Drug Design, Development and Therapy最新文献

Purpose: Tacrolimus could induce hepatotoxicity during clinical use, and the mechanism was still unclear, which posed new challenge for the prevention and treatment of tacrolimus-induced hepatotoxicity. The aim of this study was to investigate the mechanism of tacrolimus-induced hepatotoxicity and provide reference for drug development target.

Methods: In this study, biochemical analysis, pathological staining, immunofluorescent staining, immunohistochemical staining, transcriptomic analysis, Western blotting was used to investigate the mechanism of tacrolimus-induced hepatotoxicity in gene knockout mice and Wistar rats.

Results: In gene knockout mice, compared to wild-type mice, CXCR2-deficiency alleviated tacrolimus-induced hepatotoxicity (P < 0.05 or P < 0.01). In Wistar rats, compared to control group, CXCL2-CXCR2, JAK3/STAT3 signaling pathway (phosphorylation of JAK3 and STAT3) were up-regulated, the expression of CIS was lowered and the expression of PIM1 was raised, inducing liver pathological change (P < 0.05 or P < 0.01); Inversely, blocking CXCR2 could reverse the expression of p-JAK3/p-STAT3 and tacrolimus-induced hepatotoxicity (P < 0.05 or P < 0.01).

Conclusion: CXCR2 activated JAK3/STAT3 signaling pathway (phosphorylation of JAK3 and STAT3) exacerbating hepatotoxicity associated with tacrolimus, meanwhile the expression of CIS was down-regulated, the expression of PIM1 was up-regulated. Blocking CXCR2 could reverse the expression of p-JAK3/p-STAT3, CIS, PIM1, and tacrolimus-induced hepatotoxicity.

Purpose: The Baolier capsule (BLEC) is a proprietary Mongolian medicine administered for treating hypercholesterolemia and atherosclerosis (AS). However, the therapeutic effects, primary bioactive ingredients, and potential mechanisms underlying hypercholesterolemia and AS remain unclear. This study aimed to investigate the pharmacological effects, principal active ingredients, and mechanisms of BLEC against hypercholesterolemia and AS.

Methods: Adeno-associated virus tail vein injection was utilized to construct liver-specific LXRα knockout ApoE^-/- mice. A high-fat diet was utilized to feed ApoE^-/- mice to build hyperlipidemia and AS mouse models. The aorta or liver stained with Oil Red O was used to assess the effect of the drugs on AS or fatty liver formation after the oral administration of BLEC, piperine, statins, or ezetimibe to the mice following the experimental protocol. Biochemical assays were utilized to evaluate the effect of the drugs on serum lipid levels and cholesterol efflux indicators. Transcriptomics was employed to investigate the effect of BLEC on liver gene expression levels. HPLC-MS/MS was used to determine BLEC and its major components in the liver. Western blotting or quantitative reverse transcription polymerase chain reaction was conducted to detect LXRα, ABCA1, ABCG5, ABCG8, and CYP7A1 expression.

Results: Here, we revealed that BLEC decreases lipid levels in the serum and liver, as well as decelerates AS by promoting cholesterol excretion. BLEC and piperine, which are the main components exposed in the target liver tissue, activate LXRα to upregulate ABCA1, ABCG5, ABCG8, and CYP7A1, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and feces. Notably, piperines demonstrated synergistic beneficial effects with atorvastatin or ezetimibe, which are two widely used hypocholesterolemic and anti-atherosclerotic drugs.

Conclusion: BLEC and its main active ingredient, piperine, promote cholesterol excretion, reduce serum cholesterol levels, inhibit AS, and exhibit good clinical application value and prospects.

In recent years, the incidence of fungal infections has been rising annually, especially among immunocompromised populations, posing a significant challenge to public health. Although antifungal medications provide some relief, the escalating problem of resistance sharply curtails their effectiveness, presenting an urgent clinical dilemma that demands immediate attention. Research has shown that fungal resistance is closely related to quorum sensing (QS), and QS inhibitors (QSIs) are considered an effective solution to this issue. Garlic, as a natural QSI, has demonstrated significant effects in inhibiting fungal growth, preventing biofilm formation, enhancing immunity, and combating resistance. This study explores the potential of garlic in mitigating fungal drug resistance and identifies its key role in inhibiting the QS mechanism, these findings offer a new perspective for the treatment of fungal infections, especially in addressing the increasingly severe problem of resistance. However, the clinical application of garlic still faces several challenges, such as ensuring the standardization of active ingredient extraction, as well as issues of safety and stability. Future research should focus on the QS mechanism and promote interdisciplinary collaboration to develop more natural, effective, and safe QSI drugs like garlic, while actively conducting clinical trials to validate their efficacy and safety. Additionally, incorporating advanced technologies such as nanotechnology to enhance drug stability and targeting, provide a more comprehensive strategy for the treatment of fungal infections. Overall, Our study provides scientific evidence supporting the potential of garlic as a novel antifungal treatment and lays the groundwork for the development of future natural QSIs for therapeutic use. It offers new insights, particularly for the treatment of immunocompromised populations and drug-resistant fungal strains.

Background: Qingre Huoxue Decoction (QRHX) is a classical Chinese herbal prescription widely used in clinical practice for the treatment of atherosclerosis (AS). Our previous study demonstrated its efficacy in stabilizing plaque and improving prognosis, as well as its ability to regulate macrophage polarization. This study aimed to further investigate the effects of QRHX on AS and explore the underlying mechanisms.

Methods: ApoE^-/- mice were fed a high-fat diet (HFD) for 8 weeks in order to establish an AS model. Oil Red O, H&E, Masson, and IHC staining were employed to assess lipid accumulation, plaque development, collagen loss and target of the aortas tissue. ELISA was employed to measure the levels of TNF-α and IL-10 in serum. Dual luciferase reporter assay was conducted to ascertain the connection between miR-26a-5p and PTGS2 in vitro. Western blot and RT-qPCR assay were conducted to assess the NF-κB signaling pathway and macrophage polarization. The effects of miR-26a-5p were tested after transfecting miR-26a-5p over-expressive lentivirus.

Results: QRHX attenuated HFD-induced plaque progression and inflammation of AS model mice. BMDM-derived exosomes (BMDM-exo) increased miR-26a-5p and decreased PTGS2 expressions, inhibited the NF-κB signaling pathway and regulated macrophage polarization in vivo. These effects of BMDM-exo were further enhanced after QRHX intervention. Dual luciferase reporter assay results showed that miR-26a-5p directly binds to the 3'-UTR of PTGS2 mRNA and regulates the expression of PTGS2. The miR-26a-5p of BMDM-exo played a key role in macrophage polarization. After overexpression of miR-26a-5p, the NF-κB signaling pathway was inhibited and macrophages were converted from M1 to M2 in vitro.

Conclusion: QRHX can exert anti-inflammatory and plaque-stabilizing effects through exosomal miR-26a-5p via inhibiting the PTGS2/NF-κB signaling pathway and regulating macrophage phenotype from M1 to M2 polarization in AS.

Objective: Modified Zuo Gui Wan (MZGW) was a combination of Zuo Gui Wan and red yeast rice used for treating osteoporosis (OP), but its mechanism remains unclear. We aimed to validate the anti-OP effect of MZGW and explore its underlying mechanism.

Methods: An ovariectomy (OVX) rat model in vivo and a RANKL-induced osteoclasts (OCs) model in vitro were established. Key active ingredients in MZGW high dose (MZGW-H) group were detected by UPLC-MS/MS. Micro-CT scans and histomorphology analysis were performed in OVX rats. 16S rRNA gene sequencing was performed to investigate the relationship between the anti-OP effect of MZGW-H and intestinal flora. CCK-8 assay was applied to examine the optimal concentration of Modified Zuo Gui Wan drug serum (MZGW-DS) on osteoclasts. The qRT-PCR and Western blotting were utilized to explore the potential anti-OP pathway of MZGW, namely the SCFA-GPR41-p38MAPK signaling pathway. GPR41 was knocked down to further reverse to verify whether the pathway was the key pathway for MZGW-DS to exert its inhibitory effect on osteoclasts.

Results: The three main blood components, Ferulic acid, L-Ascorbic acid and Riboflavin, were examined mainly by UPLC-MS/MS. 16S rRNA gene sequencing showed that MZGW-H changed the metabolism of SCFAs. In vivo studies verified that MZGW-H ameliorated microstructure damage, improved histological changes and reduced TRAP, BALP, and BGP in OVX rats by regulating the SCFA-GPR41-p38MAPK signaling pathway. CCK-8 revealed that 5% MZGW-DS group was the most optimal concentration of MZGW-DS to inhibit osteoclast differentiation. In vitro, MZGW-DS was better than peripheral blood concentration of SCFAs in inhibiting osteoclasts. After the knockout of GPR41, MZGW-DS could not inhibit the expression of osteoclast-related protein (CTSK and NFATc1) via SCFA-GPR41-p38MAPK signaling pathway.

Conclusion: MZGW-H effectively ameliorates OVX-induced osteoporosis partially achieved by increasing SCFAs metabolism and modulating the SCFA-GPR41-p38MAPK signaling pathway.

Objective: This study aimed to evaluate the predictive performance of published amisulpride population pharmacokinetic (PopPK) models in schizophrenia patients with an external data set and establish remedial dosing regimens for nonadherent amisulpride-treated patients.

Methods: A systematic search was conducted on PubMed, Embase, and Web of Science to identify PopPK models for evaluation. The evaluation process involved analyzing 390 serum concentration samples obtained from 361 Chinese adult inpatients diagnosed with schizophrenia. Model predictability was evaluated by prediction-based and simulation-based diagnostics. Based on validation results, a modified PopPK model was constructed to characterize amisulpride pharmacokinetic in our patients. Monte Carlo simulation was employed to investigate non-adherence scenarios and the impact of subsequently administered remedial regimens.

Results: In the five assessed published models, four included trough concentrations from schizophrenia patients, and one combined single-dose data from healthy older adults and trough concentrations from older adults with Alzheimer's disease. The PE for population and individual predictions ranged from -92.89% to 27.02% and -24.82% to 4.04%, respectively. In the simulation-based diagnostics, the NPDE results indicated noticeable bias in all models. Therefore, a modified one-compartment model, with estimated creatinine clearance(eCLcr) as covariates on the apparent clearance (CL/F) of amisulpride, was developed. For delays in medication dosing, if the delay is within 12 hours, take half the missed dose right away, then resume the normal schedule; if the delay is up to 24 hours, just continue with the regular dosing schedule.

Conclusion: Existing published models lack the necessary reliability for cross-center application. Future prospective studies are required to assess our model before integrating it into clinical practice. Model-based simulations provided a rational approach to propose remedial strategies for delayed or missed doses.

Purpose: Intervertebral disc degeneration (IDD) is a leading cause of low back pain, and developing new molecular drugs and targets for IDD is a new direction for future treatment strategies. The aim of this study is to investigate the effects and mechanisms of tomatidine in ameliorating lumbar IDD.

Methods: Nucleus pulposus cells (NPCs) exposed to lipopolysaccharides were used as an in vitro model to investigate changes in the expression of extracellular matrix components and associated signaling pathway molecules. A lumbar instability model was used to simulate IDD. Tomatidine (Td) was then administered intraperitoneally, and its effects were evaluated through histopathological analysis.

Results: In vitro, Td significantly promoted ECM anabolism, inhibited ECM catabolism, and reduced oxidative stress and ferroptosis in LPS-stimulated NPCs. When Nrf2 expression was inhibited, oxidative stress and ferroptosis were exacerbated, and the protective effects of Td on NPCs were lost, suggesting the Nrf2/HO-1/GPX4 axis is critical for the therapeutic effects of Td. In vivo, histopathological analysis demonstrated that Td ameliorated IDD in a murine model.

Conclusion: Td alleviates IDD in vitro and in vivo by activating the Nrf2/HO-1/GPX4 pathway to inhibit ferroptosis in NPCs. This mechanism suggests Td is a promising candidate for IDD treatment.

Objective: To investigate whether oxyresveratrol (OXY) can alleviate irinotecan (CPT-11)-induced intestinal toxicity and whether the combination of these two drugs can enhance the inhibition of colorectal cancer cells.

Methods: The CCK-8 assay was used to assess the inhibitory effects of OXY and CPT-11, both as monotherapies and in combination, on the proliferation of colorectal cancer cell lines HCT116 and SW620. Mice were grouped (8/mice/group) into: control, CPT-11, low-dose OXY+CPT-11, high-dose OXY+CPT-11. Each trial was conducted as an independent experiment. A mouse diarrhea model induced by CPT-11 was established to observe the general condition, diarrhea score, spleen and colon of each group of mice. Bioinformatics tools were employed to predict the targets of OXY and CPT-11, followed by GO and KEGG enrichment analyses.

Results: CPT-11 inhibited the growth of colorectal cancer cells in a dose-dependent manner, and OXY combined treatment had additive effects. Mice in the CPT-11 group experienced significant weight loss and severe diarrhea, while the co-administration of OXY alleviated these adverse effects. Bioinformatics analysis revealed that the targets of OXY and CPT-11 were enriched in pathways such as PI3K/Akt and cell cycle, suggesting that the combination therapy might exert a synergistic effect by modulating these pathways.

Conclusion: The combination of OXY and CPT-11 enhances the inhibitory effect on colorectal tumor cells and reduces the intestinal toxicity induced by CPT-11. This study provides a novel strategy for colorectal cancer chemotherapy.

Purpose: Triple-negative breast cancer (TNBC) is a disease associated with high incidence and high mortality, which is a major problem threatening women's health. Xiaoyao Sanjie Decoction (XYSJD) exhibits remarkable therapeutic efficacy on TNBC; however, the underlying mechanism is unclear. This study verified the efficacy of XYSJD and its active component in the treatment of TNBC and explored its potential mechanism.

Methods: Ultra-high performance liquid chromatography-hybrid quadrupole orbitrap mass spectrometry (UHPLC-Q Exactive HFX-MS) was applied to explore the main chemical constituents of XYSJD. The key targets and potential mechanisms of XYSJD in the treatment of TNBC were predicted through network pharmacology, bioinformatics analysis and molecular docking. The effects of XYSJD against TNBC cells were evaluated by CCK-8 assay, EdU assay, wound healing assay, transwell assay, Hoechst-PI staining and flow cytometry. The mechanism of action was validated by Western blot analysis. Finally, the effect and mechanism of XYSJD and Que on TNBC were further verified by the tumor formation model.

Results: UHPLC-Q Exactive HFX-MS identified a total of 9 compounds in XYSJD. Network pharmacological methods identified 206 targets for anti-TNBC. Bioinformatics analysis suggests that the EZH2/AKT1 signaling pathway might play an important role in the effects of XYSJD against TNBC. Gene Ontology enrichment analysis showed that the biological process of XYSJD in TNBC treatment mainly involved apoptosis. XYSJD and Que were observed to have a good anticancer effect in vivo and in vitro. In addition, quercetin could induce the apoptosis of TNBC cells by decreased the expression levels of EZH2/AKT1 signaling pathway. Furthermore, AKT1 overexpression, treatment with the AKT activator (SC79) and EZH2 overexpression could reverse apoptosis induced by quercetin in TNBC cells.

Conclusion: This study revealed the anti-TNBC efficacy of XYSJD. Quercetin, the effective component of XYSJD, promoted apoptosis of TNBC cells via blockade of the EZH2/AKT1 signaling pathway. These findings aim to provide a more reliable basis for the clinical application of XYSJD in the treatment of TNBC.

Objective: This study aims to support the selection of PCSK9 inhibitors for patients requiring lipid management within medical institutions. By quantitatively evaluating four PCSK9 inhibitors, we provide evidence-based guidance for optimal selection in this patient population.

Methods: According to the Rapid Guide for Drug Evaluation and Selection in Chinese Medical Institutions (Second Edition) released in 2023, relevant databases such as PubMed, Cochrane, Embase, drug labels, and clinical guidelines were searched for drug information. Using a percentage scoring method, we systematically evaluated 4 PCSK9 inhibitors marketed in China for safety, efficacy, economy, pharmacological properties, and other attributes.

Results: The final assessment result scores from highest to lowest were evolocumab (78.00 points), alirocumab (77.24 points), inclisiran (72.89 points), and tafolecimab (65.33 points). Evolocumab was the best in the economy, alirocumab scored the highest in terms of efficacy and other attributes, and inclisiran had the strongest performance in terms of pharmacological properties.

Conclusion: For lipid management in medical institutions, evolocumab, alirocumab, inclisiran, and tafolecimab may be prioritized accordingly based on evaluation results.