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Ectopic Cushing's syndrome in a patient with DIPNECH and metastatic lung carcinoid.
Endocrinol Diabetes Nutr (Engl Ed)
Sara Ribeiro, Telma Moreno, Maria Lume +7 more
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare precursor to lung carcinoids. We report a case of ACTH-dependent Cushing's syndrome in a 73-year-old female patient with metastatic lung carcinoid arising on a background of DIPNECH. She presented with lower limb oedema, hypokalaemia, hypertension, and de novo diabetes. Clinical suspicion for hypercortisolism was confirmed by abnormal cortisol tests. A thoracic CT scan showed multiple lung nodules suggestive of DIPNECH and biopsy of one of the nodules identified an ACTH-expressing carcinoid tumour. A PET-Ga-68-DOTATOC revealed pulmonary and multiple tumour lesions in the ganglia, bone and liver with overexpression of somatostatin receptors. A liver biopsy demonstrated involvement by a well-differentiated neuroendocrine neoplasia, consistent with metastasis. Hypercortisolism was managed with octreotide and metyrapone, but the patient succumbed to complications 14 months post-diagnosis. This case suggests DIPNECH's potential to progress to hyperfunctioning, metastatic carcinoids and highlights the necessity for vigilant long-term surveillance and early intervention.
Reviving the Mitochondria: A Hopeful Horizon in Refractory Heart Failure.
Cureus
Zeeshan Ahmed, Fnu Abdul Rehman, Syed Faqeer Hussain Bokhari
Refractory heart failure (HF) remains a pressing clinical challenge despite substantial progress in pharmacologic and device-based interventions. While current therapies target neurohormonal, hemodynamic, and metabolic derangements, a crucial element of cellular dysfunction often remains overlooked: mitochondrial health. Mitochondrial dysfunction plays a central role in the pathogenesis and progression of HF, contributing to bioenergetic failure, oxidative stress, and cardiomyocyte death. Recent advances in mitochondrial-targeted therapies have opened new possibilities for treating HF at its energetic roots. This editorial explores the pathophysiological role of mitochondria in HF, reviews emerging therapeutic strategies aimed at restoring mitochondrial function, and outlines key challenges that must be addressed to translate these innovations into clinical practice.
The ADNP-Mediated Transcriptome Response to Ketamine Impairs the Cytoskeletal Protein Axis.
J Mol Neurosci
Claudio Peter D'Incal, Ligia Mateiu, Kevin De Man +3 more
De novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene cause the autistic Helsmoortel-Van der Aa syndrome with patients showing mild to disastrous phenotypes impacting brain functioning, behavior, and organ functions. In this respect, two treatment strategies have been proposed to alleviate symptoms in patients with this syndrome: (1) the ADNP-derived octapeptide investigational drug NAP (davunetide), which enhances ADNP's ability to target cytoskeletal deficits, and (2) subnarcotic levels of ketamine, which are suggested to increase endogenous ADNP mRNA levels. Here, we focus on the perspective of ketamine and investigated the transcriptomic response of low-dose and high-dose ketamine applications at different time points, experimentally controlled by the non-toxic drug NAP, in lymphoblastoid cell lines obtained from individuals with Helsmoortel-Van der Aa syndrome. Transcriptome profiling was performed at baseline conditions, followed by dose (low or high) and time (40 min or 4 h)-dependent ketamine application in patient and control lymphoblastoid cell lines. We showed that ketamine affected ADNP expression levels in a dose- and time-dependent manner with only toxic ketamine concentrations increasing ADNP protein levels. Ketamine application also triggered a transcriptomic response with profound gene expression alterations centered around processes such as immune response-regulating signaling pathways and cell fate commitment at low-dose ketamine, together with organelle assembly and cytoskeletal dysregulation at high doses. A parallel control experiment with NAP under the same experimental conditions did not induce detectable gene expression differences in patient-derived cell lines. The ketamine-induced cytoskeletal alterations were functionally studied using immunoblotting, showing a disturbed expression of α-tubulin, β-actin, and to a minor extent microtubule-associated protein EB3 in patient-derived lymphoblastoid cells. Ketamine upregulates wild-type ADNP transcript and protein levels in a dose- and time-dependent manner in patient-derived lymphoblastoid cell lines from individuals with Helsmoortel-Van der Aa syndrome, while inducing a transcriptomic response that affects key processes including immune system signaling and cytoskeletal organization.
Surgical treatment and somatostatin experience in growth hormone-secreting pituitary macroadenoma due to novel AIP mutation.
J Pediatr Endocrinol Metab
Kıymet Karagöz, Emine Şeyma Eken, Gülin Karacan Küçükali +9 more
Somatotropinomas are extremely rare in children and frequently associated with genetic causes. Among pituitary gigantism, approximately 30 % are attributed to the aryl hydrocarbon receptor-interacting protein (AIP) gene mutations, whereas other genetic causes are less common. These mutations cause more aggressive tumors that are challenging to control with a single intervention and often exhibit resistance to somatostatin analogs (SSAs). Our aim is to present a pediatric patient with a somatotropinoma due to a novel AIP variant who responded positively to SSA therapy following a single surgical intervention.
Association between plasma mid-regional pro-adrenomedullin levels and muscle properties.
Geriatr Gerontol Int
Hiroshi Akasaka, Yasuharu Tabara, Kazuki Fukuma +10 more
Adrenomedullin exerts a vasodilative effect and is thought to be associated with skeletal muscle properties by regulating microcirculation. This cross-sectional study aimed to clarify the possible association in older adults aged ≥65 years.
Development and Characterization of trans-Cinnamaldehyde-Entrapped Zeolitic Imidazole Framework‑8 as an Antibacterial Agent for Food Safety Applications.
ACS Omega
Zeynep Sevimli Yurttas, Rosana G Moreira, Elena Castell-Perez
This study shows successful synthesis, characterization, and demonstration of antibacterial activity of trans-cinnamaldehyde (TC)-loaded ZIF-8 nanoparticle complexes, highlighting their potential in the safety of food preparation surfaces and antimicrobial packaging, pH-responsive drug delivery surface cleaning, and biofilm prevention applications. The best ratio of TC to zinc + 2- was 1:2 in terms of a higher entrapment efficiency. The ZIF-8 nanoparticles were in the range of 100-200 nm and consistent with entrapment efficiency trends, while the poly-l-lysine (PL) coating increased the size beyond 300 nm. SEM and TEM images confirmed that TC entrapment did not change the morphology of the ZIF-8 nanoparticles. Gas adsorption analysis yielded a high BET surface area, which decreased upon TC entrapment. FTIR spectra exhibited distinctive peaks of ZIF-8 and TC in the nanoparticles, further confirming the successful synthesis procedure. Release studies indicated a burst release of TC in PBS, with water- and alcohol-based media enabling more gradual and sustained release.
Case Report: Improvement in cognitive functioning following setmelanotide initiation in a patient with Bardet-Biedl syndrome.
Front Endocrinol (Lausanne)
Menjin Kuk, Jesse Richards, Rachel A Ross
Bardet-Biedl syndrome (BBS) is a rare genetic condition that results from mutations in a variety of genes crucial for ciliary transport. Consequently, patients with BBS present with a wide array of clinical signs and symptoms that include multiple organ systems. In particular there is a high burden of metabolic disturbances, such as obesity, hyperphagia, and type 2 diabetes, due to the impaired leptin-melanocortin-4 receptor (MC4R) pathway that prevents appropriate activation of MC4R that is normally responsible for signaling hunger and satiety. As such, setmelanotide, an MC4R agonist, has been approved for use to target the obesity and hyperphagia experienced by patients with BBS. Here we report a case of a patient with BBS who was started on setmelanotide for weight management following her BBS diagnosis. One month following treatment initiation, the patient not only endorsed reduced appetite, but also demonstrated a significant improvement in cognitive and affective functioning, as noted in her mental status exam and her performance on the Wechsler Adult Intelligence Scale Fourth Edition (WAIS-IV) tests, when compared to results prior to starting setmelanotide. Although previous studies have reported improved quality of life measures in patients with BBS following setmelanotide initiation, this is the first report of improved cognitive and affective functioning following initiation of the medication, highlighting the need to assess the effects of setmelanotide beyond the metabolic domain in patients with BBS.
A Case of Acromegaly With Parasellar Meningioma With Oculomotor Palsy Responding to and Maintained With Oral Octreotide Therapy.
AACE Endocrinol Diabetes
Muhammed Kizilgul, Ammar Ahmed, Lindsey Sloan +3 more
Meningiomas are the most frequently occurring primary central nervous system tumors. Recommended treatment options for large, growing, or symptomatic meningiomas typically involve surgical removal (when possible) and/or radiation therapy. There is no sufficient evidence of effective systemic therapies for recurrent meningioma.
Neurohumoral Dysregulation in Acute Myocardial Infarction With Chronic Kidney Disease: Implications for Prognosis and Management.
Cureus
Oksana Polianska, Victor Tashchuk, Olha Hulaha +3 more
Background Acute myocardial infarction (AMI) and chronic kidney disease (CKD) often coexist, and both are associated with neurohumoral imbalances that may worsen cardiovascular outcomes. Reduced kidney function can contribute to arterial stiffness and activation of the renin-angiotensin-aldosterone system (RAAS), which promotes vasoconstriction, sodium and water retention, myocardial remodeling, and fibrosis, mechanisms that exacerbate both cardiac and renal dysfunction. Endothelial injury is also common in these patients, and von Willebrand factor (vWF) serves as a recognized marker of endothelial dysfunction, contributing to thrombotic risk and microvascular impairment. Objective To explore the cross-sectional associations between renal function and the biomarkers aldosterone, angiotensin-converting enzyme (ACE), atrial natriuretic peptide (ANP), and vWF in patients with AMI and heart failure. Methods In this cross-sectional study, 106 patients hospitalized for AMI and heart failure were stratified by estimated glomerular filtration rate (GFR) into Group 1 (≤90 mL/min) and Group 2 (>90 mL/min). While CKD is conventionally defined as GFR <60 mL/min, the ≤90 mL/min cutoff was chosen to evaluate biomarker variation across a broader renal function range, including early decline. All eligible patients from the study period were included; no formal power calculation was performed. Neurohumoral markers were measured via enzyme-linked immunosorbent assay (ELISA). Heart failure was an inclusion criterion for all participants. Results Baseline characteristics were comparable between groups. Aldosterone and ACE were higher in patients with GFR ≤90 mL/min (p-values 0.01-0.05; below the prespecified α = 0.01). ANP and vWF did not differ between groups, which may reflect limited sensitivity to early renal function differences or other physiological influences. Conclusion The observed association between reduced GFR and elevated aldosterone and ACE suggests RAAS-related neurohumoral activation in AMI patients with heart failure. The lack of difference in ANP and vWF highlights potential marker-specific limitations. Targeting RAAS and other relevant pathways may offer therapeutic benefits for improving outcomes in this population; however, such approaches require confirmation in prospective interventional trials. These findings are exploratory and hypothesis-generating, underscoring the need for larger, longitudinal, and interventional studies to clarify the prognostic and therapeutic implications.
The emerging role of human transmembrane RGD-based counter-receptors of integrins in health and disease.
Cell Mol Biol Lett
Carlos Cabañas, Elisa Rossi, Ruben A Bartolomé +4 more
Most of the canonical Arg-Gly-Asp (RGD)-containing integrin ligands are extracellular matrix proteins, such as fibronectin, vitronectin and fibrinogen, which regulate cell-ECM adhesion processes. However, during the last years, several reports have demonstrated the existence of non-canonical RGD-containing integrin ligands that are cell surface transmembrane proteins. At variance with the canonical extracellular matrix integrin ligands, the RGD-containing cell surface integrin ligands are involved in cell-cell adhesion processes and function as "integrin counter-receptors". We propose in this review grouping these transmembrane proteins, which include endoglin, cadherin-5, cadherin-6, cadherin-17, ADAM15, and L1CAM, under the newly coined acronym RGD-ICRs (RGD-containing Integrin Counter-Receptors). We present and discuss the structure of RGD-ICRs, their RGD-based interactions with integrins, the specific signaling pathways triggered in different cell types, as well as their pathophysiological involvement. It can be postulated that RGD-ICRs constitute an emerging group of non-canonical RGD-based integrin counter-receptors. In spite of being encoded by different and independent genes and involved in different pathophysiological processes, all of them appear to have undergone a strong evolutionary convergence in order to acquire the same functional capacity to bind integrins via the RGD motif. Importantly, these RGD-ICRs are also emerging as novel biomarkers and therapeutic targets, with promising clinical potential in a wide array of pathologies.
Prolactin's diverse physiological roles and the clinical significance of hyperprolactinemia.
Ginekol Pol
Katarzyna Bocianska, Hubert Bochynski, Maksymilian Markwitz +1 more
This review aims to provide a comprehensive overview of prolactin biology, encompassing its molecular heterogeneity, neuroendocrine regulation, and multifaceted roles in human health and disease, focusing on hyperprolactinemia.
High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation.
Physiol Int
B Székács, S Várbíró, L Debreczeni
We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients.
Elamipretide in the Management of Barth Syndrome: Current Evidence and a Case Report.
Mol Genet Metab
Neil Jacob, Daniel Schecter, Molly Marshall +5 more
Barth syndrome is an exceedingly rare and potentially fatal X-linked mitochondrial disease arising from pathogenic variants in TAFAZZIN (TAZ), leading to defects in mature cardiolipin synthesis and its integration into the mitochondrial inner mitochondrial membrane. Clinical features that may be severe include cardiomyopathy, cyclic neutropenia, skeletal myopathy, and growth delay. Currently, no FDA-approved therapies exist. Elamipretide (ELAM) has been shown to stabilize cardiolipin and improve mitochondrial bioenergetics in pre-clinical and clinical studies in older individuals with Barth syndrome. Here we describe a case of prenatally identified Barth syndrome-related severe left ventricle (LV) non-compaction cardiomyopathy, where ELAM was initiated shortly after birth for clinical heart failure and was associated with significant and sustained clinical improvement leading to an inactive status on the heart transplant list with eventual anticipated delisting. We provide a review of the current literature including the pathophysiology of Barth syndrome, the mechanism of action of ELAM, and its clinical applications.
Electron Capture Dissociation for Discovery Top-Down Proteomics of Peptides and Small Proteins on Chromatographic Time Scales.
J Am Soc Mass Spectrom
Lester S Manly, Anne M Roberts, Joseph S Beckman +1 more
Bottom-up proteomics introduces proteoform ambiguity due to the loss of connectivity between peptides and their original proteoforms. Top-down proteomics (TDP) removes the ambiguity through the direct identification and characterization of intact proteoforms and their respective post-translational modifications (PTM). Electron capture dissociation (ECD) is an efficient and gentle peptide and protein fragmentation strategy that can be used for both bottom-up and top-down approaches. Here, we used an Agilent 6550 Q-TOF mass spectrometer retrofitted with an e-MSion ECD cell. Top-down sequencing capabilities of the cell were evaluated by sequencing of intact peptides and proteins on high-performance liquid chromatography (HPLC) time scales. Amyloid beta 1-40 (Aβ40) was first tested due to its pathophysiological role in Alzheimer's disease and served as our large peptide standard. We sequenced Aβ40 via reverse-phase HPLC-MS and achieved 95% sequence coverage on chromatographic time scales utilizing a data-dependent acquisition (DDA)-based method. Acetone-precipitated protein extracts from human brain were then separated by HPLC and analyzed with a DDA method, which identified 16 proteoforms between 2 and 17 kDa with sequence coverage ranging from 7 to 90% based on proteoform size and composition. In addition to proteoform identification, ECD fragmentation distinguished multiple isoaspartate modifications from aspartate, as well as accurately differentiating leucine from isoleucine residues directly from the human brain sample. Here, we observed isoaspartate within a thymosin beta-4 proteoform. Additionally, we demonstrated the differentiation of leucine and isoleucine within a subunit of ubiquitin. This study advances the application of LC-Q-TOF instrumentation for discovery-based top-down proteomics utilizing ECD as enabled by the e-MSion ECD cell.
Association between circulating biomarkers and atrial fibrillation burden in patients with paroxysmal atrial fibrillation: a subanalysis of the RACE V study.
Open Heart
Maria Hee Jung Park Frausing, Michiel Rienstra, Mads Brix Kronborg +7 more
Biochemical markers of inflammation, coagulation and myocardial stress have been associated with both prevalent and incident atrial fibrillation (AF), but little is known about the relationship between biomarker expression and AF burden.
Effectiveness and safety of thymopentin for infection prophylaxis in peritoneal dialysis patients: a retrospective study.
BMC Nephrol
Xueying Chen, Yilin Ruan, Jingyuan Xie +5 more
Patients undergoing peritoneal dialysis are at high risk of infection, which significantly impacts morbidity and mortality. This retrospective study aimed to evaluate the association of thymopentin use with infection risk, immune function, and inflammatory markers in peritoneal dialysis patients.
Efficacy and safety of anti-obesity drugs in metabolic dysfunction-associated steatotic liver disease: An updated review.
World J Gastroenterol
Marcio J Concepción-Zavaleta, Jenyfer M Fuentes-Mendoza, Jhean G Gonzáles-Yovera +7 more
Obesity is a major driver of metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). As the global prevalence of obesity continues to rise, the burden of MASLD/MASH is increasing, posing significant challenges to healthcare systems. The use of anti-obesity medications (AOMs) in this population is complex due to altered hepatic metabolism, safety concerns, and potential hepatotoxicity. Recent advances in pharmacologic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), dual GLP-1/glucose-gastric inhibitory polypeptide (GIP) agonists, and triple GLP-1/GIP/glucagon agonists, have shown promising metabolic effects in the general population. Among these, GLP-1 RAs (e.g., liraglutide and semaglutide) consistently demonstrate hepatic benefits, including reductions in hepatic steatosis, improvements in liver enzyme profiles, and attenuation of fibrosis progression. Tirzepatide, a dual GLP-1/GIP agonist, has shown superior weight loss effects compared to GLP-1 receptor agonist monotherapy, with emerging but still limited data on hepatic outcomes in MASLD/MASH. Retatrutide, a triple agonist, has produced the most pronounced metabolic effects to date, although its impact on liver histology remains underexplored. Other AOMs, such as bupropion-naltrexone and phentermine-topiramate, require cautious use due to potential hepatotoxicity. Importantly, advanced MASLD may alter drug pharmacokinetics, underscoring the need for individualized therapy and close monitoring. This review provides an updated synthesis of the efficacy and safety of current and emerging AOMs in patients with MASLD/MASH and highlights the urgent need for further research to define optimal pharmacological strategies in this high-risk population.
Nociceptor neurons suppress alveolar macrophage-induced Siglec-F+ neutrophil-mediated inflammation to protect against pulmonary fibrosis.
Immunity
Carlos H Hiroki, Mortaza F Hassanabad, Manon Defaye +22 more
Pulmonary fibrosis results from persistent and pathological tissue repair, which is therapeutically challenging to attenuate and often fatal. The immune processes involved in fibrosis remain ill defined. Using a bleomycin-induced lung fibrosis murine model, we discovered that vagal TRPV1+ nociceptors are protective. Pharmacological ablation or genetic deletion of nociceptors resulted in worsened fibrosis and outcomes. Without nociceptors, alveolar macrophages aberrantly produced vasoactive intestinal peptide (VIP), leading to cytokine TGF-β1-mediated alternative proinflammatory Siglec-F+ neutrophil recruitment to the lung with a high propensity for neutrophil extracellular trap (NET) formation. VIP inhibition or Vip deletion in hematopoietic cells improved outcomes and attenuated Siglec-F+ neutrophil recruitment to the lungs in nociceptor-deficient mice, while VIP administration had the opposite effect. Thus, nociceptors are essential regulators of inflammation during pulmonary fibrosis. These findings provide mechanistic insights into how the nervous system impacts the progression of fibrotic lung diseases.
Safety and Efficacy of Cerebrolysin for Neurorecovery After Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of 14 Randomized Controlled Trials.
Cureus
Parag N Patel, Devang Mangal, Krunal Patel
Cerebrolysin, a neurotrophic compound, has been investigated as a neurorestorative therapy in acute ischemic stroke, although findings are inconsistent due to limitations in study inclusion and outcome reporting. This systematic review and meta-analysis evaluated the efficacy and safety of Cerebrolysin in improving neurological and functional outcomes following acute ischemic stroke. Fourteen randomized controlled trials (N = 2,884 patients) comparing Cerebrolysin to placebo were included. The primary outcome was change in the National Institutes of Health Stroke Scale (NIHSS) score from baseline to follow-up, while secondary outcomes included functional independence (modified Rankin Scale (mRS) 0-2), serious adverse events (SAEs), mortality, and hemorrhagic transformation. Risk of bias was assessed using the revised Cochrane Risk of Bias (RoB 2.0) tool, and certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Pooled analysis showed that Cerebrolysin significantly improved neurological recovery (mean difference in NIHSS change: +1.39; 95% confidence interval (CI): 0.53-2.25; p = 0.020). Functional independence showed a non-significant trend in favor of Cerebrolysin (risk ratio (RR) = 1.31; 95% CI: 0.90-1.91; p > 0.05). No significant differences were observed in SAEs (RR = 1.08; 95% CI: 0.84-1.40), mortality (RR = 0.86; 95% CI: 0.68-1.09), or hemorrhagic transformation (RR = 0.55; 95% CI: 0.32-0.92). These findings suggest that Cerebrolysin significantly enhances early neurological recovery after ischemic stroke, with a comparable safety profile. Further high-quality trials are warranted to confirm its impact on long-term functional outcomes.
From tradition to evidence: exploring the neurochemical basis of medicinal plants in anxiety therapy.
World J Biol Psychiatry
Acharya Balkrishna, Upasana Agarwal, Deepika Arya +2 more
Anxiety disorders are associated with dysfunction in key neurotransmitter systems like, GABAergic, serotonergic, dopaminergic, noradrenergic, and endocannabinoid, alongside oxidative stress, neuroinflammation, and hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. Conventional pharmacotherapies offer symptomatic relief but often cause adverse effects and dependency. This review explores medicinal plants as alternative anxiolytic agents due to their multi-targeted mechanisms of action.