Search Results (1,839)

Breast cancer ranks as the fifth-most-prevalent malignancy worldwide, characterized by high heterogeneity and multifactorial etiology across molecular subtypes. Despite advancements in conventional therapies, including surgery and chemotherapy, persistent challenges such as treatment-related adverse effects and acquired drug resistance necessitate alternative therapeutic strategies. Matrine, a naturally occurring alkaloid derived from Sophora flavescens, has demonstrated significant anticancer potential through multiple mechanisms. Experimental evidence indicates that matrine exerts inhibitory effects on tumor cell proliferation, promotes apoptosis, and attenuates metastatic progression via modulation of critical signaling pathways, particularly PI3K/Akt, JAK/STAT, NF-κB, MAPK/ERK, and Wnt/β-catenin. This review systematically examines subtype-specific responses to matrine treatment, highlighting its potential utility in precision oncology for distinct breast cancer classifications. Furthermore, we evaluate matrine’s capacity to synergize with standard chemotherapeutic regimens, potentially overcoming drug resistance while reducing required dosages. By integrating current preclinical and clinical findings, this analysis provides new perspectives on matrine’s therapeutic applications and underscores the imperative for translational studies to establish optimized treatment protocols for clinical implementation. Full article

Diabetes mellitus (DM) is a multifactorial metabolic disorder characterized by chronic hyperglycemia and systemic metabolic dysregulation. Although ginsenosides, the primary bioactive components of Panax ginseng Meyer, exhibit regulatory effects on glucose and lipid metabolism, their precise mechanisms and key targets in DM remain incompletely understood. Unlike previous studies focusing solely on crude extracts or individual ginsenosides, this study integrates network pharmacology, molecular docking, and molecular dynamics (MD) simulations to systematically elucidate the multi-target mechanisms of ginsenosides, with experimental validation using the ginsenoside derivative AD-1. Network pharmacology identified 134 potential targets, with protein–protein interaction (PPI) analysis revealing 25 core targets (such as NFKB1, HDAC1, ESR1, and EP300). Molecular docking and MD simulations showed that ginsenosides have stable binding conformations with these targets and exhibit excellent dynamic stability. Notably, in vivo experiments using AD-1 in streptozotocin-induced type 1 diabetic mice confirmed its therapeutic efficacy, significantly downregulating key diabetic markers (e.g., NFKB1 and HDAC1) in pancreatic tissues—a finding unreported in prior studies. This study not only revealed the multitarget pharmacological mechanism of ginsenosides but also highlighted the therapeutic potential of AD-1. These findings provide a foundation for further mechanistic studies and suggest new strategies for the application of novel ginsenoside derivatives in diabetes therapy. Full article

Astaxanthin (ASX) is a xanthophyll carotenoid mainly derived from marine microalgae such as Haematococcus pluvialis and Chlorella zofingiensis, as well as the yeast Phaffia rhodozyma. Its chemical nature structure, rich in conjugated double bonds, carbonyl, and hydroxyl groups, confers potent antioxidant and anti-inflammatory properties. ASX modulates oxidative stress via the PI3K/Akt-Nrf2 pathway and suppresses NF-κB-mediated inflammatory responses, reducing cytokine levels such as TNF-α, IL-6, and iNOS. ASX exerts dual apoptotic effects, cytoprotective in non-transformed cells and pro-apoptotic in cancer cells through p53 activation. Sustainable extraction techniques, especially supercritical CO₂, have improved its industrial applicability. Recent findings highlight ASX’s role in stem cell biology, enhancing proliferation, supporting lineage-specific differentiation, and protecting against oxidative and inflammatory damage, which is a crucial issue for regenerative medicine applications. These multifaceted molecular effects support ASX’s therapeutic potential in chronic diseases, including diabetes, cardiovascular pathologies, and cancer. This review outlines ASX’s natural sources, extraction methods, and biological mechanisms, emphasizing its application in oxidative stress- and inflammation-related conditions. Full article

Background: MicroRNAs (miRNAs) in follicular fluid (FF) are being recognized as important regulators of ovarian function and biomarkers of reproductive success. This systematic analysis investigates FF-derived miRNAs and their relationship to polycystic ovarian syndrome (PCOS) and in vitro fertilization (IVF) outcomes. Methods: Following PRISMA recommendations, 21 original papers were included that looked at miRNA expression in FF or granulosa cells from women undergoing IVF, with or without PCOS. The study design, miRNA profiling methodologies, IVF protocols, and clinical results were gathered and analyzed. Results: Across the investigations, 15 miRNAs were regularly implicated, including miR-132, miR-320, miR-222, miR-224, miR-146a, and miR-93. Downregulation of miR-132 and miR-320 was consistently detected in PCOS and associated with decreased steroidogenesis. Elevated miR-222 and miR-146a were linked to insulin resistance and follicular inflammation. In IVF, miR-202-5p and miR-224 were elevated in high-quality embryos and successful cycles, indicating that they have roles in granulosa cell proliferation and estrogen synthesis. MiRNA dysregulation was linked to critical pathways, such as PI3K/AKT, NF-κB, TGF-β, and WNT. Conclusions: Specific FF miRNAs are consistently linked to PCOS pathogenesis and IVF effectiveness. Their use into noninvasive biomarker panels could improve embryonic selection and personalized reproductive care. Full article

Natural compounds have garnered increasing interest as potential antitumor agents due to their multifaceted biological activities and relatively low toxicity profiles. This review focuses on three well-studied natural molecules: rhein, curcumin, and resveratrol, analyzing and comparing their antitumor potential across a variety of cancer models. For each compound, we present an integrated perspective encompassing natural sources, physicochemical properties, pharmacological and pharmacokinetic characteristics, and the latest in vitro and in vivo evidence of anticancer activity. Special attention is given to the molecular mechanisms underlying their antitumor effects, including the modulation of cell cycle regulators, induction of apoptosis, inhibition of metastasis and angiogenesis, and regulation of key signaling pathways such as NF-κB, PI3K/Akt/mTOR, STAT3, and MAPKs. Although numerous studies highlighted their therapeutic promise, significant barriers remain—particularly related to poor solubility and limited bioavailability—which have hindered clinical translation, especially in the case of rhein. Advances in nanotechnology-based drug delivery systems offer promising solutions to these limitations, enabling improved targeting and enhanced efficacy. This review underscores the need for continued preclinical and clinical investigations to fully elucidate the therapeutic value of these compounds and support their integration into modern oncological treatment strategies. Full article

Cyanobacterial extracts offer significant potential for the development of new natural antioxidants and biologically active compounds with applications in various industries. Data on the genus Tolypothrix are limited; therefore, the aim of the present study was to investigate the anticancer, antioxidant and anti-inflammatory activity of extracts prepared from strains of this genus. Cytotoxicity and anticancer activity were evaluated by in vitro tests with four cell lines using the MTT assay. The assessment of antioxidant activity was performed by the DPPH and ABTS methods in combination with the calculation of the total phenolic content. Anti-inflammatory activity was investigated using the LPS-stimulated macrophage model (RAW264.7) and subsequent measurement of the levels of secreted cytokines IL-6 and TNF-α. The lipid content and fatty acid composition of the non-polar extracts were determined by gas chromatography (GC). To elucidate the mechanism of cytotoxicity/anticancer action of the non-polar extracts, the effects of stearidonic acid, which was detected in four of the studied cyanobacterial strains, were additionally tested on the same cell lines. A molecular docking analysis was performed simulating the interaction between stearidonic acid and its target molecules and receptors (ALOX5, COX-2, NF-kB and PPAR-γ). In all cancer cell lines (but not in the normal one), dose-dependent cytotoxic effects were observed after exposure to different concentrations of non-polar Tolypothrix extracts. The most pronounced inhibitory effect was observed on the HT-29 cell line, with an IC₅₀ value of 106.27 µg/mL. A dose-dependent antioxidant effect was established for all tested extracts, measured by both DPPH and ABTS methods. All non-polar extracts reduced the production of pro-inflammatory cytokines IL-6 and TNF-α in LPS-stimulated macrophages RAW264.7, and the effects were dose-dependent. Analysis of the fatty acid composition revealed 26 different fatty acids. Our conclusion is that the Tolypothrix strains exhibit anticancer, antioxidant, and anti-inflammatory activity and could be a promising source for the production of natural products. Full article

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality globally, prompting the investigation of novel therapeutic targets. Progranulin (PGRN), a glycoprotein initially associated with neurodegenerative disorders, has emerged as a critical protective agent in cardiovascular health. Recent studies indicate that PGRN exerts its protective effects through various mechanisms, including the modulation of inflammatory pathways, enhancement of mitochondrial function, and promotion of vascular integrity. By engaging with key signaling pathways, such as PI3K/Akt, NF-κB and Wnt/β-catenin, PGRN mitigates oxidative stress and fosters an environment conducive to cardiac repair following ischemic injury. Furthermore, PGRN’s role in lipid metabolism and vascular smooth muscle cell behavior highlights its complexity in influencing atherogenesis and vascular homeostasis. This review synthesizes current knowledge regarding PGRN’s protective mechanisms in CVD, emphasizing its potential as a therapeutic target and paving the way for innovative approaches to prevent and treat cardiovascular diseases, ultimately improving patient outcomes in this critical area of public health. Full article

The neurotrophic system includes neurotrophins, such as brain-derived neurotrophic factor (BDNF) and its precursor proBDNF, which play conflicting roles in neuronal survival and apoptosis, with their balance having a significant impact on neurodegenerative outcomes. While BDNF is widely acknowledged as a potent neurotrophin that promotes neuronal survival and differentiation, its precursor, proBDNF, has the opposite effect, promoting apoptosis and neuronal death. This review highlights the new and unique aspects of BDNF/proBDNF interaction in the modulation of neuronal apoptotic pathways in neurodegenerative disorders. It systematically discusses the cross-talk in apoptotic signaling at the molecular level, whereby BDNF activates survival pathways such as PI3K/Akt and MAPK/ERK, whereas proBDNF activates p75NTR and sortilin to induce neuronal apoptosis via JNK, RhoA, NFkB, and Rac-GTPase pathways such as caspase activation and mitochondrial injury. Moreover, this review emphasizes the factors that affect the balance between proBDNF and BDNF levels within the context of neurodegeneration, including proteolytic processing, the expression of TrkB and p75NTR receptors, and extrinsic gene transcription regulators. Cellular injury, stress, or signaling pathway alterations can disrupt the balance of BDNF/proBDNF, which may be involved in apoptotic-related neurodegenerative diseases like Alzheimer’s, Parkinson’s, and Huntington’s diseases. This review provides a comprehensive framework for targeting neurotrophin signaling in the development of innovative therapies for neuronal survival and managing apoptotic-related neurodegenerative disorders, addressing the mechanistic complexity and clinical feasibility of BDNF/proBDNF interaction. Full article

Background/Objectives: This study aimed to investigate the effects of thyroxine replacement therapy (TRT) on serum Maresin 1 and nuclear factor kappa beta (NF-kB) levels in patients with Hashimoto’s thyroiditis (HT). Methods: A total of 90 patients were included in this study, 60 with HT and 30 without. Patients in the HT group were divided into two groups according to whether they received TRT. Group 1 included 30 patients who underwent TRT, and Group 2 comprised 30 patients who were newly diagnosed with HT, either euthyroid or hypothyroid. The analysis included serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), thyroid peroxidase antibody (TPOAb), Maresin 1, and NF-kB. Results: The serum NF-kB level in the TRT group was significantly higher than that in the control and non-TRT groups. In the subgroup analysis of patients who did not receive TRT, the serum NF-kB level in euthyroid patients was significantly lower than that in hypothyroid patients. Maresin 1 levels in the control group were significantly higher than those in patients who did and did not receive TRT. The serum Maresin 1 level in the TRT group was significantly lower than that in the untreated group. Maresin 1 levels were higher in the euthyroid group than in the hypothyroid group. TPOAb levels were positively correlated with NF-kB and negatively correlated with Maresin 1. Conclusions: TRT maintains the euthyroid state in patients with HT, but may not contribute positively to the pro-anti-inflammatory balance in these patients. Full article

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review examines recent advances in combating P-gp-mediated resistance, including the development of novel P-gp inhibitors, innovative drug delivery systems (e.g., nanoparticle-based delivery), and strategies to modulate P-gp expression or activity. These modulation strategies encompass targeting relevant signaling pathways (e.g., NF-κB, PI3K/Akt) and exploring drug repurposing. While progress has been made, overcoming P-gp-mediated resistance remains crucial for improving patient outcomes. Future research directions should prioritize the development of potent, selective, and safe P-gp inhibitors with minimal off-target effects, alongside exploring synergistic combination therapies with existing chemotherapeutics or novel agents to effectively circumvent multidrug resistance in hematological malignancies. Full article

Alcoholic beverages play a significant role in social engagement worldwide. Excessive alcohol causes a variety of health complications. Alcohol-induced liver disease (ALD) is responsible for the bulk of linked fatalities. The activation of immune mechanisms has a crucial role in developing ALD. No effective medication promotes liver function, shields the liver from harm, or aids in hepatic cell regeneration. Alcohol withdrawal is one of the most beneficial therapies for ALD patients, which improves the patient’s chances of survival. There is a crucial demand for safe and reasonably priced approaches to treating it. Exploring naturally derived phytochemicals has been a fascinating path, and it has drawn attention in recent years to modulators of inflammatory pathways for the prevention and management of ALD. In this review, we have discussed the roles of various immune mechanisms in ALD, highlighting the importance of intestinal barrier integrity and gut microbiota, as well as the roles of immune cells and hepatic inflammation, and other pathways, including cGAS-STING, NLRP3, MAPK, JAK-STAT, and NF-kB. Further, this review also outlines the possible role of phytochemicals in targeting these inflammatory pathways to safeguard the liver from alcohol-induced injury. We highlighted that targeting immunological mechanisms using phytochemicals or herbal medicine may find a place to counteract ALD. Preclinical in vitro and in vivo investigations have shown promising results; nonetheless, more extensive work is required to properly understand these compounds’ mechanisms of action. Clinical investigations are very crucial in transferring laboratory knowledge into effective patient therapy. Full article

Congenital diaphragmatic hernia (CDH) is a complex disorder whereby improper formation of the diaphragm allows herniation of the internal organs into the thoracic cavity, resulting in pulmonary hypoplasia among other complications. Although epithelial dysfunction is central to CDH pathology, relatively little attention has been paid to the underlying mechanisms orchestrating epithelial malfunction. Proinflammatory signaling downstream of impaired mechanotransduction due to in utero lung compression has been elucidated to drive epithelial cell phenotypes. This has been illustrated by a reduction in nuclear YAP and the upregulation of NF-kB in CDH models. In this review, we draw from recent findings using emerging technologies to examine epithelial cell mechanisms in CDH and discuss the role of compression as a central and, crucially, sufficient driver of CDH phenotypes. In recognition of the limitations of using genetic knockout models to recapitulate such a heterogenic and etiologically complicated disease, we discuss alternative models such as the established nitrofen rat model, air–liquid interface (ALI) cultures, organoids and ex vivo lung explants. Throughout, we acknowledge the importance of involving mechanical compression in the modeling of CDH in order to faithfully recapitulate the disease. Finally, we explore novel therapeutic strategies from stem cell and regenerative therapies to precision medicine and the importance of defining CDH endotypes in order to guide treatments. Full article

Microbially synthesized postbiotics have unique properties and advantages; however, systematic studies on the efficient production and biological functions of postbiotics from Bacillus subtilis are limited, which greatly restricts their applications. In this study, we obtained a novel crude exopolysaccharide (EPS) postbiotic from Bacillus subtilis H4. We systematically optimized the EPS production strategy using single-factor analysis, Plackett–Burman design, the path of steepest ascent method, and response surface methodology. The optimized EPS yield was significantly improved, with a maximum yield of 15.01 g/L under the addition of 4.12% soy peptone, 8.99% sucrose, and 0.06% MnSO₄. We found that EPS is a neutral, heterogeneous polysaccharide with a pyranose ring, with a molecular weight of 44,304.913 kDa and a melting point of 218 °C. It consists of glucose, galactose, arabinose, glucosamine, and mannose at a molar ratio of 58.85:19.81:14.75:10.89:6.58. EPS exhibits strong antioxidant capacities, scavenging ABTS and DPPH radicals with IC50 values of 1 and 6 mg/mL, respectively. Moreover, it shows notable anti-inflammatory properties, dramatically inhibiting the lipopolysaccharide (LPS)-induced elevation of nitric oxide (NO) levels and over-activation of the TLR4-NF-κB signaling pathway. These findings highlight the potential of EPS as a multifunctional bioactive compound, offering great promise for its application in the food, clinical, and feed industries. Full article

Neuroinflammatory responses are central to the pathogenesis of neurodegenerative diseases, affecting cells of both neuronal and glial origin that respond to immune-driven inflammatory stimuli. The PI3K/mTOR signaling pathway is essential for the regulation of these neuroinflammatory processes and is therefore a promising target for therapeutic intervention. Here, we investigated the consequences of PI3K/mTOR pathway inhibition on neuroinflammation employing PF-04691502, an agent with combined PI3K and mTOR inhibitory activity. We treated SH-SY5Y, C6, BV-2, and Mo3.13 cell lines with PF-04691502 at concentrations of 0.1, 0.5, and 1 µM to assess the modulation of neuroinflammatory responses. To induce inflammation, cells were stimulated with lipopolysaccharide (LPS, 1 μg/mL) and interferon-gamma (IFN-γ, 100 U/mL). The results from the MTT assays demonstrated that PI3K/mTOR inhibition preserved cell viability at 0.5 and 1 µM across all of the cell lines, indicating its potential to mitigate inflammation-driven cytotoxicity. Subsequent ELISA assays revealed a marked decrease in the NF-κB and pro-inflammatory cytokine levels, confirming the effective suppression of inflammation through PI3K/mTOR inhibition. In addition, the SH-SY5Y cell line was exposed to MPP+ to simulate Parkinson’s disease (PD)-like toxicity; then, cell viability, PD-associated markers, and apoptotic indicators were assessed. Our results indicate that inhibition of the PI3K/mTOR signaling axis may alleviate neurodegenerative processes by modulating both neuroinflammatory responses and apoptotic pathways. These findings highlight the therapeutic promise of targeting PI3K/mTOR in the context of neurodegenerative disorders and support the need for further validation through in vivo and clinical investigations. Full article

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. These lesions are the result of the aberrant cell signaling step proteins, which normally regulate cell proliferation. Mitogen-activated protein kinase (MAPK) pathways and tyrosine kinase receptors are involved in tumorigenesis of low-grade gliomas. High-grade gliomas may carry similar mutations, but loss of epigenetic control is the dominant molecular event; it can occur either due to histone mutations or inappropriate binding or unbinding of DNA on histones. Therefore, despite the absence of genetic alteration in the classic oncogenes or tumor suppressor genes, uncontrolled transcription results in tumorigenesis. Isocitric dehydrogenase (IDH) mutations do not predominate compared to their adult counterpart. Embryonic tumors include medulloblastomas, which bear mutations of transcription-regulating pathways, such as wingless-related integration sites or sonic hedgehog pathways. They may also relate to high expression of Myc family genes. Atypical teratoid rhabdoid tumors harbor alterations of molecules that contribute to ATP hydrolysis of chromatin. Embryonic tumors with multilayered rosettes are associated with microRNA mutations and impaired translation. Ependymomas exhibit great variability. As far as supratentorial lesions are concerned, the major events are mutations either of NFkB or Hippo pathways. Posterior fossa tumors are further divided into two types with different prognoses. Type A group is associated with mutations of DNA damage repair molecules. Lastly, germ cell tumors are a heterogeneous group. Among them, germinomas manifest KIT receptor mutations, a subgroup of the tyrosine kinase receptor family. Full article