Drug Design, Development and Therapy最新文献

Cerebral ischemia-reperfusion injury (CIRI) is clinically characterized by high rates of morbidity, disability, mortality, and recurrence as well as high economic burden. The clinical manifestations of CIRI are often accompanied by gastrointestinal symptoms such as intestinal bacterial dysbiosis and gastrointestinal bleeding. Gut microbiota plays an important role in the pathogenesis of CIRI, and its potential biological effects have received extensive attention. The gut microbiota not only affects intestinal barrier function but also regulates gastrointestinal immunity and host homeostasis. Traditional Chinese medicine (TCM), a multi-component and multi-targeted drug, has shown remarkable effects and few adverse reactions in the prevention and treatment of CIRI. Notably, the effect of TCM on CIRI by regulating gut microbiota and maintaining gastrointestinal homeostasis has gradually become a hot topic. This review summarizes the functional role of the gut microbiota in the development and progression of CIRI and the therapeutic effects of TCM on CIRI by improving gut microbiota dysbiosis, affecting gut microbiota metabolism, and maintaining host immunity. The active ingredients of TCM used for the treatment of CIRI in relevant studies were saponins, triterpenoids, phenolics, and alkaloids. In addition, the clinical effects of TCM used to treat CIRI were briefly discussed. This review established the clinical significance and development prospects of TCM-based CIRI treatments and provided the necessary theoretical support for the further development of TCM resources for the treatment of CIRI.

Objective: Neuronal damage is criminal to cognitive dysfunction, closely related to endoplasmic reticulum stress (ERS). However, due to the pathogenesis of endotoxin-induced long-term cognitive dysfunction is not fully clarified, there is still a lack of effective treatment. This study was conducted to explore the protective effects and mechanism of rosmarinic acid (RA) against ERS in endotoxin-induced cognitive dysfunction in mice and neuronal injury in cells.

Methods: The efficacy of RA was evaluated using an endotoxin-induced cognitive dysfunction mice model and an in vitro neuronal injury model. Brain injury was assessed using behavioral tests and hematoxylin and eosin (HE) staining. Western blotting and Immunohistochemistry (IHC) were performed to determine NeuN, GRP78, PERK, ATF6, IRE1α, and MANF expression levels. Molecular docking was used to assess the associated mechanisms.

Results: Behavioral tests indicated that 20 and 40 mg/kg RA significantly improve endotoxin-induced cognitive dysfunction without dose differences. Histological analysis revealed no significant alterations in the number, morphology, and arrangement of neurons in the hippocampus and amygdala. However, 40 mg/kg RA treatment significantly decreased the hippocampal level of PERK protein and increased MANF in CA1 and DG in mice. Furthermore, our data showed that 120 μM RA pretreatment significantly inhibited LPS-conditioned culture-induced GRP78, PERK, and MANF upregulation in vitro. Finally, molecular docking studies suggested that RA could directly interact with GRP78, PERK, and IRE1, but not with MANF.

Conclusion: RA plays a protective role in improving cognitive function against endotoxemia-associated encephalopathy in mice via inhibiting the GRP78/PERK/MANF pathway.

Purpose: To determine the effect of dexmedetomidine on the ED₅₀ and ED₉₅ of sufentanil in patient-controlled intravenous analgesia (PCIA) after cesarean section.

Patients and methods: Parturients who underwent elective cesarean section (n = 80) were randomly assigned to either the sufentanil group (S group) or the dexmedetomidine-sufentanil combination group (DS group). Patients in the S group received a combination of sufentanil, 5 mg of tropisetron, and saline, whereas patients in the DS group were administered 1.5µg/kg of dexmedetomidine in addition to sufentanil, 5 mg of tropisetron, and saline. The ED₅₀ and ED₉₅ of sufentanil were determined by Dixon sequential method. We used probit regression to calculate the ED₅₀, ED₉₅, and 95% confidence intervals for sufentanil in each group.

Results: The ED₅₀ and ED₉₅ for sufentanil in the S group were 1.634 (95% CI: 1.476-1.810)µg/kg and 2.035 (95% CI: 1.841-3.312)µg/kg, respectively. The ED₅₀ and ED₉₅ for sufentanil in the DS group were 1.275 (95% CI: 1.187-1.353)µg/kg and 1.503 (95% CI: 1.406-1.824)µg/kg. The VAS scores with rest at t₅ and with movement at t₄- t₅ were lower in the DS group (P< 0.05). The t₂-t₅ Ramsay scores in the DS group were higher than those in the S group (P< 0.05). The doses of sufentanil and tramadol were markedly reduced in the DS group, while the onset of first lactation occurred significantly earlier in the DS group (P< 0.05). Compared with the S group, the DS group had a lower incidence of nausea, vomiting, and skin itching (P< 0.05), and lower frequency of patient-controlled analgesia (PCA) episodes (P< 0.05), and better postoperative pain satisfaction (P< 0.05).

Conclusion: The 1.5µg/kg dexmedetomidine can significantly decrease the ED₅₀ and ED₉₅ of sufentanil in patient-controlled intravenous analgesia after cesarean section, provide good postoperative analgesia and sedation, and promote the earlier occurrence of first lactation.

Purpose: The major cardiac voltage-gated sodium channel Na_V1.5 (I_Na) is essential for cardiac action potential initiation and subsequent propagation. Compound Chinese medicine Wenxin Keli (WXKL) has been shown to suppress arrhythmias and heart failure. However, its active components have not been fully elucidated. This study focused on identifying the active inhibitor of I_Na in WXKL and exploring their mode of action in electrophysiological conduction.

Methods: A chemical fraction library was constructed from an aqueous extract of WXKL and screened using an automated patch-clamping system in cells stably expressing the Na_V1.5 gene SCN5A. Candidate fractions with I_Na-inhibition activity were analyzed by HPLC-ESI-IT-TOF-MS and GC-MS to identify the ingredients. Na_V1.5 blocker molecules identified by single-cell electrocardiogram were tested in hiPSC-derived cardiomyocytes. We evaluated the SCN5A inhibitory potential of Wenxin Keli effective monomer employing molecular docking and molecular dynamics simulation approaches.

Results: A primary screen of the WXKL chemical library identified five fractions that significantly inhibited the Na_V1.5 channel, with one of them rich in poly-saturated fatty acids. Molecular structural characterization revealed the presence of lauric acid, myristic acid, palmitic acid, and stearic acid in the active subfraction. Electrophysiological characterization demonstrated lauric acid (LA) as the most effective monomer for I_Na-inhibition with an IC₅₀ at 27.40 ± 12.78 μM. LA shifted the steady-state inactivation of I_Na to more negative potentials and decreased the amplitude of extracellular field potential in hiPSC-derived cardiomyocytes. We demonstrate for the first time that naturally poly-saturated fatty acid, lauric acid, as a potential novel I_Na blocker. Molecular docking and molecular dynamics simulation suggested that LA binds to the Na_V1.5 protein, with a significant binding affinity forming interactions with functionally essential residues and blocks the inward flow of Na⁺. Mechanistically, lauric acid acts on the fast inactivation of Na_V1.5 alter electrophysiology conduction of hiPSC-derived cardiomyocytes and contribute to the antiarrhythmic effect of WXKL.

Conclusion: Lauric acid is a potent blocker for sodium channel Na_V1.5 and alleviates arrhythmia via inhibiting I_Na.

Background: YYD601 is a new dual delayed-release formulation of esomeprazole, developed to enhance plasma exposure and prolong the duration of acid suppression.

Purpose: This study aimed to evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of YYD601 20 mg following single and multiple oral administrations in healthy, fasting adult Koreans, and to compare these outcomes to those of the conventional esomeprazole 20 mg capsule.

Methods: A randomized, open-label, two-period crossover study was conducted in 28 participants, who were divided into two treatment groups: one group received YYD601 20 mg, and the other received conventional esomeprazole 20 mg, once daily for five consecutive days. Blood samples for PK analysis were collected pre-dose and up to 24 hours post-dose. The primary PK parameters (AUC_last and AUC_τ) were evaluated. PD endpoints included integrated gastric acidity, percentage of time with intragastric pH > 4 over 24-hour and nighttime intervals, and percent change in serum gastrin levels after multiple dosing.

Results: A total of 22 participants completed the study. YYD601 displayed more prolonged plasma concentration-time profiles than the conventional formulation, although the extent of the systemic exposure (AUC values) showed no statistically significant difference between the two formulations. With regard to the 24-hour gastric acid inhibition, YYD601 was comparable to the conventional formulation. The YYD601 showed a greater tendency for acid inhibition at night, as indicated by the percentage change of time with nocturnal acid breakthrough and other PD parameters. Both treatments were well tolerated, with no serious adverse events reported.

Conclusion: Through extended systemic exposure of esomeprazole, YYD601 produces gastric acid suppression that is comparable to that of the conventional esomeprazole formulation, with a greater tendency to suppress acid at night. YYD601 20 mg was safe and well tolerated following single and multiple oral administrations, supporting its use as an effective alternative to conventional esomeprazole therapy.

Clinical trial registry: http://clinicaltrials.gov, NCT03985319 (Date of registration: May 29, 2019; Study period: between July 2019 and March 2020).

Introduction: The mechanism of remimazolam, a benzodiazepine that activates γ-aminobutyric acid a (GABAa) receptors, in cerebral ischemia/reperfusion (I/R) injury is not well understood. Therefore, we explored whether remimazolam activates protein kinase B (AKT)/glycogen synthase kinase-3β (GSK-3β)/nuclear factor erythroid 2-related factor 2 (NRF2) to attenuate brain I/R injury in transcerebral I/R-injured rats and transoxygenic glucose deprivation/reperfusion (OGD/R)-injured SY5Y cells.

Material and methods: Remimazolam was added at the beginning of cell and rat reperfusion, and the PI3K/AKT inhibitor LY294002 was added to inhibit the AKT/GSK-3β/NRF2 pathway 24 h before cellular OGD/R treatment and 30 min before rat brain I/R treatment. The viability and apoptosis rate of SY5Y cells, neurological deficit score, cerebral infarction volume and morphological changes of rat brain cells as well as the protein expression of Bax, Bcl2, Caspase 3, Cleaved-Caspase 3 and the number of TdT-mediated dUTP Nick-End Labeling (TUNEL)-positive cells in the penumbral region were detected. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), NRF2, heme oxygenase 1 (HO-1), AKT, P-AKT, GSK-3β, P-GSK-3β protein expression, and nuclear translocation of NRF2 were measured in cell and animal assays.

Results: Reduced SY5Y cell viability and increased apoptosis caused by OGD/R injury, elevated neurological deficit scores and cerebral infarct volume induced by brain I/R injury in rats, cerebral cell injury, as well as elevated Bax, Cleaved-Caspase 3, decreased Bcl2, and increased number of TUNEL-positive cells in rat brain tissue were all moderated by remimazolam. Decreased GSH-Px, SOD and Elevated MDA, ROS induced by OGD/R-injured SY5Y cells and brain I/R-injured rats were moderated by remimazolam. Meanwhile, remimazolam increased NRF2, HO-1, P-AKT, P-GSK-3β, and the nuclear accumulation of NRF2. The PI3K/AKT inhibitor LY294002 reversed the role of remimazolam in brain I/R injury.

Conclusion: This study demonstrates that remimazolam activates the AKT/GSK-3β/NRF2 pathway, thereby attenuating oxidative stress and apoptosis to protect against brain I/R injury.

Non-alcoholic fatty liver disease (NAFLD) is the major cause of chronic liver disease worldwide, with no universally recognized effective treatments currently available. In recent years, ginseng and its principal active components, such as ginsenosides, have shown potential protective effects in the treatment of these liver diseases. In NAFLD, studies have demonstrated that ginseng can improve hepatic lipid metabolism, reduce inflammatory responses, and inhibit oxidative stress and fibrosis, thereby attenuating the progression of NAFLD. Additionally, ginseng inhibits oxidative stress by scavenging free radicals and enhancing antioxidant enzyme activities, and it can impede fibrosis by interfering with the fibrotic signaling pathways. These combined effects contribute to attenuating the progression of NAFLD. These findings highlight the promise of ginseng as a potential therapeutic candidate for the treatment of NAFLD. However, despite the significant efficacy of ginseng in human NAFLD treatment, the number and quality of clinical studies remain limited, with a lack of large-scale, multicenter clinical trials to confirm these effects. Moreover, the pharmacokinetic properties of different ginsenosides, optimal therapeutic dosages, and the safety of long-term use require further investigation. This review summarizes the existing evidence on the mechanisms of action of ginseng and its active components in human NAFLD, assesses their potential as therapeutic options, and proposes future research directions to provide stronger scientific support for clinical application. Additionally, we performed a network pharmacology analysis of ginseng in relation to NAFLD to identify and investigate potential targets of ginseng in the treatment of NAFLD. This analysis aims to provide a theoretical foundation for the development of ginseng -based drugs for combating NAFLD.

Background: Melanoma is a highly lethal form of skin cancer, and effective treatment remains a significant challenge. SPP86 is a novel potential therapeutic drug. Nonetheless, the specific influence of SPP86 on autophagy, particularly its mechanisms in the context of DNA damage and apoptosis in human melanoma cells, remains inadequately understood. Thus, this study aims to explore the effects of SPP86 on autophagy and to elucidate its association with cell proliferation, apoptosis, and DNA damage in melanoma cells.

Methods: This study assessed the anti-tumor effects of SPP86 on cell viability, colony formation, apoptosis, and DNA damage in two melanoma cell lines, A375 and A2058. Concurrently, the underlying mechanisms, including the PI3K/AKT signaling pathway and autophagy modulation, were also elucidated.

Results: The study demonstrated that SPP86 exerts anti-tumor effects in melanoma cells through multiple mechanisms: it induces apoptosis, causes DNA damage, inhibits cell proliferation, and suppresses the PI3K/AKT signaling pathway. Importantly, the inhibition of autophagy appears to be a critical component of SPP86' s mode of action, with the modulation of autophagic processes influencing the cytotoxicity against melanoma cells.

Conclusion: These promising findings suggest that SPP86 is a potential drug candidate for the treatment of melanoma, warranting further research and development.

Purpose: Osteosarcoma (OS) is the most common malignant tumor associated with poor patient outcomes and a limited availability of therapeutic agents. Scutellarein (SCU) is a monomeric flavone bioactive compound with potent anti-cancer activity. However, the effects and mechanisms of SCU on the growth of OS remain unknown.

Methods: The Cell Counting Kit-8, colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays were used to analyze cell proliferation ability in vitro. TLR4/TRAF6/NF-κB signaling transduction was investigated by RNA sequencing analysis, quantitative real-time polymerase chain reaction, Western blotting, NF-κB luciferase reporter assay, immunofluorescent staining, and immunoprecipitation. Molecular docking and cellular thermal shift assay were employed to confirm the binding interaction between SCU and TLR4. The effects of SCU and TLR4 overexpression on OS growth were analyzed using a xenograft tumor model and immunohistochemical staining.

Results: SCU was found to significantly inhibit OS cell proliferation, and RNA sequencing analysis suggested that the NF-κB pathway is closely associated with this process. Further studies revealed that SCU inhibited the canonical NF-κB pathway through its binding with TLR4, which disrupted the interaction of TLR4 and TRAF6. Moreover, SCU also repressed NF-κB signal transduction by inhibiting TLR4 expression. Furthermore, SCU was revealed to suppress OS cell proliferation by targeting TLR4 in vitro and in vivo.

Conclusion: SCU exhibited a dual impact by inhibiting TLR4 expression and disrupting TLR4-TRAF6 interaction, resulting in NF-κB inactivation, thereby blocking OS growth.