Biomolecules & Therapeutics最新文献

Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein involved in macrophage polarization, apoptosis, and inflammation, and carcinogenesis. The expression of CHI3L1 is significantly increased in various inflammatory and immunological diseases, such as rheumatoid arthritis, Alzheimer's disease, and atopic dermatitis. Several studies suggest that CHI3L1 may be a viable therapeutic target for these diseases, given its ability to release various pro-inflammatory cytokines, including interleukin (IL)-1β, IL-4, IL-6, IL-13, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Therefore, CHI3L1 likely plays a role in the development of a broad spectrum of inflammatory diseases. However, the precise pathophysiological and pharmacological mechanisms by which CHI3L1 contributes to these diseases remain to be fully elucidated. This review synthesizes recent findings on the functional roles of CHI3L1 across diverse inflammatory conditions, highlighting its involvement in critical signaling pathways. Moreover, preclinical research underscores the therapeutic potential of CHI3L1 inhibition. Thus, targeted CHI3L1 interventions represent a compelling therapeutic strategy warranting further clinical exploration and validation.

Seborrheic dermatitis (SD) is a chronic inflammatory skin disorder that primarily affects areas with increased sebaceous gland activity, and is characterized by erythematous scaly lesions. Malassezia utilizes sebum lipids to produce free fatty acids that may disrupt the epidermal barrier and trigger inflammation in eczematous lesions. However, the pathogenesis and mechanisms underlying the exaggerated inflammatory response and sebogenesis regulation in SD remain unknown. Activation of pattern recognition receptors, including Toll-like receptors (TLRs), is crucial for initiating innate immunity. In the present study, we evaluated the efficacy of a novel antimicrobial cosmetic ingredient, AMPamide, and elucidated its molecular mechanisms underlying the suppression of inflammation and sebogenesis in SD. Specifically, we investigated the inhibitory effect of AMPamide on TLR activation and its impact on downstream signaling pathways in LPS-stimulated HaCaT cells. The effects of AMPamide on lipid production and the expression of related regulatory factors in IGF-1-stimulated SZ95 sebaceous gland cells were also examined. These analyses were performed using RT-qPCR, western blotting, immunofluorescence staining, and Nile Red staining. AMPamide exhibited anti-inflammatory and skin barrier-strengthening effects by inhibiting TLR4/6 expression and multiple signaling pathways. Additionally, AMPamide attenuated lipid overproduction and the expression of related regulatory factors in IGF-1-stimulated SZ95 sebaceous gland cells. Therefore, the observed effects of AMPamide on LPS-stimulated human keratinocytes were mediated via blockade of the TLR-MyD88-MAPK and NF-κB signaling pathway. These results revealed that AMPamide may be a potential therapeutic agent for SD that inhibits TLR4/6 activation.

Interstitial lung disease (ILD) represents a heterogeneous group of diseases in which inflammation and/or fibrosis in the pulmonary interstitium results in an impaired gas exchange, difficulties in breathing, and reduced quality of daily life, and contributes to elevated global morbidity and mortality rates. ILD is an umbrella term, with idiopathic pulmonary fibrosis (IPF) being a prime focus because of its progressive and severe form. Out of 300 underlying etiologies, ILD is one of the major reasons for global morbidity and mortality. This review offers a comprehensive overview of six main categories of ILD covering autoimmune, idiopathic interstitial pneumonia, hypersensitivity pneumonitis, drug-induced, infection-related, and unclassified ILD that underscore the complexity of diagnosis and treatment challenges. This review also provides an evidence-based overview of recent advancements in the diagnosis and management of ILD, with precision pharmacotherapy, multidisciplinary care, and emerging therapeutic strategies. From clinical trial data, it also recommends the disease-specific use of pharmacological agents-such as pirfenidone and nintedanib for IPF, and mycophenolate mofetil for connective tissue disease-associated ILD. The manuscript also emphasizes the evolving role of non-pharmacological interventions, including the 6-minute walk test and pulmonary rehabilitation, in enhancing functional capacity and quality of life. To address the current global health concerns, topics of post-COVID-19 ILD and immune checkpoint inhibitor-associated lung disease are integrated. Additionally, future directions are explored, including the role of lung transplantation and novel antifibrotic therapies like anti-Transforming Growth Factor (TGF)-β antibody cocktails. Together, these insights aim to refine diagnostic precision, personalize treatment, and improve clinical outcomes across the heterogeneous ILD spectrum.

Out of at least 20,000 human proteins fewer than 700 are targeted by drugs. Arrestins regulate G protein-coupled receptors, the largest family of signaling proteins in animals, as well as many receptor-independent signaling pathways. Humans express four arrestin subtypes, two of which are ubiquitous and were already shown to serve as versatile hubs of cellular signaling. So far, arrestin proteins are not directly targeted by any drugs. Here we describe potential targets on arrestins and/or interacting proteins, possible approaches for the development of targeting compounds, expected biological outcomes, and possible research and therapeutic value of targeting the interactions of arrestins with receptors and other signaling and trafficking proteins.

Xylene is an aromatic hydrocarbon widely used as a solvent and emitted from numerous commercial products in industrial or indoor settings. Epidemiological studies of occupational exposure indicate that xylene primarily targets the central nervous system, producing neurobehavioral impairments and other neurological disorders. Both environmental and occupational exposure to volatile organic compounds, therefore, raise concerns about neurodevelopmental risk; however, the specific neurotoxicity of xylene in developing neurons remains poorly characterized. Here, we investigated the effects of xylene (2 or 5 mM) on developing mouse hippocampal neurons, with a focus on Ca²⁺ homeostasis, presynaptic function, and electrophysiological activity. We assessed Ca²⁺ homeostasis with selective inhibitors of voltage-gated Ca²⁺ channels and organelle-specific Ca²⁺ indicators. Presynaptic activity was evaluated in transgenic mouse pups expressing a genetically encoded pH sensor within the synaptic vesicle lumen. Xylene suppressed cytosolic Ca²⁺ transients by inhibiting P/Q-type Ca²⁺ channels, thereby reducing Ca²⁺ uptake into the endoplasmic reticulum. It also decreased Ca²⁺ influx at both presynaptic and postsynaptic sites, impairing synaptic vesicle exocytosis and endocytosis. Electrophysiological and morphological analyses further showed reduced spontaneous firing and hindered synaptic maturation. Collectively, these findings provide mechanistic insight into the neurotoxic actions of xylene and underscore its potential hazard to brain development and function.

Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to skeletal muscle atrophy by promoting oxidative stress, inflammation, and protein degradation. This study investigated the therapeutic potential of trans-resveratrol and hesperidin (tRES-HESP) supplementation, alone or in combination with aerobic exercise, in ameliorating MGO-induced muscle dysfunction in mice. ICR mice were divided into five groups and treated with MGO, tRES-HESP, treadmill exercise, or both interventions over eight weeks. Muscle mass, grip strength, endurance performance, histopathology, and molecular biomarkers were assessed. Combined treatment with tRES-HESP and exercise significantly improved muscle function and morphology, restored muscle mass, and suppressed fibrosis. In terms of signaling pathways, the protective effects were associated with activation of the AMPK/SIRT1/PGC-1α pathway for mitochondrial biogenesis, stimulation of the AKT/mTOR pathway for muscle protein synthesis, suppression of MuRF1-mediated protein degradation, and upregulation of MyoD and MyHC, key markers of muscle regeneration and structural integrity. Additionally, inflammatory balance was restored via suppression of pro-inflammatory IL-6 and elevation of anti-inflammatory IL-10 levels. These findings highlight the synergistic benefits of combining polyphenol supplementation with aerobic exercise as a promising strategy for mitigating muscle atrophy under metabolic stress conditions.

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder characterized by pruritus, skin barrier dysfunction, and immune dysregulation. It significantly impacts the quality of life and increases the risk of infections, sleep disturbances, and psychological distress. AD pathogenesis involves genetic predisposition, environmental triggers, microbiome alterations, and immune dysfunction. Traditional treatments such as topical corticosteroids, calcineurin inhibitors, and systemic immunosuppressants provide symptomatic relief but often fail to provide long-term disease control. The emergence of targeted biologics and Janus kinase inhibitors has transformed AD management by offering more precise and effective therapeutic options. However, treatment responses vary, highlighting the need for biomarker-driven personalized therapies. In this review, we explore the evolving therapeutic landscape of AD, emphasizing the emerging role of biomarker-guided treatment strategies. We highlight recent discoveries of therapeutic (OX40, IgE, IL-5, IL-31, IL-22, thymic stromal lymphopoietin) and diagnostic (TARC/CCL17, MDC/CCL2, filaggrin, sphingosine-1-phosphate, CXCL2) biomarkers that offer promising avenues for patient stratification and treatment monitoring. This review offers novel insight into how the convergence of biomarker research and therapeutic innovation can address current gaps in AD care. Future research should focus on refining biomarker-guided treatment strategies, optimizing therapeutic combinations, and addressing unmet patient needs. The integration of biomarker-guided strategies into routine clinical practice represents a critical step toward long-term disease control and improved quality of life for AD patients.

Endolichenic fungi (ELF), symbionts of lichens, have been reported to produce diverse bioactive secondary metabolites with promising pharmaceutical potential. In this study, we isolated and identified an ELF, EL001668 (KACC 83020BP), from Cetraria laevigata Rass., and assessed its crude extract and bioactive compounds against colorectal cancer (CRC) stem cell activity. cis-10-nonadecenoic acid (c-NDA), isolated through bioactivity-guided fractionation exerted substantial inhibitory effects on CRC stemness, such as the suppression of spheroid formation and the downregulation of the key stem cell markers ALDH1, CD44, and CD133. Comparative analysis with the omega-3 fatty acids EPA and DHA, with well-established properties, showed that c- NDA exerted comparable or superior inhibitory effects against the markers and phenotypic traits of stemness. Besides, the crude extract of EL001668 exhibited greater suppression of certain markers in comparison to the individual compounds. These findings suggest that c-NDA, in conjunction with ELF-derived compounds, holds potential as a novel therapeutic candidate targeting CRC stem cells. Taken together, the current study demonstrated that c-NDA, similar to EPA and DHA, may possess adjunct or complementary effects in cancer treatment and other diseases.

Tumor dormancy represents a clinically significant but poorly understood state in which disseminated cancer cells persist in a quiescent, non-proliferative state, evading conventional therapies and driving late relapse. This review summarizes recent advancements in experimental models-both in vitro and in vivo-that recapitulate the full spectrum of dormancy, including its induction, maintenance, and reactivation. Crucial intrinsic pathways such as ERK/p38 signaling shifts, epigenetic remodeling, and metabolic adaptations and microenvironmental and immune-mediated cues that regulate dormant cell fate are discussed. Therapeutic strategies aimed at maintaining dormancy, reactivating dormant cells for elimination, or directly targeting their survival pathways have been highlighted. By integrating insights from model systems, molecular regulation, and therapy, this review aims to provide a comprehensive framework that informs future efforts to target dormant cancer cells and ultimately reduce recurrence and improve patient outcomes.