content assay. Similarly, GDF11 treatment reduced the expression of bone-related molecules including Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein-2 (BMP2). Furthermore, ex vivo and in vivo studies confirmed the inhibitory effect of GDF11 on vascular calcification. Mechanistically, GDF11 treatment reduced the levels of NF-κB signaling molecules including NLRP3, phosphorylated p65, IL-6, and IL-1β in VSMCs. Additionally, GDF11 siRNA-induced VSMC calcification was repressed by NF-κB inhibitor PDTC treatment. Taken together, these findings suggest that GDF11 alleviates vascular calcification through inhibiting the NF-κB signal. Modulation of GDF11 may represent a therapeutic strategy for vascular calcification.
MOTS-c Peptide Attenuated Diabetic Cardiomyopathy in STZ-Induced Type 1 Diabetic Mouse Model.
Cardiovasc Drugs Ther
Nan Wu, Caijie Shen, Jian Wang +2 more
Diabetic cardiomyopathy (DCM) pathogenesis is a common complication of diabetes, but effective treatments remain limited. Mitochondrial-derived peptide MOTS-c has shown therapeutic promise in animal models of various heart diseases, but its efficacy in DCM is unknown. This study investigates the effects of MOTS-c treatment in a mouse model of type 1 diabetes-induced DCM.
Exploring factors behind Arginine-Vasopressine deficiency in endoscopic endonasal surgery for PitNET: a single-center analysis of 349 patients.
Neurosurg Rev
Raffaele De Marco, Alice Antico, Nunzia Prencipe +8 more
Arginine-Vasopressine deficiency (AVP-D), formerly known as Central Diabetes Insipidus, is a well-known complication in surgery for sellar/parasellar masses. Although less frequent in endoscopic series than transcranial and microscopic transsphenoidal ones, AVP-D has been variably related to different factors. Focusing the work on pituitary Neuroendocrine Tumors (PitNET), all patients who were treated endoscopically at a single centre were retrospectively reviewed to analyze the occurrence of this complication. Patient's characteristics, radiological information, and operative data were collected for patients who underwent surgery for PitNET at the same Institution by a single surgeon in the period 2016-2022. AVP-D was diagnosed in the presence of new-onset hypotonic polyuria with or without hypernatremia and was defined persistent if required a treatment with desmopressine/DDAVP for more than 6 months. Out of 349 patients (mean age at surgery 57.5 years old) 44 (12.6%) developed AVP-D (25 transient and 19 permanent). Younger age, the presence of an intraoperative CSF leak, the maximum diameter of the lesion, its suprasellar extension (considering the presence of a visual deficit), consistency of the lesion (distinguishing 4 classes, soft, soft-fibrous, fibrous and fibrous-firm), the extent of resection and the functioning status showed some relationship at univariate analysis (p < 0.05) with this complication. Larger diameter and longer operative time were seen more frequently in permanent AVP-D. A more solid intraoperative consistency with the presence of adherences (class 4 vs. class 1, OR 11.14, 95%CI 1.20-103.4) and the appearance of an intraoperative CSF-leak (OR 8.27, 95%CI 3.92-17.47) maintained a statistical significance in the multivariate logistic regression, with an older age being a protective factor in developing this deficiency (OR 0.96, 95%CI 0.95-0.99). The recognition of factors that can predict the onset of AVP-D with a certain degree of accuracy enables the entire staff to pay greater attention to the patient at risk in the postoperative period, thus preventing AVP-D complications.
A 50-year journey in the development of treatment for benign prostatic hyperplasia.
NPJ Aging
Andrew V Schally, George Theodoropoulos, Wei Sha +2 more
Recent research underscores the crucial role of hormone regulation in benign prostatic hyperplasia (BPH) and the therapeutic promise of growth hormone-releasing hormone (GH-RH) antagonists. BPH incidence in aging men doubled over three decades, driven by prostatic enlargement and lower urinary tract symptoms (LUTS). Aging-related changes in GH-RH and luteinizing hormone-releasing hormone (LH-RH) biology promote BPH through hormonal and inflammatory processes. Traditional therapies provide symptomatic relief but often fail to prevent progression. This review explores the 50-year extensive development of LH-RH and GH-RH peptide analogs from discovery to delivery and their potential in BPH treatment. In preclinical studies, GH-RH antagonists reduced prostate volume, improved LUTS, and modulated inflammation mediated by NF-κB and IGF-I. Clinical trials are needed to validate antagonist efficacy and safety. Given BPH's public health impact among the aged, and especially among aging Veterans, integrating GH-RH antagonists into management strategies may offer precision-based therapeutic advancements.
[Study of the role of biomarkers in determining the course of non-alcoholic fatty liver disease in children with obesity].
Vopr Pitan
A M Lebedeva, E V Pavlovskaya, M E Bagaeva +5 more
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world, especially among children. Studying the role of biomarkers in determining the course of NAFLD in obese children will make it possible to identify the disease at an early stage, assess the risks of progression and select individual approaches to therapy. The purpose of the research was to study the diagnostic role of noninvasive biomarkers in determining the severity of liver steatosis and fibrosis in obese children. Material and methods. 78 children from 11 to 17 years of age with exogenous constitutional obesity were examined. The children were divided into two groups: group 1 (n=59) - children with obesity and non-alcoholic fatty liver disease (NAFLD), group 2 (n=19) - children without NAFLD; in group 1, subgroups of children with simple liver steatosis (n=45) and non-alcoholic steatohepatitis (NASH) were identified (n=14). The study of lipid metabolism (total cholesterol, HDL, LDL, triglycerides), carbohydrate metabolism (glucose, insulin, HOMA-IR), blood serum level of fibroblast growth factor-21 (FGF-21), cytokeratin-18 (СK18), apoptosis factor associated with the FAS ligand (FASL), and visfatin has been conducted. All patients underwent ultrasound examination of the abdominal organs and liver elastography to determine the degree of liver fibrosis on the METAVIR scale and the degree of steatosis using a controlled attenuation parameter (CAP). Results. The level of the biomarkers CK-18 and FASL were significantly higher in children from Group 1 compared to those without NAFLD (1.26 [0.44; 1.57] vs 0.47 [0.43; 0.59] ng/mL, p=0.008 and 36.33 [25.57; 45.94] vs 22.55 [20.27; 26.41] pg/mL, respectively). Moreover, these levels increased with the degree of obesity. In patients with NASH, FASL levels showed a positive correlation with the degree of obesity (r=0.40), CK-18 with the stage of liver fibrosis (r=0.50), and visfatin with transaminase activity (r=0.65), fibrosis (r =1.0), and hepatic steatosis degree (r=0.60). FGF-21 demonstrated only weak correlations with the other studied biomarkers. The HIS and APRI indices were significantly higher in patients with NASH (46.46 [40.75; 53] vs 42.11 [36.88; 47.09], p=0.0006 and 0.25 [0.18; 0.36] vs 0.18 [0.15; 0.21], p=0.04 in patients with hepatic steatosis; and vs 40.02 [36.4; 44.85] and 0.16 [0.12; 0.22] in patients from Group 2, respectively). All patients had PNFI>9, indicating the presence of significant fibrotic changes. Correlation analysis showed that HIS and APRI indices were strongly associated with the degree of steatosis, alanine aminotransferase activity, and right liver lobe size. Conclusion. The use of biomarkers makes it possible to complement ultrasound diagnostics of NAFLD, providing more complete information about the severity of the disease without invasive procedures. The development and application of noninvasive methods for the diagnosis and prediction of NAFLD will in some cases avoid liver biopsy.
Association of ventricular-arterial coupling with biomarkers involved in heart failure pathophysiology - the STANISLAS cohort.
Eur J Heart Fail
Hannes Holm, Martin Magnusson, Amra Jujić +10 more
Impaired left ventricular-arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population-based cohort of middle-aged individuals.
Gut neuropeptide involvement in Parkinson's disease.
Am J Physiol Gastrointest Liver Physiol
Hayley N Templeton, Stuart A Tobet, Luke A Schwerdtfeger
Parkinson's disease (PD) is a neurodegenerative disorder affecting over 10 million people. A key pathological feature of PD is the accumulation of misfolded α-synuclein (aSyn) protein in the substantia nigra pars compacta. Aggregation of aSyn can form Lewy bodies that contribute to dopaminergic neuron degeneration and motor symptoms, such as tremor, rigidity, and bradykinesia. Beyond the central nervous system, aSyn aggregates have been detected in the gastrointestinal (GI) tract, suggesting a link between peripheral aSyn and nonmotor PD symptoms. GI symptoms, often preceding motor symptoms by up to 20 years, highlight the bidirectional communication between the central nervous system and the enteric nervous system (gut-brain axis) in PD. Although microbiome alterations and intestinal inflammation have been associated with PD, functional impacts on gut-brain signaling or aSyn aggregation remain unclear. Intestinal neuropeptides are key modulators of gut-brain communication, alter immune response to pathogens and environmental toxins, and may contribute to the function of the luminal gut barrier. Dysregulation of gut neuropeptide signaling, including vasoactive intestinal peptide, neuropeptide Y, calcitonin gene-related peptide, ghrelin, cholecystokinin, glucagon-like peptide 1, and substance P, have been associated with pathologic effects of PD in animal models. Despite their potential role in pathogenesis and disease modulation, gut neuropeptide roles in PD are underexplored. This article reviews current knowledge surrounding microbial metabolite and immune influences on gut neuropeptide signaling, aSyn aggregation in the enteric nervous system, and downstream neuroimmune pathway alterations within the context of PD and its mouse models.
Anti-β2GPI/β2GPI complex promotes thrombosis by activating the P2Y2/MAPKs pathway to increase human neutrophil peptides.
PLoS One
Xin Guan, Wen Liu, Tianfeng Gao +5 more
Anti-β2 glycoprotein I (Anti-β2GPI) antibodies are a heterogeneous group of antiphospholipid antibodies targeting β2 glycoprotein I (β2GPI). High titer of anti-β2GPI antibodies is a risk factor for thrombosis in antiphospholipid syndrome (APS). Although it has been shown that anti-β2GPI antibodies can induce neutrophil activation involved in thrombosis, the underlying mechanism remains unclear. In this study, we analyzed the clinical data of thrombotic patients who were positive or negative for anti-β2GPI antibodies, as well as healthy individuals. The results showed that the percentage and absolute count of neutrophils, serum levels of human neutrophil peptides (HNPs), and HNP mRNA levels were significantly higher in the anti-β2GPI-positive patient group compared to the healthy control group. Notably, when compared to the anti-β2GPI-negative patient group with similar neutrophil percentages and counts, the serum HNPs levels were also significantly elevated in the anti-β2GPI-positive patient group. In vitro, we further showed that anti-β2GPI and β2GPⅠ complex (anti-β2GPI/ β2GPⅠ complex) induced a concentration - and time-dependent increase in HNPs, which was mediated through P2Y2 receptors on the surface of neutrophils. Meanwhile, we found that intracellular signaling pathways P38MAPK (P38 mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase) were also involved in the generation of HNPs. We also found that high levels of human neutrophil peptide-1 (HNP-1) could induce the production of procoagulant factors von Willebrand factor (vWF) and P-selectin in endothelial cells through the nuclear factor-κB (NF-κB) signaling pathway, which increased the risk of thrombosis.
ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.
Mol Psychiatry
Guy Shapira, Gidon Karmon, Gal Hacohen-Kleiman +6 more
Essential for brain formation and protective against tauopathy, activity-dependent neuroprotective protein (ADNP) is critical for neurogenesis and cognitive functions, while regulating steroid hormone biogenesis. As such, de novo mutations in ADNP lead to syndromic autism and somatic ADNP mutations parallel Alzheimer's disease progression. Furthermore, clinical trials with the ADNP fragment NAP (the investigational drug davunetide) showed efficacy in women suffering from the tauopathy progressive supranuclear palsy and differentially boosted memory in men (spatial) and women (verbal), exhibiting prodromal Alzheimer's disease. While autism is more prevalent in boys and Alzheimer's disease in women, both involve impaired neurogenesis. Here, we asked whether ADNP sex-dependently regulates neurogenesis. Using bromodeoxyuridine (BrdU) as a marker of neurogenesis, we identified two-fold higher labeling in the hippocampal sub-ventricular zone of ADNP-intact male versus female mice. Adnp haplo-insufficient (Adnp+/-) mice or mice CRSIPR/Cas9-edited to present the most prevalent neurodevelopmental ADNP syndrome mutation, p.Tyr718* (Tyr) showed dramatic reductions in male BrdU incorporation, resulting in mutated females presenting higher labeling than males. Treatment with NAP compensated for the male reduction of BrdU labeling. Mechanistically, hippocampal RNAseq revealed male-specific Tyr down-regulation of endoplasmic reticulum unfolded protein response genes critical for sex-dependent organogenesis. Newly discovered mitochondrial accessibility of ADNP was inhibited by the Tyr718* mutation further revealing female-specific Tyr downregulation of mitochondrial ATP6. NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases.
Association of FGF21 with Metabolic and Cardiovascular Diseases: A Mendelian Randomization Analysis.
Exp Clin Endocrinol Diabetes
Qingwen He, Yuguang Li, Renqiang Yu +1 more
Studies have covered a possible relevance between fibroblast growth factor 21 (FGF21) and obesity-related metabolic complications and cardiovascular disease (CVD). Nevertheless, whether FGF21 is a causative factor in these diseases is not known. Using a bidirectional, two-sample Mendelian randomization (MR) approach, this study sought to establish a causal relationship between FGF21 and seven metabolic diseases and six CVDs. A large-scale meta-analysis dataset of genome-wide association studies (GWAS) was analyzed to generate summary-level statistics for FGF21. The diseases we studied included non-alcoholic fatty liver disease (NAFLD), obesity, type 2 diabetes (T2DM), hypertension, gestational diabetes (GDM), gestational hypertension (GHTN), pre-eclampsia or eclampsia (PE), atherosclerosis, cardiomyopathy (CMP), coronary heart disease (CHD), coronary atherosclerosis, heart failure (HF), myocardial infarction (MI) and the corresponding summary GAWS data were retrieved from the FinnGen Biobank and IEU Open GWAS Project database. The inverse variance-weighted (IVW) algorithm was the primary approach utilized for the MR analysis. The MR-Egger regression and MR-PRESSO tests were implemented to evaluate horizontal pleiotropy. The heterogeneity of instrumental variables was subsequently assessed utilizing Cochran's Q statistics.When diseases are used as exposures, MR analysis results of the IVW method indicated that NAFLD (Beta=- 0.047, 95% CI=- 0.08 to - 0.014; p=0.006), obesity (Beta=0.087, 95% CI=0.021-0.153; p=0.009), T2DM (Beta=0.071, 95% CI=0.037-0.106; p<0.001) correlated causally with FGF21. Nevertheless, FGF21 was not causally related to the remaining metabolic diseases and CVDs, according to the results of the MR analysis (p>0.05). It was demonstrated that the aforementioned results were robust and devoid of pleiotropy.Our study supports a causal association between NAFLD, obesity, and T2DM with FGF21. No substantial evidence exists to establish a causal relationship between FGF21 and other diseases. This study provides opportunities for the early prevention and innovative therapy of NAFLD, obesity, and T2DM.
Amylin: From Mode of Action to Future Clinical Potential in Diabetes and Obesity.
Diabetes Ther
Špela Volčanšek, Andrijana Koceva, Mojca Jensterle +2 more
Precision diabetology is increasingly becoming diabetes phenotype-driven, whereby the specific hormonal imbalances involved are taken into consideration. Concomitantly, body weight-favorable therapeutic approaches are being dictated by the obesity pandemic, which extends to all diabetes subpopulations. Amylin, an anorexic neuroendocrine hormone co-secreted with insulin, is deficient in individuals with diabetes and plays an important role in postprandial glucose homeostasis, with additional potential cardiovascular and neuroprotective functions. Its actions include suppressing glucagon secretion, delaying gastric emptying, increasing energy expenditure and promoting satiety. While amylin holds promise as a therapeutic agent, its translation into clinical practice is hampered by complex receptor biology, the limitations of animal models, its amyloidogenic properties and pharmacokinetic challenges. In individuals with advanced β-cell dysfunction, supplementing insulin therapy with pramlintide, the first and currently only approved injectable short-acting selective analog of amylin, has demonstrated efficacy in enhancing both postprandial and overall glycemic control in both type 2 diabetes (T2D) and type 1 diabetes (T1D) without increasing the risk of hypoglycemia or weight gain. Current research focuses on several key strategies, from enhancing amylin stability by attaching polyethylene glycol or carbohydrate molecules to amylin, to developing oral amylin formulations to improve patients' convenience, as well as developing various combination therapies to enhance weight loss and glucose regulation by targeting multiple receptors in metabolic pathways. The novel synergistically acting glucagon-like peptide-1 (GLP-1) receptor agonist combined with the amylin agonist, CagriSema, shows promising results in both glucose regulation and weight management. As such, amylin agonists (combined with other members of the incretin class) could represent the elusive drug candidate to address the multi-hormonal dysregulations of diabetes subtypes and qualify as a precision medicine approach that surpasses the long overdue division into T1DM and T2DM. Further development of amylin-based therapies or delivery systems is crucial to fully unlock the therapeutic potential of this intriguing hormone.Graphical abstract available for this article.
Immunohistochemistry and molecular biology studies of apelin and apelin receptor in queen placenta.
Vet Res Commun
Sara Pastore, Cecilia Dall'Aglio, Margherita Maranesi +7 more
Placenta is a tissue where vasculogenesis, blood pressure and blood flow are dramatically important to allow normal embryonic and foetal growth and requires the production of numerous growth factors, hormones and transcription factors. Apelin is a pleiotropic peptide, and its major action relates to energy metabolism, cardiovascular function, body fluid homeostasis via its receptor. The involvement of the apelinergic system during pregnancy in veterinary medicine has been investigated only in bitches. Thereafter, the aim of our study was to investigate, for the first time, presence and distribution of this system in the queen placenta at mid- and end-gestation. Ten pregnant mixed-breed queens were used. The animals were equally divided into two groups based on the stage of pregnancy (mid and end gestation) and, with the written consent of their owners, were subjected to ovariohysterectomy or non-conservative caesarean section. The Real-Time PCR (RT-PCR) analysis showed the presence of transcripts for apelin and its receptor in all the foetal and maternal placenta samples processed. The immunohistochemical (IHC) study evidenced the presence and the distribution of positive immunoreactions for apelin and its receptor in all the samples observed. In particular, in the placental labyrinthic portion, apelin and apelin receptor immunopositivity was evident in the cytoplasm of trophoblasts and endothelial cells. The uterine glands also exhibited a positive immune reaction for apelin and corresponding receptor. Based on our results, apelin and its receptor, also in the queen placenta, could be an important system involved in the physiological development of placenta, embryo and foetal growth.