Search Results (13,085)

Phytol, an acyclic diterpene alcohol and a key lipophilic side-chain moiety of chlorophyll, is widely distributed in nature. It exhibits potent antioxidant, anti-inflammatory, analgesic and broad-spectrum antibacterial activities. Notably, phytol can also effectively inhibit melanin production, repair the skin barrier, and exert profound anti-aging effects, making it a highly promising ingredient for daily skincare with substantial industrial application value. The skincare benefits of phytol are primarily achieved by constructing a multi-dimensional regulatory network involving defense, modulation and repair. Compared to conventional retinol-based skincare ingredients, phytol exhibits superior biocompatibility, mild irritation, and remarkable safety advantages. Nevertheless, its application is hindered by inherent limitations, including strong hydrophobicity, spontaneous aggregation tendency, and poor photothermal stability. These drawbacks severely restrict its dispersibility, storage stability and percutaneous bioavailability in aqueous cosmetic formulations. To address these deficiencies, nanodrug delivery systems (NDDS), such as liposomes, nanoemulsions, solid lipid nanoparticles and PLGA nanoparticles, have been widely employed. These nanocarriers can penetrate the skin barrier via the size effect, enabling targeted skin delivery and long-term controlled release of phytol. This review systematically summarizes the biological sources and metabolic fate of phytol, as well as its multi-mechanistic pharmacological effects on the skin. Furthermore, we outline the current application status and industrial development trends of phytol in mainstream cosmetics worldwide. This work aims to provide theoretical basis and forward-looking references for the development of high-efficiency, safe and stable phytol-derived skincare raw materials and topical formulations. Highlights: (1) Phytol, a natural acyclic diterpene alcohol, exerts multi-dimensional skincare effects including antioxidant, anti-inflammatory, whitening, anti-aging, and skin barrier repair activities via a defense–modulation–repair regulatory network. (2) Phytol may act as a mild, non-irritating functional alternative to retinoids, targeting PPAR/RXR pathways and avoiding TRPV1-mediated irritation, making it suitable for sensitive skin. (3) Poor water solubility and instability hinder phytol’s translation; nanodelivery systems effectively improve solubility, permeability, and sustained release. Full article

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules that induce the selective degradation of a protein of interest by recruiting an E3 ubiquitin ligase, thereby triggering ubiquitination and proteasomal clearance. As part of the broader targeted protein degradation (TPD) paradigm, PROTACs offer a powerful strategy to eliminate pathogenic proteins that are difficult to modulate with traditional occupancy-based inhibitors. However, their clinical translation is often limited by poor aqueous solubility, suboptimal cellular permeability, and off-target effects. Notably, some PROTACs retain potent biological activity despite limited membrane permeability, owing to their catalytic mechanism of action, which allows even a small number of molecules reaching the target site to drive substantial protein degradation and produce important pharmacological effects. Growing evidence supports the application of PROTAC-based approaches in neurodegenerative diseases, where the selective removal of toxic or misfolded proteins is particularly attractive. This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development. Full article

Hepatocellular carcinoma (HCC) remains difficult to control because recurrence, impaired hepatic reserve, and treatment resistance limit durable benefit. Natural products and traditional Chinese medicine (TCM) provide resources that range from drug-lead discovery to adjunctive multicomponent therapy. This review integrates pharmacological and clinical evidence for purified compounds, semisynthetic derivatives, extracts, formulas, and delivery systems. It focuses on metabolic reprogramming and redox homeostasis, stress responses and regulated cell death, tumor cell plasticity and vascular remodeling, and the immune microenvironment and host response. Recent studies have strengthened selected mechanistic claims through chemical probes, functional perturbation, and resistance models. Clinical research has concentrated on recurrence control after surgery or minimally invasive treatment and on combinations with transarterial chemoembolization, targeted agents, and immunotherapy. Randomized trials and prospective cohorts suggest potential benefit in specific settings, although product standardization, external validation, and long-term follow-up remain limited. Major translational barriers include uncertain active constituents, inadequate batch comparability, missing tumor-exposure data, and sparse herb–drug interaction studies. Future development should match target validation, pharmacokinetics, safety assessment, and clinical endpoints to each product class and clarify whether a candidate is best positioned as a drug lead, adjunctive therapy, or supportive intervention. Full article

Background/Objective: Traditionally derived from the dried leaves of Microcos paniculata L., Microctis folium (M. folium) has been employed to manage various inflammatory and metabolic conditions. Despite its reported hypolipidemic potential, the active constituents contributing to this effect and their molecular mechanisms of action remain to be determined. Therefore, this study aimed to systematically identify the active hypolipidemic constituents of M. folium and elucidate their mechanisms of action through an integrated strategy combining chemical profiling, pharmacokinetic screening, network pharmacology, and experimental validation. Methods: UPLC fingerprint and UPLC-QQQ-MS/MS were employed to characterize and quantify the chemical constituents of M. folium. Pharmacokinetic analysis was conducted to identify systemically absorbed compounds. Network pharmacology was applied to predict potential targets and signaling pathways. The lipid-lowering effects were subsequently validated in vitro using an oleic acid/palmitic acid (OA/PA)-induced lipid accumulation model in HepG2 cells and in vivo in a Triton WR-1339-induced hyperlipidemia mouse model. Results: UPLC fingerprint analysis identified 15 common peaks among 21 batches of M. folium, with similarity values ranging from 0.885 to 0.990, indicating good chemical consistency. Eighteen representative compounds were quantified, among which flavone C-glycosides and phenolic acids were predominant. Pharmacokinetic results demonstrated that multiple M. folium’s constituents were absorbed into systemic circulation. Network pharmacology analysis identified 73 potential targets related to hyperlipidemia and highlighted the PI3K-Akt signaling pathway as a key regulatory pathway. In vitro experiments showed that M. folium’s compounds significantly reduced intracellular lipid accumulation and oxidative stress in OA/PA-induced HepG2 cells. Furthermore, in vivo studies demonstrated that vitexin, ferulic acid, isoferulic acid, and N-trans-feruloyltyramine significantly reduced serum and hepatic lipid levels, including TC, TG, and LDL-c, alleviated hepatic steatosis, and improved liver injury and oxidative stress markers in Triton WR-1339-induced hyperlipidemic mice. Conclusions: M. folium exerts significant lipid-lowering effects through multi-component and multi-target mechanisms involving regulation of lipid metabolism and oxidative stress, partly mediated by activation of the PI3K-Akt signaling pathway. These findings provide a scientific basis for the development of M. folium’s natural agents for the treatment of hyperlipidemia. Full article

Myocardial bridging (MB) is a congenital coronary anomaly in which a segment of an epicardial coronary artery courses intramurally beneath the myocardium for part of its length, resulting in dynamic compression during systole. Once considered a largely benign incidental finding, accumulating evidence has demonstrated MB to be a clinically significant substrate for myocardial ischemia, arrhythmia, and sudden cardiac death (SCD), particularly under conditions of elevated adrenergic drive such as vigorous physical exercise. The prevalence of MB is highly dependent on the diagnostic modality used, ranging from approximately 0.5–2.5% on coronary angiography to 15–85% on post-mortem and advanced intravascular imaging studies, reflecting a substantial detection gap- in particular on routine cardiac screening tests. This review critically examines the current evidence base regarding MB in the context of competitive and recreational sport. We address: (1) the pathophysiology of exercise-induced hemodynamic compromise in MB; (2) the limitations of existing screening modalities—including electrocardiography, echocardiography, exercise stress testing, and advanced coronary imaging in identifying athletes at risk; (3) the clinical management of symptomatic MB, encompassing pharmacological therapy, coronary revascularization strategies, and catheter-based interventions; and (4) physical activity guidance for athletes with known or suspected MB. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal cell carcinoma (RCC), representing approximately 80% of cases globally. Despite improved diagnosis and therapy, treatment of aggressive or metastatic ccRCC remains challenging due to acquisition of primary or secondary resistance. Among the dysregulated signaling mechanisms identified in ccRCC, the mechanistic target of rapamycin (mTOR) and the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) pathways play central roles in regulating various biological functions such as metabolism, inflammation, tumor growth, and survival. However, the molecular crosstalk between mTOR and NF-κB signaling in ccRCC progression and therapeutic resistance remains poorly understood. Therefore, in our current study, we aimed to investigate the interplay between mTOR and NF-κB signaling in ccRCC. We analyzed tumor tissue samples from human ccRCC patients. For validation of mTOR and NF-κB signaling, we used two human ccRCC cell lines, A498 and 786-O. Using pharmacological inhibitors of mTOR and IKK/NF-κB signaling, Torin-1 and MLN120B, respectively, we assessed the functional relationship between these two pathways employing immunoblotting, EdU-based immunocytochemistry, and functional assays. Our findings reveal that both mTOR and NF-κB pathways are aberrantly activated in human ccRCC tissues. Phosphorylation of IκBα, S6, and 4E-BP1 was increased compared with matched adjacent control tissue. In A498 and 786-O cells, pharmacological inhibition of mTOR or IKK/NF-κB altered key readouts of the reciprocal pathway, including AKT, S6, 4E-BP1, IκBα and p65 phosphorylation. Both inhibitors reduced cell number and EdU incorporation, with stronger anti-proliferative effects observed after Torin-1 treatment. Pharmacological inhibition of either pathway altered key readouts of the other pathway, supporting a reciprocal functional association between mTOR- and NF-κB-associated signaling in the ccRCC models analyzed. Our findings support a functional association between mTOR- and NF-κB-associated signaling in the ccRCC models and provide a rationale for further mechanistic studies evaluating combined pathway modulation. Full article

Chronic pain continues to be a major global health burden and is frequently refractory to conventional pharmacologic and conservative therapies. Spinal cord stimulation (SCS) has emerged as an important neuromodulatory treatment for selected patients with chronic neuropathic and mixed pain syndromes. Since its introduction in the 1960s, SCS has evolved from paresthesia-based tonic stimulation into more adaptive and personalized neuromodulation. This review summarizes the current evidence regarding the mechanisms, clinical applications, technological advances, and future directions of SCS therapy. Mechanistically, SCS modulates nociceptive transmission through dorsal column and dorsal horn pathways, inhibitory neurotransmitter systems, wide-dynamic-range neuronal activity, and supraspinal pain-processing networks. Technological advances have expanded available stimulation paradigms, including burst stimulation, high-frequency stimulation, closed-loop evoked compound action potential-controlled systems, and differential target multiplexed stimulation. These approaches aim to improve analgesic durability, reduce the burden of paresthesia, and address mechanisms such as neuroinflammation and neural habituation. Clinically, SCS is used for conditions including failed back surgery syndrome, complex regional pain syndrome, painful diabetic neuropathy, ischemic limb pain, and emerging non-traditional pain states. However, outcomes remain variable and are influenced by psychological readiness, pain phenotype, anatomic factors, trial response, neurophysiologic markers, and patient engagement. Complications such as lead migration, infection, implantable pulse generator malfunction, and loss of efficacy remain important considerations. Future progress in SCS will likely depend on artificial intelligence, remote monitoring, biomarker-guided programming, and integration with multidisciplinary chronic pain care. Full article

Cannabidiol (CBD), the principal non-psychoactive phytocannabinoid of Cannabis sativa, exhibits diverse pharmacological activities through interactions with multiple molecular targets. Thus, breast, colorectal, and lung cancers arise from distinct molecular mechanisms. This study investigated the potential multi-target pharmacological mechanisms of CBD using an integrated approach combining network pharmacology and molecular docking. CBD-associated targets from three prediction platforms were intersected with disease-associated genes for each cancer type, yielding 143 overlapping targets that formed a significantly enriched protein–protein interaction network. Maximal Clique Centrality (MCC) analysis identified 10 hub proteins, including SRC, SIRT1, PTGS2 (COX-2), PPARG, NFKB1, MMP2, IGF1R, ESR2, ESR1, and EGFR, which represent key regulators of hormone signaling, inflammation, cell proliferation, and tumor progression. Molecular docking against these targets, benchmarked using each protein’s authentic co-crystallized ligand, predicted predominantly moderate binding affinities for CBD. Compared with the corresponding reference ligands, CBD generally exhibited lower predicted binding affinity, although comparable or slightly stronger scores were observed for PTGS2, ESR2, and EGFR. Independent validation using AutoDock Vina demonstrated overall agreement with the MOE docking results, supporting the robustness of the predicted binding profiles. Collectively, these findings suggest that CBD may exert its biological activity through coordinated modulation of multiple cancer-related signaling pathways rather than a single molecular target. By integrating pooled cancer-associated network pharmacology with co-crystallized ligand benchmarking, this study provides a computational framework for prioritizing biologically relevant CBD targets for future experimental validation. These findings should be regarded as hypothesis-generating rather than evidence of clinical efficacy. Full article

Extravillous trophoblast (EVT) differentiation is essential for placental development and successful pregnancy, yet the molecular mechanisms regulating this process remain incompletely understood. CREB-binding protein (CREBBP) and E1A-binding protein p300 (EP300) are closely related lysine acetyltransferases that function as transcriptional co-activators. Previous studies reported that EP300 depletion impairs EVT differentiation whereas CREBBP depletion has little or no effect. We found that CREBBP mRNA expression was approximately one-third of EP300 expression in trophoblast stem cells (TSCs) and differentiated trophoblast lineages. To investigate whether differential CREBBP and EP300 expression explains this asymmetry in EVT differentiation initiation, we combined siRNA-mediated knockdown, CRISPR-generated CREBBP-deficient TSCs, pharmacological inhibition, and lentiviral Crebbp overexpression during EVT differentiation. While CREBBP depletion alone produced minimal phenotypic effects, CREBBP-deficient cells displayed increased sensitivity to the CREBBP/EP300 inhibitor A-485, with inhibitory effects appearing at lower A-485 concentrations in cells with reduced CREBBP level. Moreover, increased CREBBP expression partially rescued the EP300-depletion phenotype, including EVT-like morphology and selected differentiation marker expression. Together, these findings demonstrate that CREBBP contributes to EVT differentiation, but its role is obscured by its lower endogenous expression. We propose that the combined contributions of CREBBP and EP300, rather than EP300-specific activity alone, influence human trophoblast differentiation efficiency. Full article

Aconitum L. species are widely recognized for their highly bioactive diterpenoid alkaloids, which contribute to their therapeutic potential and substantial toxicity. While Asian and European Aconitum species have been extensively studied in traditional medicine, phytochemistry, pharmacology, and toxicology, North American species remain comparatively underexplored. This review examines the ethnobotanical records, phytochemical data, toxicological mechanisms, and reported biological activities of North American Aconitum species, with emphasis on A. delphiniifolium and A. columbianum, the only native North American species with published alkaloid characterization. The literature was collected from scientific databases and ethnobotanical sources, with comparisons made to the better-studied Asian medicinal species, A. carmichaelii. Available research indicates that North American Aconitum species have limited documented medicinal use, although Alaskan Native groups historically used Aconitum-derived poisons in whale hunting. Phytochemical studies identified at least fifteen diterpenoid alkaloids in A. delphiniifolium and A. columbianum, including several compounds also found in A. carmichaelii with reported analgesic, anti-inflammatory, neuroprotective, and cytotoxic activities. However, direct pharmacological studies on North American species are lacking. These findings suggest that limited exploration of North American Aconitum reflects historical and research bias rather than the absence of therapeutic potential and highlights a significant research gap to support further metabolomic, pharmacological, and toxicological investigations of North American Aconitum species. Full article

Juniperus species are a rich source of pharmacologically important secondary metabolites, including terpenoids, lignans, flavonoids, and phenolic compounds. However, the commercial utilization of these metabolites is limited by the plant’s slow growth, poor natural regeneration, and environmental variability affecting metabolite accumulation. Integrating plant tissue culture with elicitation strategies is a promising approach for sustainably producing these valuable compounds. This review summarizes the diversity, biological activities, and biotechnological significance of secondary metabolites in Juniperus, focusing on tissue culture systems and enhancement of metabolite biosynthesis through elicitors. It critically evaluates the current knowledge of the effects of signaling compounds such as methyl jasmonate (MeJA), jasmonic acid (JA), and salicylic acid (SA), as well as other abiotic and biotic elicitors including silver nanoparticles (AgNPs), chitosan, and chito-oligosaccharides. Particular attention is given to their effects on podophyllotoxin, phenolic, flavonoid, and other bioactive metabolite accumulation. Elicitation responses appear to depend strongly on species, culture system, elicitor type, and treatment conditions. This review also highlights major knowledge gaps, particularly the limited understanding of the regulatory mechanisms controlling secondary-metabolite biosynthesis in Juniperus species. Overall, the available evidence suggests that integrating optimized elicitation strategies with transcriptomics, metabolomics, and metabolic engineering could improve our understanding of secondary metabolite regulation and facilitate the development of sustainable Juniperus tissue culture platforms for producing high-value natural products. Full article

Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones that transport fatty acids and other hydrophobic molecules, playing essential roles in cellular lipid metabolism, signaling, and brain function. Within the central nervous system, FABP3, FABP5, and FABP7 facilitate the trafficking of long-chain polyunsaturated fatty acids and endocannabinoids, thereby modulating key regulatory pathways including the endocannabinoid system (ECS), peroxisome proliferator-activated receptor (PPAR) signaling, and dopaminergic neurotransmission. Peripherally, FABP1 and FABP4 contribute to hepatic drug metabolism, kidney excretion, and inflammatory processes in both tissues, with implications for the pharmacokinetics of substances of abuse. This narrative review synthesizes the current literature on FABPs and their involvement in substance use and addiction-related behaviors. Evidence from transgenic knockout models, pharmacological inhibition studies, and adeno-associated virus vector approaches demonstrates that manipulation of FABP subtypes can alter reward-related behaviors across multiple substances, including THC, ethanol, nicotine, and cocaine. Reduction or knockout of FABP7 alters THC metabolite levels in a sex-dependent manner. FABP3 shows involvement with dopamine receptor expression; however, interaction between FABP3 modulation and specific substances has sparsely been investigated. FABP5 has vastly diverging interactions with addictive behavior and appears to be substance dependent, as downregulation reduces cocaine self-administration, but knockout enhances nicotine conditioned place preference (CPP) and increases brain uptake of THC. Combined deletion of FABP5 and 7 additionally reduces cocaine CPP and reinstatement, while showing promising decreases in ethanol consumption paradigms. FABPs may be a potential therapeutic target for treating substance use disorders and underlying reward deficiency mechanisms underlying addiction and further research is required to elucidate specific mechanistic effects and eliminate potential adverse consequences of chronic FABP modulation. Full article

Skin photoaging resulting from chronic ultraviolet A (UVA) exposure is closely associated with mitochondrial dysfunction and impaired cellular homeostasis. Mitophagy is an important mitochondrial quality control process, but the role of FUNDC1-associated mitophagy-related activity in skin photoaging remains incompletely understood. Here, we investigated the function and regulatory mechanisms of FUNDC1 in UVA-induced photoaging models. FUNDC1 expression was reduced in UVA-exposed human dermal fibroblasts (HDFs) and in photoaged mouse skin. FUNDC1 knockdown aggravated photoaging-associated phenotypes, mitochondrial dysfunction, and altered autophagy/mitophagy-related activity, whereas FUNDC1 overexpression attenuated these changes in vitro and in vivo. Pharmacological modulation further showed that Rapa partially counteracted FUNDC1 knockdown-associated effects, while Mdivi-1 weakened the protective effects associated with FUNDC1 overexpression, supporting the involvement of mitophagy-related mitochondrial quality control. Mechanistically, miR-137-3p was upregulated during UVA-induced photoaging and negatively regulated FUNDC1 expression through the predicted FUNDC1 3′UTR binding site. In addition, FUNDC1 was concerned with proteasome-dependent regulation of P53 protein stability. BAZ1B was identified as a candidate P53-associated ubiquitination regulator that participated in FUNDC1-associated regulation of P53 ubiquitination and stability. LC-MS/MS analysis combined with site-directed mutagenesis further manifested that P53 K292 was a major ubiquitination site involved in BAZ1B-associated regulation of P53 stability. In vivo, BAZ1B knockdown attenuated FUNDC1-associated protection against UVA-induced skin photoaging and reduced P53 ubiquitination. Collectively, these findings indicate that FUNDC1 can attenuate UVA-induced skin photoaging by preserving mitophagy-related mitochondrial homeostasis and modulating BAZ1B-associated P53 stability, with miR-137-3p acting as an upstream negative regulator of FUNDC1. Full article

Background and Objectives: Acute rhinosinusitis is associated with a substantial deterioration in quality of life, including symptoms such as nasal obstruction, facial pressure, cough, and sleep disruption. Growing interest in non-pharmacological management strategies has been observed, particularly among populations in whom systemic treatments may be limited, such as pediatric patients and pregnant individuals. NESOSPRAY HE-G is a nasal device containing a filmogenic glycerol formulation designed to create a protective barrier and induce an osmotic effect, thereby promoting nasal decongestion and mucosal protection. Materials and Methods: A randomized, double-blind, placebo-controlled study was conducted to assess the performance and safety of NESOSPRAY HE-G (n = 20) compared with a saline comparator (n = 20) in patients aged 3 years and older presenting with acute rhinosinusitis and a baseline Rhino-Sinusitis Severity Score (RSSS) of at least 25/50. The investigational product was administered as three sprays per nostril, four times daily, over a maximum period of 15 days or until symptom resolution. Efficacy was primarily evaluated through changes in the total RSSS and in key symptoms, including nasal congestion, facial pain, cough, sleep disturbance, and fever. Safety assessments included monitoring adverse events (AE) and evaluating local tolerability. Results: Baseline characteristics were comparable between groups. Treatment with NESOSPRAY HE-G resulted in a statistically significant reduction in total RSSS from Day 2 onwards, with sustained effects throughout the study period. Improvements were also observed across individual symptoms, including early relief of nasal congestion and reductions in cough and facial pain, with faster onset compared to the comparator. Sleep quality showed progressive improvement. Resolution of fever occurred in both groups, with an earlier effect observed in the NESOSPRAY HE-G arm. No serious adverse events (SAE) or hypersensitivity reactions were reported. The product demonstrated good tolerability. Conclusions: NESOSPRAY HE-G provides rapid and sustained alleviation of symptoms associated with acute rhinosinusitis. Its topical mode of action, based on osmotic activity and barrier formation, represents a suitable non-pharmacological option, particularly for patients seeking alternatives to systemic therapies or presenting contraindications to such treatments. Full article

Ancient cultures have long studied plants for medicinal use. Today, multidisciplinary research focuses on re-evaluating these plants to discover drugs for treating various diseases, including psychiatric disorders. Pre-Columbian Mesoamerican cultures described three plants (Montanoa tomentosa, Montanoa frutescens, and Montanoa grandiflora) for treating both anxiety and depression disorders, which were called cihuapahtli in Nahuatl. This narrative review describes and analyzes the ethnobotanical use and phytochemical, pharmacological, behavioral, and toxicological effects of cihuapahtli, which can contribute to the discovery of anxiolytic and antidepressant drugs. The results show a significant advance in identifying bioactive phytochemicals, including triterpenes, diterpenes, monoterpenes, and sesquiterpenes, as well as sterols, flavonoids, and alkaloids. In particular, the mechanism of action underlying their anxiolytic and antidepressant effects involves the activation of oxytocinergic neurons in the paraventricular nucleus of the hypothalamus, as well as that of the GABAergic system by targeting GABA_A receptors. The three Montanoa species have the potential to help us develop anxiolytic and antidepressant drugs; however, future studies are still required to evaluate toxicity, dose standardization, possible variability in plant-derived compounds, pharmacokinetic parameters, and pharmacological interactions. Only then will preclinical evidence be sufficiently robust to justify translational studies evaluating the safety and efficacy of these plant extracts for the development of anxiolytic and antidepressant phytomedicines. Full article