Biomolecules & Therapeutics最新文献

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.

Sepsis is a leading cause of mortality in hospitals with a lack of reliable biomarkers and specialized therapeutics. Recently, highly secreted tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4, was found to be a potential theranostic target for hypercytokinemic severe sepsis. In this study, using the minipig sepsis model inoculated with cecum slurry, we demonstrated that increases in WARS1 levels were associated with severity of sepsis and showed strong correlations with RBC count and the levels of HGB, HCT, EPO, lactate, and PLT count in the acute phase of sepsis. Further, administration of the WARS1 neutralizing antibody to the septic minipigs inhibited the increase in the overall SOFA score with a significantly lower P/F ratio, which was accompanied by the suppression of proinflammatory cytokine and chemokine expressions as well as EPO production, a decrease in AST and ALT levels, and inflammatory immune cell infiltration in the lung. Taken together, these findings provide a novel insight into the pathophysiology of acute phase of sepsis and suggest the clinical application of WARS1 neutralizing therapeutics in the treatment of sepsis.

The accumulation of free fatty acids (FFAs) in hepatocytes is a key characteristic of metabolic dysfunction-associated steatotic liver disease (MASLD), which leads to lipid peroxidation and ultimately results in ferroptosis. Currently, there is an absence of efficacious therapeutic options available for the management of MASLD. Consequently, an in-depth exploration of the roles of FFAs and ferroptosis in the progression of MASLD may reveal hitherto unidentified therapeutic targets. In the study, we established an early lesion model of MASLD, namely NAFL, and comprehensive analyses of lipid metabolism, hepatocellular injury, iron homeostasis, and ferroptosis were performed. The HFD and FFAs treatment significantly elevated the expression of enzymes associated with lipid synthesis, including ACC1 and FASN, leading to enhanced lipid accumulation in hepatocytes. Additionally, HFD and FFAs resulted in increased iron loading and a reduction in the levels of the antioxidant enzyme GPX4, which ultimately triggers ferroptosis. In contrast, the administration of melatonin effectively inhibited the activity of lipid synthesis-related enzymes, decreased hepatic lipid deposition, alleviated free fatty acid-induced iron dysregulation, and mitigated liver damage. Mechanistically, melatonin has been shown to attenuate hepatocyte ferroptosis by modulating the KEAP1/NRF2/HO-1 pathway, which in turn diminishes free fatty acids-induced oxidative stress. In conclusion, melatonin alleviates MASLD progression by curbing FFAs-induced oxidative stress and ferroptosis. These findings provide valuable insights into the mechanisms underlying MASLD progression and highlight melatonin as a potential therapeutic agent for the management of MASLD.

Small molecules that induce protein polymerization represent an emerging class of compounds with diverse therapeutic potential. This review provides a comprehensive overview of five such molecules: arsenic trioxide (As₂O₃), BI-3802, NVS-STG2, paclitaxel, and verteporfin. These compounds target different proteins (PML-RARα, BCL6, STING, β-tubulin, and p62, respectively) and exhibit varied mechanisms of action. Some, like As₂O₃ and BI-3802, induce polymerization leading to protein degradation, while others, such as NVS-STG2, activate protein function through polymerization. Paclitaxel, distinct from these, induces the stabilization of tubulin polymers. Verteporfin, on the other hand, uniquely causes covalent cross-linking of its target and other cellular proteins. This review explores the molecular mechanisms, structural insights, and therapeutic implications of these compounds, highlighting their potential in targeted protein degradation, cancer treatment, and modulation of cellular processes, such as autophagy and immune response. The diverse effects of these molecules underscore the complexity of protein polymerization in cellular function and disease, opening new avenues for drug discovery and development.

In this study, we explored the effects of taxifolin, a flavonoid compound, on the expression of the MUC5AC mucin gene in airway epithelial cells. Human pulmonary epithelial NCI-H292 cells were pretreated with taxifolin for 30 min prior to stimulation with phorbol 12-myristate 13-acetate (PMA) for 24 h. We also investigated the influence of taxifolin on the PMA-induced activation of the NF-κB signaling pathway. Our results demonstrated that taxifolin inhibited both glycoprotein production and MUC5AC mRNA expression triggered by PMA. This inhibition occurred through the prevention of IκBα degradation and the nuclear translocation of NF-κB p65. These findings suggest that taxifolin suppresses mucin gene expression by modulating the NF-κB signaling pathway in human pulmonary epithelial cells.

RNA therapeutics represent a disruptive technology that has transformed drug discovery and manufacturing, gaining significant prominence during the COVID-19 pandemic. RNA therapeutics encompass diverse molecules like antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), RNA aptamers, and messenger RNAs (mRNAs), which can function through different mechanisms. RNA therapeutics are increasingly used to treat various diseases, including neurological disorders. For example, ASO therapies such as nusinersen for spinal muscular atrophy and eteplirsen for Duchenne muscular dystrophy are successful applications of RNA-based treatment. Emerging ASO treatments for Huntington's disease and amyotrophic lateral sclerosis are also promising, with ongoing clinical trials demonstrating significant reductions in disease-associated proteins. Still, delivery of these molecules remains a pivotal challenge in RNA therapeutics, especially for ASOs in penetrating the blood-brain barrier to target neurological disorders effectively. Nanoparticle-based formulations have emerged as leading strategies to enhance RNA stability, reduce immunogenicity, and improve cellular uptake. Despite these advances, significant hurdles remain, including optimizing pharmacokinetics, minimizing off-target effects, and ensuring sustained therapeutic efficacy. Regulatory frameworks are evolving to accommodate the unique challenges of RNA-based therapies, including ASOs with efforts underway to establish comprehensive guidelines for RNA therapeutics, yet there are also sustainable manufacturing issues that need to be considered for long-term feasibility. By addressing these challenges, RNA therapeutics hold immense potential to revolutionize treatment paradigms for neurological disorders. Looking forward, the future of RNA therapeutics in neurology appears promising but requires continued interdisciplinary collaboration and technological innovation.

Asthma is an allergic inflammatory disease of the lungs characterized by eosinophilic inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR). Exposure to environmental endotoxins, such as lipopolysaccharide (LPS), can exacerbate asthma severity. Phosphodiesterase (PDE) inactivates cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate, thereby aggravating inflammation. Accordingly, PDE inhibitors could be used to treat asthma. Herein, we studied the effects of BRL-50481 (BRL), a PDE7 inhibitor, in a murine model of ovalbumin (OVA)-induced allergic asthma with co-exposure to LPS. Mice were sensitized, challenged with OVA, and subsequently exposed to LPS. Mice were administered with BRL prior to the OVA challenge. We observed that BRL treatment could suppress hallmark features of asthma, including mediators of eosinophilic and neutrophilic inflammation, such as expression of antigen-specific immunoglobulin (Ig) E, interleukin (IL)-13, IL-6, and mucus hypersecretion. Mice co-exposed to OVA and LPS exhibited marked AHR, which was improved in BRL-treated mice because of inhibition of mucus overproduction. In conclusion, given that PDE7 inhibitors can regulate allergic inflammatory responses, these agents could be potential candidates for treating asthma.

Liver cancer stem cells (LCSCs) play a significant role in the development, metastasis, treatment resistance, and recurrence of hepatocellular carcinoma (HCC). Targeting LCSCs offers a novel strategy to overcome treatment resistance in HCC. Myricetin, a flavonol from the flavonoid family, is known for its diverse biological activities, including anticancer effects. However, its potential for eradicating LCSCs had not been thoroughly investigated prior to this study. This study evaluated the effects of myricetin on LCSCs derived from Huh7 and Hep3B cell lines both in vitro and in vivo. LCSCs were treated with myricetin to assess cell proliferation, cell cycle arrest, apoptosis induction, autophagy regulation, stemness and EMT marker expression, and tumor growth suppression using a chicken embryo CAM model. Additionally, the combination therapy of myricetin with chloroquine, an autophagy inhibitor, was explored. Myricetin significantly inhibited the proliferation of Huh7- and Hep3B-derived LCSCs and suppressed tumor growth in the CAM model. It induced cell cycle arrest at the G0/G1 phase and triggered apoptosis through intrinsic and extrinsic pathways. Myricetin also stimulated autophagy by inhibiting the PI3K/AKT/mTOR pathway, reduced the expression of stemness markers, including Sox2, Oct4, Nanog, and ALDH1A1, and suppressed EMT. Combining myricetin with chloroquine enhanced apoptotic effects and further downregulated stemness markers by inhibiting STAT3 activation, demonstrating greater efficacy than myricetin alone. The findings establish myricetin, either as a standalone treatment or in combination with chloroquine, as a promising therapeutic candidate for targeting LCSC growth and overcoming chemotherapy resistance in HCC.