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A Case of an Invisible Pancreatic Neuroendocrine Tumor Decoded by Endoscopic Ultrasound.
Cureus
Jenny Joseph, Syed Alishan Nasir, Rakhee Mangla
Endoscopic ultrasound (EUS) is a highly sensitive modality of imaging for detecting small pancreatic masses that may be missed on other cross-sectional imaging. We report a 61-year-old woman who presented with recurrent symptomatic, predominantly postprandial, hypoglycemic episodes, which were confirmed on continuous glucose monitoring. Pertinent medical history included a remote use of tirzepatide, a dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, for weight loss. Mixed-meal testing performed four months after discontinuation of tirzepatide demonstrated hypoglycemia with inappropriately normal insulin and C-peptide levels and a high proinsulin level. Contrast-enhanced computed tomography (CT) of the abdomen and pelvis was negative for pancreatic masses. Due to high clinical suspicion for an insulinoma, EUS was pursued, and a 12-mm hypoechoic mass was identified in the pancreatic body. EUS-guided fine needle biopsy demonstrated a well-differentiated, World Health Organization (WHO) grade 1 pancreatic neuroendocrine tumor with immunostaining consistent with insulinoma. Later, she underwent pancreatic tumor enucleation with complete resolution of symptoms postoperatively. This case highlights the diagnostic utility of EUS in patients with biochemically suspected insulinoma and negative cross-sectional imaging. EUS not only improves mass detection but also facilitates tissue acquisition, supporting timely surgical management of small pancreatic neuroendocrine tumors.
Use of Glucagon-Like Peptide 1 Receptor Agonists and the Associated Risk of Hospitalisation in Bipolar Disorder, From a Nationwide Cohort, 2009-2024.
Acta Psychiatr Scand
Heidi Taipale, Mark Taylor, Markku Lähteenvuo +3 more
Diabetes, obesity and bipolar disorder often co-occur and may have shared pathophysiology. Glucagon-like peptide 1 receptor agonists (GLP-1RA) treat diabetes and obesity but their impact on bipolar disorder is unknown. In this era of stagnated pharmacotherapy, we examined psychiatric hospitalisation and absence from work due to sick leave as potential measures of relapse in people diagnosed with bipolar disorder who were also prescribed antidiabetic medications, including GLP-1RA.
Aesthetic Use of Poly-L-Lactic Acid and Hyaluronic Acid Fillers in Medication-Driven Weight Loss Due to GLP-1 Receptor Agonists: Real-World Case Series from Latin America.
Clin Cosmet Investig Dermatol
Luiz E T Avelar, Priscilla Sarlos, Christine Guarnieri +8 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly prescribed for diabetes and obesity management. The medication-driven weight loss (mdWL) induced by GLP-1RAs may lead to facial hollowing, laxity, and wrinkle accentuation. Minimally invasive strategies are needed to restore facial harmony in this population.
Glucagon-like peptide-1 receptor agonists in movement disorders: From Parkinson's disease to the broader spectrum - Mechanisms, evidence, and future directions.
Clin Park Relat Disord
Ahmed Dahshan, Marwa Ibrahim Mahfouz Khalil, Shaimaa I El-Jaafary +1 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have emerged as potential neuroprotective agents in neurodegenerative disorders. GLP-1 signaling modulates key pathogenic pathways relevant to movement disorders, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and impaired proteostasis, with receptors widely expressed in motor-related brain regions. This narrative reviewaimed to summarize current mechanistic, preclinical, and clinical evidence regarding the role of GLP-1RAs across the spectrum of movement disorders.
Heat stress reveals bidirectional cross talk between the heat shock response and UPRER in C. elegans.
G3 (Bethesda)
Athena Alcala, Toni Castro Torres, Rebecca Aviles Barahona +3 more
Organisms rely on coordinated stress responses to maintain cellular homeostasis. Perhaps the best-known example of multiple stress inputs converging onto a single response is the integrated stress response, which reduces global translation under various stressed conditions to reduce the protein folding burden of the cell. Similarly, most stress responses generally involve coordination of additional protein homeostasis (proteostasis) pathways, including increased expression of chaperones to refold proteins, as well as activation of clearance mechanisms, such as autophagy and the ubiquitin proteasome system. Our study investigates how heat stress can influence coordinated activation of both cytosolic and endoplasmic reticulum (ER) chaperones, exploring bidirectional cross talk between canonical activators of the cytosolic heat-shock response (HSR) and the unfolded protein response of the ER (UPRER). Using robust transcriptional reporters in the Caenorhabditis elegans model system, we explore a noncanonical activation of the UPRER under heat stress by the coordinated effects of XBP-1 and HSF-1. We further investigate inter-tissue communications of stress whereby neuronal or glial activation of the UPRER can result in heterotypic enhancement of the HSR in peripheral cells and can increase thermotolerance. This work highlights the complex convergence of cellular stress responses, a phenomenon that may reflect a general strategy wherein localized stress can activate numerous proteostasis pathways to prevent whole-cell and whole-organism damage.
N-terminal modifications as fate switches in neurodegeneration: a mechanistic review.
Front Aging Neurosci
Disha Mukherjee, Sampath Raghul Kannan, Ramasamy Tamizhselvi
The accumulation of aberrant proteins or their impaired clearance leads to neurodegenerative diseases (NDs). The protein amino terminus (Nt) and its modifications determine the fate of proteins and their cellular effects. Nt acetylation, Nt methylation, and Nt myristoylation are protein Nt modifications implicated in the pathogenesis of proteinopathies like Alzheimer's, Parkinson's, and Huntington's diseases by regulating the protein lifespan, folding, and interaction with protein/DNA. In particular, Nt acetylation shields proteins from degradation or targets them for the same, thereby affecting their fate. Distinct enzymes catalyze Nt acetylation, Nt methylation, and Nt myristoylation, and these modifications compete for the nascent polypeptide at the ribosomal exit tunnel. Dysregulation of Nt modifications initiates the protein aggregation cascade and could potentially induce neuroinflammation and neurodegeneration. Here, we review Nt modifications and their emerging roles in the pathogenesis of NDs. Further, we highlight the crosstalk among distinct Nt modifications and explore how their convergence may shape disease vulnerability and progression.
Immune cell senescence and chronic bone diseases: osteoimmune mechanisms and therapeutic perspectives.
Front Immunol
Zhi Wen, Min Yu, Siren Li +5 more
Immune cell senescence is an important intermediary linking organismal ageing, chronic low-grade inflammation, and disordered bone metabolism. With advancing age, immune cells undergo systemic functional remodeling and exhibit a series of characteristic alterations, including reduced proliferative capacity, skewed differentiation, abnormal migration and homing, impaired phagocytic and clearance functions, and changes in their secretory profile. These changes persistently disrupt the osteoimmune microenvironment and ultimately promote enhanced bone resorption, suppressed bone formation, and deterioration of bone quality. This Review centers on the immunological basis of bone homeostasis and systematically summarizes the major biological features of immune cell senescence, with a particular focus on the key cellular mechanisms through which it drives chronic bone disease. It further analyses its pathological manifestations and disease-specific differences in osteoporosis, osteoarthritis, rheumatoid arthritis, and diabetes-related bone disease. Current evidence indicates that the contribution of immune cell senescence varies across different diseases: its pathogenic association appears to be relatively more direct in osteoporosis and rheumatoid arthritis, whereas in osteoarthritis and diabetes-related bone disease it more often acts as a contributor to inflammatory amplification and microenvironmental deterioration. At present, intervention strategies targeting immune cell senescence mainly focus on modulation of macrophage polarization, immune-mediated clearance of senescent cells, restoration of adaptive immune homeostasis, and MSC-related improvement of the local microenvironment, but overall these approaches remain at the preclinical or early translational stage. Future studies should integrate single-cell sequencing, spatial transcriptomics, and multi-omics approaches to define local immune cell senescence landscapes and establish robust biomarker systems, thereby promoting the transition from mechanistic research to precision intervention in chronic bone diseases.
Lilrb4a Suppression Reprograms Microglia to Mitigate APOE4-Associated Amyloid Plaques and Cerebral Amyloid Angiopathy in Association With a PPAR-Linked Pro-Clearance State.
Adv Sci (Weinh)
Changxu Nie, Ruixi Yang, Xiaotong Wang +10 more
The mouse gene Lilrb4a, an ortholog of human leukocyte immunoglobulin-like receptor B4 (LILRB4), is markedly upregulated in microglia in Alzheimer's disease models and has been implicated in Apolipoprotein E (APOE)-related signaling. However, its contribution to amyloid pathology under an APOE4 background remains unclear. Here, 5xFAD mice carrying human APOE4 were used to assess the impact of Lilrb4a reduction by genetic deletion or antisense oligonucleotide treatment. Both approaches significantly reduced cortical amyloid plaque burden and APOE4-associated cerebral amyloid angiopathy without altering amyloid-β (Aβ) production. Bulk RNA sequencing identified enrichment of peroxisome proliferator-activated receptor (PPAR)-related and broader metabolic pathways in Lilrb4a-deficient mice. Consistently, biochemical analyses showed reduced p-SHP-2, NF-κB-p65, and p-STAT1, increased p-STAT3, and induction of anti-inflammatory and clearance-associated effectors, including Arg-1, TGF-β, and Cyp2e1. In primary microglia, pharmacological interrogation supported a functional contribution of PPAR-γ signaling to the enhanced Aβ uptake and degradation associated with Lilrb4a suppression, whereas PPAR-γ agonism recapitulated key pro-clearance phenotypes in vitro and attenuated amyloid pathology in vivo. Together, these data support Lilrb4a as an APOE4-associated microglial checkpoint candidate linked to impaired amyloid clearance and identify a PPAR-linked pro-clearance program as a potential downstream component of this response.
Cardiac sympathetic afferent denervation improves cardiac post-ischemic remodeling by maintaining autonomic tone.
Int J Cardiol Heart Vasc
Xin Lai, Shun Wang, Hui Chen +2 more
The autonomic imbalance can negatively affect left ventricular (LV) remodeling following a myocardial infarction (MI). Ganglionated plexi (GP) play a crucial role in autonomic nervous system imbalance. Cardiac sympathetic afferent denervation (CSAD) has been shown to have beneficial effects in addressing this imbalance.
Dual Aetiology of Diabetes Insipidus in Pregnancy: Vasopressinase-Mediated and Central Mechanisms.
Case Rep Nephrol
Philani Ezekiel Mkhize, Pauli van Heerden, Tholakele Sabela +2 more
Diabetes insipidus (DI) is a heterogeneous disorder characterised by polyuria and polydipsia due to impaired arginine vasopressin (AVP) secretion or action. We describe a 36-year-old pregnant woman who presented at 28 weeks' gestation with weakness, severe hypokalaemia from renal potassium wasting, hypernatraemia and polyuria with dilute urine. Vasopressinase-mediated DI was suspected; there was no response to AVP, but desmopressin (dDAVP) produced a rapid clinical improvement, confirming the diagnosis. However, postpartum recurrence of symptoms prompted further evaluation, with imaging suggestive of lymphocytic infundibuloneurohypophysitis, necessitating reinitiation of dDAVP. This case highlights the diagnostic complexity of DI in pregnancy and the need to remain vigilant for central causes, even when vasopressinase-mediated DI is initially suspected.
Topical Steroid-Induced Cushing Syndrome in an 18-Month-Old Child: A Case Report.
Cureus
Salman Almansour
Topical corticosteroids are widely used in pediatric dermatology and are generally considered safe when used appropriately; however, prolonged or inappropriate use, particularly of high-potency agents, may lead to significant systemic adverse effects. This case report describes an 18-month-old female who presented with rapid weight gain and cushingoid features following prolonged application of clobetasol propionate for diaper dermatitis. Clinical evaluation revealed generalized obesity, moon facies, facial plethora, and dorsal hypertrichosis, while laboratory investigations demonstrated markedly suppressed afternoon serum cortisol levels (~2 µg/dL; pediatric reference range: 3-13 µg/dL) and plasma adrenocorticotropic hormone (ACTH) levels <5 pg/mL (pediatric reference range: 10-60 pg/mL), consistent with hypothalamic-pituitary-adrenal axis suppression. Imaging studies exclude adrenal pathology. Discontinuation of the offending agent and close clinical monitoring resulted in gradual improvement of clinical features and partial recovery of HPA axis function. This case underscores the potential for potent topical corticosteroids to induce systemic complications in infants and highlights the importance of cautious prescribing, caregiver education, and early recognition of steroid-related adverse effects in pediatric patients.
Balenine alleviates neurodegeneration and inflammation in a mouse model of Parkinson's disease.
Biochim Biophys Acta Gen Subj
Yusaku Chukai, Konatsu Arisumi, Genta Yasunaga +7 more
Carnosine, an imidazole dipeptide, has potential for treating neurodegenerative diseases, including Parkinson's disease. However, carnosine-degrading enzymes limit its bioavailability. In this study, we established a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinson's disease and intranasally administered balenine, a carnosine analog featuring a methylated imidazole that is resistant to degradation enzymes, to target the brain via the olfactory epithelium. MPTP + balenine-treated mice demonstrated improved recognition scores in the object location test. They also exhibited a significantly increased tyrosine hydroxylase-positive cells and reduced expression of glial fibrillary acidic protein, an inflammatory marker, indicating that balenine mitigated neurodegenerative damage and inflammation in mice with MPTP-induced Parkinson's disease. Proteomic analysis revealed that activation of the KEAP1-NFE2L2 pathway, neddylation, and GSK3B and BTRC:CUL1-mediated degradation of NFE2L2. Collectively, these results highlight the efficacy of intranasal drops of balenine in Parkinson's disease and their potential to improve neurodegenerative disease prognosis.
Ready-to-use, in situ formed collagen/RGD/hyaluronic acid hydrogel: accelerating full-thickness wound healing.
Biomaterials
Tiemei Zheng, Siqi Li, Yusen Li +6 more
A robust strategy was developed to customize the hydrogel's composition, concentration, and crosslink density, thereby providing a method for the screening and optimization of skin repair hydrogels. Specifically, methyltetrazine-modified collagen (Col-T), norbornene-modified RGD peptide, and norbornene-modified hyaluronic acid with varying degrees of modification (HA-Nlow, HA-Nmed, and HA-Nhigh), were synthesized. Upon mixing Col-T, RGD-N, and one of the HA-N derivatives, a bioorthogonal reaction was immediately initiated, thereby forming an in situ crosslinked, shape-adaptable hydrogel. An extracellular matrix-mimetic hydrogel composed of collagen, RGD peptide, and hyaluronic acid was optimized using human epidermal stem cells (hEpdSCs), human dermal fibroblasts (HDFs), and human umbilical vein endothelial cells (HUVECs). The optimized hydrogel effectively promoted the hEpdSCs proliferation, the proliferation and migration of HDFs, and the migration and tubular formation of HUVECs. In comparison, GelMA exhibited significant cytotoxicity against hEpdSCs due to the use of photoinitiator LAP. The hydrogel exhibited anti-hemolytic, pro-coagulant, and tissue-adhesive properties, and significantly accelerated the healing of 15 mm × 15 mm full-thickness wound after a single application without any additives. This hydrogel was associated with enhanced hair follicle-like structure formation and reduced inflammation-related responses in the wound area. Furthermore, its ready-to-use and biodegradable nature made it highly suitable for clinical applications.
Angiotensin Receptor Neprilysin Inhibitor in Heart Failure With Preserved Ejection Fraction and Secondary Mitral Regurgitation: The PRAISE-MR Randomized Trial.
Circulation
Sebastiaan Dhont, Sara Moura Ferreira, Xavier Galloo +9 more
Atrial functional mitral regurgitation (AFMR) characterizes a high-risk phenotype in heart failure with preserved ejection fraction (HFpEF). Although sacubitril/valsartan reduces functional mitral regurgitation (MR) in HF with reduced EF (HFrEF), its impact on exercise hemodynamics and the dynamic burden of AFMR in HFpEF remains to be elucidated.
Sex-linked Lung Estrobolome May Contribute to Pulmonary Hypertension Penetrance of Bmpr2 R899X Mutation via an ET-1 high Endoregulatory Macrophage Phenotype.
bioRxiv
O Loya, E S Villarreal, A Carneiro +6 more
Mutations in the bone morphogenetic protein receptor 2 (BMPR2) are a major genetic driver of pulmonary arterial hypertension (PAH), yet their penetrance is strikingly sex-biased: females are disproportionately affected, while males experience poorer outcomes. While hormonal and chromosomal factors have been implicated, the biological basis for this disparity remains not fully understood. Here, we investigated the role of the lung microbiome in sex-linked PAH pathogenesis. We hypothesized that increased BMPR2 mutation penetrance in females is partly driven by the accumulation of potent vasoactive molecules, such as endothelin-1 (ET-1), in response to lung microbiome dysbiosis. Using humanized Bmpr2 +/R899X mice, we integrate lung metagenomics with basic functional immune profiling to show that females develop a distinct microbiome profile, characterized by increased microbial-derived lipopolysaccharide (LPS), potentially fueling the pathogenic effects of the estrogen metabolite 16α-hydroxyestrone (16α-OHE). These signals converge on macrophages, where co-exposure led to a hyperactivated state characterized by enhanced phagocytosis and ET-1 secretion. Tissue-level analyses confirmed immune cell infiltration and spatial association with elevated ET-1, providing evidence that these factors may contribute to the onset of sex-linked PAH. Taken together, these findings identify a previously unrecognized microbiome-estrogen-immune axis that amplifies BMPR2 dysfunction and provides a mechanistic basis for female-biased disease penetrance.
Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells.
Inflamm Regen
Li Xing, Bo Lu, Xiangyang Zhu +5 more
Mesenchymal stromal cells (MSCs) possess therapeutic potential largely reliant on intact mitochondrial function to maintain reparative function. However, obesity compromises MSC metabolism and reparative capacity. MOTS-c, a mitochondria-derived peptide, is known to regulate cellular metabolism, but its role in human MSC biology remains unclear. We hypothesized that restoring MOTS-c signaling rescues the impaired functionality of adipose-derived MSCs from individuals with obesity.
Influence of serum chloride concentrations on the renin-angiotensin-aldosterone system in dogs with congestive heart failure.
Am J Physiol Renal Physiol
Darcy Adin, Yang Qu, Oliver Domenig +1 more
Chloride is a key determinant of macula densa signaling and renin release, but its relationship with systemic renin-angiotensin-aldosterone system (RAAS) activity in naturally occurring heart failure is incompletely defined. We evaluated associations between serum chloride concentration and circulating RAAS metabolites in 147 dogs (20 healthy, 39 preclinical heart disease, 88 congestive heart failure [CHF]). Circulating angiotensin metabolites, aldosterone, and ACE and ACE2 activity were quantified by liquid chromatography-mass spectrometry. Associations between serum chloride and RAAS components were assessed using HC3 robust multivariable linear regression adjusted for sex, ACE inhibitor use, and serum bicarbonate. Dogs with CHF had higher circulating RAAS metabolites than healthy and preclinical dogs. Serum chloride was inversely correlated with multiple RAAS metabolites, including Ang I (rₛ = -0.515) and Ang 1-7 (rₛ = -0.546; both P < 0.0001). Lower serum chloride was independently associated with higher concentrations of angiotensin peptides (Ang I, II, III, IV, and Ang 1-7) and aldosterone, with each 5 mmol/L decrease corresponding to 32-45% increases in angiotensin metabolites and a 39% increase in aldosterone (all adjusted P ≤ 0.02). Hypochloremia (<100 mEq/L) identified a distinct RAAS phenotype characterized by higher downstream angiotensin metabolites, including Ang II, III, and IV (all adjusted P ≤ 0.03). Chloride was not associated with ACE or ACE2 activity. Serum chloride is independently associated with systemic RAAS activation in dogs with heart disease, supporting an association between lower serum chloride concentrations and enhanced upstream of RAAS pathway flux.
Therapeutic potential of ELABELA in alleviating hereditary hypertrophic cardiomyopathy.
J Adv Res
Chao Ye, Tao Xu, Hai Yang +13 more
Hereditary hypertrophic cardiomyopathy (HCM) is a common genetic heart disease associated with heart failure and sudden cardiac death. Current therapies are limited, and the myosin inhibitor mavacamten is constrained by safety concerns and restricted applicability. ELABELA (ELA), an endogenous ligand of the apelin receptor (APJ), plays an important role in cardiovascular regulation, but its involvement in HCM remains unclear.
Brain kappa opioid receptor availability across stress and social buffering conditions: A positron emission tomography study in coppery titi monkeys.
Neuroscience
Claudia Manca, John P Paulus, Alita J D Almeida +6 more
Social connectedness strongly influences health and longevity, and adult pair bonds provide psychological benefits distinct from other social relationships. Oxytocin (OT), corticotropin-releasing hormone (CRH), and opioids play an important role in pair bond formation and maintenance. OT modulates the stress response via the hypothalamic-pituitary-adrenal (HPA) axis, while the kappa (κ) opioid system may modulate OT signaling in contexts of stress and separation. Here, 20 male and female coppery titi monkeys (Plecturocebus cupreus), a unique non-human primate model for the study of pair bonding and social buffering, were exposed to a physical stressor under three social conditions: baseline (no stressor, partner present), stress (stressor, no partner) and buffering (stressor, partner present). We predicted stress would engage the dynorphin/κ-opioid receptor system, reflected in reduced κ-opioid receptor (KOR) availability measured via [11C]GR103545 Positron Emission Tomography (PET) and lower cerebrospinal fluid (CSF) OT, whereas partner presence would attenuate this response. The social buffering effect was successfully replicated: cortisol was significantly elevated during stress relative to baseline in both sexes, with no significant difference between the buffering and baseline conditions. PET imaging revealed condition- and sex-specific differences in [11C]GR103545 binding potential across limbic regions, including the amygdala, hippocampus, and hypothalamus. Females exhibited lower CSF OT levels during stress than at baseline and Spearman correlations revealed no significant associations between plasma and CSF OT. These findings highlight the complex interactions among κ-opioid signaling, OT, and HPA axis activity during social buffering and provide preliminary evidence for region- and sex-specific KOR modulation in a pair-bonded primate model.
Spontaneously Hypertensive Rats Exhibit Reduced Facial Pain Sensitivity with Altered Electrophysiology and Transcriptomics in the Trigeminal Ganglia.
J Pain
Basak Donertas-Ayaz, Niall P Murphy, Airam N Vivanco-Estela +7 more
Hypertension has been associated with altered nociceptive thresholds in humans and animal models, but the relationship between blood pressure (BP) and pain sensitivity remains inconsistent. Here, we investigated trigeminal nociception in male spontaneously hypertensive rats (SHRs) compared with normotensive Wistar-Kyoto (WKY) rats using operant facial pain assays, trigeminal ganglion (TG) electrophysiology, and bulk RNA sequencing with cell-type deconvolution. SHRs exhibited reduced thermal and mechanical facial pain sensitivity relative to WKY controls; however, measured systolic BP did not robustly explain the strain difference in thermal pain behavior. Whole-cell recordings of TG neurons revealed increased hyperpolarization-activated cyclic nucleotide-gated (HCN)-mediated currents and voltage-gated potassium currents in SHRs, while voltage-gated sodium currents were unchanged despite reduced expression of Scn8a, Scn9a, and Scn10a. Transcriptomic analysis further demonstrated broad downregulation of ion channel and sensory transduction genes in SHRs, including Hcn1, Hcn4, Kcnq3, Kcnq4, Piezo2, and Trpm8. Cell-type deconvolution revealed strain-dependent shifts in TG composition, including alterations in sensory neurons and non-neuronal populations such as immune cells, satellite glia, endothelial cells, pericytes, and Schwann cells. Together, these findings show that reduced trigeminal nociception in SHRs is associated with changes in TG ion channel function, sensory gene programs, and cell-type composition, while not being robustly explained by measured systolic BP. PERSPECTIVE: This study shows that reduced trigeminal pain in SHRs is associated with changes in ion channel function, gene expression, and TG cell-type composition, while not being robustly explained by measured systolic BP.