Pharmaceuticals最新文献

Background: The growing interest in developing new bioactive agents from natural sources led to medicinal and aromatic plants. These plants provide valuable phytochemicals that can serve as natural preservatives, food additives, and flavorings, with various applications. The aim of this study is to evaluate the potential of Juniperus oxycedrus berries' supercritical extract through preliminary screenings related to in vitro antibacterial activity, as well as bioinformatics assessments of absorption and toxicity. Methods: Supercritical carbon dioxide (CO₂) was used to extract the bioactive phytochemical compounds from the berries. The extract was characterized using spectrophotometric methods and reverse-phase high-performance liquid chromatography (RP-HPLC). The antibacterial potential was tested against Staphylococcus aureus ATCC 25923, where the Minimal Inhibitory Concentration and the Minimal Bactericidal Concentration were determined. Additionally, the influence of the extract on the growth curve kinetics of S. aureus was assessed. For the bioinformatics analyses, SwissADME and ProTox-3.0 prediction software were utilized, focusing on the identified phenolic compounds as fingerprint molecules. Results: The results demonstrated that exposure to the juniper extract inhibited bacterial growth, resulting in a prolonged lag phase of 6 to 8 h, depending on the concentration of the extract. The software predictions revealed that the investigated phenolic compounds might exhibit high gastrointestinal absorption, along with potential interactions with metabolic mediators and pathways. Conclusions: The in vitro and in silico findings support the application of J. oxycedrus berries extract as an alternative or complementary strategy for pharmacological treatment and food applications aimed at targeting S. aureus.

Background/Objectives: Taiwan cinnamon leaves have been reported to be effective in improving chronic diseases. Herein, cinnamon leaf extract (CLE) and nanoemulsion (CLEN) were prepared to explore their effects in improving sexual dysfunction in rats. Methods: Following extraction with 80% ethanol and analysis by UPLC-MS/MS, CLEN was prepared using an optimal ratio of soybean oil, lecithin, Tween 80, deionized water, and CLE. A total of 48 male rats and 48 female rats were used, with the former being induced with erectile dysfunction, followed by treatment with CLEN or CLE at two doses (100 mg/kg and 50 mg/kg) for 4 weeks. After conducting the penile reflex test, male rats were paired with female rats for measurement of sexual behavior and ICP/MAP. Following sacrifice, α-SMA, nNOS, and β-III tubulin expression areas were measured by histochemical analyses; SMC/collagen ratio by Masson's trichrome staining; and NO, cGMP, and PDE5 levels by ELISA kits. Results: CLEN was more effective than CLE in increasing intromission frequency, decreasing intromission and ejaculation latency, and recovering erectile response for improving copulatory and ejaculatory performances. A higher maximum ICP/MAP ratio was shown for CLEN through elevation of neurovascular function and erectile capacity. Additionally, CLEN efficiently reduced fibrosis, enhanced neuronal marker expression, and increased the SMC/collagen ratio, leading to penile tissue protection and neural regeneration. Both treatments showed elevated levels of NO and cGMP with a reduction in PDE5, probably through modulation of the NO-cGMP signaling pathway. Conclusions: CLEN was more effective than CLE in restoring erectile function in rats. Some more clinical trials are needed to verify this finding.

The global spread of multidrug-resistant (MDR) Gram-negative bacteria, particularly extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii, presents a significant public health challenge by limiting effective antimicrobial treatment options. Cefepime, a fourth-generation cephalosporin with broad-spectrum activity, is increasingly compromised by β-lactamase production, efflux pumps, and porin loss. In response, novel cefepime-based β-lactam/β-lactamase inhibitor (BL/BLI) combinations have been developed to overcome these resistance mechanisms. This review examines preclinical and clinical studies on cefepime-based BL/BLI combinations, specifically cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, and cefepime/nacubactam, as found in the PubMed database. Key findings include the restoration of activity against class A ESBLs with cefepime/enmetazobactam, while cefepime/taniborbactam and cefepime/zidebactam show broader inhibition of serine β-lactamases and selected metallo-β-lactamases. Additionally, zidebactam and nacubactam target penicillin-binding protein 2, enhancing bactericidal potency. Preclinical and early-phase clinical trial data indicate potent in vitro activity and favorable pharmacokinetic/pharmacodynamic (PK/PD) profiles. Specifically, the combination of cefepime with enmetazobactam has demonstrated an optimal Cmax/MIC ratio of 8-10, supporting its efficacy in treating MDR Gram-negative infections. Phase III studies are ongoing to confirm efficacy in complicated infections. Cefepime-based BL/BLI combinations are emerging as promising carbapenem-sparing agents, offering broad-spectrum activity, dual mechanisms of action, and encouraging clinical outcomes. These findings support their inclusion in antimicrobial stewardship strategies aimed at mitigating resistance.

Background: Cholestatic liver injury (CLI) is characterized by complex pathogenesis; however, oxidative stress-mediated inflammatory response due to bile acid accumulation in the liver is considered a primary cause. Cynarin (CN), an artichoke phytochemical, has demonstrated different biological activities, including antioxidant and anti-inflammatory ones. The current study aimed to explore the potential hepatoprotective effect of CN on CLI induced by alpha-naphthyl isothiocyanate (ANIT) in mice and investigate the possible involved mechanisms. Methods: Mice received CN (25 and 50 mg/kg) for four consecutive days and were challenged with ANIT (75 mg/kg) once on the second day. Liver injury was examined through biochemical determination of liver injury biomarkers and confirmed by histopathological evaluation. Oxidative stress biomarkers and pro-inflammatory cytokines were detected in the hepatic tissue. RT-PCR, Western blotting, and ELISA were applied to address gene and protein expression of potential underlying molecular targets, including thioredoxin-interacting protein (TXNIP), NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and high-mobility group box 1 (HMGB1). Moreover, nuclear factor kappa-B (NF-κB) activation was determined by immunohistochemical analysis. Results: Our findings revealed that CN remarkably ameliorated ANIT-induced hepatic necro-inflammatory changes and biliary duct injury and restored redox balance in the liver. Mechanistically, CN markedly decreased the expression of TXNIP, NLRP3, active caspase-1, gasdermin D N-terminal (GSDMD-N), interleukin (IL)-1β, and IL-18, which were elevated upon ANIT administration. Moreover, CN suppressed ANIT-induced expression of HMGB1 and NF-κB. Conclusions: Our findings suggest that CN has a protective effect against ANIT-induced CLI in mice that is associated with modulation of the TXNIP/NLRP3 and HMGB1/NF-κB signaling cascades.

Background/Objectives: Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder. Current AD therapies offer minimal benefits and do not prevent or repair neuronal damage. More effective therapeutic approaches are needed to restore normal bioenergetics and metabolic function to AD neurons. Simufilam is a small-molecule oral drug that targets filamin A, a scaffolding protein in brain cells. Phase III clinical trials of simufilam failed to show any significant cognitive or functional improvements in AD patients. The purpose of this study is to identify and explain the molecular mechanisms that may have contributed to this drug's lack of clinical success. Methods: Our study investigates the effects of simufilam on amyloid processing, neuronal health, and mitochondrial functioning in the SH-SY5Y human neuronal cell model. SH-SY5Y cells were differentiated into neurons using 10 µM retinoic acid. Undifferentiated and differentiated SH-SY5Y were exposed to simufilam (5 µM, 50 µM; 24 hr). Results: Simufilam did not affect the expression of genes involved in amyloid processing. Amyloid precursor protein (APP), β-secretase, and α-secretase mRNA levels in simufilam-treated SH-SY5Y cells were all unchanged compared to untreated cells. However, amyloidogenic β-secretase protein was significantly increased (fold change 1.17) at 50 µM of simufilam only in differentiated SH-SY5Y cells without affecting APP or α-secretase protein expression. Simufilam at the 50 µM concentration reduced brain-derived neurotrophic factor protein levels (fold change 0.7) only in differentiated SH-SY5Y. Further, simufilam did not improve mitochondrial genes or structure. Conclusions: Our results align with clinical outcomes and indicate that insufficient activity across multiple tests of ability to impact processes related to neuronal health can serve as a preliminary indicator of limited clinical utility.

Background/Objectives: Synovial sarcoma (SS) is a rare and aggressive soft-tissue malignancy characterized by complex molecular alterations and poor prognosis, highlighting the need for targeted immunotherapeutic strategies. This study aimed to design a rational multi-epitope vaccine targeting the FKBP10 oncoprotein to elicit effective immune responses against SS. Methods: Transcriptomic data from the GEO dataset GSE144190, comprising 10 tumor and 9 normal tissue samples, were analyzed to identify differentially expressed genes (DEGs). Results: Our findings revealed significantly upregulated FKBP10 with a log2 fold change of 3.55, baseMean expression of 1521.84, and adjusted p-value of 8.37 × 10^-26. Mutational analysis across 7782 sarcoma samples indicated a low alteration frequency of ~1.5%, primarily missense variants. Functional mapping showed FKBP10 as a hub interacting with multiple collagen chains and chaperone proteins, implicating its role in extracellular matrix organization and protein folding. Linear B-cell epitope prediction identified 17 epitopes (6-21 amino acids), while T-cell mapping yielded 10 MHC class I and 9 MHC class II high-affinity epitopes, all antigenic (VaxiJen > 0.5) and non-allergenic. A multi-epitope vaccine was constructed incorporating a 50S ribosomal protein L22 adjuvant, linkers, and a 6× histidine tag. Physicochemical analysis showed a molecular weight of 36.43 kDa, pI 6.97, instability index 31.79, aliphatic index 64.88, and GRAVY -0.509, indicating stability and hydrophilicity. Structural modeling validated 82.5% residues in favored regions. Molecular docking revealed strong binding with TLR4 (-9.7 kcal/mol) and TLR9 (-9.4 kcal/mol), and 200 ns molecular dynamics simulations confirmed stable RMSD trajectories, low RMSF at binding residues (<4 Å), persistent hydrogen bonding, compact radius of gyration (38-42 Å for TLR4; ~20 Å for TLR9), favorable total energy (-1400 to -1500 kcal/mol for TLR4; -650 to -720 kcal/mol for TLR9), and stable SASA (~52,000-54,000 Ų). Conclusions: These findings demonstrate that the FKBP10 multi-epitope vaccine is structurally stable, immunogenic, and capable of engaging key innate immune receptors, supporting its potential as a promising immunotherapeutic candidate for synovial sarcoma.

The rapid global spread of antimicrobial resistance (AMR) has significantly reduced the effectiveness of many modern antibiotics, creating an urgent need for alternative therapeutic strategies. One promising approach is the revival and repurposing of older antimicrobial agents whose clinical potential was previously limited by toxicity concerns, pharmacokinetic challenges, or the availability of newer drugs. Recent advances in drug delivery, dosing optimization, and antimicrobial stewardship have renewed interest in these compounds as viable options for the treatment of multidrug-resistant infections. The aim of this review is to provide a comparative, clinically oriented analysis of selected "old" antibiotics, fosfomycin, colistin, streptomycin, and vancomycin, with emphasis on their current therapeutic roles, pharmacokinetic/pharmacodynamic (PK/PD) targets, toxicity mitigation strategies, resistance mechanisms, and evidence supporting combination therapies and alternative routes of administration. This narrative review was conducted using a structured PubMed search and manual reference screening, focusing on clinical, PK/PD, and translational studies relevant to the contemporary use of legacy antibiotics. The review summarises current evidence on the re-emerging clinical applications of these agents, each discussed in the context of historical use, mechanism of action, resistance patterns, and newly identified indications. Attention is given to novel formulations, combination strategies, and alternative routes of administration that enhance efficacy while limiting toxicity, including applications in biofilm-associated infections. Overall, strategic repurposing of older antibiotics represents a valuable complementary approach in the fight against AMR and may extend the therapeutic lifespan of existing agents in an era of limited antibiotic innovation.

Background/Objectives: Herbal retention enema is widely used in Traditional Chinese Medicine for the management of endometriosis; however, its clinical efficacy and safety have not been systematically evaluated. Methods: Ten electronic databases were searched up to May 2025 to identify randomized controlled trials evaluating herbal retention enema as a standalone treatment for endometriosis. Primary outcomes included total effective rate and pain-related measures. Risk of bias was assessed using the Cochrane RoB 2 tool. Results: Nine randomized controlled trials involving 614 participants were included. Compared with Western medical therapies, herbal retention enema was associated with greater overall clinical effectiveness (OR = 2.87) and significant improvement in dysmenorrhea. When compared with oral herbal medicine, herbal retention enema demonstrated a higher total effective rate (OR = 7.13). A trend toward improved pregnancy outcomes was observed (p = 0.05). No serious adverse events related to herbal retention enema were reported, and systemic adverse effects were less frequent than with hormonal therapies. Conclusions: Herbal retention enema may represent a potential complementary option for symptom management in endometriosis; however, the certainty of evidence remains low due to important methodological limitations in the included trials. However, given methodological limitations and heterogeneity among studies, further high-quality randomized controlled trials with standardized outcomes and long-term follow-up are required.

Background: Ulcerative colitis (UC) is a chronic inflammatory disease marked by mucosal injury and immune dysregulation. Gegen Qinlian Decoction (GQD) shows therapeutic potential, but extraction-dependent reproducibility remains unclear. Methods: We systematically searched PubMed, Scopus, and Web of Science for studies evaluating GQD aqueous decoctions or ethanolic extracts in DSS-induced colitis. Main outcome: Disease Activity Index (DAI). Key additional outcomes: colon length and histological injury; cytokines and microbiota were also assessed. Random-effects models with Hartung-Knapp-Sidik-Jonkman adjustment, subgroup analyses, and exploratory dose-response meta-regression were applied. Results: Eight studies were included (aqueous: 5; ethanolic: 3; 209 mice). GQD significantly improved DAI (SMD -2.17; p < 0.00001; I² = 43%), colon length (MD 1.18 cm; p < 0.00001; I² = 88%), and histological injury (SMD -3.02; p < 0.0001; I² = 51%). For DAI, both preparations favored GQD, with absent heterogeneity in aqueous studies (I² = 0%) vs. substantial variability in ethanolic extracts (I² = 75%). For histology, subgroup differences suggested a larger effect size with ethanolic extracts, with higher heterogeneity (I² = 60% vs. 0%). In the aqueous subset, GQD reduced inflammatory markers and increased microbial diversity. Dose-response meta-regression was performed within the aqueous subset as an exploratory analysis. Conclusions: Aqueous decoctions showed the most reproducible profile across key endpoints, whereas ethanolic extracts were more variable despite a larger histology point estimate, indicating that the extraction matrix meaningfully influences translational consistency in preclinical research.

One of the greatest challenges of our era, and of modern medicine, is the accelerating rise of antimicrobial resistance (AMR) [...].