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Endothelin-1 in the failing Fontan: pathobiology, precision therapeutics, and future trial design.
Front Pediatr
Iman Maiza
The Fontan circulation, devised as definitive palliation for single-ventricle congenital heart disease, imposes systemic venous hypertension, loss of pulmonary arterial pulsatility, and restricted preload reserve. These hemodynamic trade-offs progressively injure the pulmonary vasculature, liver, and lymphatic system, producing late morbidities including elevated pulmonary vascular resistance, Fontan-associated liver disease (FALD), protein-losing enteropathy, and arrhythmias. Endothelin-1 (ET-1), a potent vasoconstrictor and profibrotic mediator, plausibly unifies these complications. Mechanistic studies demonstrate ET-1 upregulation in failed Fontan lungs, activating PLC-Ca2+, RhoA/ROCK, and MAPK/ERK cascades to drive vasoconstriction and remodeling. In cirrhotic livers, ET-1 localizes to stellate cells, promoting contraction and fibrogenesis, mechanisms biologically relevant to congestive FALD. Clinical cohorts consistently show elevated ET-1 correlating with hospitalization, exercise intolerance, and arrhythmias. Trials of endothelin-receptor antagonists (bosentan, ambrisentan, macitentan) demonstrate reassuring safety and suggest benefit when outcomes emphasize ventilatory efficiency or hepatic endpoints rather than peak oxygen consumption, which is physiologically constrained in Fontan physiology. Given the mixed results of existing trials, a framework is outlined that stratifies Fontan patients into pulmonary-inefficiency, congestive-hepatic, lymphatic, and arrhythmia-dominant phenotypes, using co-primary endpoints such as VE/VCO2 slope, elastography, and biomarker panels. By linking ET-1 biology to pragmatic trial design, this approach emphasizes targeted strategies that may stabilize the circulation, extend transplant candidacy, and improve long-term outcomes.
Longitudinal and cross-sectional associations of myocardial stress markers with kidney function and chronic kidney disease in the BiomarCaRE project.
Sci Rep
Jie-Sheng Lin, Tanja Zeller, Wolfgang Koenig +16 more
Given the complex relationship between cardiovascular disease (CVD) and chronic kidney disease (CKD), CVD-related markers may serve as CKD biomarkers. We examined associations of three major CVD-markers [mid-regional pro-adrenomedullin (MR-proADM), MR-pro-atrial natriuretic peptide (MR-proANP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)] with CKD. Cross-sectional analyses included up to 61,830 participants, and longitudinal analyses (NT-proBNP only) 4205 individuals. Kidney function was assessed by estimated glomerular filtration rate (eGFR) using creatinine, cystatin C, or both (eGFRcr-cys). Markers were categorized into four groups. Cross-sectional analyses found that higher levels of all three markers were consistently associated with lower eGFR and higher CKD prevalence. For example, per 1 standard deviation (SD) increase in log-transformed NT-proBNP, corresponding to a 2.71-fold increase in the original concentration, was associated with -2.35 (-2.49, -2.21) ml/min/1.73m2 lower eGFRcr-cys, and the highest NT-proBNP group had a 5.72-fold higher odds of CKDcr-cys (eGFRcr-cys < 60 ml/min/1.73m2) compared with the lowest. Associations with eGFR were stronger among participants with CVD and diabetes. In longitudinal analyses, participants with higher baseline NT-proBNP had faster declines in eGFR, with a 10-year decline of -1.37 (-1.77, -0.98) ml/min/1.73m2 eGFRcr-cys per 1 SD increase, and higher CKD incidence. These findings suggest MR-proADM, MR-proANP, and NT-proBNP as CKD biomarkers.
Neurogenic Inflammation and Immune Dysregulation in Psoriasis: Mechanistic Pathways and Emerging Interventions.
Am J Pathol
Hemraj Singh, Rajeev Taliyan
Psoriasis is a chronic, immune-mediated inflammatory disorder characterized by keratinocyte hyperproliferation and systemic immune dysregulation. The neuroimmune axis, linking sensory nerve activity, neuropeptide signaling, and immune responses, is central to disease pathogenesis. Structural remodeling of sensory nerves enhances the release of neuropeptides such as Substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and neuropeptide Y, which activate dendritic cells, promote T-cell proliferation, and stimulate keratinocyte cytokine production, sustaining a neurogenic inflammatory loop. Psychological stress exacerbates inflammation through hypothalamic-pituitary-adrenal (HPA) axis dysregulation, altering cortisol signaling and systemic immune responses. Intracellular pathways, including mitogen-activated protein kinase, PI3KAktmTOR, JAKSTAT, and NF-κB, along with epigenetic modifications, integrate neural and immune signals, contributing to disease chronicity and heterogeneity. Targeting neuroimmune interactions through neuropeptide antagonists, neuromodulation, stress management, and precision immunotherapies reduces cutaneous inflammation and addresses systemic comorbidities. This review synthesizes molecular, cellular, and clinical insights into the neuroimmune-HPA axis network in psoriasis, highlighting its therapeutic potential for personalized and multidisciplinary management.
Perinatal High-Fat Diet Induces Vascular Hypercontractility via DNA Hypomethylation of Endothelin Receptors and PKC-LTCC Axis Activation in Male Offspring.
Mol Nutr Food Res
Qiutong Zheng, Huamei Jian, Qinyuan He +4 more
Excessive fat intake is a well-established risk for hypertension; perinatal nutritional imbalances could increase vascular risks, but underlying mechanisms remain unclear. Endothelin-1 (ET-1), a potent vasoconstrictor, is implicated in cardiovascular diseases. This study aimed to address this gap by investigating ET-1 receptor-mediated pathways with high-fat-diet (HFD) during pregnancy and lactation. Vascular function, Ca2 + signaling, molecular expression, and DNA methylation were assessed in mesenteric arteries (MA) of offspring. HFD offspring exhibited increased fetal/adult weight, thickened MA wall, and enhanced ET-1-mediated vasoconstriction. Mechanistically, perinatal HFD upregulated ET-1 receptors (ETAR/ETBR) via hypomethylation of their gene promoters (Ednra/Ednrb), which augmented ET-1-induced Ca2 + currents, fluorescence Ca2 + transients, and vascular tone. Which relied on the PKC-LTCC axis (strengthened by PKC activator and LTCC agonist) and altered intracellular Ca2 + handling (via ryanodine receptors and sarcoplasmic/endoplasmic reticulum Ca2 +-ATPase), but were independent of IP3 receptors. ETAR/ETBR blockers attenuated the hypercontractility, confirming receptor-mediated effects. This is the first study to reveal that perinatal HFD persistently enhances vascular re-activity via DNA hypomethylation of ET receptors and PKC-LTCC axis. These findings not only reveal a mechanism linking perinatal HFD to adult vascular hypercontractility but also highlight ET receptors and DNA methylation as potential targets for early intervention of developmental origins of cardiovascular disease.
Pentapeptide-18 as an anti-aging candidate: Spectroscopic characterization and molecular interaction analysis.
Comput Biol Chem
Dilan Akhan, Bilge Bicak, Elif Akalin +1 more
Skin aging is predominantly associated with the progressive breakdown of the dermal extracellular matrix (ECM), leading to visible manifestations such as wrinkle development caused by repetitive facial muscle movements and a gradual reduction in collagen and elastin synthesis. This degeneration is intensified by external factors including ultraviolet exposure, tobacco use, and nutritional imbalance, which interfere with major intracellular signaling pathways-namely TGF-β, TNF-α, MAPK, PI3K/AKT, and NF-κB-that collectively regulate inflammatory responses, oxidative stress, and ECM remodeling. Pentapeptide-18 (Leuphasyl®), a bioactive peptide known for its neuromodulatory properties, has demonstrated the ability to mitigate wrinkle formation by inhibiting neurotransmitter release, while simultaneously improving skin hydration, elasticity, and texture. In this study, the anti-aging activity of Pentapeptide-18 was comprehensively examined through a combination of experimental analyses and computational modeling. Structural optimization and electronic property evaluation were performed using density functional theory (DFT) calculations with the 6-31 + +G(d,p) basis set, complemented by frontier molecular orbital (HOMO-LUMO) and molecular electrostatic potential (MEP) analyses. Theoretical vibrational frequencies were assigned via potential energy distribution (PED) analysis and validated experimentally using FTIR, ATR-FTIR, and Raman spectroscopy. Additionally, molecular docking and molecular dynamics simulations were employed to investigate the binding behavior of Pentapeptide-18 with key molecular targets implicated in skin aging, including TGF-β, TNF-α, MAPK, PI3K/AKT, and NF-κB. Pharmacokinetic and drug-likeness properties were further assessed through ADMET (absorption, distribution, metabolism, excretion, and toxicity). The collective findings provide mechanistic insight into the molecular interactions and stability of Pentapeptide-18, reinforcing its potential as a safe, effective, and non-invasive candidate for advanced anti-aging skin care applications.
Beyond the membrane: Internalization and compartmentalization of insulin‑like growth factor 1 receptor signaling in cancer pathogenesis and treatment (Review).
Int J Oncol
Tiehong Zhang, Ling Li, Chunling Du
The insulin‑like growth factor 1 receptor (IGF‑1R) plays a central role in tumor initiation, progression and response to treatment. IGF‑1R internalization and compartmentalization have profound effects on tumor biology, extending beyond classical signaling associated with receptors at the cell membrane. Following internalization, IGF‑1R alters its intracellular localization and induces new signaling functions. These changes affect the duration and spatial dynamics of signal activation, thereby influencing tumor cell proliferation, migration and the development of drug resistance. However, the exact molecular mechanisms that mediate these processes remain elusive, and the inherent complexity of the downstream signaling network continues to limit the clinical translation of IGF‑1R‑targeted therapies. The present review systematically summarizes the current knowledge on the molecular mechanisms of IGF‑1R internalization and compartmentalization, highlighting their roles in tumor progression and treatment response. The recent advancements and persistent challenges in this field are also critically discussed, aiming to provide a theoretical foundation and new insights for the development of more efficient and effective therapeutic plans that specifically target IGF‑1R.
The Effect of GLP-1 Receptor Agonists on Alanine Aminotransferase and Other Metabolic Parameters in Youths with Obesity: A Systematic Review and Meta-Analysis.
Child Obes
Lauren A Hertzer, Robert M Siegel, Roohi Y Kharofa +2 more
While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lower body mass index (BMI) in youths with obesity, less is known about their effect on metabolic parameters such as alanine aminotransferase (ALT), high-density lipoprotein, low-density lipoprotein, and hemoglobin A1c levels. We conducted a systematic review of the existing literature and a meta-analysis to determine the effect of GLP-1 RAs on metabolic parameters.
Congenital Erythropoietic Porphyria with Persistent Severe Biochemical Abnormalities and a Non-Mutilating Clinical Course: A Case Report.
Reports (MDPI)
Supriya Peshin, Ehab Takrori, Kaneez S Khan +4 more
Background and Clinical Significance: Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by a deficiency of uroporphyrinogen III synthase, leading to the accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. Case Presentation: We report a 32-year-old woman diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade, yet who followed a relatively non-mutilating clinical course. Genetic testing identified a low-penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without the need for transfusion therapy or stem cell transplantation. Conclusions: This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.
Impact of chronic oxytocin on gaze and pupil dynamics during live dyadic interactions in children with autism.
Psychoneuroendocrinology
Jellina Prinsen, Nicky Daniels, Matthijs Moerkerke +2 more
Reciprocal gaze, the mutual exchange of eye contact, plays a key role in human communication and bonding, yet it is often experienced as challenging for individuals with autism. In recent years, administration of the neuropeptide oxytocin is increasingly considered a novel approach for supporting social experiences in children with autism, but insights regarding its effects on mutual gaze or pupil dynamics remain limited-particularly regarding how chronic, repeated dosing impacts these processes. This double-blind, randomized, placebo-controlled trial examined the effects of four weeks of chronic intranasal oxytocin administration on gaze behavior and pupil dynamics during live dyadic interactions in school-aged children with autism (aged 8-12 years, 15 oxytocin, 20 placebo). While the overall duration of fixations toward the face remained unchanged, oxytocin altered the distribution of gaze, resulting in a more balanced pattern of looking toward and away from the face of a live interaction partner, an effect observed only in the oxytocin group and not in the placebo group. In addition, the four-week oxytocin administration period induced a relative increase in pupil dilation, an index of sympathetic arousal and attentional engagement, with this heightened autonomic responsivity showing a moderate association with children's self-reported feelings of secure attachment. Together, these findings indicate that repeated oxytocin administration may modulate gaze parameters in live social interactions in children with autism. While cautiously encouraging, future work will be needed to further delineate whether these changes meaningfully reflect ameliorated experience and comfort in social settings.
Neuroendocrine plasticity and crosstalk in pubertal development.
J Neuroendocrinol
Carol Fuzeti Elias, Xingfa Han, David Garcia-Galiano +1 more
Puberty is a critical developmental stage during which individuals acquire the capacity for sexual reproduction. This transition involves a series of complex biological events primarily orchestrated by the activation of the hypothalamo-pituitary-gonadal (HPG) axis. Central to this process are gonadotropin-releasing hormone (GnRH) neurons, which play a key role in regulating reproductive maturation and function throughout life. However, the precise mechanisms that trigger the pubertal increase in GnRH activity remain incompletely understood. Evidence from our laboratory indicates that a profound remodeling of the hypothalamus is crucial for sexual maturation. In this review, we discuss findings from our research utilizing a combination of RNA sequencing, conditional genetic manipulation with mouse models and viral vectors, and systems neuroscience approaches. Our results reveal that the pubertal transition involves changes in the chemical phenotype and site-specific innervation of key hypothalamic neurons. Among these neuronal populations, those expressing growth hormone-releasing hormone (GHRH), kisspeptin, or dopamine transporter (DAT) are the focus of this review. Building upon data from other laboratories, our findings offer new insights into the neural and molecular mechanisms by which the hypothalamus orchestrates sexual maturation.
Discovery and classification of new reptile cathelicidins by genome mining: study of their structure and genomic organization in Testudines and Squamata.
Dev Comp Immunol
Andrea Otazo-Pérez, Manuel R López, Sergio González-Acosta +2 more
Cathelicidins, a diverse family of host defence peptides (HDPs) in vertebrates, are recognized for their potential in combating resistant microorganisms and their varied biological functions. While extensive studies have focused on mammalian cathelicidins, those in reptiles remain largely unexplored. In this study, we conducted a genome mining analysis that identified 287 cathelicidin genes across reptilian orders Testudines and Squamata. Of these genes, we identified 219 complete cathelicidin protein sequences and 68 cathelicidin-like gene copies that appear to be pseudogenes or gene fragments lacking intact open reading frames. We established for the first time a classification for reptile cathelicidins of the cited orders based on their sequence and structure, observing six types for Testudines and six for Squamata, suggesting a common ancestral lineage. Furthermore, we investigated the genomic arrangement of these cathelicidin genes, uncovering that they are grouped into clusters with variability in the gene number and in their organization. Cathelicidin derived mature peptides were classified into nine groups based on their sequences and physicochemical properties. This comprehensive study enhances the understanding of the cathelicidin family in reptiles, clarifying their genomic organization and describing the different types present. These classifications pave the way for future studies on the functions and specialization of each identified cathelicidin group. Moreover, they enable potential structure-activity studies of the peptides, establishing a foundation for differentiating their key features.
Incretin-Based Dual and Triple Agonists in Overweight or Obese Individuals: A Systematic Review and Meta-Analysis.
Cardiol Rev
Zhi Hong Chan, Abdousamad Said Omar, Kieran Gill +11 more
Incretin-based dual and triple agonists have emerged as effective options for obesity management, offering enhanced weight loss through multi-receptor agonism. However, data on their efficacy and safety remain limited. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of these emerging agents. A comprehensive literature search was conducted using PubMed, the Cochrane Library, and Google Scholar from inception to June 2025 to identify randomized controlled trials evaluating tirzepatide, retatrutide, or mazdutide in obese adults. Clinical outcomes were assessed using the random-effects model and pooled as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). A total of 10 randomized controlled trials, including 3236 participants, were analyzed. Incretin polyagonists significantly reduced body weight compared to placebo (MD -11.47; 95% CI: -14.00 to -8.95). Significant reductions were also observed in waist circumference (MD -9.40; 95% CI: -11.91 to -6.89), glycated hemoglobin (MD -0.96; 95% CI: -1.16 to -0.75), and fasting plasma glucose (MD -26.89 mg/dL; 95% CI: -33.48 to -20.30). However, the use of dual and triple agonists was associated with a higher risk of any adverse events (AEs) (RR 1.13; 95% CI: 1.08-1.19), including gastrointestinal AEs (nausea, vomiting, diarrhea, constipation), AEs leading to withdrawal (RR 1.96; 95% CI: 1.17-3.30), and hypoglycemic episodes (RR 3.08; 95% CI: 1.61-5.89). No significant difference was found in serious AEs (RR 0.87; 95% CI: 0.65-1.14). In conclusion, incretin-based polyagonists were associated with significant weight reduction and improved metabolic outcomes compared to placebo.
Carbamazepine disrupts the hypothalamic-pituitary-testicular axis and induces hormonal imbalances and sperm damage through activating GABBR2 to inhibit AC/cAMP/PKA pathway.
Biochem Pharmacol
Jingya Li, Ziao Liu, Min Pan +5 more
Carbamazepine (CBZ), a widely prescribed antiepileptic drug, is known to cause male reproductive toxicity, yet the underlying biological pathways remain poorly characterized. This study comprehensively investigated the impact of CBZ on the hypothalamic-pituitary-testicular (HPT) axis using integrated in vivo and in vitro models to decipher the precise molecular mechanisms involved. Rats subjected to long-term exposure (12 weeks) to CBZ at doses of 100, 200, and 400 mg/kg showed structural damage in the hypothalamus, pituitary, and testes. Concurrently, serum levels of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone were reduced, indicating impairment of the HPT axis function. In-depth mechanistic studies demonstrated that CBZ suppressed the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway by upregulating the expression of gamma-aminobutyric acid type B receptor subunit 2 (GABBR2) protein, thereby triggering apoptosis of hypothalamic GnRH neurons. When GABBR2 was knocked down in GT1-7 cells (an immortalized mouse hypothalamic GnRH neuronal cell line), the AC/cAMP/PKA inhibition induced by CBZ was significantly attenuated, apoptosis was reduced, and GnRH secretion was partially restored. These findings indicate that activation of GABBR2, by repressing the AC/cAMP/PKA pathway, plays a pivotal role in CBZ-induced apoptosis of hypothalamic neurons, reduction of GnRH levels, and disruption of the HPT axis. This provides a new perspective for understanding CBZ-induced male reproductive toxicity.
Therapeutic Effects of MOTS-c in the Valproic Acid-Induced Autism Model in Rats: Role of Tetrahydrobiopterin and Brain-Derived Neurotrophic Factor.
Mol Neurobiol
Sıla Güvenir Seven, Hakan Sahin, Gözde Erkanlı Şentürk +5 more
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and repetitive behaviors, with currently limited therapeutic options. Oxidative stress is suggested as significant in ASD pathophysiology, making antioxidant strategies a promising therapeutic direction. Exercise reduces oxidative stress, alleviates ASD symptoms, and increases tetrahydrobiopterin (BH4) and brain-derived neurotrophic factor (BDNF) levels through AMP-activated protein kinase (AMPK) activation. MOTS-c, a mitochondrial-derived peptide acting through AMPK, mimics the effects of exercise but reportedly does not cross the blood-brain barrier (BBB). Considering the challenges in exercise adherence in ASD, our study hypothesizes that MOTS-c could increase circulating BH4 and BDNF, both of which are BBB-permeable, and alleviate oxidative stress and ASD symptoms. To evaluate this hypothesis, we investigated the effects of MOTS-c in the valproic acid-induced rat model of autism. Pregnant Sprague-Dawley rats received intraperitoneal 500 mg/kg valproic acid or saline on embryonic day 12. Female and male offspring were treated with 0.5 mg/kg/day MOTS-c or saline intraperitoneally from postnatal days 21 to 46. Following behavioral testing, animals were sacrificed, and histological and biochemical analyses were performed. Valproic acid exposure led to impaired sociability, repetitive behaviors, anxiety, cerebellar Purkinje cell loss, and increased oxidative stress and neuronal damage in the prefrontal cortex. These alterations were reversed by MOTS-c, except for anxiety and neocortical damage. No significant changes in plasma BH4 or BDNF levels were detected. Through its neuroprotective and antioxidant effects independent of BH4 and BDNF, MOTS-c may alleviate autism-like behaviors, suggesting its potential as a therapeutic candidate for ASD.
Mechanism of Scoparone Against Knee Osteoarthritis: A Study Integrating Network Pharmacology, Animal Experiments, and Molecular Docking.
J Orthop Res
Linshuai Shi, Lei Zhao, Xinqi Li +2 more
Knee osteoarthritis (KOA) is a degenerative joint disease commonly seen in middle-aged and elderly individuals. With the increasing aging population, the incidence of KOA has been rising annually, yet there remains no definitive cure. Studies have shown that scoparone exhibits potent anti-inflammatory effects in treating inflammatory diseases, but its specific mechanism in KOA remains unclear. Network pharmacology was employed to systematically predict the putative therapeutic targets and signaling pathways of scoparone against KOA. The resulting candidate genes and pathways were subsequently examined by molecular docking and then experimentally verified in a well-established KOA mouse model. ELISA, HE staining, immunohistochemical staining, and western blot were used to detect the expression of related factors. Network pharmacology analysis initially identified 15 intersecting target genes of scoparone in the treatment of KOA. These target genes were primarily enriched in 46 signaling pathways, with the most significant involvement in focal adhesion, Ras-related protein 1 (RAP1) signaling pathway, high-affinity IgE Fc receptor (FcεRI) signaling pathway. Molecular docking results revealed that prostaglandin-endoperoxide synthase 2 (PTGS2), insulin-like growth factor 1 receptor (IGF1R), and cathepsin K (CTSK) exhibited the highest binding affinity with scoparone. Animal experiments demonstrated that scoparone reversed the abnormal expression of PTGS2, IGF1R, and CTSK in the knee cartilage of KOA mice. Additionally, scoparone suppressed inflammation and extracellular matrix degradation in KOA mice by modulating the RAP1 signaling pathway and the FcεRI/spleen tyrosine kinase (Syk) signaling pathway. These findings provide a critical theoretical foundation for further research and development of scoparone in the treatment of KOA.
Styrylquinoline Derivatives as IGF1R Inhibitors.
ACS Med Chem Lett
Patryk Zioła, Katarzyna Malarz, Marcin Pacholczyk +4 more
Styrylquinoline analogues exhibiting antiproliferative activity against glioblastoma multiforme were tested for tyrosine kinase inhibition. A preliminary structure activity relationship analysis based on previous results showed that the styrylquinoline fragment is a promising privileged structure. The addition of appropriate pharmacophores to both the quinoline structure and the benzene ring, which was attached to the 2-position, significantly altered the antiproliferative properties. Namely, OH or NO2 substituents had a positive effect on activity, while F and OAc molecular fragments had a negative impact. Screening conducted on a panel of receptor tyrosine kinases revealed the high potential of the tested compounds for use as insulin-like growth factor 1 receptor inhibitors. Molecular docking performed on the insulin-like growth factor 1 receptor unphosphorylated inactive conformation supports screening results suggesting high binding affinity of the active styrylquinoline derivatives.
Cathelicidin CATH-2 suppresses the NF-κB/ROS/NLRP3 signaling pathway via regulating mTOR-dependent autophagy during Streptococcus suis infection.
Vet Res
Liuyi Xu, Yilin Lu, Shichao Xu +10 more
Cathelicidin CATH-2 has been reported to exert potent anti-inflammatory activity in different species though neutralizing stimuli such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA). CATH-2 has been shown to inhibit Streptococcus suis (S. suis)-induced activation of dendritic cells and macrophages by binding to LTA. However, the exact mechanism of this prophylactically anti-inflammatory activity remains unclear. Therefore, we investigated the anti-inflammatory activity and mechanism of CATH-2 in mice peritoneal macrophages pretreated with CATH-2 followed by S. suis infection. The results showed that CATH-2 pretreatment significantly reduced S. suis-induced transcription and secretion of interleukin (IL)-1β, IL-6, and IL-12. CATH-2 also downregulated NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) expression and apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, and inhibited the maturation of IL-1β, suggesting that CATH-2 inhibits NLRP3 activation. In addition, CATH-2 significantly inhibited S. suis-induced phosphorylation of p65 and extracellular signal-regulated kinase (ERK). Further study showed that CATH-2 inhibited S. suis-induced reactive oxygen species (ROS) by upregulating the expression of ROS scavenging genes including catalase (CAT) and superoxide dismutase 1 (SOD1). Mechanistically, transcriptome analysis revealed that CATH-2 regulated the protein kinase B (ATK)/mammalian target of rapamycin (mTOR) pathway, which was evident by the downregulation of phosphorylated (p)-ATK and p-mTOR induced by CATH-2. Notably, CATH-2 induced autophagy and autophagic flux. Inhibition of mTOR using rapamycin enhanced the CATH-2-induced autophagic efficacy, demonstrating that CATH-2 induces mTOR-dependent autophagy. However, inhibition of autophagy using 3-methyladenine (3-MA) reversed the reduction in the expression of p-p65, p-ERK, and IL-1β induced by CATH-2. Our study reveals that CATH-2 inhibits the nuclear factor kappa-B (NF-κB)/NLRP3-mediated inflammatory response through the induction of mTOR-dependent autophagy during S. suis infection, which provides new insight into the anti-inflammatory pathways of antimicrobial peptides.
The Counter-Regulatory Renin-Angiotensin System: A Surprising Ally in the Field of COVID-19.
Infect Disord Drug Targets
Mariali Palacios-Cruz, Jairo Castellar-Lopez, Juan Manuel Pretelt +2 more
Over the past four years, SARS-CoV-2 and COVID-19 have become global health crises, spurring extensive research on virus behavior, complications, and treatments. The virus interacts with a component of the renin-angiotensin system (RAS), altering inflammatory, hypertrophic, and hemodynamic responses via binding to ACE2 found in organs like the heart, lungs, and kidneys.
Nonmetastatic Pulmonary Carcinoid Presenting With Carcinoid Syndrome Despite Negative 5-HIAA: A Case Report.
Case Rep Endocrinol
Aditya Chauhan, Muhammed Kizilgul, Emilian Racila +1 more
Carcinoid syndrome from pulmonary carcinoids without hepatic metastases is rare and diagnostically challenging when biochemical markers are normal.
Emerging neurobiological targets in psychiatric treatment.
Eur Neuropsychopharmacol
Agampodi Ishan De Zoysa, Janani Govinnage, Frank Giorlando +3 more
Despite significant advancements in psychopharmacology, there are inadequate treatment options for many psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia, and anxiety disorders. This review explores emerging neurobiological targets beyond conventional monoaminergic approaches, focusing on sodium channels, Neuropeptide Y (NPY), Neurokinin 1 (NK1) receptors, P2 × 7 purinergic receptors, Sigma-1 receptors, and Orexin. Recent evidence suggests that sodium channel modulators, such as evenamide, may offer therapeutic benefits for treatment-resistant schizophrenia by stabilizing glutamatergic neurotransmission. NPY-based therapies have potential in stress-related disorders, foreshadowing rapid anxiolytic and antidepressant effects through modulation of the stress response. NK1 receptor antagonists, although inconsistent in mood disorders, show promise in addiction treatment by reducing substance cravings. The P2 × 7 receptor, a key regulator of neuroinflammation, has been implicated in mood disorders, and its pharmacological inhibition may provide neuroprotective benefits. Additionally, Sigma-1 receptor agonists, including Blarcamesine and Pridopidine, have shown neuroprotective and cognitive-enhancing properties, making them attractive candidates for psychiatric and neurodegenerative disorders. Orexin receptor antagonists, such as suvorexant and seltorexant, have potential in mood disorders and substance dependence, highlighting the broader therapeutic applications of targeting the orexinergic system. While these emerging therapeutic targets hold promise, challenges remain in translating preclinical findings into effective clinical applications. Large-scale, placebo-controlled trials are necessary to establish their efficacy and safety. The identification of biomarkers for patient stratification will be critical in the hitherto elusive goal of developing precision medicine approaches. Targeted pharmacological interventions offer a path toward more effective, well-tolerated, and potentially individualized treatment options for patients with severe mental illness.