Drug Design, Development and Therapy最新文献

Background: Bypass signaling plays an important role in mediating osimertinib resistance in lung adenocarcinoma (LUAD) with epidermal growth factor receptor (EGFR) mutations; however, the role of abnormally activated motor neuron and pancreas homeobox 1 (MNX1) in mediating osimertinib resistance in EGFR-mutant LUAD is unknown.

Methods: Bioinformatics and immunohistochemistry(IHC) analysis identified the MNX1 expression levels in LUAD. The effects of MNX1 and osimertinib on LUAD cell proliferation, invasion, migration, and apoptosis were evaluated using the cell counting kit-8, scratch, EdU, chamber transwell, and flow cytometry assays in vitro. In vivo, the effect of MNX1 expression on tumorigenicity was evaluated using subcutaneous transplanted tumors in nude mice.

Results: Bioinformatics databases and tumor tissue analysis revealed elevated MNX1 expression in LUAD tumor tissues, with high MNX1 expression correlating with poor prognosis. The receiver-operating characteristic(ROC) curve demonstrated that MNX1 has high specificity and sensitivity in diagnosing LUAD from the TCGA dataset. Multivariable COX analysis identified MNX1 as independent prognostic factors for overall survival (OS) in LUAD. Nomogram and calibration plots indicated that combining MNX1 with clinical factors could well predict 1-, 2-, and 3-year OS probabilities in LUAD. Additionally, abnormally activated MNX1 promoted LUAD cell proliferation, invasion, and migration and inhibited apoptosis. MNX1 expression was higher in EGFR-mutant LUAD cells and correlated with osimertinib resistance. The combination of MNX1 depletion and osimertinib suppressed LUAD cell growth and proliferation, inhibited xenograft tumor growth, and reversed osimertinib resistance in vivo. Abnormally activated MNX1 affected PD-L1 expression and induced epithelial-mesenchymal transition (EMT), reversing osimertinib resistance in LUAD cells via the EGFR signaling pathway.

Conclusion: This study demonstrated that abnormally activated MNX1 promoted LUAD cell growth and proliferation and acquired resistance to osimertinib through AKT-mediated EMT and PD-L1. Therefore, MNX1 may be a promising prognostic biomarker and therapeutic target for osimertinib resistance in EGFR-mutant LUAD.

Polycystic ovary syndrome (PCOS) is a prevalent and multifaceted endocrine disorder characterized by hyperandrogenism, ovarian dysfunction, and insulin resistance. This review aims to synthesize current evidence from both allopathic medicine and Traditional Chinese Medicine (TCM) to clarify the pathophysiological mechanisms of PCOS and evaluate the therapeutic potential of integrative management strategies. We first outline key epidemiological, genetic, and hormonal features that underpin PCOS, with particular emphasis on insulin resistance, chronic inflammation, and dysregulated gonadotropin secretion. We then summarize core TCM treatment principles and describe how herbal medicine, acupuncture, and combined therapies modulate endocrine pathways, improve metabolic homeostasis, and regulate immune-inflammatory responses. Clinical studies further suggest that TCM-based interventions may enhance ovulatory function, improve metabolic parameters, and alleviate hyperandrogenic symptoms, supporting their complementary role alongside allopathic treatments. Finally, current limitations-including variability in TCM pattern diagnosis, heterogeneity of herbal preparations, and methodological constraints in mechanistic research-are highlighted to guide future investigations. Overall, this review underscores the clinical relevance and potential value of integrative approaches that bridge traditional and modern medical frameworks in the comprehensive management of PCOS.

Objective: This study aimed to investigate the anti-inflammatory and antioxidant effects of ozone on liver and kidney tissues as an adjuvant therapy in the treatment of sepsis in individuals with diabetes.

Materials and methods: 46 Swiss Albino mice were divided into six groups: control (C), diabetes (D), diabetes + ozone (DO), diabetes + cecal perforation (DCP), diabetes + cecal perforation + ozone (DCPO), and diabetes + ozone + cecal perforation (DOCP). The diabetes groups received 125 mg/kg intraperitoneal (i.p). Streptozotocin (STZ). The DCPO and DOCP groups received 1 mL (20 µg mL^{- 1} i.p.) ozone. Liver and kidney tissues were collected 24 hours later. Tissue samples were stored under appropriate conditions for histopathological and biochemical analyses.

Results: Histopathological analysis of liver and kidney tissue revealed that all acute inflammatory markers were more pronounced in the DCP group compared to the C, D, and DO groups. Acute inflammatory markers were lower in the ozone-treated groups compared to the DCP group. In the diabetes and sepsis groups, malondialdehyde (MDA) levels increased in both liver and kidney tissues, while catalase (CAT) activity decreased. MDA levels were lower in the ozone-treated groups, and CAT activity was higher than in the no-ozonized groups. Blood urea nitrogen (BUN), creatinine, AST, and ALT levels were significantly higher in the DCP group compared to the C, D, and DO groups. Conversely, these values were lower in the DCPO and DOCP groups compared to the DCP group.

Conclusion: Our findings suggest that ozone therapy may alleviate inflammatory and oxidative stress-related damage to the liver and kidneys caused by diabetes and sepsis. Additionally, ozone therapy appears to reduce serum markers of liver and kidney function such as AST, ALT, BUN, and creatinine.

Introduction/objective: Patients undergoing induced abortion frequently experience acute visceral pain and preoperative anxiety, the latter of which is known to increase anesthetic requirements. This study aimed to determine the median effective dose (ED50) and the 95% effective dose (ED95) of propofol in combination with oxycodone for alleviating visceral pain, specifically testing the finding that anxiety increases the needed propofol dose.

Methods: Female patients, who were scheduled for elective abortion surgeries, with PAS-7 ≥8 were classified as anxious group (Group A), while those with PAS-7 < 8 were classified as non-anxious group (Group N). Both groups received an intravenous dose of 0.10 mg/kg of oxycodone prior to surgery.And 2 to 3 minutes later, the first patient in the sequence received an initial dose of 3.50 mg/kg of propofol, with subsequent doses determined by Dixon's up-and-down method.

Results: The ED50 (95% CI) for propofol was 1.96 mg/kg (1.87-2.05) in Group N and 2.42 mg/kg (2.30-2.53) in Group A; the ED95 (95% CI) was 2.10 mg/kg (2.03-2.39) and 2.60 mg/kg (2.50-2.95), respectively. The lack of overlap in the 95% confidence intervals indicates a statistically significant difference between groups.

Conclusion: The combination of 0.10 mg/kg oxycodone and propofol was effective for visceral pain suppression during artificial abortion. Notably, patients with anxiety required higher doses of propofol to achieve satisfactory pain relief during abortion surgeries.

Trial registration: This human study was approved by the Medical Ethics Committee of the People's Hospital of Qiannan (QNZY-QNYZKYRC-23-0801) and registered at https://www.chictr.org.cn/ (Date: 09/26/2023, ChiCTR2300076169).

Background: Antimicrobial drug discovery urgently requires innovative strategies to combat the growing threat of multidrug-resistant pathogens. The 2-C-methylerythritol 4-phosphate (MEP) pathway, essential in many pathogenic bacteria yet absent in humans, represents an attractive source of selective antibacterial targets. Within this pathway, the enzyme IspE is a promising candidate for inhibitor development.

Methods: We screened a halogen-enriched fragment library to identify inhibitors of IspE from Klebsiella pneumoniae and Escherichia coli. We validated our hits through biochemical assays, followed by structure-activity relationship (SAR) studies to optimize the fragments inhibitory activity. Mode-of-inhibition experiments were conducted to determine the mechanism of enzyme inhibition.

Results: Screening identified a fragment-like compound 1 and several additional hits that inhibited K. pneumoniae IspE and E. coli IspE at micromolar concentrations. SAR analysis generated optimized fragments with enhanced potency. Mode-of-inhibition assays revealed that these fragments act as competitive inhibitors with respect to the natural substrate, 4-diphosphocytidyl-2-C-methylerythritol (CDP-ME).

Conclusion: This newly identified fragment class provides a promising foundation for the development of IspE inhibitors. The findings highlight the utility of fragment-based screening approaches for discovering novel antimicrobial agents targeting the MEP pathway.

Background: Artesunate (AS) has great pharmacokinetic and clinical value. However, a comprehensive and up-to-date study exclusively focusing on AS direct binding proteins has not yet been conducted.

Methods: We performed a systematic, data-driven mapping of AS-binding protein via HuProt™ 20K human proteome microarray. To characterize the biological features of AS-binding proteins through a series of bioinformatic analyses.

Results: Firstly, AS targeted ubiquitin-mediated proteolysis, mineral absorption, Salmonella infection and glycolysis/gluconeogenesis. Among them, ubiquitin-mediated proteolysis has highest confidence scores, chaperone complex and ubiquitin-like protein conjugating enzyme activity were enriched in this set. Secondly, we showed that the bioactivity of AS encompasses a multifaceted range of health-promoting effects. Collectively, this study provided a valuable resource for AS-binding proteins. Furthermore, protein biological function is determined by their three-dimensional structure, when a protein fails to fold into its native structure, the proteins undergo mislocalisation/abnormal accumulation/degradation, leading to conformational diseases (CDs).

Conclusion: Considering that AS could target ubiquitin-proteasome system (UPS) and encompass a multifaceted range of health-promoting effects, a comprehensive understanding of the regulatory effects of AS on the UPS and its intrinsic mechanisms will enhance its ability to serve as a protective agent to fight against CDs.

Purpose: Thoracic surgery is one of the postoperative surgical procedures with the most severe pain. This study aimed to assess whether intraoperative subanesthetic esketamine could reduce the proportion of elderly patients experiencing moderate-to-severe pain following thoracoscopic lung resection.

Patients and methods: A total of 136 elderly patients undergoing thoracoscopic pulmonary surgery were randomly assigned to two groups: the esketamine group (0.25 mg/kg loading, 0.25 mg/kg/h infusion) and the control group (received normal saline). The primary outcome was the proportion of patients experiencing moderate-to-severe pain on the first postoperative day (POD1), defined as a Numerical Rating Scale (NRS) pain score ≥4 during coughing. The secondary outcomes were the postoperative Athens Insomnia Scale (AIS), Hospital Anxiety and Depression Scale (HADS) scores, opioid consumption, hemodynamics, and adverse events.

Results: The primary outcome incidence was lower in the esketamine group (51.5% [35/68]) than in the control group (69.1% [47/68]; relative risk [RR], 0.75; 95% confidence interval [CI], 0.56-0.99; P = 0.035). The proportion of patients with moderate-to-severe pain in the esketamine group decreased by 25.5%. The analysis revealed an absolute risk reduction (ARR) of 17.6% and a number needed to treat (NNT) of 5.7 (rounded to 6). The incidence of postoperative sleep disturbance (PSD) on POD1 (23.5% vs 44.1%; RR, 0.53; 95% CI, 0.32-0.88; P = 0.011) is lower in patients who receive esketamine. Compared to the control group, the esketamine group demonstrated lower HADS scores and reduced opioid consumption, without significant differences in hemodynamic parameters or an increased incidence of neuropsychiatric adverse events.

Conclusion: This study demonstrated that intraoperative subanesthetic esketamine reduced the proportion of moderate-to-severe pain in elderly patients after thoracoscopic surgery, decreased the incidence of sleep disturbances, improved anxiety and depression scores, and lowered opioid consumption, without increasing neuropsychiatric adverse events.

Background: Sufentanil-induced cough (SIC) frequently occurs during the induction of general anesthesia and may result in serious clinical complications, occasionally posing life-threatening risks. In clinical practice, we observed that oliceridine-a G protein-biased μ-opioid receptor agonist-demonstrates a potent suppressive effect on SIC. This study aimed to evaluate the efficacy of oliceridine in preventing SIC and to assess any associated adverse events.

Methods: In this prospective, randomized, double-blind, placebo-controlled trial, 286 adult patients undergoing elective surgery under general anesthesia were enrolled and randomly assigned to receive either 2 mg oliceridine (OS group) or an equal volume of normal saline (SS group) before intravenous administration of sufentanil. The primary outcome was the incidence of SIC. Secondary outcomes included the severity of cough, vital sign changes, and adverse events.

Results: The incidence of SIC was 42.66% in the SS group and 0% in the OS group (95% upper confidence bound ≈ 2.6%; P < 0.001). Among the SS group, mild, moderate, and severe cough occurred in 12.59%, 26.57%, and 3.50% of patients, respectively. No significant differences were observed in systolic or diastolic blood pressure, heart rate, or SpO₂ between the two groups at baseline or 2 minutes post-sufentanil administration. The incidence of adverse events was low and comparable between groups, with no reported cases of apnea, nausea, or vomiting.

Conclusion: Pretreatment with 2 mg oliceridine demonstrated favorable effevtiveness in suppressing SIC without significant adverse effects. Oliceridine appears to be a safe and effective prophylactic strategy for preventing SIC and may have valuable clinical utility in anesthesia practice.

Primary or acquired resistance to standard chemotherapy and novel targeted therapies remains a common cause of relapsed/refractory acute myeloid leukemia (AML). The five-year overall survival rate for AML patients remains poor. Exploring novel therapeutic pathways may offer effective strategies to address this challenge. The Integrated Stress Response (ISR) is a signaling pathway that maintains cellular homeostasis by reducing global protein synthesis in response to external and internal stressors. Recent studies have demonstrated that ISR exerts a dual role in AML. Moderate activation of ISR supports hematopoietic and leukemia stem cell maintenance and promotes AML progression, whereas hyperactivation of ISR induces apoptosis and reduces myeloid cell leukemia-1 (MCL-1) expression. MCL-1 overexpression contributes to venetoclax resistance. However, MCL-1 inhibitors have shown disappointing cardiac toxicity in clinical studies. Hyperactivation of the ISR can indirectly suppress MCL-1 and help reverse venetoclax (ABT-199) resistance, as reported in previous studies. Our previous study also indicates that ISR activation can reverse venetoclax resistance in AML cells. These findings support the ISR as a novel therapeutic target in AML. However, the mechanisms by which ISR influences stemness and resistance are not yet fully understood. This review integrates current mechanistic insights and preclinical evidence to highlight the ISR as both a key driver of leukemogenesis and a promising target for overcoming drug resistance in AML. We searched the literature up to October 2025 in PubMed, Google Scholar, and ClinicalTrials.gov using terms related to AML, ISR signaling, venetoclax, and ISR kinases.

Background: Allicin is a monomer compound derived from traditional Chinese medicine, which has demonstrated significant efficacy in the treatment of cancer, neuroinflammation, gastrointestinal diseases, and other conditions. However, the specific mechanism of action of Allicin in combating cardiovascular diseases remains insufficiently clarified, which limits its application in therapy.

Methods: Network pharmacology and molecular docking techniques were employed to explore the potential targets and signaling pathways of Allicin in the treatment of as atherosclerosis (AS). The regulatory effects of Allicin on cell apoptosis, aortic plaques, and lipid levels were assessed through TUNEL staining, Oil Red O staining, HE staining, GPO-PAP, and COD-PAP. Additionally, immunofluorescence assay was conducted to validate the screened key targets.

Results: Based on the analysis of network pharmacology and molecular docking techniques, 94 predicted overlapping target genes were identified from the target genes of Allicin and AS-related target genes; Among them, Allicin exhibits a strong binding affinity for five main targets (CASP3, NF-κB1, BTK, MAPK3, and PARP1), and these targets were found to play important role in the anti-apoptotic mechanism of Allicin. Furthermore, Allicin could inhibit the progression of plaques, down- regulating the expressions of CASP3 and NF-κB1, and up-regulate the expressions of BTK, MAPK3, and PARP1 in vivo and in vitro.

Conclusion: The present results show that Allicin may improves AS by regulating the main targets of macrophage apoptosis.