Search Results (6,405)

Background/Objectives: Astrocytoma, IDH-mutant, CNS WHO grade 3, is a diffuse glioma with poor prognosis, molecularly defined by IDH mutations and frequently co-occurring TP53 and ATRX alterations. This study aimed to delineate the genomic landscape and identify clinically relevant molecular features of astrocytoma, IDH-mutant, CNS WHO grade 3 using this resource. Methods: Patients in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) database were selected based on histological diagnosis of “anaplastic astrocytoma”, confirmed IDH1/2 mutation, and exclusion of CDKN2A/B homozygous deletions. We analyzed frequencies of somatic mutations, copy number alterations (CNAs), structural variants (SVs), assessed co-occurrence/exclusivity patterns, and explored associations with available demographic and limited survival data. Results: The most common somatic mutations were in IDH1 (98.0%), TP53 (94.8%), and ATRX (55.2%). The observed ATRX mutation frequency was lower than some historical reports (e.g., ~86%). Other recurrent alterations included phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (6.9%), Notch receptor 1 (NOTCH1) (6.9%), and platelet-derived growth factor receptor alpha (PDGFRA) (mutations 4.3%; CNAs also observed). Conclusions: This study provides a comprehensive genomic characterization of astrocytoma, IDH-mutant, CNS WHO grade 3 using the AACR GENIE database, confirming core mutational signatures while also highlighting potential variations in alteration frequencies, such as for ATRX. The findings establish a valuable real-world genomic benchmark for this tumor type, while promoting the need for continued data integration with robust clinical outcomes to identify actionable prognostic and therapeutic targets. Full article

Background/Objectives: Benign prostatic hyperplasia (BPH) is a prevalent urological disorder in aging men, characterized by the enlargement of prostate epithelial and stromal cells, which leads to lower urinary tract symptoms. Paeonol, a bioactive compound derived from Moutan Cortex (Paeonia suffruticosa), exhibits multiple pharmacological properties; however, its therapeutic potential in BPH remains unclear. This study aimed to elucidate the mechanisms of paeonol in BPH treatment using network pharmacology and in vivo experiments. Methods: Network pharmacology and molecular docking were conducted to identify potential targets of paeonol against BPH. For the in vivo study, testosterone-induced BPH rat models were employed, and efficacy was evaluated through prostate weight assessment, histological examination, and the quantitative real-time polymerase chain reaction (qRT-PCR) analysis of prostate tissues. Results: In silico analysis revealed key signaling pathways involved in apoptosis, proliferation, phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt), and inflammation. Paeonol administration significantly reduced prostate weight, volume, and histological hyperplasia in BPH rats. qRT-PCR analysis demonstrated that paeonol may suppress dihydrotestosterone production by inhibiting 5α-reductase 2 (5AR2) and the androgen receptor (AR), while also downregulating local growth factors, alpha serine/threonine-protein kinase (Akt1), nuclear factor-κB (NF-κB), and glutathione reductase (GR) expression. Conclusions: These findings provide novel insights into the multitargeted therapeutic potential of paeonol in BPH by inhibiting 5AR and AR and suppressing proliferation via NF-κB and Akt pathway modulation. Full article

Background/Objectives: Liver fibrosis is a progressive consequence of chronic liver injury that can evolve into cirrhosis, liver failure, or hepatocellular carcinoma, representing a major global health burden. Fibrogenesis is driven by hepatic stellate cell (HSC) activation, excessive extracellular matrix deposition, and structural disruption of liver tissue, with transforming growth factor-β (TGF-β) signaling and inflammatory mediators as central pathways. Current therapies primarily target the underlying causes, which may halt disease progression but rarely reverse established fibrosis. This review aims to outline current and emerging therapeutic strategies for liver fibrosis, informing both clinical practice and future research directions. Methods: A narrative synthesis of preclinical and clinical evidence was conducted, focusing on pharmacological interventions, microbiota-directed strategies, and innovative modalities under investigation for antifibrotic activity. Results: Bile acids, including ursodeoxycholic acid and derivatives, modulate HSC activity and autophagy. Farnesoid X receptor (FXR) agonists, such as obeticholic acid, reduce fibrosis but are limited by adverse effects. Fatty acid synthase inhibitors, exemplified by denifanstat, show promise in metabolic dysfunction-associated steatohepatitis (MASH). Additional strategies include renin–angiotensin system inhibitors, omega-3 fatty acids, and agents targeting the gut–liver axis. Microbiota-directed interventions—probiotics, prebiotics, symbiotics, antibiotics (e.g., rifaximin), and fecal microbiota transplantation—are emerging as potential modulators of barrier integrity, inflammation, and fibrogenesis, though larger clinical trials are required. Reliable non-invasive biomarkers and innovative trial designs, including adaptive platforms, are essential to improve patient selection and efficiently evaluate multiple agents and combinations. Conclusions: Novel modalities such as immunotherapy, gene editing, and multi-targeted therapies hold additional potential for fibrosis reversal. Continued translational efforts are critical to establish safe, effective, and accessible treatments for patients with liver fibrosis. Full article

Objective: The aim of this study was to evaluate the accuracy of machine and deep learning approaches on radiomics features obtained by Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) and contrast enhanced mammography (CEM) in the characterization of breast cancer and in the prediction of the tumor molecular profile. Methods: A total of 153 patients with malignant and benign lesions were analyzed and underwent MRI examinations. Considering the histological findings as the ground truth, three different types of findings were used in the analysis: (1) benign versus malignant lesions; (2) G1 + G2 vs. G3 classification; (3) the presence of human epidermal growth factor receptor 2 (HER2+ vs. HER2−). Radiomic features (n = 851) were extracted from manually segmented regions of interest using the PyRadiomics platform, following IBSI-compliant protocols. Highly correlated features were excluded, and the remaining features were standardized using z-score normalization. A feature selection process based on Elastic Net regularization (α = 0.5) was used to reduce dimensionality. Synthetic balancing of the training data was applied using the ROSE method to address class imbalance. Model performance was evaluated using repeated 10-fold cross-validation and AUC-based metrics. Results: Among the 153 patients enrolled in the studies, 113 were malignant lesions. Among the 113 malignant lesions, 32 had high grading (G3) and 66 had the HER2+ receptor. Radiomic features derived from both CEM and DCE-MRI showed strong discriminative performance for malignancy detection, with several features achieving AUCs above 0.80. Gradient Boosting Machine (GBM) achieved the highest accuracy (0.911) and AUC (0.907) in differentiating benign from malignant lesions. For tumor grading, the neural network model attained the best accuracy (0.848), while LASSO yielded the highest sensitivity (0.667) for detecting high-grade tumors. In predicting HER2+ status, the neural network also performed best (AUC = 0.669), with a sensitivity of 0.842. Conclusions: Radiomics-based machine learning models applied to multiparametric CEM and DCE-MRI images offer promising, non-invasive tools for breast cancer characterization. The models effectively distinguished benign from malignant lesions and showed potential in predicting histological grade and HER2 status. These results demonstrate that radiomic features extracted from CEM and DCE-MRI, when analyzed through machine and deep learning models, can support accurate breast cancer characterization. Such models may assist clinicians in early diagnosis, histological grading, and biomarker assessment, potentially enhancing personalized treatment planning and non-invasive decision-making in routine practice. Full article

Hair loss (alopecia) is a common disorder caused by an interruption in the body’s cycle of hair production. This pathology negatively affects the psychoemotional state of patients and significantly reduces their quality of life. The currently available medical treatments (including minoxidil therapy) are effective in arresting the progression of the disease; however, they allow only partial regrowth of hair at best. A significant clinical result occurs only with regular drug use. There is still great interest in finding new drugs for the treatment of alopecia. In this study, we aimed to examine the effect of an aqueous dispersion of unmodified fullerene C60 (ADF) on hair growth. ADF, produced by a unique technology, is biocompatible and non-toxic. Nu/nu mice were subcutaneously injected (2 μg/animal) every two days for a period of 11 days with ADF and, for control purposes, with phosphate-buffered saline (PBS). It was shown that ADF stimulated hair growth. Histological analysis of the nu/nu mice skin areas showed that animals treated with ADF had significantly more (about twice as many) hair follicles in the anagen phase compared to mice treated with PBS. The effect on hair growth persisted even after discontinuation of ADF administration. Analysis of gene expression demonstrated that ADF affected the Wnt-signaling pathway, increased the expression of the Wnt10b (wingless-type Mouse Mammary Tumor Virus integration site family, member 10B) factor, angiogenetic factors, and downregulated tumor necrosis factor-alpha levels. We propose that the mechanism of ADF action is likely related to its ability to attract macrophages to the hair follicle microenvironment and promote their polarization to the M2 phenotype. In addition, using molecular modeling, we tried to substantiate our hypothesis about the interaction of ADF with the adenosine A2A receptor, which may cause a decrease in tumor necrosis factor-alpha production. Thus, ADF may become a promising drug for the development of new approaches to the treatment of alopecia associated with immune disorders. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

Background: This study was aimed to comprehensively investigate the clinical and molecular characteristics, treatments, and outcomes of young patients with lung cancer in the new era of cancer treatment. Methods: Clinical data from patients aged 18 to 45 with lung cancer, treated at our hospital from January 2014 through January 2024, were systematically collected and analyzed. Results: This study enrolled a total of 343 patients, with a predominance of females, never-smokers, and those diagnosed at an advanced stage. Adenocarcinoma was the most common histology (72.0%), and rare tumors could also be seen in young patients, such as pulmonary sarcomatoid carcinoma and pulmonary mucoepidermoid carcinoma. The mutation rate of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in NSCLC patients were 35.9% (111/309) and 14.2% (44/309), respectively. PD-L1 expression was assessed in 55 patients, with 14 showing high expression (≥50%) and 24 showing negative expression (<1%). The median overall survival (mOS) for the entire cohort was 80.2 months, with a 5-year survival rate of 55.7%. For patients with stage I, II, and III disease, the mOS had not yet been reached, whereas the mOS for stage IV patients was 39.7 months. Targeted therapy, particularly second-generation ALK tyrosine kinase inhibitors (TKIs), significantly improved the prognosis of patients with driver gene mutations. Chemotherapy combined with immunotherapy was beneficial for patients with progressive disease or driver gene negativity in NSCLC and was associated with improved OS in small cell lung cancer (SCLC). Female, family history of lung cancer, positive driver genes, and first-line use of second-generation ALK-TKIs are independent prognostic factors in young patients with advanced NSCLC. Conclusions: Our findings highlight the importance of early diagnosis, targeted therapy, and immunotherapy in improving outcomes for young patients with lung cancer. Full article

Lung cancer is the leading cause of cancer mortality globally, despite the advancements in screening and management. Survival rates for lung cancer remain suboptimal, largely due to late-stage diagnoses and tumor heterogeneity. Recent advancements in artificial intelligence and radiomics provide a promising outlook for lung cancer screening, diagnosis, personalized treatment, and prognosis. These advances use large-scale clinical and imaging datasets that help identify patterns and predictive features that may be missed by human interpretation. Artificial intelligence tools hold the potential to take clinical decision-making to another level, thus improving patient outcomes. This review summarizes current evidence on the applications, challenges, and future directions of artificial intelligence (AI) in lung cancer care, with an emphasis on early diagnosis and personalized treatment. We examine recent developments in AI-driven approaches, including machine learning and deep neural networks, applied to imaging (radiomics), histopathology, biomarker analysis, and multi-omic data integration. AI-based models demonstrate promising performance in early detection, risk stratification, molecular profiling (e.g., programmed death-ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR) status), and outcome prediction. These tools may enhance diagnostic accuracy, optimize therapeutic decisions, and ultimately improve patient outcomes. However, significant challenges remain, including model heterogeneity, limited external validation, generalizability issues, and ethical concerns related to transparency and clinical accountability. AI holds transformative potential for lung cancer care but requires further validation, standardization, and integration into clinical workflows. Multicenter collaborations, regulatory frameworks, and explainable AI models will be essential for successful clinical adoption. Full article

Background: Vandetanib is a clinically approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in the treatment of medullary thyroid cancer. Recent studies have also suggested potential activity against the SARS-CoV-2 main protease (Mpro), indicating dual therapeutic relevance. However, its clinical use is limited by photosensitivity side effects, the molecular basis of which remains poorly understood. This study aims to elucidate the conformational, spectroscopic, and electronic properties of vandetanib underlying its photoreactivity. Methods: Density functional theory (DFT) was employed to explore vandetanib’s conformational landscape, electronic structure, and spectroscopic behavior. Low-energy conformers were identified and compared with experimental crystal and NMR data. Time-dependent DFT (TD-DFT) calculations were used to simulate UV–Vis absorption spectra and assign key electronic transitions. Results: Eight low-energy conformer clusters, including the global minimum structure, were identified. The global minimum was validated by consistency with crystal and experimental NMR data, emphasizing the role of conformational averaging. TD-DFT simulations successfully reproduced the two main UV–Vis absorption bands, with the primary band (~339 nm) assigned to a HOMO–1 → LUMO charge-transfer excitation between the N-methyl piperidine and quinazoline rings, pinpointing a structural contributor to photoreactivity. Additionally, the N-methyl piperidine ring was identified as a major metabolic hotspot, undergoing multiple biotransformations potentially linked to phototoxicity. Conclusions: This study provides molecular-level insights into the structural and photophysical origins of vandetanib’s photosensitivity. The findings improve understanding of its adverse effects and can inform the safer design of EGFR-targeting drugs with reduced phototoxic risks. Full article

Background and Objectives: Obstructive sleep apnea (OSA) represents an increasing public health concern, closely linked with cardiovascular, metabolic, and neurocognitive disorders, as well as impaired quality of life. The complex pathophysiology of OSA involves upper airway dysfunction, oxidative stress, and inflammation, with endothelial dysfunction considered central to its associated comorbidities. Despite notable advances in OSA research, the biological mechanisms driving these complications remain insufficiently understood. The present study aimed to examine the associations between redox status, proinflammatory biomarkers, and the gene expression of full-length receptor for advanced glycation end products (flRAGE) and transforming growth factor beta 1 (TGF-β1) in relation to the presence and severity of OSA. Materials and Methods: The study cohort comprised 125 participants with diagnosed OSA and 42 controls without evidence of OSA. General and clinical characteristics were recorded for all participants. Laboratory analyses included the assessment of redox and inflammatory markers in serum and plasma, while flRAGE and TGF-β1 messenger ribonucleic acids (mRNA) were quantified in peripheral blood mononuclear cells. Results: Patients with OSA demonstrated elevated oxidative stress and inflammation, characterized by increased total antioxidant status (TAS) and C-reactive protein CRP levels, together with reduced concentrations of soluble RAGE (sRAGE). The severity of OSA, indicated by the apnea-hypopnea index, increases total oxidative status (TOS) and TGF-β1 mRNA, while sRAGE decreases. The sRAGE–ROS-related factor was negatively associated with OSA, whereas the redox status factor showed a positive association. TOS was independently and positively correlated with OSA severity. Conclusions: Individuals with OSA exhibit a state of enhanced oxidative stress and inflammation. Increasing severity of OSA was associated with rising TOS and TGF-β1 mRNA expression, accompanied by declining sRAGE concentrations. A combined redox–inflammatory biomarker profile was found to be associated with both the presence and severity of OSA. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, limiting the efficacy of conventional targeted therapies. As a result, novel therapeutic strategies are urgently needed. Photodynamic therapy (PDT), which relies on the activation of photosensitizers (PSs) by light to induce cytotoxic effects, has emerged as a promising alternative for TNBC treatment. Furthermore, the conjugation of PSs with targeting peptides has demonstrated enhanced selectivity and therapeutic efficacy, particularly for porphyrin-based photosensitizers. In this study, we report the synthesis of novel porphyrin–peptide conjugates designed to selectively target the epidermal growth factor receptor (EGFR), which is frequently overexpressed in TNBC. The conjugates were prepared via thiol displacement of the meso-nitro group in a 5,15-diarylporphyrin scaffold using EGFR-binding peptides. Photodynamic activity was evaluated in two EGFR-overexpressing TNBC cell lines. Cellular uptake of the conjugates correlated with EGFR expression levels, and PDT treatment resulted in differential induction of necrosis, apoptosis, and autophagy. Notably, the conjugates significantly inhibited EGFR-expressing cell line migration, a critical hallmark of metastatic progression. These findings underscore the potential of EGFR-targeted porphyrin–peptide conjugates as promising PDT agents for the treatment of TNBC. Full article

The epidermal growth factor receptor (EGFR), as an important target protein for inhibiting and intervening in osteoporosis, is associated with cell migration, proliferation, and apoptosis. Peptides derived from food have been shown to have a strong affinity for EGFR, thereby regulating downstream cellular-signaling pathways and participating in stimulating bone formation. However, it is still a “black box” as to how active peptides affect the conformational changes in the EGFR-binding domain when interacting with its ligand EGF. To shed light on the roles, peptides in EGFR binding, which is involved in the osteoblast differentiation, a high EGFR affinity soybean peptide (HEP) was isolated and purified from soy yogurt. Firstly, the osteogenic activity of HEP was identified through cellular alkaline-phosphatase (ALP) and calcium influx. HEP promoted ALP activity from 0.01897 ± 0.00165 to 0.04051 ± 0.00402 U/mg after 100 μM of peptide treatment, and free intracellular calcium ions and calcium deposition both increased in a dose-dependent manner at 1–100 μg/mL. Secondly, the interaction between HEP and EGFR was detected by bioinformatics, spectroscopy analysis, and Western blot. The Molecular docking results showed that HEP (VVELLKAFEEKF) exhibited high affinity among all the peptides, with -CDOCKER energy values of 184.077 kcal/mol on one EGFR. Moreover, a different loop conformation has been detected in HEP, comparing it to that of EGF, which influences HEP interactions with EGFR. GlU3, LEU4, and LEU5 (HEP) match GLU40, LEU26, and GLU40 (EGF). Moreover, the CD data showed that HEP could interact with extracellular domain protein of EGFR, but the secondary structure did not change after HEP was mixed with Mutant extracellular domain protein. Furthermore, treatment with HEP increased the expression of EGFR and the activation of the PI3K-RUNX2-signaling pathway. These results suggested that HEP may have the function of promoting bone remodeling, which could promote the binding between EGF and EGFR and may be used as a potential active factor for functional food development to prevent osteoporosis. Full article

Rhabdomyolysis is characterized by the breakdown of skeletal muscle tissue, frequently leading to acute kidney injury (AKI). Traditional conservative treatments have shown limited effectiveness in modifying the disease course, thereby necessitating targeted pharmacological approaches. Zileuton (Z), a selective inhibitor of 5-lipoxygenase (5-LOX), has demonstrated efficacy in enhancing renal function recovery in animal models of AKI induced by agents such as cisplatin, aminoglycosides, and polymyxins. The present study aimed to evaluate the therapeutic potential of a single dose of Z in mitigating rhabdomyolysis-induced AKI (RI-AKI) via modulation of myeloid-derived suppressor cells (MDSCs). Male C57BL/6 mice were assigned to four experimental groups: Sham (intraperitoneal administration of 0.9% saline), Z (single intraperitoneal injection of Z at 30 mg/kg body weight), glycerol (Gly; single intramuscular dose of 50% glycerol at 8 mL/kg), and glycerol plus Z (Z + Gly; concurrent administration of glycerol intramuscularly and Z intraperitoneally). Animals were sacrificed 24 h post-glycerol injection for analysis. Zileuton administration significantly improved renal function, as indicated by reductions in blood urea nitrogen (BUN) levels (129.7 ± 17.9 mg/dL in the Gly group versus 101.7 ± 6.8 mg/dL in the Z + Gly group, p < 0.05) and serum creatinine (Cr) levels (2.2 ± 0.3 mg/dL in the Gly group versus 0.9 ± 0.3 mg/dL in the Gly + Z group p < 0.05). Histopathological assessment revealed a marked decrease in tubular injury scores in the Z + Gly group compared to the Gly group. Molecular analyses demonstrated that Z treatment downregulated mRNA expression of macrophage-inducible C-type lectin (mincle) and associated macrophage infiltration-related factors, including Areg-1, Cx3cl1, and Cx3CR1, which were elevated 24 h following glycerol administration. Furthermore, the expression of NLRP-3, significantly upregulated post-glycerol injection, was attenuated by concurrent Z treatment. Markers of mitochondrial biogenesis, such as mitochondrial DNA (mtDNA), transcription factor A mitochondrial (TFAM), and carnitine palmitoyltransferase 1 alpha (CPT1α), were diminished 24 h after glycerol injection; however, their expression was restored upon simultaneous Z administration. Additionally, Z reduced protein levels of BNIP3, a marker of mitochondrial autophagy, while enhancing the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), suggesting that Z ameliorates RI-AKI severity through the regulation of mitochondrial quality control mechanisms. Zileuton also decreased infiltration of CD11b(+) Gr-1(+) MDSCs and downregulated mRNA levels of MDSC-associated markers, including transforming growth factor-beta (TGF-β), arginase-1 (Arg-1), inducible nitric oxide synthase (iNOS), and iron regulatory protein 4 (Irp4), in glycerol-injured kidneys relative to controls. These markers were elevated 24 h post-glycerol injection but were normalized following concurrent Z treatment. Collectively, these findings suggest that Zileuton confers reno-protective effects in a murine model of RI-AKI, potentially through modulation of mitochondrial dynamics and suppression of MDSC-mediated inflammatory pathways. Further research is warranted to elucidate the precise mechanisms by which Z regulates MDSCs and to assess its therapeutic potential in clinical contexts. Full article

Ceramide 1-phosphate (C1P) is a key regulator of cell proliferation and survival in both normal and transformed cells. Major pathways implicated in the mitogenic actions of C1P include activation of the mitogen-activated protein kinases (MAPKs) ERK1-2 and JNK, as well as stimulation of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, the product of retinoblastoma, or the sphingomyelin synthase (SMS)/diacylglycerol (DAG)/protein kinase C-alpha (PKC-α) pathway. C1P-stimulated cell proliferation can also be mediated through enhanced secretion of vascular endothelial growth factor (VEGF) in macrophages or by releasing lysophosphatidic acid (LPA) in myoblasts. Also, the production of low levels of reactive oxygen species (ROS) can mediate the stimulation of cell growth by C1P, particularly in macrophages. Upregulation of the PI3K/Akt/mTOR pathway is also involved in the inhibition of cell death by C1P, which can also contribute to cell survival by blocking the activity of the ceramide-generating enzymes acid sphingomyelinase (ASMase) and serine palmitoyl transferase (SPT). Moreover, C1P-promoted cell survival involves upregulation of inducible nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Using photosensitive C1P analogues, it could be concluded that promotion of cell growth and inhibition of cell death were elicited by intracellularly generated C1P in a receptor-independent manner. The aim of the present review is to evaluate in detail the implication of the CerK/C1P axis in controlling cell proliferation and survival in mammalian cells, as well as to discuss and update on the molecular mechanisms by which C1P can accomplish these actions. Full article

Leptin, an adipocyte-derived hormone, plays a central role in the regulation of energy homeostasis by acting on distinct hypothalamic nuclei. This review explores recent advances in our understanding of leptin’s region-specific actions within the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamus, highlighting their contributions to appetite regulation, energy expenditure, and neuroendocrine function. In the hypothalamic arcuate nucleus, leptin’s differential regulation of pro-opiomelanocortin and agouti-related peptide/neuropeptide Y neurons is now complemented by the identification of novel leptin-responsive neuronal populations—such as those expressing prepronociceptin, basonuclin 2, and Pirt—as well as a growing array of cellular and molecular modulators, including secreted factors like angiopoietin-like growth factor, zinc-α2-glycoprotein, and spexin, intracellular regulators such as Rap1, growth factor receptor-bound protein 10, and spliced X-box binding protein 1. In the ventromedial hypothalamus, leptin integrates with both peripheral (e.g., cholecystokinin) and central (e.g., pituitary adenylate cyclase-activating polypeptide) signals, while epigenetic mechanisms, such as those mediated by Jumonji domain-containing protein D3, regulate leptin receptor expression and sensitivity. The dorsomedial hypothalamus is increasingly recognized for coordinating leptin’s effects on metabolism, circadian rhythms, and respiration through distinct neuronal populations, including a subset of neurons co-expressing GLP-1 receptors that mediate leptin’s metabolic effects. In the lateral hypothalamus, leptin modulates reward-driven feeding via GABAergic neuronal populations—circuits that are particularly susceptible to disruption following early life trauma. Together, these insights reveal a sophisticated neurobiological framework through which leptin orchestrates systemic physiology. Understanding the heterogeneity of leptin signaling opens new avenues for restoring leptin sensitivity and developing personalized therapeutic strategies to combat obesity and related metabolic disorders. Full article