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High-fat diet-induced obesity enhances stress vulnerability and promotes a PTSD-like phenotype in rats.
Prog Neuropsychopharmacol Biol Psychiatry
Carmit Cohen, Joseph Zohar, Doron Todder +1 more
The association between post-traumatic stress disorder (PTSD) and subsequent obesity is well-established in humans, however, whether obesity exacerbates vulnerability to PTSD remains underexplored. To investigate this, we employed a rat model fed either a high-fat diet (HFD; 60 % kcal from fat) or a control diet (CD). After confirming significant body mass index differences between HFD and CD groups, rats were exposed to predator scent stress (PSS) or a sham-PSS control. Behavioral phenotyping was conducted using the elevated plus maze (EPM) and acoustic startle response (ASR) to classify stress response profiles, supplemented by the forced swim test to assess depressive-like behavior and the Morris water maze to evaluate spatial learning and memory. Neural cytoarchitecture and molecular mechanisms were examined via Golgi-Cox staining and immunohistochemistry, targeting shared modulators of the orexigenic and anxiolytic systems in the hippocampus and hypothalamus. Our findings reveal that HFD-induced obesity promotes a PTSD-like phenotype, exacerbates depressive-like behavior, and impairs spatial learning and memory acquisition. Morphological alterations in the hippocampus and amygdala of HFD-fed rats resembled those in PSS-exposed CD-fed rats, regardless of stress exposure, suggesting common neurostructural changes. Furthermore, HFD-induced obesity modulated region-specific expression of neuropeptide Y (NPY), NPY-Y1 receptor, and glucocorticoid receptor immunoreactivity in hippocampal and hypothalamic nuclei. These results underscore a bidirectional interplay between diet-induced obesity and stress-related disorders, highlighting the critical role of the orexigenic and anxiolytic systems and their neurobiological underpinnings in mediating these effects.
Activity Changes of the Hypothalamus-Pituitary Hormonal Axis in Peripubertal Female Rats.
Dev Reprod
Eun-Young Jeon, Sung-Ho Lee
Little is known about the regulation of gene expression related to the hypothalamus-pituitary (HP) axis around the onset of normal puberty. In the present study, we examined the expression profiles of genes in HP hormone circuit on every other day from postnatal day (PND) 29 to PND 43. Average vaginal opening (VO) date was PND 37 (66%), and the weight of reproductive organs increased significantly from PND 37. Serum steroid hormone levels significantly increased on PND 39. The appearance of a number of Graafian follicles and corpora lutea on PND 37. Generally, our polymerase chain reactions (PCR) results showed that most of the expression of hypothalamus and pituitary factors tended to increase after VO, and the patterns were rather unstable and no significant peak pattern such as LH surge shown in proestrus adults. The mRNA levels of gonadotropin-inhibitory hormone (GnIH)-GPR147 and neurokinin B(Tac)-TacR3 mostly reached a peak in the last period of the experimental schedule. In pituitary, mRNA level of gonadotropin subunits (Cgα, LH-β and FSH-β) also significantly increased on later experimental period. In conclusion, we could confirm the rapid growth and maturation of reproductive organs immediately after VO, and dynamic changes in gene expression of the HP axis factors. The gene expression patterns at peripubertal period were incomplete and unstable without showing the preovulatory LH surge-related gene expression pattern in adults. The present study on neuroendocrine control of peripubertal sexual maturation may offer a basis for understanding normo- and/or patho-physiological status of puberty.
Epithelial Heparan Sulfate Promotes Staphylococcus aureus Corneal Infection by Inhibiting Cathelicidins.
Proteoglycan Res
Kazutaka Hayashida, Jeffrey D Esko, Richard D Gallo +3 more
Cathelicidins are short cationic peptides with potent microbicidal activities and comprise an important arm of host innate immunity. Many cell types can produce cathelicidins, but they are mainly expressed by recruited immune cells and are induced in epithelial cells during infection. Although the mechanisms of bacterial killing by cathelicidins have been largely elucidated in vitro, those that regulate their activities in vivo are less well understood. Bacterial pathogens often co-opt host extracellular matrix (ECM) components and their functions to escape host defense; however, it is unclear whether such mechanisms exist against cathelicidins. Several studies have demonstrated that host heparan sulfate (HS) inhibits LL-37, the human cathelicidin, suggesting that bacteria might exploit HS to evade killing by cathelicidins. However, precisely how HS inhibits LL-37 and possibly other cathelicidins remains unknown, and the role of the HS-cathelicidin interaction in infectious disease has not been rigorously studied. Here, we found that deleting CRAMP, the murine cathelicidin, significantly increases the susceptibility of mice to Staphylococcus aureus corneal infection. We also determined that heparan compounds bind to CRAMP with low nanomolar affinity, the secondary structure of CRAMP is required for HS binding, and HS binding to CRAMP inhibits CRAMP binding to target bacterial cells. Furthermore, we found that heparan compounds inhibit the killing of S. aureus by cathelicidins derived from several mammalian species in a 2-O-sulfate-dependent manner. Additionally, we demonstrate for the first time that conditional deletion of HS2ST, the enzyme responsible for 2-O-sulfation of HS, in corneal epithelial cells significantly reduces the susceptibility of mice to corneal infection. Altogether, these data uncover an endogenous inhibition mechanism of cathelicidins where 2-O-sulfated epithelial HS tightly binds and neutralizes the antibacterial activity of cathelicidins.
Increased cathelicidin LL-37 colonic expression is associated with tumor progression in colorectal cancer.
J Physiol Pharmacol
J Wlodarczyk, L Dziki, J Fichna
Colorectal cancer (CRC) remains a major global health challenge, with increasing incidence and limited treatment options. The antimicrobial peptide cathelicidin (LL-37) has been implicated in both tumorigenic and tumor-suppressive roles, but its precise function in CRC progression remains unclear. This study investigates the LL-37 expression in CRC and its association with key molecular pathways, including vitamin D signaling and G protein-coupled receptors (GPCRs). We analyzed LL-37 mRNA expression in 25 CRC tissue samples and matched healthy colonic mucosa using quantitative real-time PCR. Additionally, we assessed the expression of potential LL-37 target receptors, including formyl peptide receptor 2 (FPR2), toll-like receptors (TLR3, TLR4), CXC chemokine receptor 2 (CXCR2), and mas-related gene X2 (MrgX2). The correlation between LL-37 expression and clinicopathological factors, including tumor stage and nodal metastases, was also evaluated. LL-37 expression was significantly upregulated in CRC tissues compared to normal mucosa (p<0.001), with higher expression in advanced-stage CRC (AJCC stage III) and tumors with nodal metastases (p=0.006). Molecular analysis revealed significantly increased FPR2 expression and reduced TLR3 expression in CRC tissue, suggesting their involvement in tumor progression. Our findings suggest a role for LL-37 in CRC progression, potentially mediated through FPR2 activation and TLR3 suppression. The observed discrepancies in LL-37 function across studies highlight its complex, context-dependent role in tumor biology. Further research is needed to elucidate the mechanistic basis of LL-37 signaling and its potential as a therapeutic target in CRC.
Dual role of ACE2 in regulating inflammation triggered by Omicron S1 and other SARS-CoV-2 Spike variants.
Front Immunol
Annamaria Pedoto, Juan M Lozano-Gil, María Ocaña-Esparza +5 more
Since the emergence of SARS-CoV-2 in late 2019, substantial efforts have been made to understand its mechanisms of pathogenicity. Although angiotensin-converting enzyme 2 (ACE2) has been identified as the main receptor for viral entry, the complexity of the host immune response to different Spike protein conformations and variants remains poorly understood. Using zebrafish larvae as an in vivo model, we show that the monomeric S1 domain of the Omicron variant triggers a potent proinflammatory response characterized by elevated Nfkb activity and increased expression of key cytokines, despite reduced recruitment and expansion of neutrophils and macrophages. Notably, monomeric S1 Omicron also promotes neutrophil cell death, suggesting an alternative mechanism of immune modulation. In contrast, the trimeric form of the Spike protein fails to induce significant inflammation or emergency hematopoiesis, likely due to its efficient neutralization by endogenous Ace2. Our results revealed that both zebrafish and human ACE2 exert a dual anti-inflammatory role: indirectly through the production of angiotensin-(1-7), and directly by binding and neutralizing the trimeric Spike. These results provide new insights into variant-specific immune responses and the multifaceted role of ACE2 in modulating SARS-CoV-2-induced cytokine storm syndrome.
One-Stop Transcatheter Pulmonary and Tricuspid Valve Replacement for Carcinoid Heart Disease Treatment.
JACC Case Rep
Nicolas Veas, Fernando J Verdugo, Jaime Álvarez +5 more
Carcinoid heart disease is a complex consequence of functional neuroendocrine tumors, characterized by progressive thickening and degeneration of the right-sided valvular apparatus, leading to valvular and heart failure. Management is challenging, requiring multidisciplinary considerations regarding tumor disease management, heart failure pharmacotherapy, and heart valve replacement in individuals with acceptable performance status.
Phascolarctobacterium faecium reduces food intake via PYY signaling, contributing to the mitigation of body weight gain in diet-induced obese mice.
Gut Microbes
Clara Bullich-Vilarrubias, Marina Romaní-Pérez, Inmaculada López-Almela +6 more
Excess energy intake contributes to adiposity in obesity. We investigated whether the human intestinal bacterium Phascolarctobacterium faecium could prevent obesity via enteroendocrine pathways in a mouse model of diet-induced obesity (DIO). Daily administration of P. faecium (2 × 109 cells/mouse) reduced food intake through the early overproduction of the satiety hormone peptide YY (PYY) compared to untreated DIO mice. Moreover, P. faecium increased the intestinal levels of branched-chain amino acids, which, in turn, stimulated PYY secretion in neuroendocrine cell cultures and also modified gut microbiota composition. A pair-feeding study demonstrated that the anorexigenic effect of P. faecium contributes to its effects in attenuating body weight gain in DIO mice, but that other mechanisms are also involved in its metabolic benefits. Specifically, P. faecium accelerated gut transit and serum lipid clearance, thereby limiting adiposity independently of food intake. This study identifies the mode of action of a human intestinal bacterium recently linked to obesity protection, providing valuable insights into host-microbe interactions governing body weight.
Macitentan and phosphodiesterase-5 inhibitor alone or in combination in newly diagnosed pulmonary arterial hypertension: a pooled analysis.
JHLT Open
Vallerie V McLaughlin, Nicolas Sauvageot, Brian Hennessy +8 more
Upfront combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5i) is guideline-recommended for low- or intermediate-risk pulmonary arterial hypertension (PAH). This study compared time to all-cause mortality for macitentan+PDE5i combination and each monotherapy.
Role of PDGF-BB in Oral Squamous Cell Carcinoma through PI3/AKT/mTOR Pathway: An Integrated Computational and Real-Time PCR-Based Approach.
Asian Pac J Cancer Prev
Georgia Benitha J, Pratibha Ramani, Selvaraj Jayaraman +2 more
This study investigates the role of PDGF-BB in oral squamous cell carcinoma (OSCC) and its impact on the PI3K/AKT/mTOR pathway. The goal is to elucidate the expression levels analysis of PDGF-BB and signaling molecules in OSCC pathogenesis, potentially identifying novel biomarkers or therapeutic targets.
Multimodal Toxicity of Acrolein and Associated Therapeutic Strategies in Central Nervous System Trauma and Disease.
Annu Rev Biomed Eng
Nicholas S Race, Koji Uchida, Philip C Burcham +1 more
Acrolein is a highly reactive α,β-unsaturated aldehyde produced endogenously through lipid peroxidation and enzymatic metabolism and exogenously via environmental exposures. Acrolein covalently adducts to DNA and proteins, leading to oxidative stress, mitochondrial dysfunction, and inflammation, including innate immune response activation via natural antibodies. Acrolein is difficult to measure in biological systems, but acrolein-bound covalent products can be measured reliably. Therapeutically, nucleophilic small molecules that scavenge acrolein such as hydralazine, phenelzine, dimercaprol, carnosine, and N-acetylcysteine (NAC) have shown neuroprotective effects in animal models of multiple sclerosis, Parkinson's disease, spinal cord injury, and traumatic brain injury. These effects include preserved membrane and mitochondrial integrity, reduced inflammation, reduced pain, and improved motor, sensory, and cognitive outcomes. Alternative strategies that enhance clearance or inhibit production of acrolein show promise but face limitations. Acrolein is a key pathophysiological mediator and a viable therapeutic target in central nervous system trauma and neurodegenerative diseases.
Dietary medium chain triglycerides impairs orexigenic action of ghrelin in mice.
Front Endocrinol (Lausanne)
Daisuke Aotani, Hiroyuki Ariyasu, Tomohiro Tanaka +10 more
Ghrelin, a stomach-derived hormone, increases food intake and body weight. Efforts have been made therefore to modulate ghrelin signaling for the treatment of obesity or emaciation. However, basic biology of the potential effects of dietary nutrients on ghrelin action has not yet been fully uncovered.
Plasma Biomarkers Associated With Heart Failure Hospitalization Among Patients With Atrial Fibrillation and Subtypes of Heart Failure.
J Am Heart Assoc
Tymon Pol, Johan Lindbäck, Jonas Oldgren +4 more
Atrial fibrillation is associated with heart failure (HF) through a complex cause-and-effect relationship. We performed multiplex screening of plasma proteins in patients with atrial fibrillation to identify biomarkers and pathways associated with hospitalization for HF. Additionally, we aimed to identify potential pathophysiological differences between HF with reduced ejection fraction and HF with preserved ejection fraction at baseline in patients with atrial fibrillation.
Safety and efficacy of upfront triple therapy including parenteral treprostinil compared to double oral therapy in PAH (TripleTRE): study protocol for a randomised trial.
ERJ Open Res
Olivier Sitbon, Gergely Agoston, Roberto Badagliacca +16 more
Pulmonary arterial hypertension (PAH) requires a complex and multidisciplinary care approach with regular follow-up visits to monitor disease progression and adaptation of treatment regimens. Current ESC/ERS Guidelines recommend initial double oral treatment (endothelin-receptor antagonist + phosphodiesterase type 5 inhibitor) in patients presenting at diagnosis with intermediate risk according to the three-strata risk score. Retrospective data analyses indicate a clinical benefit for upfront triple combination therapy including parenteral prostacyclins (PCA) in intermediate and high-risk patients. The multicentric TripleTRE trial aims to investigate the effect of initial triple combination therapy including parenteral PCA on risk status, compared to double oral in a prospective setting in patients at intermediate-high risk at diagnosis according to the four-strata risk score.
Clinical efficacy and effects on hypothalamic-pituitary-adrenal axis function of proscar combined with selective serotonin reuptake inhibitor in post-stroke depression.
World J Psychiatry
Ming-Yang Xu, Yi Lu, Guo-Mei Shi +3 more
Post-stroke depression (PSD) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction and neurotransmitter deficits. Selective serotonin reuptake inhibitors (SSRIs) are commonly used, but their efficacy is limited. This study investigated whether combining SSRIs with traditional Chinese medicine (TCM) Free San could enhance their therapeutic effects.
Dynamic Slide-Ring Hydrogels with Dityrosine-Driven pH-Responsive Fluorescence: Enabling 3D Printing, Enhanced Drug Delivery and Regenerative Therapy.
Adv Healthc Mater
Yong Li, Maoya Xu, Hongkui Li +6 more
The development of intelligent hydrogels with multifunctional capabilities holds great promise for advancing medical applications. In this work, we developed a dynamic slide-ring supramolecular hydrogel with dual molecular innovations: a dityrosine (DY)-driven pH-responsive fluorescence core in four-arm PEG (4A-PD) and Arginine-Glycine-Aspartic acid peptide (RGD) peptide-functionalized hyperbranched polyglycerol (HPG)-modified α-cyclodextrin (CHR) for enhanced cell adhesion and drug loading. The host-guest interactions between 4A-PD and CHR form a network with shear-thinning, rapid self-healing, and UV-triggered covalent stabilization, enabling room-temperature extrusion-based 3D printing. The printed constructs exhibit high shape fidelity and porous architectures that promote RGD-mediated cell adhesion and proliferation. The DY core imparts the hydrogel with pH-dependent blue fluorescence (emission peak: 400 nm), allowing real-time microenvironmental monitoring. HPG modification of α-CD significantly enhances the drug-loading capacity, demonstrated by the sustained release of tobramycin (TOB) for effective infection control. In a full-thickness infected rat wound model, the TOB-loaded hydrogel accelerates wound closure (97.67% ± 0.56% by day 14), promotes collagen deposition, and modulates inflammation (reduced IL-6, increased IL-10), while enhancing angiogenesis. This multifunctional hydrogel integrates 3D printing, drug delivery, and responsive sensing, offering a versatile platform for regenerative medicine.
Advances in Incretin-Based Therapies for MAFLD: Mechanisms and Clinical Evidence.
Clin Pharmacol Ther
Wenqi Dong, Haiming Zhang, Shaowei Mu +3 more
The global prevalence and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), are steadily rising, making them the most common chronic liver diseases worldwide. However, therapeutic options for MAFLD are currently limited. Glucolipid dysregulation drives MAFLD pathogenesis through intertwined glucose metabolic imbalance and lipid accumulation. Patients with type 2 diabetes mellitus (T2DM) are particularly prone to developing MASH and are at a higher risk of progressing to cirrhosis and hepatocellular carcinoma. The coexistence of MAFLD and T2DM correlates with clinical prognosis and elevates the risk of extrahepatic complications. Given the close association between MAFLD and T2DM, glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have been approved for the treatment of T2DM and obesity, were the first to be investigated in patients with MAFLD/MASH. Recently, beyond GLP-1RAs, novel combination agents integrating glucose-dependent insulinotropic peptide receptor (GIPR) and/or glucagon receptor (GCR) agonists have also been explored. A large number of phase II randomized clinical trials have demonstrated significant improvements in body weight, insulin resistance, and liver parameters. Thus, GLP-1RAs and dual/triple agonists are promising for MAFLD/MASH, especially in those with obesity or T2DM. This study explores mechanisms and clinical evidence of incretin-based therapies for MAFLD by targeting its core pathogenesis-glucolipid disorders. With growing evidence, it also forecasts the broad clinical prospects on MAFLD treatment.
Effects of glucagon-like peptide-1 receptor agonists on patients with metabolic dysfunction-associated steatohepatitis: protocol for a systematic review and sequential meta-analysis.
Syst Rev
Mei-Jun Wang, Yu-Nuo Jiang, Pei-Pei Li +1 more
Metabolic dysfunction-associated steatohepatitis (MASH), a progressive subtype of steatotic liver disease, imposes a substantial global health burden due to its association with obesity and metabolic syndrome. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrate therapeutic potential through pleiotropic mechanisms, including appetite regulation, metabolic enhancement, and anti-inflammatory activity. However, clinical evidence remains limited by methodological heterogeneity and insufficient long-term efficacy data, necessitating a rigorous systematic evaluation.
Golgi-targeted copper delivery strategy via enhancing copper-dependent proteins' activity for fascia regeneration.
J Control Release
Rui Wang, Yiru Xu, Qimanguli Saiding +5 more
Copper-dependent proteins (such as lysyl oxidase, LOX) require copper acquisition within the Golgi apparatus to achieve enzymatic activation, and insufficient activation of these proteins is a key factor limiting fascia regeneration. To address this issue, this study, for the first time, proposes and validates a Golgi-targeted copper delivery system (LNP-ATOX1/GHK-Cu@PCL-GelMA). In this system, GHK-Cu serves as a stable copper source to provide a sustained release of Cu ions for cellular uptake, while lipid nanoparticles (LNPs) are used to deliver mRNA encoding the copper chaperone ATOX1. Upregulation of ATOX1 facilitates the transport of copper into the Golgi apparatus via ATP7A/B, thereby enhancing the activity of copper-dependent proteins. In addition, ATOX1 promotes the copper-dependent translocation of ATP7A and Rac1 to the plasma membrane, synergistically accelerating neovascularization. In vitro studies demonstrated that this material system significantly increased copper accumulation within the Golgi apparatus, elevated LOX activity to 1.78 times that of the control group, and enhanced angiogenic capacity. In a rabbit fascia defect model, this strategy effectively promoted collagen alignment and neovascularization, improving extracellular matrix reconstruction and facilitating fascia regeneration. In conclusion, this work establishes a novel Golgi-targeted copper delivery strategy, providing a practical therapeutic approach for regenerative disorders caused by insufficient activation of copper-dependent proteins, such as fascia defects.
Sex-dependent endocrine and cellular effects of the GnRH antagonist degarelix in rabbits and cell models.
Am J Transl Res
Mo Zhao, Rong Wei, Yaojuan Lu +9 more
Degarelix is a long-acting gonadotropin-releasing hormone (GnRH) antagonist that suppresses gonadotropin and sex steroid secretion via competitive blockade of the GnRH receptor (GnRHR). Although its systemic endocrine effects have been clearly identified, its direct effects on non-pituitary-derived cells, as well as the roles of sex and context-dependent pharmacological properties, remain largely unexplored.
Bone sialoprotein: a multifunctional regulator of bone remodelling and tumour progression.
Bone Res
Valentina Kottmann, Philipp Drees, Erol Gercek +1 more
Bone sialoprotein (BSP) is a major non-collagenous protein of the bone extracellular matrix and an important regulator of bone formation and resorption. BSP is produced by bone cells and chondrocytes and present in the bone matrix, cells, dentin and cartilage. However, its aberrant expression in primary tumour tissues and the sera of cancer patients with metastases implicates BSP in tumour biology and progression. The Arg-Gly-Asp (RGD) motif of BSP may be crucial not only for the attachment of metastasising cells to the bone surface but also for tumour growth, survival and activity. This review examines the structure and functions of BSP, including its roles in angiogenesis, bone formation, osteoclast differentiation and activity and cancer cell proliferation, survival, complement evasion, adhesion, migration and invasion. Growing evidence highlights BSP as a key mediator of tumour pathophysiology, skeletal metastasis development and associated bone remodelling. These processes are driven through RGD-integrin binding, the integrin/BSP/matrix metalloproteinase axis, integrin-independent signalling pathways, epithelial-to-mesenchymal transition and potentially post-translational modifications. A deeper understanding of BSP's role in tumour progression may reinforce its potential as a prognostic and diagnostic tumour biomarker and aid the development of anti-BSP antibodies or targeted inhibitors for skeletal metastases and bone diseases.