Drug Discoveries and Therapeutics最新文献

Excessive free radicals in the skin cause oxidative stress, damaging cells and leading to aging, melasma, and inflammation. This study developed a liposome system for co-delivering antioxidants to enhance their efficacy in deeper skin layers. Four phenolic compounds were screened for antioxidant activity using DPPH, nitric oxide scavenging, and lipid peroxidation assays. Gallic acid and curcumin, showing the strongest activity, were selected for liposome encapsulation via an emulsification method, with particle size reduction by probe sonication. High-performance liquid chromatography (HPLC) was used for chemical analysis, and particle morphology was examined with transmission electron microscopy. Studies on skin penetration, retention, and release were conducted. The optimized liposome (LP4) had a small particle size (< 150 nm), an unilamellar structure, and high entrapment efficiency (99% gallic acid and 92% curcumin). LP4 promoted effective skin retention of curcumin with slow penetration, while the release of gallic acid and curcumin from LP4 followed a Higuchi kinetic model and Zero-order kinetic model, respectively. This delivery system demonstrates potential for targeted antioxidant delivery, offering enhanced protection against oxidative damage in the skin.

The immunoregulatory activity of human gut bacteria has attracted attention in recent years. To assess the innate immune-stimulatory activity of various samples in vivo efficiently, we previously introduced a silkwormbased assay as a novel alternative method. The method has been used for over a decade to screen for substances with potential physiological activity. In this study, we prepared heat-killed cells of four strains of human gut bacteria (Bacteroides ovatus, B. thetaiotaomicron, B. uniformis, and Akkermansia muciniphila) and assessed their innate immune-stimulatory activity within the silkworm model. Our findings indicate that the sample from either B. ovatus or B. thetaiotaomicron has immunostimulatory activity in the silkworm, in contrast to B. uniformis and A. muciniphila. Moreover, a pathogenicity assessment using the silkworm infection model was conducted to determine the safety of these bacterial strains for human consumption when considered as food ingredients. None of the four gut bacterial strains exhibited pathogenic effects in silkworms, with Pseudomonas aeruginosa serving as a positive control of the pathogenicity test. These results suggest that the silkworm-based assay can distinguish between the immunostimulatory effects of different human gut microbes and may enhance the safety evaluation of microbial ingredients.

This study sought to investigate the temporal variations in serum calcium concentrations among patients with acute type B aortic dissection (ATBAD) following initial diagnosis, document the incidence of severe complications, and evaluate their potential associations. In this retrospective analysis, we examined 42 consecutive patients diagnosed with ATBAD at Zhejiang Hospital between April 2019 and April 2024. Serum-ionized calcium levels were measured at admission and 24 hours post-admission. Based on changes in calcium levels, patients were categorized into either the elevated or decreased groups. Univariate and multivariate logistic regression analyses were performed to compare clinical characteristics and assess the incidence of severe complications following the initial diagnosis. The study further explored the association between 24-hour serum calcium levels, their dynamic changes, and the occurrence of severe complications in patients with ATBAD. The results showed that the decreased group had a significantly higher frequency of severe complications, including mortality, cardiac complications, acute renal failure, and organ hypoperfusion (P < 0.05), while no significant differences were observed for neurological or pulmonary complications (P > 0.05). Logistic regression revealed that a decline in serum calcium levels within 24 hours was an independent risk factor for severe complications (OR = 16.722, P = 0.03). The receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.864. Decreased serum calcium concentration is an independent predictor of severe complications in ATBAD patients, significantly associated with mortality, cardiac complications, acute kidney injury, and inadequate organ perfusion. No significant correlation with neurological and pulmonary complications was observed.

Bighead carp (Aristichthys nobilis) has garnered significant attention due to its potential health benefits, yet its bioactive protein components remain largely unexplored. In this study, two proteins S3 and Z1 were isolated from Aristichthys nobilis using ammonium sulfate precipitation and serial column chromatography guided by their in vitro antitumor activity. Both proteins were found to be homogeneous in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with a purity exceeding 95% as confirmed by reverse-phase high performance liquid chromatography (RP-HPLC). Electrospray ionization tandem mass spectrometry (ESI-MS/MS) analysis revealed their precise molecular weights to be 44.335 kDa for S3 and 43.028 kDa for Z1. Their amino acid sequences were elucidated through tandem mass spectroscopy and transcriptome unigene analysis, identifying S3 as phosphoglycerate kinase and Z1 as creatine kinase. Furthermore, secondary structure was measured by circular dichroism and three-dimensional structure was predicted by modeling software. The antitumor potential of S3 was evaluated by an in vitro assay, yielding an IC₅₀ value of 26.3 ± 2.9 μM against the HT-29 cell line. Z1 demonstrated antiproliferative activity in vitro with IC₅₀ values of 21.8 ± 1.4, 22.3 ± 2.1, and 22.3 ± 2.5 μM against HT-29, HeLa, and HepG2 cell lines, respectively. Notably, Z1 was found to enhance glucose metabolism and significantly increase the production of lactic acid and CO₂ in tumor cells. These findings suggest that bighead carp (A. nobilis) could serve as a promising source for both antitumor agents and functional food ingredients.

Recently, increased attention has been paid to the consideration of individual characteristics, including sex and age, in the context of medication use and adverse events. However, the characteristics and patterns of adverse events reported in the Japanese Adverse Drug Event Report (JADER) database stratified by sex and age have not yet been clarified. This study aimed to clarify the characteristics and patterns of adverse event reports in the JADER database over a 20-year period (April 2004-March 2024). Data were stratified into 20 groups based on sex and age (aged 0-9 years, 10-19 years, 20-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, 80-89 years, and ≥90 years). The female/male ratio of adverse event reports in JADER was 0.95. The largest group comprised males in their 70s. Adjusting for the proportion of adverse event reports in each group according to the demographic composition in 2015 highlighted that the reporting rates of adverse events were higher in people aged ≥70 years and that females aged 20-49 years reported more adverse events than males. Medical history, causative drugs, and adverse events reported to JADER were characterized by combinations of sex and age. Our results provide additional insights into the interpretation of previous studies using JADER. In addition, the results of this study will help understand the characteristics of adverse event reports contained in JADER and conduct appropriate subgroup and sensitivity analyses.

This study aimed to investigate in detail the efficacy of switching from etanercept reference product (RP) to etanercept biosimilar in patients with rheumatoid arthritis (RA) under real-world clinical conditions using clinical indices and musculoskeletal ultrasound (MSUS). This interventional, multicenter, open-label, single-arm clinical trial involved 24- or 52-week follow-up. This study enrolled patients with RA who had been treated with etanercept-RP for ≥ 24 weeks, achieved clinical low disease activity (LDA) or remission, and switched from etanercept-RP to etanercept biosimilar. This study included 20 patients. Of the 17 patients, 16 (94.1%; 95% confidence interval [CI]: 71.3-99.9) remained in LDA/remission on DAS28-ESR at 24 weeks. The dose of 50 mg/week was reduced to 25 mg/week at 24 weeks, and LDA/remission was sustained until 52 weeks in 9 (81.8%, 95% CI: 48.2-97.7] of 11 participants. DAS28-ESR, DAS28-CRP, SDAI, and CDAI scores showed no apparent worsening. The median total PD score remained 0. The switch from etanercept-RP to etanercept biosimilar and subsequent dose reduction demonstrated favorable outcomes, including MSUS evaluation.

Opioids are commonly prescribed for the management of moderate to severe pain, but their use is associated with dependency and other adverse effects. For decades, the development of safe and effective non-addictive alternatives for treating moderate to severe pain has seen limited progress. On January 30, 2025, the U.S. Food and Drug Administration approved suzetrigine, the first Nav1.8 inhibitor, for the treatment of moderate to severe acute pain. Nav1.8 is a voltage-gated sodium channel that is selectively expressed in peripheral nociceptive neurons, which are responsible for transmitting pain signals. By highly selectively inhibiting the Nav1.8 channel, suzetrigine can effectively alleviate pain. Unlike opioids, this drug does not induce euphoria or excitement in the brain, thereby eliminating concerns about addiction. Suzetrigine offers a novel therapeutic option and a potential combination for multimodal analgesia, with the promise of transforming acute pain management and establishing new treatment standards.

Alopecia areata (AA) is a common and recurrent type of hair loss. Despite oral administration of baricitinib exerts a good effect on refractory AA, the long-term administration of baricitinib carries significant side effects, poor compliance, and the efficacy is difficult to maintain after drug withdrawal. Therefore, the exploration of a safe and effective local administration of baricitinib to treat AA is of great clinical importance. However, baricitinib has a large molecular weight and is barely soluble in water, while the hair follicle lies deep, thus conventional topical dosage forms are ineffective. This study investigated the efficacy of local injection of baricitinib-loaded mesenchymal stem cell exosomes (EVs) in the treatment of AA. First, we constructed baricitinib loaded EVs (EV-B) and established AA mouse model by intravenously injection with murine INF-γ according to previous literature reports. The therapeutic effects of EV-B on hair regrowth were recorded and the underlying mechanism was also analyzed by Luminex protein biochip test and western-blot. Compared to control group, the baricitinib, EV and EV-B groups exhibited improved hair coverage in the AA mouse model. Besides, EV-B group achieved the optimal effect. The underlying mechanism might be attributed to the improvement of drug delivery efficiency as well as the synergistic effect of EVs, leading to better inhibition of JAK-STAT pathway and upregulation of the Wnt/β-catenin pathway. Our findings proved the effectiveness of EV-B on the treatment of AA, and might provide a new therapeutic approach for AA in future clinical application.

Selpercatinib is a selective rearranged during transfection (RET) kinase inhibitor effective for the treatment of RET-positive non-small cell lung cancer, thyroid cancer, and other cancers. However, its clinical use requires careful management because of dose-dependent adverse effects and pharmacokinetic interactions. Given the multiple factors influencing selpercatinib blood levels, we hypothesized that establishing a therapeutic drug monitoring system for selpercatinib could help reduce adverse events and optimize efficacy. Therefore, we herein developed a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for measuring selpercatinib blood levels to facilitate therapeutic drug monitoring in clinical practice. Proteins were precipitated with acetonitrile, and selpercatinib and the internal standard (gefitinib) were separated via HPLC-UV. The calibration curve was linear over 0.5-8.0 µg/mL with a coefficient of determination (r²) equaling 0.9996. Intra- and interday validation coefficients were both under 2.80%. The corresponding measurement precision ranged from - 1.50% to 12.60% and - 1.32% to 7.50%, respectively, with recoveries exceeding 94.43%. Thus, this study establishes a simple and sensitive method for quantifying selpercatinib in human plasma. Future studies will analyze plasma samples from patients treated with selpercatinib and utilize this method to explore the relationships among plasma concentration, efficacy, and adverse events to define the therapeutic concentration range.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and functional impairments. Despite extensive research, its pathogenesis remains incompletely understood, and effective treatments are limited. This study explored the therapeutic potential of agarwood in AD by integrating network pharmacology, protein-protein interaction (PPI) network analysis, and single-cell expression analysis. The results revealed that agarwood compounds may modulate key inflammatory genes such as NFKB1, STAT1, and TLR4, alleviating neuroinflammation; enhance the expression of HSP90 and regulate KDR signaling to improve blood-brain barrier (BBB) integrity; and promote the activity of PTPN11 and CXCR4 to support oligodendrocyte precursor cell (OPC) repair and remyelination. Single-cell expression analysis highlighted cell-type-specific expression patterns, particularly in OPCs and endothelial cells, underscoring their relevance in AD pathology. Agarwood's multi-dimensional therapeutic potential positions it as a promising candidate for the development of novel AD treatments.