Search Results (286)

Hormonal contraceptives (HCs) are widely used and generally well tolerated; however, their neuroendocrinological effects remain underappreciated in clinical decision-making. Beyond ovulation suppression, HCs influence brain function by modulating key neurotransmitters such as GABA, serotonin, and dopamine, as well as neurosteroids like allopregnanolone and β-endorphin. These interactions help explain why some users experience mood swings, anxiety, or changes in sexual desire, while others report improvements in well-being. In this narrative review, we explore how different estrogenic and progestin components affect central pathways involved in emotional regulation and cognition. Evidence suggests that estradiol or estetrol-based formulations combined with anti-androgenic progestins like drospirenone or nomegestrol acetate may offer a more favourable neuroendocrine profile, particularly in women with a history of mood disorders or hormonal sensitivity. Understanding these neuroendocrine mechanisms may support more personalized contraceptive choices, particularly in women with mood disorders and hormonal vulnerability. Full article

Prolactin is a hormone with demonstrated roles in the brain, including neurogenesis, neuroprotection, learning, stress response or memory consolidation. To determine the prolactin expression in the rat hippocampus during aging and to resolve some controversies related to the presence of prolactin in the hippocampus, the aim of this study was to analyze whether changes occur in the expression of prolactin during different stages of life. To determine this, we designed an experimental study in which we analyzed the expression and location of prolactin in the rat hippocampus, Ammon’s horn and Dentate Gyrus, during different stages of life (prepubertal, postpubertal, young adult, adult and old) and checked if there are differences related to sex. Overall, the results obtained show that prolactin is present in the rat hippocampus and that prolactin is synthesized, as deduced from the findings obtained via ELISA, immunohistochemistry, qPCR and in situ hybridization. After analyzing the correlation between serum and hippocampal prolactin levels and comparing the amounts of Prl mRNA and the hormone, the results obtained suggest that hippocampal prolactin has a dual origin: local synthesis of the hormone and its passage from the blood. On the other hand, the amounts of prolactin and its mRNA in the hippocampus vary with sex and age, suggesting the existence of age-related sexual dimorphism. The results obtained suggest that hippocampal aging is related to a decrease in the hippocampal prolactin system, which helps to better understand brain aging. Full article

Macrophages are a heterogenous population of cells that adopt specific phenotypes in response to signals from their dynamic microenvironment. Apart from being key players in innate immunity and in the maintenance of tissue homeostasis, macrophages are also important drivers of low-grade inflammation, which is associated with different chronic conditions including stress and cancer. The activation of macrophages during chronic stress and cancer results in their multifaceted pathogenic roles. Macrophages residing in the tumor microenvironment are commonly known as tumor-associated macrophages and favor or inhibit tumor growth depending on the microenvironmental cues and their activation state. Activated macrophages display a continuum of properties rather than a distinct proinflammatory or anti-inflammatory dichotomy. Emerging evidence suggests that prolonged tissue residency restricts the plasticity of macrophages, while recruited monocytes are more plastic and their differentiation into tumor-associated macrophages during stress can result in a dual imprinting from both the existing stress-induced inflammation and the tumor microenvironment. In addition, the immunomodulation of the tumor microenvironment and reprogramming of tumor-associated macrophages toward the anti-tumor phenotypes have emerged as promising therapeutic approaches. In this review, we will focus on how the persistent inflammatory state underlying chronic stress affects macrophages as well as the macrophages’ contribution to various aspects of tumor growth and progression, highlighting a therapeutic potential of modulation of the macrophage-mediated immunosuppressive tumor microenvironment. Full article

Chronic neuroinflammation and oxidative stress play an important role in the onset and progression of neurodegenerative disorders, including Alzheimer’s disease, which can ultimately lead to neuronal damage and loss. The mechanisms of sustained neuroinflammation and the coordinated chain of events that initiate, modulate, and then lead to the resolution of inflammation are increasingly being elucidated, offering alternative approaches for treating pathologies with underlying chronic neuroinflammation. Here, we propose a new multitarget approach to address chronic neuroinflammation and oxidative stress in neurodegenerative disorders by activating the formyl peptide receptor 2 (FPR2) combined with the potentiation of hydrogen sulfide (H₂S) release. FPR2 is a key player in the resolution of inflammation because it mediates the effects of several endogenous pro-resolving mediators. At the same time, H₂S is an endogenous gaseous transmitter with anti-inflammatory and pro-resolving properties, and it can protect against oxidative stress. Starting from potent FPR2 agonists identified in our laboratories, we prepared hybrid compounds by embedding an H₂S-donating moiety within the molecular scaffold of these FPR2 agonists. Following this approach, we identified several compounds that combined potent FPR2 agonism with the ability to release H₂S. The release of H₂S was assessed in buffer and intracellularly. Compounds 7b and 8b combined potent FPR2 agonist activity, selectivity over FPR1, and the ability to release H₂S. Compounds 7b and 8b were next studied in murine primary microglial cells stimulated with lipopolysaccharide (LPS), a widely accepted in vitro model of neuroinflammation. Both compounds were able to counterbalance LPS-induced cytotoxicity and the release of pro-inflammatory (IL-18, IL-6) and anti-inflammatory (IL-10) cytokines induced by LPS stimulation. Full article

From a previously performed proteomics screen, GPP130, or Golgi phosphoprotein of 130 kDa, was identified as a potential substrate of the proprotein convertase 7 (PC7; PCSK7). GPP130 is a type-II transmembrane protein with a luminal domain containing endosomal and Golgi-retrieval determinants, enabling a unique trafficking route. Most of the previous work on GPP130 relates to its binding and retrograde trafficking of the Shiga toxin. However, its cellular biology and its biochemical characterization remain understudied. Recently, GPP130 was reported to be implicated in cell cycle progression and cell proliferation in head and neck cancer cells. This led us to analyze the cBioPortal for Cancer Genomics, revealing that the GPP130/GOLIM4 gene is amplified in many cancers, including lung, ovarian, and cervical. This observation led us to use the A549 lung cancer cell line to investigate the growth-regulating roles of endogenous and overexpressed GPP130 and to analyze the impact of its cleavage/shedding by PC7 and/or Furin on cellular growth. Our cell-based assays suggest that GPP130 is a novel pro-protein convertase substrate that increases cell proliferation in A549, SKOV3, and HeLa cells, and that the latter activity is enhanced following its cleavage by PC7 and/or Furin into a membrane-bound N-terminal product and secreted C-terminal fragments. This novel work sheds light on the cell biology of the poorly characterized GPP130, its proliferative activity, and modulation upon its shedding by PC7 and Furin in lung cancer progression. Full article

Defects in lysosomal cholesterol handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann–Pick type C disease (NPCD), where cholesterol export from the endosomal–lysosomal system is impaired due to variants of either NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2). Therapeutic options for NPCD are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as new drug targets for NPCD using patient-derived skin fibroblasts. Treatment with JQ1, a prototype BET protein inhibitor, raised the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose-, time-, and patient-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by pharmacologic inhibition of NPC1 and of histone deacetylase (HDAC) activity, respectively. Taken together, bromodomain proteins should be further explored as therapeutic drug targets for lysosomal diseases like NPCD, and as new components regulating lysosomal function and cholesterol metabolism. Full article

Background: Oral semaglutide, a GLP1-receptor agonist (GLP1-RA), shows promise in efficacy and compliance, especially amid the global shortage of injectable GLP-1 RAs. Its short-term effectiveness remains unexplored. Objective: This real-world observational study assessed the short-term effectiveness of oral semaglutide after three months of therapy. Methods: Patients with type 2 diabetes from four Italian diabetes centers, who received an initial prescription of oral semaglutide, were reassessed after three months. Primary outcomes included glycated hemoglobin (HbA1c) and body weight reduction; secondary outcomes involved changes in lipid parameters and cardiovascular risk. Results: Among 167 participants (mean age 66.5 years, mostly obese, baseline HbA1c 8.4% ± 1.5), 83.2% received a 7 mg dose. After three months, HbA1c significantly declined (8.4% to 7.1%, −1.3%, p < 0.001), alongside body mass index (BMI) (30.9 kg/m² to 29.6 kg/m², p < 0.0001). The target HbA1c ≤ 7% was achieved by 54.5%, and 34.7% reached ≤6.5%. Patients losing >5% of their initial weight (30.5%) saw the largest HbA1c drop (−1.9%). Those with newly diagnosed diabetes or a duration < 5 years showed superior responses (p = 0.001), while no significant differences were found based on the timing of drug administration. Oral semaglutide replaced or supplemented prior therapies, allowing discontinuation of dipeptidyl peptidase 4 inhibitors (DPP4i), sulfonylureas, glinides, and acarbose, and deprescription of thiazolidinediones. A significant reduction in cardiovascular risk was observed (p = 0.04), together with a significant reduction in lipid parameters. Conclusions: Oral semaglutide showed significant short-term efficacy, reducing HbA1c, body weight, and cardiovascular risk in three months, making it a valuable therapeutic option. Full article

For centuries, the most prevalent antler abnormalities observed worldwide have been attributed to trauma. However, detailed pathological investigation of these cases has not yet been carried out. In free-living fallow deer (Dama dama), we identified a chronic osteomyelitis-like condition—Pedunculitis Chronica Deformans (PCD)—using pathological and radiological diagnostics. We propose that inflammation during post-casting wound healing and consequent scar formation can trigger the development of PCD. In this study, we characterize the pathomorphology of PCD and introduce a scoring system to describe its severity. Furthermore, we describe the histoanatomy of the junction between the pedicle and the surrounding skin—an area essential for the integrity of the integument—which, when compromised, may predispose cervids to PCD. Our findings suggest that the most common antler abnormality results from a pathological fracture associated with PCD, which can be further complicated by fatal meningoencephalitis and brain abscesses. PCD-related lesions, while less frequently observed, can also be identified in roe deer (Capreolus capreolus) and red deer (Cervus elaphus), with species-specific differences. These findings overlap with cases reported in other cervid species, suggesting a more general disorder of antler formation. Describing this condition provides a basis for assessing its epidemiology and understanding its relevance to wildlife health. Full article

Prolactin is a hormone for which actions on the central nervous system such as neurogenesis and neuroprotection have been described by acting on specific receptors. The presence of prolactin receptors in the brain, including the hippocampus, is well documented; however, it is unknown whether these receptors change with age and whether they are related to sex. For this reason, a study of the expression of prolactin receptors, in the short and long isoforms, in the hippocampus of male and female rats has been carried out by qPCR and in situ hybridization, with a densitometric analysis in the following life stages: prepubertal, postpubertal, young adult, adult, and old. The results revealed the greater expression of the long isoform than of the short isoform in males, but not in females, with significant differences between males and females and in the different life stages studied. With significant differences, the highest expression of both isoforms appeared in male rats in the postpubertal stage, and the lowest expression was observed in adult and old animals. In situ hybridization showed differences in the localization of PRLR mRNA expression in CA1, CA3, and DG depending on the age and sex of the rats. The results obtained suggest that hippocampal aging is related to a decrease in prolactin receptors, which helps to better understand brain aging. Full article

The kisspeptin/kisspeptin receptor (KISS1/KISS1R) system has emerged as a vital regulator of various physiological processes, including cancer progression, metabolic function, and reproduction. KISS1R, a member of the G protein-coupled receptor family, is crucial for regulating the hypothalamic/pituitary/gonadal axis. A growing number of KISS1R agonists are currently being investigated in clinical trials, whereas the number of antagonists remains limited. Most existing ligands are synthetic peptides, with only a few small-molecule compounds, such as musk ambrette, having been identified. In this article, we provide an overview of the KISS1/KISS1R system and its involvement in diseases such as reproductive disorders, cancer, diabetes, and cardiovascular disease. We also highlight the various technologies used to identify KISS1R ligands, including radioligand binding assays, calcium flux assays, IP1 formation assays, ERK phosphorylation assays, qRT-PCR, and AI-based virtual screening. Furthermore, we discuss the latest advances in identifying KISS1R agonists and antagonists, highlighting ongoing challenges and future directions in research. These insights lay the groundwork for future research aimed at leveraging this system for developing innovative therapeutic strategies across a range of medical conditions. Full article

Secreted protein acidic rich in cysteine (SPARC), one of the extracellular matrix proteins, is highly induced during inflammation. We investigated the pathophysiological regulation and role of SPARC in vascular inflammation in a rat model of hypertension created using deoxycorticosterone acetate (DOCA, 40 mg/kg/week, s.c.) and salt (1% in drinking water). DOCA–salt administration time-dependently increased systolic blood pressure during the 3-week treatment period, blunted endothelium-dependent vasodilation, and increased monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in the aorta. SPARC expression transiently increased until week 2 in the DOCA–salt rat aorta. Interestingly, aortic SPARC levels correlated with blood pressure and the levels of MCP-1 and LOX-1 during 0–2 weeks. The AT₁ receptor blocker, losartan, suppressed the overexpression of SPARC, and in vitro treatment with angiotensin II enhanced the production of SPARC in rat aortic endothelial cells. Exposure to recombinant SPARC protein induced overexpression of MCP-1 and LOX-1 mRNA in endothelial cells. Bioactive forms of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), excessive activation of which contributes to pathological states and overexpression of which is reported to be induced by SPARC, were increased in the DOCA–salt rat aorta. These results suggest that SPARC is induced by the vascular renin–angiotensin system and causes inflammation in the early stages of hypertensive vascular injury, and that activation of ADAMTS1 might be related to the proinflammatory effects of SPARC. Full article

The p21-activated kinases (PAKs) are a group of evolutionarily conserved serine/threonine protein kinases and serve as a downstream target of the small GTPases Rac and Cdc42, both of which belong to the Rho family. PAKs play pivotal roles in various physiological processes, including cytoskeletal rearrangement and cellular signal transduction. Group II PAKs (PAK4-6) are particularly closely linked to human tumors, such as breast and pancreatic cancers, while Group I PAKs (PAK1-3) are indispensable for normal physiological functions such as cardiovascular development and neurogenesis. In recent years, the association of PAKs with diseases like cancer and the rise of small-molecule inhibitors targeting PAKs have attracted significant attention. This article focuses on the analysis of PAKs’ role in tumor progression and immune infiltration, as well as the current small-molecule inhibitors of PAKs and their mechanisms. Full article

The pituitary gland regulates essential physiological processes in mammals. Despite its importance, research on its anatomy and ultrastructure in dolphins remains scarce. Using non-invasive imaging technology (MRI) and a novel skull-opening and dissection protocol, this study characterizes the dolphin pituitary through immunohistochemistry (IHC) and transmission electron microscopy (TEM). A total of 47 pituitaries were collected from stranded common bottlenose dolphins (Tursiops truncatus). common dolphins (Delphinus delphis), and Atlantic spotted dolphins (Stenella frontalis). as well as from captive common bottlenose dolphins. MRI allowed visualization of the gland’s anatomy and its spatial relationship with the hypothalamus and surrounding structures. A modified skull-opening and pituitary extraction protocol ensured the preservation of the adenohypophysis and neurohypophysis for detailed analysis. Histological, immunohistochemical, and ultrastructural studies confirmed the gland’s structural organization, identifying eight distinct adenohypophyseal cell types: corticotrophs (ACTH), somatotrophs (GH), gonadotrophs (FSH and LH), lactotrophs (LTH), melanotrophs (MSH), thyrotrophs (TSH), follicular cells, and capsular cells. This study presents the first immunolabelling of thyrotrophs in cetacean adenohypophysis and the first detailed ultrastructural characterization of adenohypophyseal cells in cetaceans, providing baseline data for future research. By integrating multidisciplinary techniques, it advances the understanding of dolphin neuroendocrinology and highlights broader implications for cetacean health, welfare, and conservation. Full article

Chitosan and collagen are natural polymers widely used in biomaterials science; however, their inherent low stability and solubility present several challenges to obtain formulations suitable for potential clinical applications. In this study, tannic acid (TA) was employed as a cross-linker to improve the properties of thin films made from chitosan and collagen. In addition, potassium silicate (PS) was added as an inorganic filler, to produce innovative biocomposite films. The impact of TA and PS on physicochemical (i.e., material homogeneity, surface free energy, degradation, and stability roughness of surface), antioxidant, hemocompatibility, as well as cellular responses was evaluated. The results demonstrated that the incorporation of TA significantly enhanced the physicochemical properties of the chitosan/collagen-based films. The addition of 5% PS resulted in an increase in surface free energy and a decrease in roughness parameters. Furthermore, both surface free energy and cellular responses improved with the increased TA concentration in the biocomposite firms. Meanwhile, the hemolysis rate remained below 5%, indicating the potential suitability of these materials for medical applications, such as coatings or scaffolds for bone or skin wound healing. Full article

Metastatic cancer poses significant clinical challenges, necessitating effective immunotherapies with minimal systemic toxicity. Building on prior research demonstrating the rWTC-MBTA vaccine’s ability to inhibit tumor metastasis and growth, this study focuses on its clinical translation by optimizing vaccine composition, dosing regimens, and freezing techniques. The vaccine formula components included three TLR ligands (LTA, Poly I:C, and Resiquimod) and an anti-CD40 antibody, which were tested in melanoma and triple-negative breast cancer (TNBC) models. The formulations were categorized as rWTC-MBT (Mannan-BAM with LTA, Poly I:C, Resiquimod), rWTC-MBL (LTA), rWTC-MBP (Mannan-BAM with Poly I:C), and rWTC-MBR (Resiquimod). In the melanoma models, all the formulations exhibited efficacy that was comparable to that of the full vaccine, while in the “colder” TNBC models, the formulations with multiple TLR ligands or Resiquimod alone performed the best. Vaccine-induced activation of dendritic cell (DC) subsets, including conventional DCs (cDCs), myeloid DCs (mDCs), and plasmacytoid DCs (pDCs), was accompanied by significant CD80+CD86+ population induction, suggesting robust innate immune stimulation. An initial three-dose schedule followed by booster doses (3-1-1-1 or 3-3-3-3) reduced the metastatic burden effectively. Gradual freezing (DMSO-based preservation) maintained vaccine efficacy, underscoring the importance of intact cell structure. These findings highlight the potential of simplified formulations, optimized dosing, and freezing techniques in developing practical, scalable immunotherapies for metastatic cancers. Full article