Drug Design, Development and Therapy最新文献

Nitric oxide (NO) plays a central role in diverse physiological processes, such as cardiovascular tone, neurotransmission, immune defense, and cellular apoptosis. NO synthase (NOS) is the enzyme that catalyzes the conversion of L-arginine to L-citrulline and NO. Three isoforms of NOS are (1) neuronal NOS (nNOS), which regulates synaptic plasticity, memory formation, and cerebral blood flow, (2) endothelial NOS (eNOS), which supports cardiovascular homeostasis by preventing platelet aggregation and leukocyte adhesion, and (3) inducible NOS (iNOS), which contributes to inflammation and tissue damage, when in excessive production. Thus, targeting iNOS without interfering with the beneficial actions of nNOS and eNOS remains a major therapeutic challenge. Given this dual nature of NO in health and disease, it is important to understand how medicinal plants and their phytochemicals modulate NO pathways. A systematic search of Scopus and PubMed databases was performed for studies published in the last ten years. Screening by title, abstract, and full text yielded 35 eligible articles examining medicinal plants and phytochemicals that influence NO signaling pathways. Preclinical evidence indicates that phytochemicals restore antioxidant defenses and suppress excessive NO and oxidative stress under inflammatory conditions while preserving or enhancing endothelial NO bioavailability. Emerging clinical findings further suggest significantly greater insulin-stimulated NO production and eNOS activation without activating iNOS or promoting inflammatory responses. Their ability to regulate NO production underscores their potential in the development of botanical drugs targeting iNOS while preserving the physiological roles of nNOS and eNOS. This review provides an overview of the potential of medicinal plants to alleviate inflammation and oxidative stress through modulation of NO production.

Purpose: Spinal cord injury (SCI) triggers a complex secondary injury process, among which inflammation and apoptosis are the key factors of nerve injury. Obacunone (Oba) is a natural limonoid that has demonstrated a variety of pharmacological effects, but its role in SCI remains unclear.

Methods: Network pharmacology and bioinformatics analysis were employed to predict the functions and mechanisms of Oba in SCI. Subsequently, in vivo validation was conducted in a mouse SCI model, with motor function recovery assessed using open field, footprint, and swimming tests. Spinal cord histomorphology was examined via hematoxylin and eosin (HE) staining and Nissl staining, while the anti‑inflammatory and anti‑apoptotic effects were evaluated by Western blot and immunofluorescence. To further elucidate the underlying mechanisms, a lipopolysaccharide (LPS)-induced inflammatory model in BV‑2 microglial cells was established to study the anti‑inflammatory mechanisms of Oba. Furthermore, a BV‑2/HT22 neuronal co‑culture system was constructed to investigate neuroprotective effects of Oba against apoptosis.

Results: In vivo, Oba treatment improved motor function, promoted neural repair, reduced inflammation and apoptosis. Correspondingly, Oba suppressed the expression of LPS-induced pro-inflammatory cytokines in BV-2 cells. In a microglia-neuron co-culture system, Oba protected HT22 neurons from microglia-mediated inflammatory apoptosis. Mechanistically, the anti‑inflammatory effects of Oba were mediated by inhibiting the activation of the TLR4/MyD88/p38 MAPK pathway.

Conclusion: This study identifies Oba as an effective compound that mitigates secondary injury by reducing inflammation and apoptosis and promotes nerve repair and functional recovery post-SCI, supporting its potential for further therapeutic development.

Intestinal health is sustained by coordinated control of mucosal immunity, epithelial barrier integrity, and the gut microbiota and its metabolites. Disruption of these tightly coupled systems contributes to a wide spectrum of disorders, ranging from infectious enteritis and inflammatory bowel disease (IBD) to ischemia-reperfusion injury and metabolic dysfunction with extra-intestinal sequelae. Baicalin (BAI), a major flavonoid from Scutellaria baicalensis, has emerged as a multi-level regulator of gut homeostasis. Across diverse preclinical models, BAI attenuates inflammatory signaling and frequently converges on NF-κB-centered networks; it also rebalances immune responses by modulating macrophage polarization and T-cell subsets, limits oxidative and ferroptotic damage through cytoprotective programs, and restores barrier function by preserving tight junctions and mucus-layer defenses. In parallel, BAI remodels microbial community structure and microbial metabolites, including short-chain fatty acids and bile-acid signaling, providing a plausible basis for benefits along gut-organ axes such as the gut-liver and gut-metabolic axes. This review integrates mechanistic evidence across these three pillars and highlights key translational gaps, including limited oral bioavailability, incomplete causal validation of proposed targets, and the need to disentangle BAI from active metabolites. We further discuss derivative design, formulation, and combination strategies to improve exposure and accelerate clinical translation.

Background: α-Mangostin (α-M) is a natural antimicrobial and anti-inflammatory compound with promising anti-acne potential; however, its poor solubility and instability limit its topical use. This study developed and evaluated chitosan-alginate hydrogel films incorporating nanoencapsulated α-M (HF α-M NPs) to enhance stability, skin penetration, and therapeutic efficacy against Propionibacterium acnes.

Methods: α-M NPs were produced by ionic gelation using chitosan and sodium tripolyphosphate, followed by alginate coating, and subsequently incorporated into chitosan-alginate hydrogel films. Nanoparticles and films were characterized using SEM, FTIR, mechanical testing, swelling behavior, degradability analysis, and in vitro drug-release studies. The anti-acne performance was assessed in a P. acnes mouse model using total plate count, histopathological evaluation, and measurement of edema and erythema.

Results: The nanoparticles exhibited a mean size of 229.7 ± 18.15 nm, PDI of 0.450 ± 0.046, and zeta potential of +40.9 ± 1.91 mV, indicating strong colloidal stability. SEM confirmed the uniform distribution of nanoparticle in the hydrogel matrix, while FTIR revealed molecular interactions between the polymers and α-M. HF α-M NPs showed improved mechanical strength, controlled swelling, and a sustained release profile compared with free α-M films. In vivo, the HF α-M NPs achieved the greatest reduction in P. acnes load (2.46 × 10¹ CFU/g), significant epithelial restoration, and the lowest edema and erythema scores, which were superior to those of free α-M and comparable to those of clindamycin gel.

Conclusion: Nanoencapsulation of α-M within a chitosan-alginate hydrogel matrix significantly enhanced its stability, release behavior, and antimicrobial and anti-inflammatory effects. HF α-M NPs represents a promising antibiotic free topical therapy for acne and merits further optimization and clinical investigation.

Background: Stachydrine, a principal bioactive alkaloid derived from Leonurus japonicus (motherwort), has attracted significant interest due to its diverse pharmacological activities and nutritional relevance. This systematic review synthesizes current evidence on its therapeutic potential across multiple organ systems. Stachydrine core pharmacological activities are: Cardiovascular protection: Stachydrine mitigates myocardial ischemia/reperfusion injury by scavenging free radicals, reducing myocardial biomarkers (CK, LDH, cTnT), and enhancing nitric oxide (NO) production. It attenuates pathological ventricular remodeling by suppressing ROS-mediated activation of NF-κB and improves cardiac calcium handling by protecting sarcoplasmic reticulum function. Antitumor effects: In cancers (e.g. hepatocellular carcinoma, breast cancer, colorectal cancer), stachydrine inhibits tumor proliferation, metastasis, and chemoresistance by targeting pathways such as TGF-β/Smad, PI3K/Akt/mTOR, and JAK2/STAT3. It also modulates the tumor microenvironment by reprogramming tumor-associated macrophages. Renoprotective actions: It ameliorates drug-induced renal fibrosis by suppressing tubular cell apoptosis via downregulation of caspase-9/caspase-12 and inhibiting inflammatory cytokine release.

Uteroprotective benefits: Stachydrine regulates uterine hemorrhage by balancing Th1/Th2/Th17/Treg immune homeostasis and modulating endothelial function (e.g. NO and endothelin-1 levels), while enhancing uterine smooth muscle contractility. Antioxidant mechanisms: It reduces oxidative stress via ROS scavenging and NOX2 pathway inhibition, thereby protecting cardiovascular and neuronal tissues. Anti-inflammatory properties: Through modulation of NF-κB, JAK2/STAT3, and AMPK/SIRT1 pathways, stachydrine alleviates acute and chronic inflammation in models ranging from arthritis to neuroinflammation.

Conclusion: This review comprehensively documents stachydrine's multi-targeted and multi-organ therapeutic potential, driven by its pleiotropic mechanisms. It provides a robust foundation for clinical translation in cardiovascular diseases, cancer, renal disorders, gynecological conditions, and inflammation-associated pathologies. Future research should prioritize high-quality clinical trials and synergistic drug-combination strategies to harness its therapeutic efficacy fully.

Background: Acute kidney injury (AKI) is a serious clinical condition marked by a rapid decline in renal function, leading to high morbidity, mortality, and healthcare burden. Despite advances in supportive care, effective pharmacologic therapies remain lacking, prompting interest in alternative approaches, including Chinese herbal medicines (CHMs).

Purpose: This review summarizes recent experimental and clinical research on CHMs for AKI, highlighting mechanisms of action, translational challenges, and future directions.

Methods: A narrative review was conducted using PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov through May 2025, with search terms including "acute kidney injury", "Chinese herbal medicine", "natural products", and "plant extracts". Both preclinical and clinical studies were included to provide a comprehensive overview.

Results: Various CHMs and traditional formulations have demonstrated renal protective effects in AKI through anti-inflammatory, antioxidant, anti-apoptotic, and mitochondrial-protective mechanisms. Key pathways targeted include NF-κB, Nrf2, PI3K/Akt, MAPK, and apoptotic regulators like Bcl-2/Bax and caspases. Notable agents include berberine, baicalin, puerarin, and multi-herb formulas such as QiShenYiQi and Jianpi Yishen Tang, which offer multi-targeted therapeutic potential.

Conclusion: CHMs present a promising avenue for AKI treatment by modulating multiple cellular pathways implicated in disease progression. While preclinical studies are encouraging, robust clinical trials and standardization of formulations are critical for validating efficacy and ensuring safety. Integrating CHMs into modern nephrology through evidence-based strategies may enhance therapeutic options for AKI and advance the development of novel, nature-derived treatments.

Purpose: There is evidence that labor pain and the doses of drugs used to treat it exhibit circadian variation. Previously, we reported that during the night, the effective dose (ED₅₀) of epidural ropivacaine for labor analgesia in 50% of patients was approximately 15% greater than that during the day. However, the influence of time of day on dose requirement at points higher on the dose-response curve is unknown. This double-blinded randomized trial aimed to determine and compare the full dose-response relationship for epidural ropivacaine administered to initiate labor analgesia during the day versus at night.

Patients and methods: We recruited 150 nulliparous parturients requesting epidural labor analgesia during the day (day group, 07:01-19:00 h) and 150 during the night (night group, 19:01-07:00 h). Within each group, we randomly allocated patients to receive one of six doses of ropivacaine (7.5, 15, 22.5, 30, 37.5, or 45 mg) diluted to 20 mL to initiate epidural analgesia. Effective analgesia was defined as a visual analogue scale pain score of ≤ 3 cm (scale: 0--10 cm) within 30 min. We generated dose-response curves for ropivacaine using probit regression and estimated the values for ED₅₀ and ED₉₅.

Results: The estimated ED₅₀ value of ropivacaine was greater during the night (22.4 [95% CI 19.9 to 24.8] mg) than during the day (17.9 [95% CI 15.7 to 20.0] mg), and the estimated ED₉₅ value was greater during the night (41.3 [95% CI 36.4 to 48.7] mg) than during the day (32.9 [95% CI 28.9 to 39.0] mg).

Conclusion: The time of day is an important factor that should be considered when selecting the dose of ropivacaine to initiate epidural labor analgesia.

Trial number and registry url: ChiCTR1900025381; https://www.chictr.org.cn/bin/project/edit?pid=42363.

Purpose: Postoperative nausea and vomiting (PONV) is a frequent complication after video-assisted thoracoscopic lung resection, particularly in patients at moderate to high risk, and substantially hinders recovery. Fosaprepitant, a neurokinin-1 (NK-1) receptor antagonist, is approved for PONV prevention; however, its efficacy in video-assisted thoracoscopic lung resection remains uncertain. This randomized trial evaluated the efficacy of fosaprepitant versus ondansetron in preventing PONV in high-risk patients undergoing video-assisted thoracoscopic lung resection.

Patients and methods: In this prospective, double-blind, randomized controlled clinical trial, 233 adults aged 18-70 years undergoing elective video-assisted thoracoscopic lung resection with an Apfel score ≥ 2 were randomized 1:1 to receive intravenous fosaprepitant 150 mg or ondansetron 8 mg, each combined with dexamethasone 5 mg. The primary outcome was the incidence of PONV at 24 hours postoperatively. Secondary outcomes included the incidence and severity of PONV at 6, 12, and 48 hours postoperatively, the use of rescue antiemetics, adverse events, and recovery outcomes.

Results: The 24-hour incidence of PONV was 31.0% [36] in the fosaprepitant group and 41.0% [48] in the ondansetron group (OR, 0.76; 95% CI, 0.53 to 1.07; P=0.112). Fosaprepitant significantly reduced PONV at 48 hours (10.3% [12] vs 20.5% [24]; OR, 0.51; 95% CI, 0.27 to 0.96; P=0.032), as well as vomiting at 24 hours (8.6% [10] vs 21.4% [25]; OR, 0.40; 95% CI, 0.20 to 0.80; P=0.006) and 48 hours (0% [0] vs 5.1% [6]; OR, 0.07; 95% CI, 0.00 to 1.32; P=0.040).

Conclusion: Fosaprepitant was superior to ondansetron in preventing early postoperative vomiting and delayed-phase PONV, and it represents an effective antiemetic strategy for high-risk thoracic surgical patients.

Trial number and registry url: Registration number, NCT05881486; https://clinicaltrials.gov.

Objective: Disruption of calcium (Ca²⁺) homeostasis has been implicated as a key pathological mechanism underlying propofol-induced neurodevelopmental and cognitive deficits. However, the mechanisms underlying propofol-induced intracellular Ca²⁺ dysregulation remain incompletely understood. Extending findings of anesthetic-induced metabolic disruptions in non-neuronal models to the central nervous system, this study aimed to elucidate the underlying mechanisms of the Ca²⁺ imbalance in neuronal cells, with implications for the safety of clinical anesthesia in pediatric populations.

Material and methods: Mouse hippocampal neurons (HT22 cells) served as an in vitro model. Cell viability was assessed using the CCK-8 assay. Intracellular Ca²⁺ dynamics were evaluated using the Fluo-4 AM Ca²⁺ fluorescent probe to investigate the mechanisms underlying propofol-induced Ca²⁺ dysregulation.

Results: Propofol exposure at 10 μM and 50 μM across all time points (2, 6, or 24 hours) showed no significant impact on cell viability. Similarly, 100 μM propofol lacked toxicity at 2 or 6 hours, but survival significantly declined after 24 hours exposure (P < 0.0001). Furthermore, 200 μM propofol decreased cell viability after 2 hours of treatment (P < 0.01), with further reduction following prolonged exposure (P < 0.05). A rapid increase in intracellular Ca²⁺ concentration was observed with 200 μM propofol (P < 0.0001), which was entirely abolished by the inhibition of the γ-aminobutyric acid type A (GABA_A) receptor. Conversely, inhibition of the inositol trisphosphate receptor (IP₃R) alone partially mitigated the propofol-induced Ca²⁺ elevation (P < 0.0001). Notably, chelation of elevated intracellular Ca²⁺ using BAPTA-AM fully prevented the propofol-induced decrease in cell viability (P < 0.01).

Conclusion: Propofol induces cytotoxicity in HT22 cells in a concentration- or time-dependent manner. Notably, cytotoxicity at 100 μM propofol was observed only after 24 hours of exposure, whereas 200 μM propofol produced rapid cytotoxicity. This rapid toxicity is mediated by activation of GABA_A receptor and IP₃R, which triggers the endoplasmic reticulum (ER) Ca²⁺ release and elevating intracellular Ca²⁺ concentration.

Objective: The aim of this study was to evaluate the effect of sugammadex on the quality of postoperative recovery among patients undergoing laparoscopic bariatric surgery.

Methods: In this randomized controlled trial, 60 patients scheduled for laparoscopic bariatric surgery were allocated to receive either neostigmine (N group) or sugammadex (S group) for neuromuscular blockade reversal. At the conclusion of surgery, the N group received intravenous neostigmine 0.04 mg/kg with atropine 0.02 mg/kg, while the S group received intravenous sugammadex 2 mg/kg. The primary outcome was the Quality of Recovery-15 (QoR-15) score at 24 hours postoperatively. Secondary outcomes included anesthesia recovery time, time to train-of-four (TOF) ratio ≥ 0.9, extubation time, time to achieve a modified Aldrete score ≥ 9, Richmond Agitation-Sedation Scale (RASS) scores, Visual Analogue Scale (VAS) pain scores after extubation, and time to first postoperative flatus/defecation.

Results: QoR-15 scores at 24 hours postoperatively were significantly higher in the S group compared with the N group (p < 0.001), with the intergroup Cohen's d was 1.547 (95% CI: 1.014 to 2.293). The S group demonstrated shorter anesthesia recovery time, time to achieve TOF ratio ≥ 0.9, extubation time, and time to modified Aldrete score ≥ 9 (p < 0.05). RASS scores immediately and 10 minutes after extubation were higher in the S group (p < 0.05). No significant differences were observed between groups in VAS pain scores at any postoperative time point or in total opioid consumption (p > 0.05). Time to first postoperative flatus/defecation were shorter in the S group (p < 0.05).

Conclusion: The sugammadex administration in patients undergoing laparoscopic bariatric surgery could expedite reversal of neuromuscular blockade, shorten anesthesia recovery time, and facilitate gastrointestinal function restoration. It also improved postoperative quality of recovery without elevating pain intensity or increasing opioid consumption.