Drug Design, Development and Therapy最新文献

Objective: This study aimed to establish a UPLC-MS/MS method for the simultaneous quantification of five antidepressants: venlafaxine (VEN) and its metabolite O-desmethylvenlafaxine (ODV), mirtazapine (MIR), sertraline (SER), escitalopram (ESC), and vortioxetine (VTX) in human plasma and saliva. By analyzing real-world therapeutic drug monitoring (TDM) data, this study aimed to identify key factors influencing drug concentrations thereby optimizing personalized treatment strategies for patients with depression and advancing precision medicine.

Methods: Following liquid-liquid extraction for plasma and protein precipitation for saliva, analyte concentrations were determined using a fully validated UPLC-MS/MS method. Validation included assessments of selectivity, linearity, accuracy, precision, extraction recovery, matrix effects, stability, and dilution integrity. The established method was applied to clinical samples, with further investigation into how clinical factors, including age, BMI, renal function (as measured by GFR), total protein (TP), albumin levels, and concomitant medications, influenced the concentration-to-dose ratio (CDR).

Results: The method demonstrated excellent linearity (5-500 ng/mL) with all validation parameters meeting acceptance criteria. The established method was successfully applied to analyze 566 plasma and 39 saliva samples. TDM revealed significant variations in target attainment rates among different antidepressants, along with varying degrees of dose-concentration correlations. Multivariate analysis demonstrated that the CDR of VEN + ODV was primarily influenced by age and GFR, while the CDR of MIR showed a significant association with BMI. The CDR of SER was affected by both BMI and TP levels. The CDR of ESC was modulated by age, concomitant medications, and renal function.

Conclusion: This study demonstrated that TDM-based individualized medication strategies can support the optimization of antidepressant efficacy. Saliva monitoring requires further validation. Clinicians should adopt dynamic, patient-specific monitoring to enhance precision medicine outcomes in depression management.

Purpose: Tegileridine, a new highly selective biased µ-opioid receptor agonist, demonstrated a favorable profile in relief of moderate-to-severe pain, but comparative data with other µ-opioid receptor agonists are sparse. We aimed to compare the analgesic efficacy of tegileridine to oliceridine with morphine as the active control in patients undergoing minimally invasive esophagectomy (MIE).

Patients and methods: We conducted a preliminary randomized trial involving patients having moderate-to-severe pain after MIE. Patients were randomized 2:2:1 to receive a loading dose of 0.75 mg tegileridine, 1.5 mg oliceridine, or 3 mg morphine, followed by a patient-controlled analgesia pump composed of the corresponding same agent over a 48-hour period. The primary endpoint was the time-weighted sum of the resting pain-intensity difference over 24 hours (rSPID_24h).

Results: A total of 75 patients were randomized and finally analyzed (n = 15 in morphine group, n = 30 in tegileridine and oliceridine groups). Neither the time-weighted rSPID_24h nor motion-SPID_24h (mSPID_24h) was statistically different among the three groups. The numerical rating pain scale (NRS) at rest or during movement was significantly less in patients receiving tegileridine compared to oliceridine (P < 0.01) within postoperative 48 hours, and there was no statistical significance between tegileridine and morphine (P > 0.05). The sum of total pain relief demonstrated a similar tendency that morphine and tegileridine were better than oliceridine at postoperative 24h (P = 0.057) and 48h (P = 0.033).

Conclusion: Tegileridine showed comparable or slightly superior analgesic efficacy to oliceridine for moderate-to-severe pain following MIE. These findings support that tegileridine may provide promising profiles for postoperative pain management.

Cardiorenal syndrome (CRS) is a disease involving two vital organs, the heart and the kidney, which has been increasingly recognized in recent years. The treatment of CRS is highly challenging due to its complex nature, rapid progression, poor prognosis, and high mortality rate. As a protein complex, nuclear factor kappa-B (NF-κB) regulates the transcription of target genes by entering the nucleus and affects cardiac and renal functions through its involvement in inflammatory reactions and oxidative stress. By evaluating established preclinical and clinical research on CRS to date, we explored the potential of NF-κB inhibition to exert unique cardiorenal protective effects as a novel treatment for CRS. In this review, we have synthesized recent advances in the structure and function of NF-κB within the cardiovascular and renal systems, and explored the mechanistic involvement of NF-κB in CRS. Innovatively, we have identified natural compounds that dually inhibit NF-κB activity in both cardiac and renal tissues, thereby conferring concurrent protection to both organs. Furthermore, we discuss the translational potential and clinical applicability of NF-κB-targeted pharmacology, which may provide critical insights for developing novel therapeutics against CRS.

Liver fibrosis, a reversible yet critical stage in chronic liver disease progression, poses a significant global health burden with limited therapeutic options. This review comprehensively explores the molecular mechanisms of endoplasmic reticulum (ER) stress and its dual role in both parenchymal and non-parenchymal cells during liver fibrosis, alongside the therapeutic potential of natural compounds that target ER stress to alleviate fibrosis. Emerging evidence underscores ER stress and oxidative stress as pivotal drivers of hepatic fibrogenesis, primarily through activating hepatic stellate cells (HSCs). We systematically summarize a wide array of natural compounds, from polyphenols to terpenoids, that demonstrate potent anti-fibrotic effects by either ameliorating maladaptive ER stress in hepatocytes or selectively inducing pro-apoptotic ER stress in activated HSCs. Despite their promise, the clinical translation of these compounds is hampered by poor bioavailability and non-specific targeting. We highlight the groundbreaking potential of biomimetic nano-delivery systems, such as cell membrane-camouflaged nanoparticles, to overcome these barriers, offering precise targeting and enhanced therapeutic efficacy. Finally, we discuss current challenges and future directions, advocating for interdisciplinary efforts to advance ER stress-targeting strategies from bench to bedside.

Introduction: Cisplatin (CP) is a chemotherapeutic agent limited by its toxic effects on the heart and kidneys, resulting in nephrotoxicity and cardiotoxicity. This study investigated the protective effects of the antidiabetic drugs linagliptin (LINA) and empagliflozin (EMPA), alone and in combination, on cisplatin-induced heart and kidney damage in non-diabetic rats.

Methods: Forty-nine rats were randomized into seven groups (n=7 each): control (saline; 10 mL/kg), cisplatin (CP; 10 mg/kg), empagliflozin (EMPA; 10 mg/kg), linagliptin (LINA; 3 mg/kg), and treatment groups (CP+EMPA, CP+LINA, and CP+EMPA+LINA). EMPA and LINA were administered orally for 10 days; CP was administered intraperitoneally on days 1 and 6 after treatment with EMPA, LINA, or both. Renal and cardiac injury biomarkers were measured in the blood. Hearts and kidney tissues from animals were extracted to assess reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations, as well as the activities of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX).

Results: The CP-treated group showed elevated renal, cardiac, and oxidative stress markers. Conversely, the activities of SOD, GPX, and CAT were reduced in the CP-treated groups compared to the control. EMPA, LINA, or combination reduced creatinine, BUN, LDH, CK-MB, troponin I, and ROS levels. LINA showed weaker antioxidant effects in the heart than in the kidney or EMPA.

Conclusion: Our findings suggest that LINA may have a weaker antioxidant effect in the heart than in the kidney or EMPA. Administration of the combinations (LINA+EMPA) affects MDA levels in CP-treated animals, with a significant reduction in the heart and kidney. Individual treatments do not significantly alter MDA levels. However, combined treatment significantly improves SOD, GPX, and CAT activities in the heart and kidney, indicating a superior protective effect, suggesting potential to mitigate CP-induced toxicity.

Spray drying is extensively utilized in pharmaceutical development because of its scalability, cost-effectiveness, and capacity to customize solid-state characteristics. This systematic review (PubMed and Scopus, 2021-2025) assesses the impact of spray drying on the bioavailability and stability of active pharmaceutical ingredients (API) and natural products within solid dispersions (SD), solid self-nanoemulsifying drug delivery systems (S-SNEDDS), and microencapsulation. A total of 27 qualifying studies were identified and offered quantitative comparisons with untreated controls. SDs yielded AUC enhancements of 9-20-fold (eg, oxyberberine approximately 9-fold, quercetin approximately 20-fold) and dissolution improvements of 2-6-fold. S-SNEDDS produced AUC enhancements of 4-9.9-fold (sorafenib approximately 4.6-fold, enzalutamide approximately 7-fold, niclosamide approximately 9.9-fold). Microencapsulation enhanced oxidative stability (eg, approximately 3-fold reduction in peroxide value pepper seed oil and encapsulation efficiency of pomegranate seed oil reaching 90%). Benefits were contingent upon the carrier, especially with PVP/PVPVA, HPMC/HPMCAS, soluplus, and maltodextrin with protein systems. Spray drying provides superior scalability and particle engineering control compared to freeze or vacuum drying, while it still poses hazards of thermal and oxidative stress. Ongoing deficiencies encompass inadequate carrier comparisons, insufficient mechanistic comprehension of drying kinetics, and issues related to scale-up and regulation. This review offers mechanistic insights and a standardized approach to facilitate future formulation development.

Purpose: Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, and its pathogenesis is closely associated with oxidative stress and impaired osteogenic differentiation. Vitamin K₂ (VK₂) has strong antioxidant properties and potent bone-forming effects, but its application in GIOP is still unclear. This study investigates the therapeutic potential of VK₂ in GIOP and elucidates its underlying molecular mechanisms.

Methods: Dexamethasone (DEX) was used to establish GIOP model within C57BL/6 mice. The bone mass was assessed using micro-computed tomography (micro-CT), hematoxylin and eosin (HE) staining, and Masson's trichrome staining in vivo. The osteoblast activity and the expression of osteogenic and ferroptosis-related markers were evaluated via immunohistochemistry (IHC), RT-qPCR, Western blotting, ALP and alizarin red staining. The mitochondrial function and lipid peroxidation of MC3T3-E1 cells were detected by flow cytometry, immunofluorescence and specific kits.

Results: VK₂ partially prevented bone mass reduction and osteoblast activity inhibition in GIOP mice. VK₂ not only reversed the DEX-induced reductions in Tb.N, BV/TV, and Tb.Th, but also significantly increased the expression of osteogenic markers, including OCN and ALP (P<0.05). Moreover, VK₂ improved DEX-induced ferroptosis, oxidative stress and mitochondrial dysfunction in MC3T3-E1 cells and promoted osteogenic differentiation in vitro, which could be reversed by ferroptosis inducer (P<0.05). VK₂ also increased the expression of NRF2, HO-1 and FSP1 which inhibited by DEX in vivo and in vitro (P<0.05). The inhibition of FSP1 and NRF2 reversed the osteogenic differentiation promotion and ferroptosis inhibition by VK₂ (P<0.05).

Conclusion: VK₂ restores mitochondrial function and reduces lipid peroxidation and ferroptosis via the NRF2/FSP1 signaling pathway, thereby facilitating osteoblast differentiation and improving bone mass in GIOP mice. This finding not only provides a fresh perspective on the etiology of GIOP but also positions ferroptosis inhibition as a promising and innovative therapeutic strategy for this condition, with VK₂ emerging as a potential candidate for clinical translation.

Lactylation, a lactate-derived post-translational modification, emerges as a master metabolic regulator of resistance to regulated cell death (RCD) across pathologies including cancer, inflammatory disorders, and degenerative diseases. By dynamically modifying histones and non-histone proteins via lactyltransferases and delactylases, lactylation orchestrates convergent molecular pathways that suppress ferroptosis, cuproptosis, and apoptosis. This review synthesizes current understanding of lactylation as a central regulator of RCD resistance in diseases, especially in cancers. We dissect the molecular machinery through which lactylation subverts ferroptosis, cuproptosis, and apoptosis; evaluate its pathophysiological implications in diverse pathologies; and discuss emerging therapeutic strategies to disrupt lactylation-mediated cell death evasion. This metabolic-epigenetic crosstalk establishes a robust shield against RCD in disease microenvironments, promoting therapeutic resistance and pathological resilience. Targeting lactylation regulators (writers/erasers) or combining lactate modulation with RCD inducers represents a promising strategy to overcome treatment-refractory conditions in cancers.

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.