Biomolecules & Therapeutics最新文献

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.

YAP is a transcription cofactor in the Hippo pathway that interacts with the TEAD family of transcription factors in the nucleus to promote CTGF expression and stimulate cell growth. YAP hyperactivation is frequently observed in fibrotic diseases. The main kinases in the Hippo pathway, MST1/2, a member of the STE20 family, promote Lats phosphorylation, leading to YAP phosphorylation, which prevents its nuclear entry and thus inhibits cell growth. High cell density induces Lats phosphorylation, causing YAP phosphorylation and its exclusion from the nucleus. Additionally, energy stress, such as glucose deprivation, induces AMPK phosphorylation, which also prevents YAP from entering the nucleus. MST3, another member of the STE20 family, has been shown to regulate cell apoptosis, migration, polarization, and ion homeostasis in previous studies. We hypothesized that MST3 is involved in Hippo pathway-mediated fibrosis. To test this, we overexpressed HA-tagged MST3 (HA-MST3) and a kinase-dead mutant (HA-MST3-KD) in MDCK cells. When cells reached a high density, HA-MST3 was activated to phosphorylate YAP, promoting its nuclear exit and inhibiting cell growth. In contrast, HA-MST3-KD cells showed reduced phosphorylated YAP, resulting in YAP retention in the nucleus, continuous cell growth, and NIH/3T3 cell fibrosis. Interestingly, YAP did not exit the nucleus in HA-MST3-KD cells treated with the YAP inhibitor verteporfin, but it did exit under metformin treatment due to energy stress, accompanied by increased AMPK and YAP phosphorylation, which inhibited MST3-KD-mediated fibrosis. These findings suggest that metformin-induced AMPK activation could provide a therapeutic approach for MST3-KD-mediated fibrosis.

Dimethyl sulfoxide (DMSO) is extensively used as a solvent in bioactive compound screening due to its capacity to solubilize a wide range of chemical compounds. This study demonstrates that DMSO significantly influences lineage commitment in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) by enhancing adipogenesis and inhibiting osteogenesis. At concentrations above 25 mM (0.32% in culture media), DMSO significantly promoted adipogenic differentiation in hBM-MSCs. Under osteogenic conditions, however, DMSO suppressed mineralization and downregulated the expression of osteoblast markers, thereby reducing osteoblast differentiation. Notably, DMSO also increased the adipocyte population within a predominantly osteogenic environment, suggesting it may shift the balance of hBM-MSC lineage commitment toward adipogenesis over osteogenesis. These findings emphasize the importance of careful consideration when utilizing DMSO as a solvent in studies involving hBMMSCs differentiation and the biological evaluation of test compounds.

Depressive amnesia, involving memory impairment and mood dysregulation, frequently co-occurs with depression and neurodegenerative diseases. Methylglyoxal (MGO), a reactive glycolytic byproduct, contributes to depressive-like behaviors and cognitive deficits. This study evaluated the therapeutic potential of 2',4',6'-trimethoxyacetophenone (TMA), a bioactive compound from Lycoris sanguinea var. koreana, in a mouse model of MGO-induced depressive amnesia. Mice received MGO (60 mg/kg) followed by TMA (5 or 20 mg/kg), and behavioral tests were conducted to assess mood, cognition, and locomotor activity. TMA significantly reduced immobility in tail suspension and forced swim tests, improved locomotion and exploration in the open field, and restored memory in novel object recognition and Y-maze tests. Histological analysis showed that TMA preserved hippocampal integrity, modulated glucocorticoid receptor expression, and reduced cortisol levels, indicating involvement in stress regulation. TMA also attenuated neuroinflammation by lowering IL-1β and microglial activation while increasing IL-10. Additionally, it reduced amyloidogenic markers, including oligomeric Aβ and amyloid precursor protein. These findings highlight the neuroprotective and antidepressant potential of TMA and support its use as a natural therapeutic candidate for treating depression-related cognitive impairment.