Drug Design, Development and Therapy最新文献

Background: Recently, opioid-sparing (OS) interventions have been proposed to facilitate rapid postoperative recovery for patients. However, the advantages of OS anesthesia strategy in laparoscopic abdominal major surgery are still unknown.

Methods: 157 patients undergoing laparoscopic major abdominal surgery were randomly assigned to two groups: Remi (77, remifentanil) and OS (80, esketamine combined with dexmedetomidine), the drugs were administered at 0.2-0.5 mg/kg/h (remifentanil or esketamine) and 0.2-0.7μg/kg/h (remifentanil or dexmedetomidine) in two syringes, respectively The primary outcome was the numeric rating scale (NRS) pain score on postoperative day (POD)1. The proportion of rescue analgesia within 48 h, extubation time, postoperative quality recover scale (PQRS), Pittsburgh Sleep Quality Index (PSQI) on POD30 were also recorded.

Results: In the postanaesthesia care unit (PACU), the NRS pain score and the proportion of rescue analgesia in Remi group was significantly higher than that in OS group (3 [1 to 3] vs 1 [1 to 3], P = 0.001; 15.6% vs 5.0%, P = 0.028, respectively), although there were no statistical differences in NRS pain score on POD1, POD7 and POD30 between groups (3 [2 to 3] vs 3 [2 to 3], P = 0.648; 2 [1 to 2] vs 2 [1 to 2], P = 0.418; 0 [1 to 1] vs 0 [1 to 1], P = 0.656, respectively). The extubation time in the OS group was longer and the proportion of dreaminess was also higher than that in the Remi group (20 [11 to 34] vs 31 [21 to 40], P < 0.01; 15.6% vs 42.5%, P < 0.01), However, the PSQI on POD30 were similar between groups (8.27±3.94 vs 8.37±3.89, P = 0.870).

Conclusion: In this study, OS anesthesia strategy during laparoscopic major abdominal surgery decreases the NRS pain scores in PACU and reduces the use of rescue analgesia, though it may prolong the extubation time and increase the proportion of dreaminess during hospitalization.

Trial registration number: ChiCTR2200060130.

Purpose: This research aims to investigate the role and potential mechanisms of Aloin in Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) through network pharmacology and experimental approaches.

Methods: Using network pharmacology methods, potential targets of Aloin and targets related to CP/CPPS were screened from public databases. The protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the core targets and pathways of Aloin against CP/CPPS. The effects of Aloin in ameliorating CP/CPPS were verified in animal experiments.

Results: A total of 235 genes interacting with Aloin in CP/CPPS were identified. PPI network analysis revealed five core targets: AKT1, EGFR, ESR1, HSP90AA1, and SRC. GO analysis yielded 2916 enrichment results, with 2562 related to Biological Process (BP), 94 to Cellular Component (CC), and 260 to Molecular Function (MF). KEGG pathway analysis identified 172 pathways. Molecular docking confirmed stable binding between Aloin and core targets. Molecular dynamics simulations further validated binding stability by analyzing Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), hydrogen bonds, Solvent Accessible Surface Area (SASA), and Gibbs free energy of Aloin-target complexes. Experimental validation showed that Aloin alleviated pain, reduced inflammatory factors, and decreased oxidative stress in a rat model of CP/CPPS. The qRT-PCR results showed that Aloin intervention reduced the mRNA expression of AKT1, EGFR, HSP90AA1, and SRC, while increasing ESR1 mRNA expression. These changes may underlie its therapeutic effects in CP/CPPS.

Conclusion: Our study revealed that Aloin exerts a beneficial effect on mitigating the pain symptoms associated with CP/CPPS, ameliorating inflammation, and reducing oxidative stress. Through network pharmacology, potential targets and signaling pathways were identified, suggesting the therapeutic promise of Aloin for CP/CPPS. These findings advocate for further exploration into its clinical efficacy and mechanistic underpinnings in the treatment of CP/CPPS.

Osteosarcoma is a highly malignant bone tumor that is resistant to radiotherapy and is associated with poor treatment outcomes and prognoses. Understanding the mechanisms of radioresistance and finding strategies to enhance the radiosensitivity is crucial for improving clinical efficacy. The aim of this review was to address the approaches for enhancing the efficacy of radiotherapy in osteosarcoma, thereby improving patient outcomes. Specifically, we have focused on the mechanisms of radiosensitization and the relationship between drugs that enhance radiosensitivity and cancer. These mechanisms involve a delay in DNA damage repair, promotion of apoptosis, inhibition of angiogenesis, and regulation of the tumor microenvironment. In addition, we have summarized the effects of these drugs on the proliferation, migration, invasion and apoptosis of osteosarcoma cell lines. Finally, we have discussed the therapeutic effects and adverse reactions of these drugs in other cancers, providing valuable guidance for clinical treatment strategies tailored to patients with osteosarcoma.

Purpose: Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. Previous studies have found that Farnesyltransferase (FTase) inhibitors improve disease progression in mouse models of endotoxemia, sepsis, and autoimmune hepatitis. PANoptosis is a novel type of programmed cell death (PCD), including pyroptosis, apoptosis, and necrosis, that plays an important role in ALF. This study was designed and investigated whether the FTase inhibitor PD083176 (d2,d3,d5) could attenuate ALF progression by modulating PANoptosis.

Methods: Combining the technical tools of computational biology, structural biology and pharmacology, we designed and obtained three high-affinity human FTase inhibitors of PD083176(d2,d3,d5). Then, these FTase inhibitors were investigated by animal experiments by administering PD083176(d2,d3,d5) (10 mg/kg) before modeling with LPS (100 μg/kg)/D-GalN (300 mg/kg) or TAA (800 mg/kg).

Results: We found that ALF induced by LPS/D-GaIN or TAA were associated with increased farnesylated protein in the liver. PD083176(d2,d3,d5) not only inhibited hepatic farnesylated proteins but also significantly attenuated liver injury and mortality in ALF mice. Importantly, PD083176(d2,d3,d5) treatment effectively inhibited hepatocyte apoptosis (Bax, Bcl-xL and TUNEL cell counts), pyroptosis (Caspase-1 and GSDMD), and necrotic apoptosis (RIPK1 and RIPK3).

Conclusion: Collectively, these findings demonstrate that PD081376(d2,d3,d5) could alleviate LPS/D-GaIN or TAA-induced ALF by regulating apoptosis, pyroptosis, and necrotizing apoptosis, which might provide a new therapeutic strategy and scalability challenge for ALF.

Purpose: This study aims to evaluate the therapeutic potential of tubeimoside I (TBMS1), a monomer compound extracted from the tubers of Chinese herb Bolbostemma paniculatum (Maxim). Franquet (Cucurbitaceae), in the treatment of liver cancer. Specifically, we sought to elucidate the underlying mechanisms through which TBMS1 exerts its anticancer effects.

Methods: The effects of TBMS1 on the viability, proliferation, and apoptosis of two liver cancer cell lines, MHCC97-H and SNU-449, were comprehensively assessed using Cell Counting Kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EDU) assay, and flow cytometry assays. To uncover the molecular mechanisms, RNA sequencing was performed to identify the downstream targets of TBMS1. Additionally, we utilized network pharmacology to predict TBMS1 targets in liver cancer and employed Venn diagram analysis to integrate these predictions with our experimental findings. Pathway enrichment analysis was conducted using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases to elucidate the biological processes involved. Furthermore, a subcutaneous xenograft tumor model was established to investigate the in vivo antitumor efficacy of TBMS1.

Results: In vitro experiments demonstrated that TBMS1 significantly enhanced cell apoptosis and inhibited the growth of liver cancer cells. Both network pharmacology predictions and RNA-seq analyses revealed that the downstream target genes of TBMS1 were highly enriched in the NF-κB signaling pathway. Notably, we observed a significant upregulation of TNFα-induced protein 3 (TNFAIP3) expression with increasing concentrations of TBMS1. In vivo studies further confirmed that TBMS1 treatment dramatically reduced the volume and weight of liver cancer tumors compared to controls.

Conclusion: Our study provides compelling evidence that TBMS1 suppresses liver cancer progression by inactivating the NF-κB pathway and regulating TNFAIP3 expression. These findings offer novel insights and a theoretical basis for the development of targeted therapies for liver cancer.

Purpose: Polygala tenuifolia Willd. (PT) is commonly used to address cognitive impairment (CI), while Magnolia officinalis Rehd. et Wils (MO) is often prescribed for gastrointestinal issues as well as CI. This study seeks to explore the impacts and mechanisms behind the combined therapy of PT and MO (PM) in treating CI, based on the concept of the gut-brain axis.

Methods: The characteristic components of PT, MO, and PM were identified using ultra-high performance liquid chromatography-tandem triple quadrupole mass Spectrometry (UPLC-MS/MS). A mouse model was established by D-gal induction, and the effects of PT, MO, and PM on CI were evaluated through behavioral tests, pathological staining, and Enzyme-Linked Immunosorbent Assay (ELISA). Subsequently, network pharmacology was used to analyze the potential mechanisms by which PM improves CI, followed by validation through Western blotting (WB), traditional Chinese medicine (TEM), Immunofluorescence (IF), and 16S rRNA.

Results: PT, MO, and PM can each alleviate cognitive decline and neuropathological damage in D-gal mice to varying degrees, reduce the expression of pro-inflammatory factors (TNF-α, IL-1β, IL-6, IFN-γ, LPS) in serum or hippocampal tissue, and increase SOD and GSH levels. Network pharmacology analysis and molecular experiments confirmed that PM upregulates the expression of tight junction s (TJs), enhances the expression of proteins in the cAMP pathway, and inhibits p-NF-κB-p65 expression. PM reverses D-gal-induced gut microbiota dysbiosis, increases the abundance of SCFA-producing bacteria, and decreases the abundance of LPS-producing bacteria.

Conclusion: PM alleviates CI by reducing inflammation and oxidative stress, protecting the blood-brain barrier (BBB) and intestinal barrier, inhibiting the NF-κB pathway, activating the cAMP pathway, and regulating gut microbiota.

Background: The aim of the study was to evaluate the pharmacokinetic (PK) properties and safety profiles of test and reference amlodipine/benazepril capsules under both fasting and fed states, determine the bioequivalence between the two formulations, and provide sufficient evidence for new drug application.

Subjects and methods: The bioequivalence study was conducted utilizing a randomized, open-label design, involving two formulations administered in a single-dose format. Healthy Chinese participants who met the eligibility criteria were administered a single dose of the test or reference amlodipine/benazepril capsule. Blood samples were taken serially for up to 168 hours post-administration during each period, and the plasma levels of amlodipine, benazepril, and benazeprilat were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. For bioequivalence evaluation, geometric mean ratios comparing the pharmacokinetic parameters of the test drug with those of the reference drug were calculated along with their corresponding 90% confidence intervals. Safety assessments were conducted throughout the duration of the study.

Results: The PK parameters of the test formulation were found to be comparable to those of the reference formulation under both fasting and fed conditions. The 90% confidence intervals (CIs) for the geometric mean ratios comparing the test and reference formulations for the peak concentration (Cmax), the area under the curve from time zero to the last measurable concentration (AUC_0-t), and the area under the curve from time zero to observed infinity (AUC_0-∞) of amlodipine, benazepril, and benazeprilat fell within the range of 80.00% to 125.00% in both groups. Both formulations were well tolerated by participants, with no serious adverse events reported throughout the trial.

Conclusion: The pharmacokinetic bioequivalence between the test and reference formulation in healthy individuals was confirmed under both fasting and fed states, meeting regulatory standards set for the study. Both drug formulations demonstrated safety and tolerability.

Background: Diabetic wounds are a significant clinical challenge due to impaired healing processes often exacerbated by elevated matrix metalloproteinases (MMPs). Cinnamomum zeylanicum, known for its anti-inflammatory and antioxidant properties, has shown potential in promoting wound healing. This study investigates the molecular docking and experimental validation of Cinnamomum zeylanicum's effects on diabetic wound healing, focusing on its interaction with matrix metalloproteinases-8 (MMP-8) and 9 (MMP-9).

Methods: Molecular docking studies were performed to predict the binding affinity of Cinnamomum zeylanicum compounds to MMP-8 and MMP-9. Diabetic wound healing was evaluated using in vivo models where wounds were induced and treated with Cinnamomum zeylanicum extract. Various parameters were measured, including wound contraction, hydroxyproline content, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels. Biochemical analyses included glucose levels, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), and histomorphological examination of skin tissues.

Results: Molecular docking results indicated a high binding affinity of Cinnamomum zeylanicum's bioactive compounds with MMP-8 and MMP-9, suggesting potential inhibition. Experimental validation showed significant improvement in wound contraction and increased hydroxyproline content, indicating enhanced collagen synthesis. Antioxidant enzyme activities (SOD, GPx, CAT) were significantly elevated, while MDA levels were reduced, reflecting decreased oxidative stress. Biochemical analysis demonstrated improved glucose homeostasis with reduced FBG and enhanced OGTT responses. Histomorphological studies revealed improved tissue architecture and re-epithelialization in treated wounds.

Conclusion: Cinnamomum zeylanicum exhibits promising potential in diabetic wound healing by modulating MMP-8 and MMP-9 activities, enhancing antioxidant defenses, and improving glucose regulation. These findings support its therapeutic application for diabetic wounds, providing a foundation for further clinical investigations.