Pharmaceuticals最新文献

The journal retracts the article "Potential Antitumor Activity of Combined Lycopene and Sorafenib against Solid Ehrlich Carcinoma via Targeting Autophagy and Apoptosis and Suppressing Proliferation" [...].

The journal retracts the article "Rosmarinic Acid Attenuates the Lipopolysaccharide-Provoked Inflammatory Response of Vascular Smooth Muscle Cell via Inhibition of MAPK/NF-κB Cascade" [...].

Background: Antimicrobial resistance and fungal contamination remain major threats to public health and agriculture, emphasizing the need for innovative alternatives. Plant-derived products are a promising alternative, and nanoformulations may further enhance their activity. Objective: This study investigated the antimicrobial potential of Ocotea indecora essential oil and its nanoemulsion. Methods/Results: The essential oil chemical characterization by GC-MS revealed sesquirosefuran (91.61%) as the main constituent. A factorial design guided the selection of an optimized nanoemulsion, which exhibited spherical nanometric droplets (79 nm and 0.029 PdI) with long-term stability. The essential oil inhibited the growth of Gram-positive and Gram-negative strains at 1 to 2 mg/mL, while the nanoemulsion enhanced bactericidal activity against Staphylococcus aureus. In contrast, antifungal assays revealed a more pronounced effect, with the nanoemulsion lowering the minimum inhibitory concentrations (625 µg/mL) against Thielaviopsis ethacetica, thereby enhancing the inhibitory activity of the essential oil (2.5 mg/mL). Morphological alterations, including thinner hyphae and impaired sporulation, were also detected, suggesting a reduction in fungal virulence. Conclusions: In summary, O. indecora essential oil shows promising antimicrobial potential, and nanoemulsification proved particularly effective in potentiating fungistatic activity while offering limited enhancement of bactericidal effects. The results support the potential of O. indecora derivatives as natural candidates for the development of novel antimicrobial strategies.

Background: Drug-induced cardiotoxicity is a primary concern in clinical practice, especially in the context of oxidative stress induced by anti-cancer, antiviral, and antidiabetic drugs. Several strategies are devised to limit cardiotoxicity, which are supportive and provide symptomatic relief. This highlights the need to develop cardioprotective agents that circumvent the oxidative stress. Bassia indica is a cardiotonic plant with antioxidant properties traditionally used in Africa, South Asia, and China. We investigated its cardioprotective effects against doxorubicin-induced cardiotoxicity (DIC). Methods: B. indica extract (BiE) was analyzed by GC-MS and HPLC. Several antioxidant assays, including DPPH, FRAP, CUPRAC, NO, and H₂O₂ scavenging, were performed. In vivo attenuation of DIC was assessed in a rat model. Results: BiE contained several bioactive flavonoids, including 2-methoxy-4-vinylphenol, ferulic acid, gallic acid, kaempferol, and coumaric acid. Antioxidant assays demonstrated potent free-radical scavenging and antioxidant activity of BiE, providing mechanistic evidence for its in vivo amelioration of DIC. BiE treatment reduced myocardial oxidative stress by increasing endogenous antioxidant levels (p < 0.01), including SOD, CAT, and GSH. It upregulated Nrf2 and lowered Keap1 levels. This was also reflected in the restoration of cardiac tissue architecture and modulation of inflammatory markers, including IL-1β and TNF-α (p < 0.01). Cardiac tissue biomarkers were also improved. Conclusions: These findings conclude that BiE exerts cardiac protection by reducing oxidative stress and inflammation through modulation of the Keap1/Nrf2 pathway and decreasing the expression of IL-1β and TNF-α.

Background: HER2-positive breast cancer patients receiving chemotherapy and targeted therapy (including anthracyclines and trastuzumab) face an elevated risk of cardiotoxicity, which can lead to long-term cardiovascular complications. Identifying predictive biomarkers is essential for early intervention. Circulating microRNAs (miRNAs), known regulators of gene expression and cardiovascular function, have emerged as potential indicators of cardiotoxicity. This study aims to evaluate the differential expression of circulating miRNAs in HER2-positive breast cancer patients undergoing chemotherapy and to assess their prognostic ability for therapy-induced cardiotoxicity using machine learning models. Methods: Forty-seven patients were assessed for cardiac toxicity at baseline and every 3 months, up to 15 months. Blood samples were collected at baseline. MiRNA expression profiling for 84 microRNAs was performed using the miRCURY LNA miRNA PCR Panel. Differential expression was calculated via the 2^-∆∆Ct method. The five most upregulated and five most downregulated miRNAs were further assessed using univariate logistic regression and receiver operating characteristic (ROC) analysis. Five machine learning models (Decision Tree, Random Forest (RF), Support Vector Machine (SVM), Gradient Boosting Machine (GBM), k-Nearest Neighbors (KNN)) were developed to classify cardiotoxicity based on miRNA expression. Results: Forty-five miRNAs showed significant differential expression between cardiac toxic and non-toxic groups. ROC analysis identified hsa-miR-155-5p (AUC 0.76, p = 0.006) and hsa-miR-124-3p (AUC 0.75, p = 0.007) as the strongest predictors. kNN, SVM, and RF models demonstrated high prognostic accuracy. The decision tree model identified hsa-miR-17-5p and hsa-miR-185-5p as key classifiers. SVM and RF highlighted additional miRNAs associated with cardiotoxicity (SVM: hsa-miR-143-3p, hsa-miR-133b, hsa-miR-145-5p, hsa-miR-185-5p, hsa-miR-199a-5p, RF: hsa-miR-185-5p, hsa-miR-145-5p, hsa-miR-17-5p, hsa-miR-144-3p, and hsa-miR-133a-3p). Performance metrics revealed that SVM, kNN, and RF models outperformed the decision tree in overall prognostic accuracy. Pathway enrichment analysis of top-ranked miRNAs demonstrated significant involvement in apoptosis, p53, MAPK, and focal adhesion pathways, all known to be implicated in chemotherapy-induced cardiac stress and remodeling. Conclusions: Circulating miRNAs show promise as biomarkers for predicting cardiotoxicity in breast cancer patients. Machine learning approaches may enhance miRNA-based risk stratification, enabling personalized monitoring and early cardioprotective interventions.

Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of SLC-391 in patients with advanced solid tumours. Methods: Using a 3 + 3 design, SLC-391 was administered orally, either once daily (from 25 mg up to 175 mg QD) or twice daily (from 75 mg to 200 mg BID) in 21-day cycles. Results: Following single and repeated dosing, SLC-391 was generally well tolerated by subjects. The maximum tolerated dose (MTD) was not reached in this study. A total of 34/35 subjects experienced at least one TEAE. Three (8.6%) subjects experienced Grade 3 TRAEs that were considered related to SLC-391. Eight SAEs were reported in five (14.3%) subjects (seven Grade 3 SAEs and one Grade 2 SAE), in 150 mg QD (3/6, 50%), 175 mg QD (1/2, 50%), and 110 mg BID (1/3, 33.3%) cohorts. Four SAEs in three (8.6%) subjects led to dose interruption, drug withdrawal, or study discontinuation. Three DLTs were reported in two subjects: one subject experienced Grade 3 hematochezia (SUSAR/DLT) at 175 mg QD, and another subject experienced Grade 3 thrombocytopenia associated with Grade 1 hematuria at 200 mg BID. The median T_max was 2.0 h. Plasma concentrations following multiple doses generally increased with higher doses and appeared to reach steady state by Day 21 and were generally dose-proportional. Twelve (12) out of 35 subjects with solid tumours achieved stable disease according to RECIST or mRECIST (mesothelioma), with durations of stable disease lasting up to 318 days on SLC-391 monotherapy. The clinical benefit rate was 34.3%. Conclusions: This first study of SLC-391 in adult subjects with advanced solid tumours demonstrated that a total daily dose of 300 mg (150 mg BID) of SLC-391 monotherapy was generally well tolerated, with no DLTs or SAEs observed at this dose. The drug's promising safety profile, along with stable disease reported for several subjects with advanced solid tumours, provides a strong rationale for the phase 1b/2a clinical investigation of SLC-391 in combination with pembrolizumab in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) (NCT05860296).

This review highlights Artemisia annua, a medicinal plant which grows in the Kingdom of Saudi Arabia, known for its abundant therapeutic properties. A. annua serves as a rich source of various bioactive compounds, including sesquiterpenoid lactones, flavonoids, phenolic acids, and coumarins. Among these, artemisinin and its derivatives are most extensively studied due to their potent antimalarial properties. Extracts and isolates of A. annua have demonstrated a range of therapeutic effects, such as antioxidant, anticancer, anti-inflammatory, antimicrobial, antimalarial, and antiviral properties. Given its significant antiviral activity, A. annua could be investigated for the development of new nutraceutical bioactive compounds to combat SARS-CoV-2. Artificial Intelligence (AI) can assist in drug discovery by optimizing the selection of more effective and safer natural bioactives, including artemisinin. It can also predict potential clinical outcomes through in silico modeling of protein-ligand interactions. In silico studies have reported that artemisinin and its derivatives possess a strong ability to bind with the Lys353 and Lys31 hotspots of the SARS-CoV-2 spike protein, demonstrating their effective antiviral effects against COVID-19. This integrated approach may accelerate the identification of effective and safer natural antiviral agents against COVID-19.

Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell's ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca²⁺ homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine's mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine's S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD.