Drug Design, Development and Therapy最新文献

Autoimmune diseases arise when the immune system attacks healthy tissues, losing tolerance for self-tissues. Normally, the immune system recognizes and defends against pathogens like bacteria and viruses. The cGAS-STING pathway, activated by pattern-recognition receptors (PRRs), plays a key role in autoimmune responses. The cGAS protein senses pathogenic DNA and synthesizes cGAMP, which induces conformational changes in STING, activating kinases IKK and TBK1 and leading to the expression of interferon genes or inflammatory mediators. This pathway is crucial in immunotherapy, activating innate immunity, enhancing antigen presentation, modulating the tumor microenvironment, and integrating into therapeutic strategies. Modulation strategies include small molecule inhibitors, oligonucleotide therapies, protein and antibody therapies, genetic and epigenetic regulation, cytokine and metabolite modulation, and nanoscale delivery systems. Post-translational modifications (PTMs) of the cGAS-STING pathway, such as phosphorylation, acetylation, ubiquitination, methylation, palmitoylation, and glycosylation, fine-tune immune responses by regulating protein activity, stability, localization, and interactions. These modifications are interconnected and collectively influence pathway functionality. We summarize the functions of cGAS-STING and its PTMs in immune and non-immune cells across various diseases, and explore potential clinical applications.

Trastuzumab deruxtecan (T-DXd) has been approved to treat various tumors. While most adverse events (AEs) associated with T-DXd are manageable, interstitial lung disease (ILD)/pneumonitis is a notable AE of special concern. This review describes the incidence, severity, and management of T-DXd-induced ILD/pneumonitis across different tumors. We conducted a systematic search of PubMed, Embase, Cochrane Library, and Web of Science for literature published up to 13 September 2024, regarding the use of T-DXd in the treatment of HER2-positive tumors. Studies included were clinical trials involving HER2-positive tumors with reported ILD/pneumonitis cases.The main data extracted from the full-text articles included the incidence and severity of T-DXd-induced ILD. 18 studies involving 3380 patients with various advanced solid malignancies were included in our review. The overall incidence of adjudicated drug-related ILD/pneumonitis was 12.40%. Although most ILD/pneumonitis cases were low-grade, the risk of ILD/pneumonitis-related death should not be overlooked. Given the prolonged exposure to the drug, careful monitoring and management of T-DXd-induced ILD/pneumonitis are critical. Management strategies include dose reduction, treatment interruption, discontinuation, corticosteroids, and supportive care. Further research is needed to clarify the risk factors and mechanisms underlying T-DXd-induced ILD/pneumonitis. This review highlights critical gaps in understanding the risk factors and mechanisms of T-DXd-induced ILD, underscoring the need for further research.

Background: Daifu Decoction (DFD), a patented herbal prescription used to prevent and treat ulcerative colitis (UC). This study aimed to reveal the effect of DFD on the relapse of UC and its mechanism via integrated retrospective clinical analysis, network pharmacology and in vivo and in vitro experimental validation.

Methods: First, the clinical data of UC patients treated with DFD were reviewed from a real-world study (RWS), and the relapse at 24 weeks after drug withdrawal was recorded to evaluate the relapse rate. Next, the chemical components of DFD were identified via ultra performance liquid chromatography‒mass spectrometry (UPLC‒MS), and the differentially expressed genes (DEGs) between UC patients in the active and remission stages were screened as disease targets related to the relapse of UC from the Gene Expression Omnibus (GEO) database. The core components, targets and key signalling pathways of DFD for preventing the relapse of UC were discussed via network pharmacology. Finally, the above results were verified via molecular docking and in vivo and in vitro experiments.

Results: A total of 475 UC patients were included, and the relapse rate of UC treated with DFD was 23.9%. Additionally, the 221 components identified by UPLC-MS and 398 DEGs related to the relapse of UC enriched the main pathway of the relapse of UC was IL-17 signaling pathway and the inflammatory-related targets, such as IL6, PTGS2, MMP7, MMP3, MMP1. Moreover, molecular docking revealed that the core components of DFD were able to bind to inflammation-related targets, and in vivo and in vitro experiments demonstrated that DFD could inhibit the IL-17 pathway, increase the level of claudin-1, and control inflammation to prevent UC relapse.

Conclusion: DFD can effectively prevent the relapse of UC which may be related to inhibiting the activation of IL-17 signalling pathway.

Objective: This study aimed to evaluate the protective effects of bosentan, a dual endothelin receptor antagonist, against skeletal muscle ischemia-reperfusion injury (IRI) in rats.

Methods: A total of 24 male Wistar Albino rats were divided into four groups: control (C, n=6), bosentan-treated (B, n=6), ischemia-reperfusion (IR, n=6), and bosentan plus ischemia-reperfusion (B+IR, n=6). Bosentan (10 mg/kg) was administered 30 minutes prior to reperfusion. In the IR and B+IR groups, ischemia was induced using vascular bulldog clamps for 45 minutes, followed by 120 minutes of reperfusion.

Results: Histological and biochemical assessments revealed significant differences among the groups. The disorganization and degeneration scores of the muscle cells in the B+IR group were significantly lower than those in the IR group (P = 0.001). The degree of interstitial edema in the IR group was markedly more severe than in the C and B groups (all P < 0.001), while the interstitial edema score in the B+IR group was significantly lower than that in the IR group (P < 0.001). The total muscle injury scores were markedly reduced in the B+IR group compared to the IR group (P < 0.001). Biochemically, TAS levels were significantly higher in the B+IR group compared to the IR group (1.03 ± 0.18 vs 0.59 ± 0.10 mmol/L, P = 0.016). Conversely, TOS (1.97 ± 0.39 vs 2.86 ± 0.43 IU/mg, P < 0.001) and OSI levels (P < 0.001) were significantly lower in the B+IR group. Additionally, paraoxonase (PON-1) enzyme activity was significantly reduced in the B+IR group compared to the IR group (P < 0.001). These findings suggest that bosentan exerts its protective effects by antagonizing endothelin-1 receptors, thereby mitigating vasoconstriction, oxidative stress, and inflammation. The observed reductions in muscle cell disorganization, interstitial edema, hemorrhage, neutrophil infiltration and oxidative stress markers underscore bosentan's potential as a therapeutic agent for managing ischemia-reperfusion injury.

Conclusion: Bosentan demonstrates significant protective effects against skeletal muscle IRI by reducing oxidative stress and inflammation through endothelin receptor antagonism. These findings underscore bosentan's potential as a therapeutic agent for mitigating ischemia-reperfusion injury in vascular surgeries and managing critical limb ischemia in clinical settings. Further research is warranted to explore the long-term effects of bosentan on muscle recovery and systemic health following ischemia-reperfusion injury.

Purpose: Vaccarin is a natural flavonoid glycoside with anti-inflammatory, antioxidant and nephroprotective effects. However, the effects of vaccarin on renal fibrosis (RF) and its molecular mechanisms remain unclear. This study aimed to investigate the effects of vaccarin on RF and its molecular mechanisms.

Methods: Network pharmacology was used to analyze the effect of vaccarin on RF, and molecular docking and molecular dynamics simulations were performed to assess the binding of nuclear factor erythroid 2-related factor 2 (Nrf2) to vaccarin. A mouse model of unilateral ureteral obstruction (UUO) was established in vivo, and human renal tubular epithelial (HK2) cells were induced with transforming growth factor-β (TGF-β) and RSL3, respectively, as an in vitro model. The anti-fibrotic effect of vaccarin was observed by histopathological staining and determination of fibrous markers. Changes in oxidative stress and ferroptosis-related markers were detected by kits, Western blot (WB), qRT-PCR and immunofluorescence (IF). Finally, Nrf2 inhibitors were added to the in vitro model to observe the effects on fibrosis and ferroptosis.

Results: Vaccarin and RF cross genes are enriched for oxidative stress. Nrf2 binds stably to vaccarin. Both in vivo and in vitro experiments showed that vaccarin treatment reduced the expression of fibrosis markers, decreased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), lipid peroxidation (LPO) and Fe²⁺, and increased glutathione (GSH) secretion. In addition, vaccarin down-regulated the expression of Long-chain acyl-CoA synthetase 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2) and NADPH oxidase 1 (NOX1), and up-regulated Nrf2 and its downstream solute transport family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression. Mechanistic studies indicated that vaccarin activated the Nrf2/SLC7A11/GPX4 pathway to inhibit ferroptosis, and this inhibition was effectively reversed by the Nrf2 inhibitor.

Conclusion: Vaccarin ameliorates RF by inhibiting ferroptosis via Nrf2/SLC7A11/GPX4 pathway.

Ischemia-reperfusion injury is a multi-tissue/organ susceptible and highly destructive disease. The complex pathological mechanisms of ischemia-reperfusion injury make its prevention and treatment highly challenging, and the development of novel drugs with pharmacological pleiotropy that can target multiple pathological mechanisms has become the focus of current drug research. Polydatin is a traditional Chinese medicine monomer with pleiotropic pharmacological effects, and existing research evidence suggests that polydatin has strong protective potential against ischemia-reperfusion injury. However, the mechanism of polydatin against ischemia-reperfusion injury is still unclear. In this review, the extensive pharmacological-pathological mechanism associations between polydatin and ischemia-reperfusion injury have been described from the perspectives of inflammatory response, oxidative stress, apoptosis, autophagy, ferroptosis, and cellular pyroptosis, which will provide references to the basic and applied research of polydatin in the field of ischemia-reperfusion injury.

Background: Specnuezhenide (SPN) is an iridoid glycoside isolated from Fructus Ligustri Lucidi, an herb prescribed for the treatment of senile osteoporosis. However, the direct role of SPN on bone metabolism remains unclear. In this study, the effects of SPN on d-galactose (d-gal)-induced mice, bone marrow mesenchymal stem cells (BMSCs), and nuclear factor-κB ligand-induced osteoclasts were examined.

Methods: Micro-computed tomography was used to observe the bone microstructure. Osteogenesis was examined using Western blotting and alkaline phosphatase staining. Osteoclastogenesis was examined using Western blotting and F-actin ring staining. Senescence-associated β-galactosidase was used to detect cell senescence. In addition, the expression of Takeda G protein-coupled receptor 5 (TGR5)/farnesoid X receptor (FXR) signaling pathway-related genes and proteins was determined through quantitative real-time polymerase chain reaction and immunofluorescence.

Results: Oral administration of SPN improved the bone microstructure in d-gal-induced mice and increased bone mineral density, bone volume, trabecular thickness, and trabecular number. SPN also upregulated the expression of the osteogenesis markers osteocalcin, bone morphogenetic protein 2, and runt-related transcription factor 2 and downregulated the expression of the osteoclasis markers tartrate-resistant acid phosphatase, nuclear factor-κB, and nuclear factor of activated T-cells in the d-gal-induced bone. Furthermore, SPN increased alkaline phosphatase staining, inhibited F-actin ring formation, and reduced the activity of senescence-associated β-galactosidase in vitro. Mechanistically, SPN activated the TGR5/FXR pathway in d-gal-induced BMSCs and osteoclasts. The protective effects of SPN were abolished after addition of the TGR5 inhibitor SBI-115 or FXR inhibitor DY268. Moreover, SPN could elevate the protein and mRNA levels of TGR5, FXR, and the downstream small heterodimer partner in d-gal-induced bone.

Conclusion: SPN alleviated senile osteoporosis and cell senescence by activating the TGR5/FXR pathway.

Background: Optimum dose of remimazolam for inducing loss of consciousness in elderly patients has been suggested by prior studies. Opioids can enhance their sedative effects, thereby permitting dose reduction. However, the dose-response of remimazolam when combined remifentanil for attenuating stress response during laryngeal mask airway (LMA) insertion in elderly female patients is still unknown. Moreover, the ideal dose of medications is especially critical in elderly patients due to their compromised cardiopulmonary function. The objective of this study was to determine the median effective dose (ED50) and ED95 of remimazolam in inhibiting the stress response associated with LMA insertion.

Methods: Sixty aged ≥ 65 and < 80 years old female patients were randomized allocated into 1 of 4 groups receiving doses of 0.2, 0.25, 0.3, and 0.35 mg/kg remimazolam. Following a dosage of 2.0 ng/mL of remifentanil, patients received different doses of remimazolam. Effective dose is defined as the prevention of stress response associated with LMA insertion, characterized by a post-sedation induction SBP variation < 20% of baseline value, jaw relaxation and absence of patient body motion during the initial 2 minutes following LMA insertion. Probit regression analysis was utilized to estimate the ED50 and ED90 values.

Results: The ED50 and ED95 of effective remimazolam of general induction for elderly female patients not suffer intubation stress response were 0.24 mg/kg (95% CI 0.20-0.27 mg/kg) and 0.37 mg/kg (95% CI 0.32-0.49 mg/kg), respectively. The incidence of hypotension was 33.3% (5/15), 46.7% (7/15), 73.3% (11/15), and 80% (12/15) in the four groups, respectively.

Conclusion: The ED50 and ED95 values of intravenous remimazolam for preventing stress response during LMA insertion were 0.24 and 0.37 mg/kg, respectively in elderly female.

Trial number and registry url: Registration number, ChiCTR2400083990, https://www.chictr.org.cn/showproj.html?proj=229006.

Purpose: Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) used for the treatment of hepatocellular carcinoma (HCC). However, the potential mechanisms remain unclear. The objective of this study is to clarify the mechanism of action of YFJP in treating HCC.

Methods: By constructing networks, the active components and molecular targets of YFJP in the treatment of HCC were explored. The TCGA database was utilized to analyze the correlation between the core target and the overall survival (OS) of patients with HCC. The regulatory effect of YFJP on T cell was evaluated by detecting samples from patients with HCC. The molecular mechanism of YFJP in treating HCC was validated through in vivo and in vitro experiments.

Results: Constructing networks and analyse indicated that the key targets of YFJP in the treatment of HCC is FoxO1. Analysis of the HCC patient cohort in the TCGA database demonstrated that FoxO1 is an independent protective factor for overall survival in patients with HCC. Pathway enrichment analysis enriched FoxO signaling pathway and Cellular senescence pathway. Prospectively collecting samples from patients with HCC suggested that YFJP treatment increased the proportion of CD8⁺ T cells. In vivo experiments showed that YFJP treatment ameliorated CD8⁺ T cell senescence in tumor-bearing mice. Western blot, flow cytometry and multi-color immunofluorescence co-staining showed that YFJP treatment increased the expression of FoxO1 in CD8⁺ T cells. The primary CD8⁺ T cells were sorted and co-cultured with an HCC cell line in vitro. Inhibiting the expression of FoxO1 in CD8⁺T cells confirmed that FoxO1 is a key target for YFJP to improve the senescence of CD8⁺ T cell.

Conclusion: FoxO1 is the key molecular target of YFJP in improving CD8⁺ T cell senescence in HCC. This study preliminarily clarified the mechanism of YFJP in regulating immunosenescence of HCC.