Drug Design, Development and Therapy最新文献

Purpose: The current study aimed to investigate the dose-response efficacy and safety of Muvz^TM (E-PR-01, a blend of V. negundo and Z. officinale) in 400 mg (High-dose [HD]) and 200 mg (Low-dose [LD]) of daily dose in physically active adults in 90 days.

Patients and methods: The study included 157 adults aged 40-60 having knee/low back joint discomfort. The primary outcome was an enhancement in the overall musculoskeletal health in 90 days. Secondary outcomes included assessing the joint discomfort following physical activity, range of motion, quality of life, and the consumption of rescue medication.

Results: E-PR-01 notably enhanced musculoskeletal health in a dose-dependent manner compared to placebo within 30 days (p<0.0001), with effects persisting through day 90 and demonstrated clinically significant difference by 13 and 10 units in the HD and LD groups, respectively. Joint discomfort reduced significantly in both the E-PR-01 groups by day 90 (p<0.0001). Furthermore, both doses of E-PR-01 improved the range of motion of the assessed joint (p<0.05) and enriched participants' overall quality of life (p<0.05) at the end of the study.

Conclusion: The study finds E-PR-01 effective for improving overall joint health, with the higher dose showing greater efficacy. These findings align with the earlier studies of E-PR-01 for knee and low back discomfort.

Purpose: Ferroptosis, characterized by iron-dependent lipid reactive oxygen species accumulation, plays a critical role in the pathophysiology of depression. Our research aims to elucidate the potential antidepressant mechanisms of asiaticoside, a bioactive compound known for its neuroprotective and immunomodulatory properties.

Methods: The antidepressant-like properties of asiaticoside in a model of chronic restraint stress (CRS)-induced depression in mice, with a particular focus on its interaction with ferroptosis-related pathways.

Results: The behavioral results revealed that asiaticoside significantly ameliorated CRS-induced depressive symptoms, as evidenced by increased sucrose preference and reduced immobility time. At the molecular level, asiaticoside enhanced the expression of brain-derived neurotrophic factor (BDNF), phosphorylated tropomyosin receptor kinase B (pTrkB), phosphorylated nuclear factor erythroid 2-related factor 2 (pNrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11), indicating its neuroprotective and antioxidative effects. In addition, asiaticoside suppressed the expression of ferroptosis markers, including ferritin light chain (FLC) and transferrin receptor only in CA1 region. Transmission electron microscopy (TEM) further confirmed that asiaticoside preserved mitochondrial integrity in CA1 neuronal cells.

Conclusion: In conclusion, our findings suggest that asiaticoside exerts its antidepressant-like effects through the modulation of BDNF/Nrf2/GPX4 signaling pathway against neuronal ferroptosis in the hippocampal CA1 region.

Background: Acute myocardial infarction (AMI) is a significant contributor to global morbidity and mortality. Allicin exhibits promising therapeutic potential in AMI as a primary bioactive component derived from garlic; however, its underlying mechanisms remain incompletely elucidated.

Methods: Our study induced AMI in mice by ligating the left coronary artery, and administered allicin orally for 28 days. The cardioprotective effects of allicin treatment were comprehensively assessed using echocardiography, histopathological examinations, intestinal barrier function, and serum inflammatory factors. The potential mechanisms of allicin were elucidated through analysis of metagenomics and serum metabolomics. Network pharmacology (NP) was used to further investigate and validate the possible molecular mechanisms of allicin.

Results: Our findings revealed allicin's capacity to ameliorate cardiac impairments, improve intestinal barrier integrity, and reduce serum IL-18 and IL-1β levels after AMI. Further analysis demonstrated that the administration of allicin has the potential to ameliorate intestinal flora disorder following AMI by modulating the abundance of beneficial bacteria, such as g_Lactobacillus, g_Prevotella, g_Alistipes, and g_Limosilactobacillus, while reducing the abundance of harmful bacteria g_Parasutterella. Additionally, it exhibits the ability to enhance myocardial energy metabolism flexibility through modulating metabolites and key enzymes associated with the fatty acid metabolic pathway. Mechanistically, NP and in vivo experiments indicated that allicin might suppress pyroptosis and reduce inflammatory response via blocked activation of the NF-κB-mediated NLRP3/Caspase-1/GSDMD pathway. Moreover, Spearman correlation analysis suggested a significant association between the allicin-induced alterations in microbiota and metabolites with cardiac function and inflammatory cytokines.

Conclusion: Our study demonstrated that allicin alleviated myocardial injury and reduced inflammatory response by inhibiting the NF-κB-mediated NLRP3/Caspase-1/GSDMD pathway while remodeling microbiota disturbance, improving serum metabolic disorder, and enhancing the intestinal barrier. These research findings offer a novel perspective on the potential therapeutic value of allicin as an adjunctive dietary supplement to conventional treatments for AMI.

Background: Diabetic liver injury (DLI) is a common complication of diabetes mellitus (DM), which seriously endangers the health of diabetic patients. Puerarin, the main active component of Pueraria lobata, has shown positive effects in lowering blood glucose and lipids, resisting oxidative stress, and protecting the liver. However, the mechanism of protective effect of Puerarin on DLI remains unclear.

Methods: Various databases were used to screen for targets of Puerarin, ferroptosis and DLI. Protein-protein interaction (PPI) network and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to predict key targets and pathways. Molecular docking was used to predict the interactions between Puerarin and core targets. KK/Upj-Ay/J (KKAy) mice and high glucose (HG)-induced AML12 cells were used to study the protective effect of Puerarin on DLI. The molecular mechanisms by which Puerarin acts were further verified by in vivo and in vitro experiments.

Results: KEGG analysis indicated that the JAK/STAT pathway might be related to the anti-DLI effect of Puerarin. Molecular docking revealed that Puerarin has good affinity for JAK2 and STAT3. In vivo, Puerarin (80 mg/kg) reduced body weight, blood glucose, blood lipids and liver function in KKAy mice fed a high-sugar, high-fat diet. Puerarin also ameliorated hepatic pathological changes and inflammatory responses, and attenuated oxidative stress and iron overload in KKAy mice. Western blotting results showed that Puerarin could regulate the expression of proteins related to JAK2/STAT3 pathway and ferroptosis pathway. In vitro, Puerarin (25, 50, 100 μM) increased cell viability and decreased steatosis and liver function indexes in AML12 cells induced by HG (30 mm) to varying degrees. More importantly, AG490 blocker experiments showed that the regulation of ferroptosis process by Puerarin was dependent on the JAK2/STAT3 pathway.

Conclusion: In conclusion, this study revealed Puerarin may regulate the ferroptosis process by inhibiting the JAK2/STAT3 pathway for the treatment of DLI.

Background: Brain energy metabolism disorders, including glucose utilization disorders and abnormal insulin sensitivity, are linked to the pathogenesis of postoperative delirium. Intranasal insulin has shown significant benefits in improving glucose metabolism, insulin sensitivity and cognitive function. However, its impact on postoperative delirium and insulin sensitivity biomarkers remains unknown.

Aim: This randomized, double-blind, placebo-controlled trial was to evaluate whether intranasal insulin reduces the incidence and severity of postoperative delirium (POD) in older patients undergoing joint replacement, and its effect on insulin sensitivity-related biomarkers.

Methods: 212 older patients (≥65 years) were randomly assigned to receive either 40 IU of intranasal insulin (n=106) or a placebo (n=106) for 8 days. The primary objective was to determine the incidence and severity of POD within 5 days after surgery, estimated using the Confusion Assessment Method (CAM) and the Delirium Rating Scale (DRS)-98. The secondary objective was insulin sensitivity, which was assessed using the homeostasis model Assessment of Insulin Resistance (HOMA-IR) and biomarkers, including total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC), and brain-derived neurotrophic factor (BDNF).

Main results: Compared to placebo, intranasal insulin significantly reduced the incidence of delirium within 5 days after surgery (8 [8.33%] vs 23 [23.23%], P = 0.004, odds ratio [OR] = 3.33 [95% CI 1.41-7.88]) and the severity of delirium (P<0.001). Intranasal insulin elevated the levels of tOC, ucOC, and BDNF in the CSF on D₀ (all P<0.001) and tOC levels in the plasma on D₀, D₁ and D₃ (all P<0.001). It elevated ucOC levels in the plasma of the insulin group on D₀ but not on D₁ and D₃ (all P<0.001). Intranasal insulin administration reduced the HOMA-IR on D₃ (P=0.002).

Conclusion: Intranasal insulin notably reduced the incidence and severity of POD in older patients undergoing joint replacement, which may be related to the elevation in osteocalcin and BDNF levels.

Trial registry numbers: Chinese Clinical Trial Registry (ChiCTR2300068073).

Purpose: Major depressive disorder (MDD) is a global health concern. Studies have demonstrated that oleanolic acid (OA) has a regulatory effect on MDD. However, OA is poorly soluble, has low oral bioavailability, and faces challenges in crossing the blood-brain barrier. In this study, building upon a previous formulation of OA cubic liquid crystal nanoparticles (OA-LCNP), we combined nanoparticles with a thermosensitive gel for nasal administration and investigated the pharmacological effects of OA-LCNP thermosensitive gel (OANG) on depression. This study aimed to evaluate the effects of OANG on depression symptoms in rats.

Methods: OANG was prepared using Poloxamer F127 and F68 as the gel matrix, and the ratios of F127 and F68 were investigated. The pharmacokinetics of OANG was studied in rats, and OA content was determined using liquid chromatography-mass spectrometry (LC-MS). The pharmacological effects of OANG on depression were evaluated in chronic unpredictable mild stress (CUMS) model rats.

Results: The phase transition temperature of the gel was 34°C, and the release of OA from OANG was slow according to the Higuchi kinetic equation. The AUC_0-t of brain tissue after nasal OANG administration was 1.21 times that observed after intravenous administration. Additionally, the brain-targeting efficiency and nasal-brain direct transfer were 29.91% and 9.44% higher, respectively, than those observed after intravenous administration, indicating the brain-targeting capability of the OANG delivery system. Network pharmacological analysis revealed that the anti-depressant effects may be linked to neuroactive ligand-receptor interactions, the PPAR signaling pathway, and efferocytosis signaling pathways. Experimental results from CUMS rats showed that the gel significantly affected interleukin (IL)-4, IL-6, acetylcholinesterase, acetylcholine, 5-hydroxytryptamine, and brain-derived neurotrophic factor, and improved depression-like behavior in rats, as measured by sucrose preference, forced swimming, and box shuttle tests.

Conclusion: The OANG nasal drug delivery system has specific brain-targeting properties and exerts anti-depressant effects.

Background: Biofilm formation often represents significant challenges in managing of bloodstream infections associated with catheter use.

Objective: Antimicrobial lock therapy serves as an adjunctive treatment for catheter-related infections, effectively eradicating or inhibiting biofilm growth.

Methods: This review synthesizes the current knowledge on antifungal lock therapy (ALT) targeting clinically common fungi, primarily Candida species, based on both in vitro and in vivo studies (animals and patients) from the past decade.

Results: Amphotericin B (AmB) and echinocandins are identified as the most promising antifungal agents for ALT. Combinations of antifungal agents with other compounds, such as farnesol, Neosartorya fischeri antifungal protein 2, 8-hydroxyquinoline-5-(N-4-chlorophenyl) sulfonamide, and polyurethane, have also shown efficacy in ALT. Additionally, ethanol, doxycycline, tigecycline, and minocycline lock solutions can be effective in treating fungal infections.

Conclusion: More comprehensive investigations and additional rigorous clinical trials are essential to thoroughly understand the safety and efficacy of ALT. This will facilitate the development of novel treatments for catheter-related fungal infections, thereby improving clinical outcomes.

The bimatoprost intracameral implant (Durysta^®) offers a sustained-release approach to glaucoma management, providing consistent intraocular pressure (IOP) reduction over several months and reducing the need for daily topical therapies. This review evaluates its pharmacology, efficacy, and safety, using data from pivotal clinical trials and recent real-world studies. The implant achieves IOP reductions comparable to topical prostaglandin analogs, with benefits for patient adherence and fewer common side effects. However, repeat administrations are associated with adverse effects such as endothelial cell loss, highlighting the need for optimized re-dosing schedules. Future research should explore its use in advanced glaucomas, cost-effectiveness, and combination with other IOP-lowering treatments. The bimatoprost intracameral implant represents a promising innovation in glaucoma therapy with potential for improved patient outcomes.

Purpose: Warfarin is an anticoagulant drug widely used for treating thromboembolism-related conditions. The main challenge with this drug is the high variability in patients response, which is influenced by both clinical, non-clinical, and genetic factors, such as VKORC1, CYP2C9, and CYP4F2. Therefore, this research aimed to evaluate the impact of clinical and genetic factors on warfarin dose adjustment and to develop a dosing algorithm for patients with cardiovascular disease.

Patients and methods: A total of 77 research subjects were selected using consecutive sampling based on the inclusion criteria of cardiac outpatients on warfarin for ≥3 months with PT-INR data, complete medical records, and willingness to participate. Exclusion criteria included vitamin K use and inability to follow up. Patients demographic data and clinical characteristics were collected from medical records. Blood samples were obtained for genetic testing of CYP4F2 rs2108622 (sequencing). Statistical analyses included both bivariate and multivariate analyses (logistic regression) with a significance level set at <0.05.

Results: Statistical analysis using the Kruskal-Wallis test showed that the CC, CT, and TT genotypes were significantly associated with warfarin dose (p = 0.02). Furthermore, the Mann-Whitney test results showed that gender did not have a significant relationship with warfarin dose (p = 0.16). The Spearman Rank correlation test showed that age (p = 0.02) and BMI (p = 0.03) had significant relationships with warfarin dose (p < 0.05). However, gender (p = 0.89) had no effect, while age (p = 0.01), BMI (p = 0.01), and genotype (p = 0.01) significantly influenced warfarin dose determination.

Conclusion: In conclusion, the combined contribution of age (8.76%), BMI (7.95%), and CYP4F2 genotype (8.29%) to warfarin dose adjustment was 25%. The linear regression model for predicting warfarin dose was determined to be y = 12.736-0.16*age + 0.55*BMI + 3.55*genotype, where 1 = CC, 2 = CT, and 3 = TT.

Melanogenesis is a biochemical process that regulates skin pigmentation, which is crucial role in protecting against ultraviolet radiation. It is also associated with hyperpigmentation conditions such as melasma and age spots, which negatively impact aesthetics and self-confidence. Tyrosinase (TYR), a key enzyme in the melanogenesis pathway, catalyzes the biosynthesis of melanin in the skin. Inhibition of tyrosinase particularly by blocking its active site and preventing the binding of natural substrates such as tyrosine, can reduce melanin production, making it a promising therapeutic target for treating hyperpigmentation. Peptides have emerged as promising therapeutics to regulate melanogenesis by minimizing the side effects associated with conventional skin whitening therapeutics. This review is designed to offer a comprehensive analysis of current strategies in peptide design aimed at optimizing anti-melanogenic activity, by focusing on the role of molecular weight, polarity, and cyclization strategies in enhancing peptide efficacy and stability. It was found that optimal peptide size was within the range of 400-600 Da. The balance between hydrophilic and hydrophobic properties in peptides is crucial for effective TYR inhibition, as higher hydrophilicity enhances affinity for the TYR active site and stronger catalytic inhibition, while hydrophobicity can contribute through alternative mechanisms. Cyclization of peptides enhances their structural stability, serum resistance, and binding affinity while reducing toxicity. This process increases resistance to enzymatic degradation and improves target specificity by limiting conformational flexibility. Additionally, the rigidity and internal hydrogen bonding of cyclic peptides can aid in membrane permeability, making them more effective for therapeutic use. Peptide optimizations through size modification, polarity change, and cyclization strategies have been shown to be promising as reliable and safe agents for melanin inhibition. Future studies exploring specific amino acid in peptide chains are required to improve efficacy and potential clinical applications of these anti-melanogenic peptides as a hyperpigmentation treatment.