High-risk neuroblastoma (HR-NB) remains a devastating pediatric malignancy characterized by MYCN amplification-induced apoptotic resistance to conventional chemotherapeutic interventions. While arsenic trioxide (As(III)) demonstrates therapeutic potential through ferroptosis induction, its clinical application is severely constrained by dose-limiting systemic toxicity and consequent inflammation-mediated COX2/PGE2 pathway activation, which confers ferroptosis resistance. Here we engineer a tumor microenvironment-responsive peptide coassembly As(III) delivery system (TCADS) that concurrently addresses these therapeutic challenges. TCADS comprises two rationally designed self-assembling peptides incorporating As(III)-binding domains, tumor-selective targeting moieties (MMP9-responsive and Tenascin C-targeting motifs), and the COX2 antagonist naproxen (NPX). In comprehensive preclinical evaluations encompassing subcutaneous and orthotopic neuroblastoma models, TCADS exhibits exceptional biocompatibility with markedly attenuated systemic toxicity and achieves enhanced tumor-selective accumulation through sequential MMP9-triggered As(III) liberation and TNC-mediated engagement of both tumor cells and cancer-associated fibroblasts, outperforming free drug combinations (As(III)+NPX). This precision-targeted approach empowers TCADS to effectively disrupt the deleterious inflammation-ferroptosis resistance cycle, thereby successfully overcoming treatment resistance and suppressing tumor progression by 85.0% and 95.4% in subcutaneous and orthotopic tumor models, respectively. This integrated paradigm of precision-targeted delivery coupled with microenvironment modulation establishes a compelling therapeutic framework for chemoresistant HR-NB and potentially other MYCN-amplified malignancies.

Myocardial ischaemia/reperfusion injury presents significant clinical challenges driven by a self-perpetuating cycle of oxidative stress and inflammation. Current therapeutic strategies fail to simultaneously address these interconnected pathological events. Here, we present T&A-Gel, a supramolecular peptide amphiphile hydrogel integrating α-tocopherol and Angiotensin-(1-7) (Ang-(1-7)) through covalent conjugation to enable localized co-delivery and synergistically disrupt this oxidative-inflammatory feed-forward circuit. Upon hierarchical self-assembly into filamentous nanofibres, T&A-Gel forms a sustained-release depot that exposes Ang-(1-7) moieties while sequestering hydrophobic α-tocopherol. This design enables α-tocopherol to scavenge excess reactive oxygen species, ameliorating oxidative mitochondrial dysfunction and reducing cardiomyocyte apoptosis, while exposed Ang-(1-7) acts as a selective Mas receptor (MasR) agonist, activating the protective MasR/PI3K/Akt signaling axis. This dual-action mechanism suppresses NF-κB nuclear translocation and inhibits pro-inflammatory cytokine cascades. In vitro, T&A-Gel significantly enhanced hypoxia/reoxygenation-injured cardiomyocyte viability. In vivo, T&A-Gel demonstrated prolonged retention with substantial reduction in infarct size and cardiac necrosis biomarkers. Quantitative analysis confirmed substantial attenuation of interstitial fibrosis and cardiomyocyte hypertrophy, translating into restored ejection fraction and reduced ventricular dilation with excellent biocompatibility. These findings establish injectable supramolecular hydrogels as a powerful strategy for disrupting the interconnected injury cascade via mechanistically complementary payloads, offering a paradigm for precision cardioprotection.

Atherosclerotic plaque rupture, driven by a vicious pathological cycle between endothelial-to-mesenchymal transition (EndMT) and chronic inflammation, represents a major therapeutic challenge in cardiovascular disease. Current clinical strategies, including statins and antiplatelet agents, fail to disrupt the EndMT-inflammation axis, while conventional TGF-β pathway inhibitors-critical for EndMT regulation-exhibit narrow therapeutic windows and systemic toxicity owing to the pleiotropic nature of TGF-β signaling. Here, we reported VRBPC, a VCAM-1-targeting, reactive oxygen species (ROS)-responsive baicalin-peptide conjugate that undergoes in situ self-assembly within atherosclerotic plaques to form a "molecular latch" that breaks the EndMT-inflammation loop. Upon VCAM-1-mediated endocytosis into activated endothelial cells, VRBPC responds to elevated ROS levels in the plaque microenvironment, triggering localized self-assembly that enhances baicalin retention and promotes its competitive binding to HSP90-a critical chaperone for TGF-β receptor stabilization. This mechanism inhibits Smad2/3 phosphorylation, reverses EndMT, and simultaneously suppresses inflammatory responses in macrophages. In vitro, VRBPC effectively restored endothelial phenotype, reduced aberrant migration, and diminished foam cell formation alongside pro-inflammatory cytokine secretion. In ApoE-/- mice, VRBPC demonstrated enhanced aortic accumulation, achieving reduced plaque area and increased collagen content-hallmarks of stabilized plaques-with excellent biocompatibility and no detectable systemic toxicity. These findings establish in situ self-assembling peptide-drug conjugates as agents that break the vicious pathological loops in atherosclerosis via microenvironment-responsiveness, offering a new paradigm for precision therapy of atherosclerosis and inflammatory vascular diseases.

The efficacy of immune checkpoint blockade is often limited by intrinsic immunosuppressive networks within the tumor immune microenvironment (TIME). Despite progress in cancer treatment, current extracellular targeted protein degradation approaches often overlook the multicellular distribution and crosstalk of immune checkpoints. Here we reported a Receptor--mediated Endolysosomal recYcling Chimera (RECYC) platform. RECYC employs a CI-M6PR-targeting aptamer that remains stable across late endosomal pH and a protein--binding peptide with moderate affinity and pH responsiveness, which together drive recycling and sustained checkpoint clearance. In ex vivo co--culture and in vivo murine models, RECYC efficiently eliminated programmed death-ligand 1 (PD--L1) expression from both tumor cells and tumor--associated myeloid cells (macrophages, neutrophils and dendritic cells). By converting an immunosuppressive TIME to an immunostimulatory state, RECYC remodeled the tumor--immune network in an anti--tumor direction, thereby enhancing CD8+T cell response and repolarizing immunosuppressive myeloid cells. Moreover, in both immune--cold and immune--hot murine cancer models, RECYC demonstrated superior anti--tumor effect compared to PD--L1 blockade treatment. Collectively, we propose an effective strategy to induce recycling and broad checkpoint clearance in the TIME, which in turn reprograms the multicellular tumor-immune network to achieve durable immunotherapy responses.

Polyetheretherketone (PEEK) implants exhibit excellent mechanical biocompatibility yet remain inherently bioinert, resulting in fibrous encapsulation that compromises osseointegration and long-term stability. Conventional surface modification strategies employing exogenous bone morphogenetic protein-2 (BMP-2) loading suffer from burst-release kinetics, supraphysiological dosing risks, and coating delamination under physiological conditions, which are fundamentally misaligned with endogenous bone healing dynamics. Here, we present an endogenous homing strategy that transforms bioinert PEEK into osteoinductive scaffolds through in situ hydrogel assembly of dual-functional self-assembling peptides. Our design integrates RADA16 self-assembling domains with BMP-2-binding motifs (B2P), which upon covalent immobilization spontaneously assemble into nanofibrous hydrogel coatings that recapitulate native extracellular matrix architecture. This modification creates a hydrophilic bioactive interface that actively sequesters endogenous BMP-2 from the local microenvironment, thereby amplifying osteogenic signaling without exogenous supplementation. In vitro experiments reveal that B2P-functionalized PEEK significantly enhanced preosteoblast migration, proliferation, and osteogenic differentiation compared with unmodified controls. In a critical-sized beagle tibial defect model, PEEK-B2P implants achieved superior osseointegration with increased bone volume fraction and bone-implant contact, forming continuous lamellar bone without fibrous interposition. These findings establish an endogenous homing paradigm that converts bioinert PEEK into bioactive implants, offering a translatable strategy for enhanced bone regeneration and implant stability.

The gradual increase in ultraviolet B (UVB) health hazards to human skin, coupled with the irritation associated with existing sunscreen products, underscores the critical need for the development of natural sunscreens to combat UVB-induced photoaging. Chuanxiong oil (CXO) and hyaluronic acid (HA) possess excellent antioxidant and anti-apoptotic properties, which are closely linked to the mechanisms of photoaging. In this study, a composite nano-system (HA-CXO-Lip) comprising chuanxiong oil (CXO) and hyaluronic acid (HA) was initially fabricated. Subsequently, both in vitro HaCaT cell models and in vivo murine photoaging models were established to systematically evaluate the therapeutic efficacy and mechanistic actions of HA-CXO-Lip against photoaging under controlled experimental conditions. The investigation encompassed comprehensive assessments of its pharmacological effects and underlying molecular mechanisms through multimodal experimental approaches. Vitro experiments showed HA-CXO-Lip significantly reduced intracellular reactive oxygen species (ROS) levels and senescence-associated β-galactosidase (SA-β-Gal) activity. Furthermore, HA-CXO-Lip restored the levels of antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and hydroxyproline (HYP), while also decreasing the levels of lipid metabolites such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). These findings indicate that HA-CXO-Lip effectively inhibits excessive oxidative stress. Additionally, HA-CXO-Lip inhibited apoptosis by reducing Bax levels and enhancing Bcl-2 expression in HaCaT cells. In vivo studies demonstrated that HA-CXO-Lip significantly reduced UVB irradiation-induced erythema and epidermal thickening in the backs of mice. It restored the orderly arrangement of collagen fibers and inhibited the activation of the core senescence pathway, AKT/mTOR, along with the downstream expression of matrix metalloproteinase 9 (MMP9), resulting in a decrease in collagen I disassembly. Additionally, HA-CXO-Lip was shown to significantly decrease the number of apoptotic cells, as indicated by the expression of the apoptosis marker cleaved cysteine aspartic protease-3 (C-Caspase-3) and the surface type I transmembrane glycoprotein (CD44), thereby further inhibiting apoptosis. The findings of this study suggest that HA-CXO-Lip can exert anti-photoaging effects through its antioxidant and anti-apoptotic properties, highlighting the synergistic efficacy of CXO and HA, which holds promise for the prevention and treatment of photoaging.

Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, faces clinical limitations due to dose-dependent cardiotoxicity that can progress to irreversible DOX-induced cardiomyopathy (DIC). This pathology is driven by mitochondrial dysfunction, with the DOX-induced hyperactivation of mitochondrial fission as a central pathological event in DIC, leading to oxidative stress and cardiomyocyte apoptosis. To address this, we developed an injectable, self-assembling peptide-drug conjugate hydrogel, Mag-Gel, for mitochondrial targeted therapy. This system enables precise intramyocardial delivery via ultrasound-guided percutaneous injection, overcoming the translational barrier of conventional invasive hydrogels by eliminating the need for invasive surgery. In vitro, Mag-Gel attenuated aberrant mitochondrial fission by upregulating Sirt3 expression 5.76-fold and enhancing inhibitory phosphorylation of DRP1 at Ser637 2.33-fold, thereby reducing reactive oxygen species (ROS) accumulation and suppressing apoptosis in cardiomyocytes. In a murine DIC model, Mag-Gel ensured sustained myocardial retention and significantly improved cardiac function, enhancing the ejection fraction and reducing fibrosis compared to free drug treatment. This work presents a clinically feasible, minimally invasive strategy for treating DIC by targeting mitochondrial homeostasis, offering a practical approach to mitigating DOX-related myocardial injury.

Pancreatic cancer (PC) is a highly aggressive malignancy with a dismal 5-year survival rate of only 12%. Currently, no effective therapeutic strategies can improve the prognosis of pancreatic cancer. The activation of quiescent pancreatic stellate cells (PSCs) and their crosstalk with pancreatic cancer cells (PCCs) lead to the formation of a fibrotic physical barrier and an immunosuppressive tumor microenvironment (TME), which severely impede drug delivery and penetration. To improve PC treatment, a dual-targeting strategy capable of simultaneously acting on PCCs and PSCs is urgently needed to revert activated PSCs (aPSCs) to their quiescent state and suppress the proliferation of PCCs. KPT-6566, a small-molecule inhibitor, shifts PSCs from an activated to a quiescent state, reprograms the tumor immune microenvironment (TIME) to enhance anti-PD-L1 immunotherapy efficacy, suppresses PCCs proliferation, and induces PD-L1 expression on PCC surfaces, thereby increasing sensitivity to PD-L1-targeted therapies. This study designs two amphiphilic peptides, C16-LLGG-COO-DPPA-1(DPPA-1@PA) and DSPE-PEG-NHS-CGKRK(CGKRK@PA), which can co-assemble to encapsulate KPT-6566 and finally form a peptide-based nanoparticle termed DP-KPT-CG@PA. This nanoparticle precisely targets PCCs and PSCs to co-deliver KPT-6566, while synergizing with a PD-L1-blocking peptide to initiate immune checkpoint blockade therapy, thereby enhancing response rates to pancreatic cancer immunotherapy.

Background The risk factors associated with niche on the cesarean scar have been reported, however, the degree of these factors associated with large niche and the accumulation effects of these risk factors on the development of large niche are unclear. Methods Large niche was evaluated by transvaginal sonography during mid-follicular phase. Logistic regression model was used to assess 32 risk factors by univariate analysis. Then, a scoring model based on the screened risk factors was generated. The performance of this model was evaluated by area under curve (AUC). Finally, the scoring model was applied in 123 women to assess the external validation. Result(s) In the training cohort study, 163 women were diagnosed with large niche. The final scoring model involves eight risk factors with the rating scores including age at delivery (30–34 years: 1 point; ≥ 35 years: 4.5 points), retroflexed uterus (8.5 points), meconium-stained amniotic fluid (4.5 points), twice CSs (4.0 points), postpartum endometritis (4.5 points), premature rupture of membranes (2.5 points), intrahepatic cholestasis of pregnancy (mild to moderate: 3 points; severe: 6.5 points), and cervical dilatation (1-3 cm: 2.0 points; 4-10 cm: 4.5 points). The accumulation effect with a cut-off value of 8.0 in the scoring was associated with the large niche after CS. Conclusion(s) This is the first scoring model to objectively quantify the risk of a large niche after CS. Optimal risk factors control by avoiding high score factors and multiple factors accumulation may eliminate the risk of large niche development.

Targeted immunomodulation for reactivating innate cells, especially macrophages, holds great promise to complement current adaptive immunotherapy. Nevertheless, there is still a lack of high-performance therapeutics for blocking macrophage phagocytosis checkpoint inhibitors in solid tumors. Herein, a peptide-antibody combo-supramolecular in situ assembled CD47 and CD24 bi-target inhibitor (PAC-SABI) is described, which undergoes biomimetic surface propagation on cancer cell membranes through ligand-receptor binding and enzyme-triggered reactions. By simultaneously blocking CD47 and CD24 signaling, PAC-SABI enhances the phagocytic ability of macrophages in vitro and in vivo, promoting anti-tumor responses in breast and pancreatic cancer mouse models. Moreover, building on the foundation of PAC-SABI-induced macrophage repolarization and increased CD8+ T cell tumor infiltration, sequential anti-PD-1 therapy further suppresses 4T1 tumor progression, prolonging survival rate. The in vivo construction of PAC-SABI-based nano-architectonics provides an efficient platform for bridging innate and adaptive immunity to maximize therapeutic potency.

In pancreatic cancer (PC), surgical resection remains the sole curative option, albeit patients undergoing resection are susceptible to postoperative pancreatic fistula (PF) formation and tumor recurrence. An unmet need exists for a unified strategy capable of concomitantly averting PF and tumor relapse to mitigate morbidity in PC patients after surgery. Herein, an original dual crosslinked biological sealant hydrogel (methacrylate-hyaluronic acid-dopamine (MA-HA-DA) and sulfhydryl-hyaluronic acid-dopamine (SH-HA-DA)) was engineered as a drug depot and loaded with polydopamine-cloaked cytokine interleukin-15 and platelets conjugated with anti-TIGIT. In vitro analyses validated favorable tissue adhesion, cytocompatibility, and stability of the hydrogels. In a PF rodent model, the hydrogel effectively adhered to the pancreatic stump, sealing the severed pancreatic end and impeding post-operative elevations in amylase and lipase. In PC murine models, hydrogels potently stimulated CD8+ T and NK cells to deter residual tumor re-growth and distant metastasis. This innovative hydrogel strategy establishes a new framework for concomitant prevention of PF and PC recurrence.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine and metabolic disorder that is closely associated with the proliferation and apoptosis of ovarian granulosa cells (GCs). Ampelopsis japonica (AJ) is the dried tuberous root of Ampelopsis japonica (Thunb.) Makino (A. japonica), with anti-inflammatory, antioxidant, antibacterial, antiviral, wound-healing, and antitumor properties; however, it is unclear whether this herb has a therapeutic effect on PCOS. Therefore, this study aimed to investigate the pharmacological effect of AJ on PCOS and reveal its potential mechanism of action. A PCOS rat model was established using letrozole. After establishing the PCOS model, the rats received oral treatment of AJ and Diane-35 (Positive drug: ethinylestradiol + cyproterone tablets) for 2 weeks. Lipidomics was conducted using liquid-phase mass spectrometry and chromatography. AJ significantly regulated serum hormone levels and attenuated pathological variants in the ovaries of rats with PCOS. Furthermore, AJ significantly reduced the apoptotic rate of ovarian GCs. Lipidomic analysis revealed that AJ modulated glycerolipid and glycerophospholipid metabolic pathways mediated by lipoprotein lipase (Lpl), diacylglycerol choline phosphotransferase (Chpt1), and choline/ethanolamine phosphotransferase (Cept1). Therefore, we established that AJ may reduce ovarian GC apoptosis by modulating lipid metabolism, ultimately improving ovulatory dysfunction in PCOS. Therefore, AJ is a novel candidate for PCOS treatment.

目的:研究合欢饮的水提物抗HCV病毒活性及其机制.方法:采用Huh7.5.1细胞建立HCV2a病毒感染模型;通过CellTiter-Glo法测定吸光度值计算得到细胞存活率(％)和Renilla Luciferase Assay Kit法测定Rluc值算得到抑制率(％)、CC50、EC50并计算SI值;通过检测荧光素酶活性观察病毒72 h内对不同浓度合欢饮的耐药性;应用Western-blot检测NS5A、NS3及NS5B蛋白表达水平.结果:合欢饮水提物抗HCV2a的CC50、EC50及SI分别为132.50、1.90、67.90μg/mL.在24、48、72 h给药后的EC50分别为18.0、5.8、2.3μg/mL.在给药浓度范围内,合欢饮水提物对NS5A及NS5B蛋白的表达均有抑制作用且呈一定的量效关系,但对NS3蛋白表达的作用不明显.结论:合欢饮的水提物可能通过改变NS5A及NS5B蛋白表达水平来抑制HCV2a病毒的复制,且长时间给药病毒无耐药性.

In pancreatic cancer, the activation of quiescent pancreatic stellate cells (PSCs) is a critical event that leads to a characteristic dense desmoplastic stroma. The fibrotic network resulting from the bidirectional cross talk between pancreatic cancer cells (PCCs) and PSCs creates a complex tumor microenvironment that considerably hinders drug delivery and penetration. To improve pancreatic cancer treatment, a promising parallelization strategy with cross‐action property is urgently required that can simultaneously act on PCCs and PSCs to normalize activated PSCs (aPSCs), that is reverse them back to quiescent phenotype. Herein, a novel parallelization delivery system (CoA‐A&B‐γPGA) with dual‐pathway PSC quiescence restoration functions is designed. Metformin downregulates the secretion of transforming growth factor‐beta in PCCs, and all‐trans‐retinoic acid re‐educates aPSCs. CoA‐A&B‐γPGA thus induces aPSC quiescence and homeostatic restoration of desmoplastic stroma in vitro and in vivo. Importantly, CoA‐A&B‐γPGA exhibits deep penetration, improved accumulation and long‐term retention, and enhanced combination chemotherapy effects in multicellular spheroid and xenograft models. Furthermore, this dual‐targeting and co‐delivery system shows high specificity and sensitivity for detecting pancreatic cancer in patient samples. The innovative but simple peptide amphiphile co‐assembly strategy provides a new paradigm to design desired nanomedicines for stroma‐enriched pancreatic cancer therapy.

Ethnopharmacological relevance: Hehuan Yin decoction (HHY), first recorded in the Jingyue Quanshu (published in 1624 A.D.), is composed of Albizia julibrissin Durazz. and Ampelopsis japonica (Thunb.) Makino. Aim of the study: This study aimed to investigate the mechanism of action of HHY in treating polycystic ovary syndrome with insulin resistance (PCOS-IR). Materials and methods: Network pharmacology and molecular docking were used to predict active compounds, potential targets, and pathways for PCOS-IR treatment using HHY. Female Sprague-Dawley rats were administered letrozole (1 mg/kg) with a high-fat diet to establish a PCOS-IR model. Thereafter, symptoms, ovarian pathology, serum insulin resistance, and sex hormone levels were determined. Western blotting was used to determine the levels of PI3Kp85 alpha, AKT, phospho (p)-AKT, and GSK313 in the ovaries of rats. Results: Network pharmacology revealed 58 components in HHY and 182 potential targets that were shared between HHY and PCOS-IR. HHY could potentially treat PCOS-IR via the insulin resistance, PI3K/AKT, HIF-1, and steroid hormone biosynthesis pathways. Molecular docking revealed that PI3K, AKT1, GSK313, IRS1, and EGFR had high affinities to HHY compounds. In the PCOS-IR rats, HHY significantly normalised the symptoms and ovarian pathology, increased follicle-stimulating hormone (FSH) and oestradiol levels in the serum, and decreased the levels of fasting plasma glucose and fasting insulin, as well as the insulin resistance index. HHY also decreased the luteinising hormone (LH) and testosterone levels and the LH/FSH ratio in the PCOS-IR rats and increased the levels of PI3K, p-AKT, and GSK313 in ovary tissue, which indicated the activation of the PI3K/ AKT pathway. Conclusions: HHY can improve PCOS-IR symptoms via multiple pharmacological pathways and may be a potential alternative therapy for the treatment of PCOS-IR.

目的 研究栝楼不同部位(瓜蒌皮、瓜蒌子、天花粉)对卷烟烟气总粒相物(Total particulate matter,TPM)诱导的人支气管上皮细胞(BEAS-2B)增殖以及白细胞介素6(IL-6)、白细胞介素8(IL-8)、肿瘤坏死因子α(TNF-α)表达的影响.方法 采用TPM 诱导BEAS-2B 建立细胞损伤模型.实验分为空白对照组、模型组(10 μg·mL-1TPM)、红霉素组(阳性对照,10 μg·mL-1 TPM+5 μg·mL-1红霉素)及瓜蒌皮、瓜蒌子、天花粉不同浓度给药组[10μg·mL-1TPM+400、800、1 200 ng·mL-1瓜蒌皮/瓜蒌子/天花粉(正丁醇提取物)].药物作用24 h后,采用MTT法检测细胞增殖情况;采用实时荧光定量PCR法检测细胞IL-6、IL-8、TNF-α mRNA的表达;采用ELISA法检测细胞上清液中IL-6、IL-8和TNF-α的含量.结果 与空白对照组比较,模型组的BEAS-2B细胞增殖受到明显抑制(P＜0.01),细胞上清液中IL-6、IL-8和TNF-α含量明显升高(P＜0.01),细胞IL-6、IL-8、TNF-α mRNA表达明显上调(P＜0.01).与模型组比较,不同浓度组的瓜蒌皮、瓜蒌子、天花粉均可以促进BEAS-2B细胞的增殖(P＜0.05,P＜0.01);400、800、1 200 ng·mL-1瓜蒌皮组的细胞上清液中的IL-6、TNF-α含量及mRNA表达明显下调(P＜0.01),800、1 200 ng·mL-1瓜蒌皮组的细胞上清液中的IL-8含量及mRNA表达明显下调(P＜0.01);400、800、1 200 ng·mL-1瓜蒌子组的细胞上清液中的IL-8、TNF-α含量及mRNA表达明显下调(P＜0.01);400、800、1 200ng·mL-1天花粉组的细胞上清液中的IL-6、TNF-α含量及mRNA 表达明显下调(P＜0.05,P＜0.01).结论 栝楼不同部位(瓜蒌皮、瓜蒌子和天花粉)正丁醇提取物可能通过促进BEAS-2B细胞增殖,抑制TNF-α、IL-6、IL-8等炎症因子表达,从而发挥其抗炎作用.

目的 研究麻杏石甘汤对邪热壅肺证小鼠肠道菌群的调节作用.方法 将BALC/B小鼠随机分成正常组、模型组与麻杏石甘组,采用乙醚轻度麻醉下鼻内接种肺炎链球菌溶液建立邪热壅肺证模型.麻杏石甘组灌胃给予15.12 g·kg-1,1次/天,持续给药14天,正常组给予等量生理盐水.给药14天后,收集各实验组小鼠粪便,采用Illumina HiSeq2000高通量测序法对各实验组小鼠粪便中微生物进行16S rRNA基因V4可变区检测,运用LEfSe分析肠道菌群的结构组成及不同菌属相对丰度变化.结果 模型组小鼠出现高热、喘促、气急、鼻翼煽动等症状,造模成功.模型组对比正常组,α多样性指数显著增加.菌落丰富度增加,梭菌属、Odoribacter、乳酸菌属菌群减少,萨特氏菌属、瘤胃球菌、副拟杆菌属菌群显著增加.麻杏石甘组与模型组相比,小鼠高热、喘促等症状得到明显改善,菌落丰富度与多样性增加,菌群中的梭菌属、乳酸菌属菌群减少,副拟杆菌属显著增加.另发现与短链脂肪酸产生相关的菌属丰度增加.结论 邪热壅肺证小鼠肠道菌群结构及其组成紊乱,麻杏石甘汤可能通过改善邪热壅肺证小鼠肠道菌群紊乱,达到有效治疗邪热壅肺证的目的.

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with high morbidity, which leads to poor quality of life. The Xianglian pill (XLP) is a classical Chinese patent medicine and has been clinically proven to be an effective treatment for UC. Purpose: The pharmacological mechanism of the key bioactive ingredients of XLP for the treatment of UC was investigated by a network pharmacology and pharmacokinetics integrated strategy. Study design and methods: Network pharmacology was used to analyze the treatment effect of nine quantified XLP ingredients on UC. Key pathways were enriched and analyzed by protein-protein interaction and Kyoto Encyclopedia of Genes and Genomes analyses. The effect of XLP on Th17 cell differentiation was validated using a mouse model of UC. The binding of nine compounds with JAk2, STAT3, HIF-1 alpha, and HSP90AB1 was assessed using molecular docking. A simple and reliable ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantification of nine ingredients from XLP in plasma and applied to a pharmacokinetic study following oral administration. Results: Nine compounds of XLP, including coptisine, berberine, magnoflorine,berberrubine, jatrorrhizine, palmatine, evodiamine, rutaecarpine, and dehydrocostus lactone, were detected. Network pharmacology revealed 50 crossover genes between the nine compoundsand UC. XLP treats UC mainly by regulating key pathways of the immune system, including Th17 cell differentiation, Jak-Stat, and PI3K-Akt signaling pathways. An in vivo validation in mice found that XLP inhibits Th17 cell differentiation by suppressing the Jak2-Stat3 pathway, which alleviates mucosal inflammation in UC. Molecular docking confirmed that eight compounds are capable of binding with JAk2, HIF-1 alpha, and HSP90AB1, further confirming the inhibitory effect of XLP on the Jak2-Stat3 pathway. Moreover, apharmacokinetic study revealed that the nine ingredients of XLP are exposed in the plasma and colon tissue, which demonstrates its pharmacological effect on UC. Conclusion: This study evaluates the clinical treatment efficacy of XLP for UC. The network pharmacology and pharmacokinetics integrated strategy evaluation paradigm is efficient in discovering the key pharmacological mechanism of herbal formulae.