Phytomedicine最新文献_第9页

The volatile oil of Acorus tatarinowii Schott ameliorates Alzheimer's disease through improving insulin resistance via activating the PI3K/AKT pathway 鞑靼菖蒲（Acorus tatarinowii Schott）的挥发油通过激活 PI3K/AKT 通路改善胰岛素抵抗，从而改善阿尔茨海默氏症。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-20 DOI: 10.1016/j.phymed.2024.156168

Junhao Huang , Zhiwei Xu , Chenshi Yu , Liu Liu , Liting Ji , Ping Qiu , Changyu Li , Xiaojie Zhou

<div><h3>Background</h3><div>Alzheimer's disease (AD) presently stands as the most prevalent neurodegenerative disease. Existing research underscores the pivotal role of insulin signaling in the progression of AD. <em>Acorus tatarinowii Schott</em> (SCP), a traditional Chinese herbal, is employed for AD treatment in China. The volatile oil of <em>Acorus tatarinowii Schott</em> (SCP-oil) is the active component. However, its impact on AD-associated insulin resistance (AD-IR) remains inadequately investigated.</div></div><div><h3>Purpose</h3><div>This study used network pharmacology and experimental to investigate the effects and mechanisms of SCP-oil on cognitive improvement in AD by inhibiting IR.</div></div><div><h3>Materials and methods</h3><div>GC-Q/TOF-MS was employed to analyze the chemical composition of SCP-oil, while network pharmacology predicted the targets associated with SCP-oil in treating AD-IR to identify its regulatory mechanism. IR in the brain was simulated by intracerebroventricular streptozotocin administration (ICV-STZ). The neuroprotective and cognitive improvement effects of SCP-oil were assessed using the Morris water maze and hematoxylin and eosin, as well as Nissl staining. The expression levels of Neun and proteins related to p-tau, tau, amyloid-beta (Aβ), apoptosis, and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway were measured using immunohistochemistry and Western blotting, respectively. Dexamethasone (DXM)-induced HT22 cells were used for IR modeling. Chemical analysis determined the glucose consumption rate, and periodic acid Schiff staining was employed to detect glycogen deposition. Western Blots were utilized to investigate the expression of characteristic AD proteins, apoptosis-related proteins, and PI3K/AKT pathway-related proteins. The apoptosis rate was detected by flow cytometry. Reverse validation was further performed using LY294002 to evaluate the pharmacodynamic effects of SCP-oil after PI3K/AKT pathway inhibition.</div></div><div><h3>Results</h3><div>A total of 25 chemical constituents were identified in SCP-oil. The network pharmacology findings indicated that SCP-oil holds the potential to ameliorate IR in the brain by activating the PI3K/AKT pathway, thereby improving AD. SCP-oil significantly improved ICV-STZ-induced cognitive dysfunction and pathological damage, reduced neuronal loss, Aβ deposition, and tau protein hyperphosphorylation, inhibited cell apoptosis, and activated the PI3K/AKT signaling pathway. Neuron loss, Aβ deposition, and tau protein hyperphosphorylation and cell apoptosis were further enhanced following treatment with LY294002, while the PI3K/AKT signaling pathway was further inhibited, and the protective effect of SCP-oil was weakened.</div></div><div><h3>Conclusion</h3><div>SCP-oil exhibited the potential to ameliorate brain IR, inhibiting cell apoptosis by activating the PI3K/AKT signaling pathway, thereby improving learning and memory ability.</div></

背景：阿尔茨海默病（AD）是目前最常见的神经退行性疾病。现有研究强调，胰岛素信号在阿尔茨海默病的发展过程中起着关键作用。在中国，鞑靼菖蒲（SCP）是一种传统的中草药，被用于治疗注意力缺失症。其挥发油（SCP-oil）是其活性成分。目的：本研究采用网络药理学和实验方法，探讨SCP油通过抑制IR改善AD认知能力的作用和机制：采用GC-Q/TOF-MS分析SCP-oil的化学成分，网络药理学预测SCP-oil治疗AD-IR的相关靶点，确定其调控机制。通过脑室内注射链脲佐菌素（ICV-STZ）模拟大脑中的IR。采用莫里斯水迷宫、苏木精和伊红以及Nissl染色法评估SCP-油的神经保护和认知改善作用。采用免疫组织化学和 Western 印迹法分别测定了 Neun 以及与 p-tau、tau、淀粉样蛋白-β（Aβ）、细胞凋亡和磷脂酰肌醇 3- 激酶/蛋白激酶 B（PI3K/AKT）通路相关的蛋白质的表达水平。地塞米松（DXM）诱导的 HT22 细胞用于红外建模。化学分析确定了葡萄糖消耗率，周期性酸性希夫染色检测了糖原沉积。采用 Western 印迹法检测 AD 特征蛋白、凋亡相关蛋白和 PI3K/AKT 通路相关蛋白的表达。流式细胞术检测细胞凋亡率。使用 LY294002 进一步进行反向验证，以评估 PI3K/AKT 通路抑制后 SCP-oil 的药效学效应：结果：SCP 油中共鉴定出 25 种化学成分。网络药理学研究结果表明，SCP-油有可能通过激活 PI3K/AKT 通路来改善大脑中的 IR，从而改善 AD。SCP-oil能明显改善ICV-STZ诱导的认知功能障碍和病理损伤，减少神经元丢失、Aβ沉积和tau蛋白高磷酸化，抑制细胞凋亡，激活PI3K/AKT信号通路。LY294002处理后，神经元丢失、Aβ沉积、tau蛋白高磷酸化和细胞凋亡进一步增强，PI3K/AKT信号通路进一步受到抑制，SCP-oil的保护作用减弱：结论：SCP-油具有改善脑IR的潜力，通过激活PI3K/AKT信号通路抑制细胞凋亡，从而改善学习和记忆能力。

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引用次数: 0

4-Hydroxydictyolactone alleviates cerebral ischemia injury by regulating neuroinflammation and autophagy via AMPK signaling pathway 4-羟基双焦内酯通过AMPK信号通路调节神经炎症和自噬减轻脑缺血损伤

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-19 DOI: 10.1016/j.phymed.2024.156157

Yu Qi , Haoyun Zhu , Yinqi Chen , Yuanlong Zhang , Shengjie Jin , Xiao Xu , Xiaohong Ma , Leiqing Chen , Min Zhao , Haoru Zhu , Pengcheng Yan

Background

Cerebral ischemia (CI), a cerebrovascular disorder, is a major contributor to disability and mortality. Marine-derived compounds are an important source of new neuroprotective drug candidates. Xenicane-type diterpenes from brown algae of the genus Dictyota have exhibited potential neuroprotective effects against CI injury, attributed to their antioxidant properties. However, whether there are other underlying neuroprotective mechanisms of xenicane diterpenes against CI is still ambiguous.

Purpose

This study aims to elucidate the neuroprotective efficacy and mechanism of 4-hydroxydictyolactone (HDTL) in the treatment of CI.

Methods

The LPS-induced BV2 cell model was used for anti-neuroinflammatory activity assay. Tandem Mass Tag (TMT)-based quantitative proteomics was employed to identify underlying mechanisms. The OGD/R-induced SH-SY5Y cell model and a MCAO mice model were used to assess the neuroprotective effect of HDTL against CI in vitro and in vivo.

Results

HDTL reduced inflammation in LPS-stimulated BV2 cells by inhibiting the IKK/IκB/NF-κB pathway and by enhancing AMPK phosphorylation. Additionally, in SH-SY5Y cells treated with OGD/R, HDTL facilitated autophagy and reduced apoptosis. The neuroprotective properties of HDTL were abrogated in AMPK- silenced SH-SY5Y cells. In MCAO mice, HDTL ameliorated CI injury as evidenced by decreases in neurological deficit scores and cerebral infarction. HDTL also promoted autophagy and reduced apoptosis in vivo through both the AMPK/mTOR and IKK/IκB/NF-κB pathways.

Conclusion

HDTL exhibits neuroprotective effects through regulating the AMPK/mTOR and IKK/IκB/NF-κB pathways. These findings suggest that HDTL is a promising therapeutic candidate for CI treatment.

背景：脑缺血（CI）是一种脑血管疾病，是导致残疾和死亡的主要原因。海洋衍生化合物是候选神经保护新药的重要来源。来自褐藻属 Dictyota 的烯类二萜因其抗氧化特性而显示出了对 CI 损伤的潜在神经保护作用。目的：本研究旨在阐明 4-hydroxydictyolactone (HDTL) 治疗 CI 的神经保护功效和机制：方法：采用 LPS 诱导的 BV2 细胞模型进行抗神经炎症活性检测。方法：采用 LPS 诱导的 BV2 细胞模型进行抗神经炎症活性检测，并采用基于串联质量标签（TMT）的定量蛋白质组学来确定其潜在机制。用OGD/R诱导的SH-SY5Y细胞模型和MCAO小鼠模型评估HDTL在体外和体内对CI的神经保护作用：结果：HDTL通过抑制IKK/IκB/NF-κB通路和增强AMPK磷酸化来减轻LPS刺激下BV2细胞的炎症反应。此外，在用 OGD/R 处理的 SH-SY5Y 细胞中，HDTL 可促进自噬，减少细胞凋亡。在AMPK沉默的SH-SY5Y细胞中，HDTL的神经保护特性被削弱。在MCAO小鼠中，HDTL可改善CI损伤，神经功能缺损评分和脑梗塞程度的下降就是证明。HDTL还通过AMPK/mTOR和IKK/IκB/NF-κB途径促进自噬，减少体内细胞凋亡：HDTL通过调节AMPK/mTOR和IKK/IκB/NF-κB途径发挥神经保护作用。这些研究结果表明，HDTL是治疗CI的一种有前途的候选疗法。

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引用次数: 0

EGCG targeting STAT3 transcriptionally represses PLXNC1 to inhibit M2 polarization mediated by gastric cancer cell-derived exosomal miR-92b-5p. EGCG靶向STAT3转录抑制PLXNC1，从而抑制胃癌细胞外泌体miR-92b-5p介导的M2极化。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-19 DOI: 10.1016/j.phymed.2024.156137

Jianfeng Yi, Zhenzhen Ye, Hao Xu, Hui Zhang, Hongtai Cao, Xin Li, Tianming Wang, Chunlu Dong, Yan Du, Shi Dong, Wence Zhou

<p><strong>Background: </strong>M2-polarized tumor-associated macrophages (TAMs) predominate in tumor microenvironment (TME) and serve primary functions in tumor progression, including growth, angiogenesis, metastasis, immunosuppression, chemoresistance, and poor prognosis. The reversal of M2 polarization provides a new treatment strategy for cancer. Presently, the molecular mechanisms of M2 polarization have yet to be fully characterized, and there is a lack of effective therapeutic targets and drugs. Cancer cells initiate an immunosuppressive TME by recruiting macrophages and promoting M2 polarization through the secretion of inflammatory factors. Accordingly, blocking cancer cell-induced TAM M2 polarization may present a more effective strategy from the perspective of cancer cells. Hedyotis diffusa Willd (HDW) possesses immunomodulatory and antitumor properties, and is a precious and direct source of small molecule natural products with a dual function of inhibition of tumor growth and tumor cell-mediated M2 polarization.</p><p><strong>Objective: </strong>To identify a new target promoting gastric cancer (GC) cell growth and GC cell-mediated M2 polarization from mRNA profiles of GC cells treated with HDW injection (HDI) and to excavate a natural product from HDI that can regulate related mRNA and inhibit the aforementioned effects.</p><p><strong>Methods: </strong>RNA sequencing (RNA-seq) was used to analyze HDI-regulated differentially expressed mRNAs (HRmRNAs) in MKN45 cells. Weighted gene co-expression network analysis (WGCNA), univariate and multivariate Cox regression analysis, KM survival curves, and association analysis between HRmRNA and clinical characteristics/tumor infiltrating immune cells (TIICs) individually were utilized to screen out the target HRmRNA associated with prognosis and M2 macrophage infiltration in GC. shRNA lentiviral vectors were used for stably silencing, and transient overexpressing plasmids were constructed for overexpression. CCK8, EdU, colony formation, migration and invasion assays were used to validate the function of drugs and molecules in GC. HDI constituent analysis was performed using UHPLC-QE-MS. A network of HDI constituent-hub transcription factor (TF)-HRmRNA was constructed based on RNA-Seq, network pharmacology and TFs prediction. Exosome isolation and identification were performed using ultracentrifugation, NTA, TEM and western blot. Apoptosis and macrophage phenotypes were determined by flow cytometric analysis. Small RNA-Seq made exosomal miRNA identification. Small molecule interaction with targets were analyzed using molecular docking, SPR and CETSA. The direct relationship between transcription factors and promoters was verified using ChIP-QPCR and dual-luciferase reporter gene assay. A nude mice xenograft tumor model was established for vivo validation.</p><p><strong>Results: </strong>HDI inhibited MKN45 cell proliferation, migration, invasion and promoted apoptosis. RNA-Seq identified 2583 H

背景：M2 极化的肿瘤相关巨噬细胞（TAMs）在肿瘤微环境（TME）中占主导地位，在肿瘤进展过程中发挥主要功能，包括生长、血管生成、转移、免疫抑制、化疗抵抗和不良预后。逆转 M2 极化为癌症提供了一种新的治疗策略。目前，M2 极化的分子机制尚未完全定性，也缺乏有效的治疗靶点和药物。癌细胞通过招募巨噬细胞并通过分泌炎症因子促进 M2 极化，从而启动免疫抑制 TME。因此，从癌细胞的角度来看，阻断癌细胞诱导的 TAM M2 极化可能是一种更有效的策略。Hedyotis diffusa Willd（HDW）具有免疫调节和抗肿瘤特性，是一种珍贵而直接的小分子天然产物来源，具有抑制肿瘤生长和肿瘤细胞介导的 M2 极化的双重功能：从注射用高密度脂蛋白（HDI）治疗的胃癌细胞的mRNA图谱中发现促进胃癌细胞生长和胃癌细胞介导的M2极化的新靶点，并从HDI中挖掘一种能调节相关mRNA并抑制上述作用的天然产物：方法：利用RNA测序（RNA-seq）分析MKN45细胞中受HDI调控的差异表达mRNAs（HRmRNAs）。利用加权基因共表达网络分析（WGCNA）、单变量和多变量Cox回归分析、KM生存曲线以及HRmRNA与临床特征/肿瘤浸润免疫细胞（TIICs）的关联分析，筛选出与GC预后和M2巨噬细胞浸润相关的目标HRmRNA。使用 CCK8、EdU、集落形成、迁移和侵袭试验来验证药物和分子在 GC 中的功能。利用超高效液相色谱-质谱联用仪（UHPLC-QE-MS）进行了 HDI 成分分析。基于RNA-Seq、网络药理学和TFs预测，构建了HDI成分-中枢转录因子（TF）-HRmRNA网络。利用超速离心、NTA、TEM和Western blot技术分离和鉴定了外泌体。通过流式细胞分析确定了细胞凋亡和巨噬细胞的表型。小 RNA-Seq 对外泌体 miRNA 进行了鉴定。利用分子对接、SPR和CETSA分析了小分子与靶标的相互作用。利用 ChIP-QPCR 和双荧光素酶报告基因试验验证了转录因子与启动子之间的直接关系。建立了裸鼠异种移植肿瘤模型进行体内验证：结果：HDI抑制了MKN45细胞的增殖、迁移和侵袭，并促进了细胞凋亡。RNA-Seq鉴定出2583个HRmRNA。结果：HDI抑制了MKN45细胞的增殖、迁移和侵袭，并促进了细胞凋亡。PLXNC1通过转移GC细胞衍生的外泌体miR-92b-5p、抑制SOCS7-STAT3相互作用并随后激活巨噬细胞中的STAT3，促进了GC细胞增殖并促进了TAMs M2极化。PLXNC1 介导的 GC 细胞衍生外泌体诱导的 M2 TAMs 促进了 GC 细胞的迁移和侵袭。PLXNC1通过MEK1/MSK1/CREB1途径调节外泌体miR-92b-5p。STAT3可转录调控PLXNC1在GC细胞中的表达。HDI成分-枢纽TF-HRmRNA网络显示，HDI中的表没食子儿茶素没食子酸酯（EGCG）可靶向STAT3转录调控PLXNC1的表达。EGCG作为一种天然产物直接与STAT3结合，减少了STAT3的核定位，从而抑制了PLXNC1的转录，并逆转了PLXNC1介导的GC细胞外泌体诱导的M2极化：结论：PLXNC1是一个新靶点，对GC细胞增殖和GC细胞介导的M2极化具有双重作用。从HDI中提取的EGCG可抑制GC细胞增殖，并靶向STAT3抑制PLXNC1介导的GC细胞外泌体诱导的M2极化，这可能是一种针对GC细胞增殖和免疫微环境的多靶点治疗药物。

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引用次数: 0

Tong-Qiao-Huo-Xue Decoction promotes synaptic remodeling via cAMP/PKA/CREB pathway in vascular dementia rats 通窍活血汤通过cAMP/PKA/CREB途径促进血管性痴呆大鼠突触重塑

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-19 DOI: 10.1016/j.phymed.2024.156166

Jiacheng Li , Haiyong Ye , Fan Xu , Yuting Yang , Chaowen Ge , Min Yao , Ping Huang , Lei Wang , Ning Wang , Xian Zhou , Dennis Chang

Background

Tong-Qiao-Huo-Xue Decoction (TQHXD) is a traditional Chinese medicinal formula widely used in the treatment of vascular dementia (VD). Although it has demonstrated good clinical efficacy, the specific molecular mechanisms underlying its therapeutic effects on VD remain unclear.

Objective

This study aimed to elucidate the neuroprotective mechanisms of TQHXD to provide a scientific basis for the clinical treatment of VD.

Methods

The chemical components of TQHXD were qualitatively analyzed using ultra-performance liquid chromatography (UPLC) and gas chromatography (GC). Network pharmacology predicted the potential protective mechanisms of TQHXD against VD. A rat model of VD was established through bilateral vessel occlusion (2-VO), and an oxygen-glucose deprivation/reperfusion (OGD/R) model was used to induce damage to neuronal cells of the hippocampus. In vivo experiments assessed changes in cerebral blood flow, learning and memory capabilities, hippocampal neuronal morphology, dendritic length, dendritic spine density, and synapse number in rats. We examined the expression of synaptic remodeling-related proteins and pathway proteins in the hippocampal region. In vitro assays evaluated cell viability, apoptosis, reactive oxygen species (ROS) levels, and expression of synaptic remodeling-related proteins and signaling pathway.

Results

Multiple active components were identified in TQHXD. KEGG enrichment analysis suggested that the therapeutic effects of TQHXD on VD may be related to the cAMP signaling pathway. Treatment with TQHXD significantly improved learning and memory performance in VD rats, improved hippocampus morphology, and increased dendritic length, dendritic spine density, and number of synapses. Furthermore, TQHXD improved cell viability, reduced apoptosis, and decreased intracellular ROS levels in vitro. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay results collectively demonstrated that TQHXD upregulated the expression of synaptic remodeling-related proteins and pathway-related proteins both in vivo and in vitro.

Conclusions

TQHXD treated VD by promoting synaptic remodeling in hippocampal neurons, likely through activation of the cAMP/PKA/CREB pathway.

背景介绍通窍活血汤（TQHXD）是一种广泛用于治疗血管性痴呆（VD）的传统中药配方。虽然该方具有良好的临床疗效，但其治疗血管性痴呆的具体分子机制仍不清楚：本研究旨在阐明 TQHXD 的神经保护机制，为 VD 的临床治疗提供科学依据：方法：采用超高效液相色谱法（UPLC）和气相色谱法（GC）对TQHXD的化学成分进行定性分析。网络药理学预测了 TQHXD 对 VD 的潜在保护机制。通过双侧血管闭塞（2-VO）建立了大鼠 VD 模型，并使用氧-葡萄糖剥夺/再灌注（OGD/R）模型诱导海马神经元细胞损伤。体内实验评估了大鼠脑血流量、学习和记忆能力、海马神经元形态、树突长度、树突棘密度和突触数量的变化。我们检测了海马区突触重塑相关蛋白和通路蛋白的表达。体外试验评估了细胞活力、凋亡、活性氧（ROS）水平以及突触重塑相关蛋白和信号通路的表达：结果：在TQHXD中发现了多种活性成分。KEGG富集分析表明，TQHXD对VD的治疗作用可能与cAMP信号通路有关。用 TQHXD 治疗可明显改善 VD 大鼠的学习和记忆能力，改善海马形态，增加树突长度、树突棘密度和突触数量。此外，TQHXD 还能在体外提高细胞活力、减少细胞凋亡和降低细胞内 ROS 水平。Western印迹、免疫荧光和酶联免疫吸附试验结果共同表明，TQHXD能在体内和体外上调突触重塑相关蛋白和通路相关蛋白的表达：结论：TQHXD可能通过激活cAMP/PKA/CREB通路，促进海马神经元的突触重塑，从而治疗VD。

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引用次数: 0

Chidan Tuihuang granule modulates gut microbiota to influence NOD1/RIPK2 pathway in cholestatic liver injury recovery. 赤丹土黄颗粒调节肠道微生物群以影响胆汁淤积性肝损伤恢复中的NOD1/RIPK2通路

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-19 DOI: 10.1016/j.phymed.2024.156164

Yuan Chen, Qichao Hu, Wenwen Zhang, Qianqian Gong, Jin Yan, Zexin Wang, Zongyuan Zhou, Xiao Ma, Yeyu Li, Xiaohua Lu, Thomas Efferth

Background: Cholestatic liver injury (CLI), which occurs if bile acids are imbalanced and the liver becomes inflamed, is difficult to treat effectively OBJECTIVE: We investigated how the Chinese patent medicine Chidan Tuihuang granule (CDTH) ameliorates cholestatic liver injury with a focus on its effects on the NOD1/RIPK2 pathway and intestinal flora METHODS: We used an ANIT-induced SD rat model of CLI to evaluate the therapeutic effects of CDTH. The experimental design included control, model, UDCA (ursodeoxycholic acid) and CDTH treatment groups. UHPLC-Q-Orbitrap-HRMS was used to analyse the blood components of CDTH. The efficacy of CDTH was assessed by liver function tests, histopathological examination (HE and TUNEL staining), transmission electron microscopy, and ELISA to measure apoptosis and inflammatory markers. Mechanistic insights were obtained using transcriptomics and RT-qPCR, while alterations in the expression of key proteins were studied using western blotting, immunohistochemistry, and immunofluorescence. Furthermore, the impact of CDTH on the gut microbiota and its associated metabolite, meso-2,6-diaminopimelic acid (DAP), which is linked to NOD1 activation, was examined and confirmed through in vitro RESULTS: The experimental results demonstrated a notable elevation in serum levels of AST, ALT, ALP, TBA, TBIL, and DBIL in the rats belonging to the model group, accompanied by the infiltration of inflammatory cells, hepatocyte degeneration, and necrosis in the liver tissue. CDTH administration significantly improved liver function and cholestasis indicators. Transmission electron microscopy and TUNEL staining revealed a marked reduction in liver cell apoptosis with CDTH treatment. ELISA results showed that CDTH effectively reduced inflammatory markers. Transcriptomic analysis showed that CDTH inhibited the NOD1/RIPK2 pathway, resulting in a significant decrease in the expression of NOD1, RIPK2 and associated genes in liver tissue. Gut microbiota analysis demonstrated that CDTH regulated intestinal flora structure, reducing the abundance of DAP-producing Gram-negative bacteria such as lactobacilli. In vitro experiments confirmed that CDTH enhanced cell viability by downregulating the DAP-mediated NOD1/RIPK2 signaling pathway secreted by intestinal bacteria CONCLUSION: CDTH ameliorated liver damage in cholestatic rats by inhibiting the NOD1/RIPK2 signaling pathway through regulation of gut flora and downregulation of DAP metabolites.

背景：胆汁淤积性肝损伤（CLI）是胆汁酸失衡和肝脏发炎时发生的肝损伤，很难有效治疗。目的：我们研究了中成药赤丹吐黄颗粒（CDTH）如何改善胆汁淤积性肝损伤，重点是其对NOD1/RIPK2通路和肠道菌群的影响。方法：我们使用ANIT诱导的SD大鼠CLI模型来评估CDTH的治疗效果。实验设计包括对照组、模型组、UDCA（熊去氧胆酸）组和 CDTH 治疗组。采用UHPLC-Q-Orbitrap-HRMS分析CDTH的血液成分。CDTH 的疗效通过肝功能测试、组织病理学检查（HE 和 TUNEL 染色）、透射电子显微镜和酶联免疫吸附试验（ELISA）来评估，以检测细胞凋亡和炎症标志物。利用转录组学和 RT-qPCR 对机理进行了深入研究，并利用 Western 印迹、免疫组化和免疫荧光对关键蛋白的表达变化进行了研究。此外，还研究了 CDTH 对肠道微生物群及其相关代谢产物介-2,6-二氨基亚庚酸（DAP）的影响，该代谢产物与 NOD1 激活有关，并通过体外实验证实了这一点结果：实验结果表明，模型组大鼠血清中谷草转氨酶（AST）、谷丙转氨酶（ALT）、谷草转氨酶（ALP）、谷草转氨酶（TBA）、谷草转氨酶（TBIL）和谷草转氨酶（DBIL）水平明显升高，同时伴有炎性细胞浸润、肝细胞变性和肝组织坏死。CDTH 能明显改善肝功能和胆汁淤积指标。透射电子显微镜和TUNEL染色显示，CDTH治疗后肝细胞凋亡明显减少。酶联免疫吸附试验（ELISA）结果显示，CDTH能有效降低炎症指标。转录组分析表明，CDTH抑制了NOD1/RIPK2通路，导致肝组织中NOD1、RIPK2和相关基因的表达显著下降。肠道微生物群分析表明，CDTH能调节肠道菌群结构，减少产生DAP的革兰氏阴性菌（如乳酸杆菌）的数量。体外实验证实，CDTH 通过下调肠道细菌分泌的 DAP 介导的 NOD1/RIPK2 信号通路，增强了细胞的活力结论：CDTH 通过调节肠道菌群和下调 DAP 代谢物，抑制 NOD1/RIPK2 信号通路，从而改善胆汁淤积大鼠的肝损伤。

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引用次数: 0

Anti-nociceptive effect of STW 5-II in rodent models of stress and post-inflammatory visceral hypersensitivity STW 5-II 在啮齿动物应激和炎症后内脏过敏模型中的抗痛觉作用。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-19 DOI: 10.1016/j.phymed.2024.156167

Ehsan Noor-Mohammadi , Tian Yuan , Casey O. Ligon , Ramy M. Ammar , Sabine Rabini , Anthony C. Johnson , Beverley Greenwood-Van Meerveld

Aims

Visceral hypersensitivity is a therapy-resistant hallmark of irritable bowel syndrome (IBS). Many IBS patients’ symptoms develop following an acute colitis, and most report that stress worsens symptoms. STW 5-II, a combination of six herbal extracts, is a clinically proven treatment for IBS, but the mechanism is uncertain. Here, we employ two well-characterized rodent models to test the hypothesis that STW 5-II attenuates chronic colonic hypersensitivity.

Main methods

Separate cohorts of male rats were used for each model of colonic hypersensitivity. The first model used repeated water avoidance stress (1hr/day for 10 days), while the second model used intracolonic trinitrobenzene sulfonic acid to induce a short-lived colitis followed by post-inflammatory visceral hypersensitivity. Both models used sham treatment controls. Colonic sensitivity was quantified as the number of abdominal contractions to graded pressures (20–60 mmHg) of isobaric colorectal distension (CRD). Phosphorylation of extracellular signal-regulated kinase (pERK) was assessed via immunohistochemistry in the brain, spinal cord, and dorsal root ganglion (DRG). STW 5-II (10 ml/kg, p.o.) or vehicle (p.o.) was administered for 7 days, prior to CRD and pERK expression.

Key findings

Rats exposed to either model developed significant colonic hypersensitivity. Both models enhanced CRD-evoked pERK in DRGs, spinal cord, and brain. STW 5-II decreased colonic hypersensitivity and reduced CRD-evoked brain, spinal, and DRG pERK.

Significance

Both models induced colonic hypersensitivity and enhanced pERK expression. STW 5-II inhibited colonic hypersensitivity and decreased noxious neuronal activation in both models, which could explain its clinically proven efficacy in relieving visceral hypersensitivity-related symptoms in IBS.

目的：内脏过敏是肠易激综合征（IBS）的一个耐药性特征。许多肠易激综合征患者的症状都是在急性结肠炎之后出现的，而且大多数人都表示压力会加重症状。STW 5-II 是六种草药提取物的复方制剂，经临床验证可治疗肠易激综合征，但其机制尚不明确。在此，我们采用了两种特性良好的啮齿动物模型来验证 STW 5-II 可减轻慢性结肠超敏反应的假设：主要方法：每种结肠超敏反应模型都使用了不同组别的雄性大鼠。第一个模型使用重复避水应激（每天 1 小时，持续 10 天），第二个模型使用结肠内三硝基苯磺酸诱发短暂结肠炎，随后出现炎症后内脏超敏反应。两种模型都使用假治疗对照组。结肠敏感性以等压结肠直肠胀气（CRD）分级压力（20-60 mmHg）下的腹部收缩次数来量化。通过免疫组化评估了大脑、脊髓和背根神经节（DRG）中细胞外信号调节激酶（pERK）的磷酸化情况。在 CRD 和 pERK 表达之前，给大鼠注射 STW 5-II（10 毫升/千克，口服）或药物（口服）7 天：主要研究结果：大鼠暴露于这两种模型均会产生明显的结肠超敏反应。两种模型都增强了DRGs、脊髓和大脑中CRD诱发的pERK。STW 5-II 降低了结肠超敏性，减少了 CRD 诱发的大脑、脊髓和 DRG pERK：两种模型都会诱发结肠超敏反应并增强 pERK 的表达。STW 5-II 可抑制两种模型中的结肠超敏反应，并降低有害神经元的激活，这可能是 STW 5-II 在缓解肠易激综合征的内脏超敏相关症状方面具有临床疗效的原因。

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引用次数: 0

Eupalinolide A attenuates trauma-induced heterotopic ossification of tendon in mice by promoting YAP degradation through TOLLIP-mediated selective autophagy Eupalinolide A通过TOLLIP介导的选择性自噬促进YAP降解，从而减轻创伤诱导的小鼠肌腱异位骨化。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-18 DOI: 10.1016/j.phymed.2024.156163

Huaji Jiang , Yan Ding , Yongfu Wu , Yingchao Xie , Qinyu Tian , Cheng Yang , Yakui Liu , Xuemei Lin , Bin Song , Hebei He , Li Wan , Xinggui Tian

Background

Inhibiting the aberrant osteogenic differentiation of tendon-derived stem cells (TDSCs) is an effective strategy for treating traumatic heterotopic ossification (HO) in tendons.

Purpose

This study aimed to investigate whether eupalinolide A (EA) could prevent tendon HO progression by suppressing the osteogenic differentiation of TDSCs.

Methods

The effects of EA on osteogenic differentiation and key signaling pathways in TDSCs were examined in vitro to assess its therapeutic potential and elucidate the underlying molecular mechanisms. Furthermore, the therapeutic efficacy of EA was evaluated in a mouse model of trauma-induced tendon HO via local injection therapy.

Results

EA significantly inhibited the osteogenic differentiation of TDSCs by targeting YAP in vitro. Specifically, EA facilitated the recruitment of E3 ubiquitin ligase HECW1, which mediated K27-linked polyubiquitination of YAP, leading to its degradation via the TOLLIP-mediated selective autophagy pathway. In vivo, EA mitigated trauma-induced tendon HO by inhibiting the YAP pathway.

Conclusions

EA could be a potential therapeutic agent for treating traumatic tendon HO. The therapeutic target HECW1 involved in YAP degradation via autophagy presents a new therapeutic avenue to attenuate the progression of traumatic tendon HO.

背景：目的：本研究旨在探讨 eupalinolide A（EA）是否能通过抑制 TDSCs 的成骨分化阻止肌腱异位骨化（HO）的进展：方法：在体外研究了EA对TDSCs成骨分化和关键信号通路的影响，以评估其治疗潜力并阐明其潜在的分子机制。此外，还通过局部注射疗法在创伤诱发肌腱HO的小鼠模型中评估了EA的疗效：结果：EA通过靶向YAP在体外明显抑制了TDSCs的成骨分化。具体而言，EA能促进E3泛素连接酶HECW1的招募，从而介导YAP的K27连接多泛素化，导致其通过TOLLIP介导的选择性自噬途径降解。在体内，EA通过抑制YAP通路减轻了创伤引起的肌腱HO：结论：EA可能是治疗创伤性肌腱HO的潜在药物。结论：EA可能是治疗创伤性肌腱HO的潜在药物，通过自噬参与YAP降解的治疗靶点HECW1为减轻创伤性肌腱HO的进展提供了新的治疗途径。

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引用次数: 0

Artemisitene induces apoptosis of breast cancer cells by targeting FDFT1 and inhibits the growth of breast cancer patient-derived organoids 青蒿素通过靶向 FDFT1 诱导乳腺癌细胞凋亡，并抑制乳腺癌患者衍生器官组织的生长。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-18 DOI: 10.1016/j.phymed.2024.156155

Dong Chen , Guangxin Li , Lianxiang Luo , Tengyu Lin , Xinyu Chu , Kangdi Liu , Tianli Lai , Yinglin Liao , Xian Lin , Jian Chen

Artemisitene (ATT) is a natural bioactive compound with anti-breast cancer activity. However, the direct target and clinical efficacy of ATT on breast cancer are still unclear. The current study aimed to identify the target protein and underlying mechanism of ATT in anti-breast cancer. Moreover, patient-derived organoids (PDOs) were employed to assess the clinical efficacy of ATT on breast cancer. Herein, molecular docking, molecular dynamics simulation, cellular thermal shift assay (CETSA) combined with Western blot, surface plasmon resonance (SPR) were applied to confirm the interactional target of ATT in breast cancer cells. Bioinformatics analysis, Western blot, flow cytometry, plasmid construction and lentivirus infection, chromatin immunoprecipitation (ChIP) assay, and quantitative real-time PCR (RT-qPCR) were performed to reveal the potential mechanism of ATT in treating breast cancer. PDOs were established to evaluate the clinical therapeutic efficiency of ATT on breast cancer. We found that ATT interacted with Farnesyl-diphosphate farnesyltransferase 1 (FDFT1) in breast cancer cells. Knockdown of FDFT1 induced NEDD4 expression and apoptosis in breast cancer cells. Overexpression of FDFT1 could rescue ATT-induced apoptosis, while interfering with FDFT1 expression decreased the level of RelA (NF-κB p65 subunit) in the nucleus in breast cancer cells. Knockdown of FDFT1 induced NEDD4 expression by regulating TNFR1/NF-κB pathway. Overexpression of FDFT1 could reverse the activation of ATT-induced TNFR1/NF-κB/NEDD4 pathway in breast cancer cells. Interestingly, the ChIP assay and RT-qPCR revealed that p65 could regulate NEDD4 transcription. Furthermore, ATT exhibited a broad-spectrum inhibitory effect on the growth of breast cancer PDOs with different pathological subtypes, and showed an excellent safety profile in comparison with that of conventional chemotherapy drugs. In summary, this work demonstrated that ATT targets FDFT1 to induce apoptosis of breast cancer cells through regulating TNFR1/NF-κB/NEDD4 pathway and suppresses breast cancer PDOs growth, which supported ATT as an effective and potential drug candidate for breast cancer treatment.

青蒿素（ATT）是一种具有抗乳腺癌活性的天然生物活性化合物。然而，青蒿素对乳腺癌的直接靶点和临床疗效仍不清楚。本研究旨在确定青蒿素抗乳腺癌的靶蛋白及其作用机制。此外，本研究还采用患者衍生的器官组织（PDOs）来评估ATT对乳腺癌的临床疗效。本文应用分子对接、分子动力学模拟、细胞热转移试验（CETSA）结合Western印迹、表面等离子体共振（SPR）等方法证实了ATT在乳腺癌细胞中的相互作用靶点。通过生物信息学分析、Western 印迹、流式细胞术、质粒构建和慢病毒感染、染色质免疫沉淀（ChIP）检测和实时定量 PCR（RT-qPCR），揭示了 ATT 治疗乳腺癌的潜在机制。我们建立了PDOs来评估ATT对乳腺癌的临床治疗效果。我们发现 ATT 与乳腺癌细胞中的二磷酸法尼基转移酶 1（FDFT1）相互作用。敲除 FDFT1 可诱导乳腺癌细胞中 NEDD4 的表达和凋亡。过表达FDFT1可挽救ATT诱导的细胞凋亡，而干扰FDFT1的表达可降低乳腺癌细胞核中RelA（NF-κB p65亚基）的水平。敲除 FDFT1 可通过调节 TNFR1/NF-κB 通路诱导 NEDD4 的表达。过表达 FDFT1 可逆转 ATT 诱导的 TNFR1/NF-κB/NEDD4 通路在乳腺癌细胞中的激活。有趣的是，ChIP 检测和 RT-qPCR 发现 p65 可以调控 NEDD4 的转录。此外，ATT 对不同病理亚型的乳腺癌 PDO 的生长具有广谱的抑制作用，与传统化疗药物相比，具有良好的安全性。综上所述，该研究表明 ATT 可通过调节 TNFR1/NF-κB/NEDD4 通路靶向 FDFT1 诱导乳腺癌细胞凋亡，并抑制乳腺癌 PDO 的生长，从而支持 ATT 成为治疗乳腺癌的有效和潜在候选药物。

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引用次数: 0

Effects of Clausena lansium leaves volatile oil emulsion against Staphylococcus aureus in mice via autophagy modulation. 香叶挥发油乳液通过调节自噬作用对小鼠体内金黄色葡萄球菌的影响

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-17 DOI: 10.1016/j.phymed.2024.156159

Lu-Ping Tang, Yan-Na Guo, Rui-Wei Mou, Shao-Shan Liang, Meng-Han Lu, Yong-Ming He

Background: Volatile oil from fresh Clausena lansium (Lour.) Skeels (Rutaceae) (common name Wampee) has been previously extracted by our group from fresh C. lansium leaf and its components were qualitative and quantitatively analyzed by GC-MS. It altered the cell membrane permeability of Staphylococcus aureus and reduced the levels of inflammation factors. However, previous in vivo reports on the anti-inflammatory and the antibacterial properties against S. aureus are scarce.

Hypothesis/purpose: To evaluate the protective in vivo effects of Wampee leaves volatile oil emulsion (WVOE) against S. aureus-induced pneumonia and elucidate the underlying mechanisms of action.

Methods: Wild-type and nucleotide oligomerization domain-like receptor protein 3 (NLRP3)-deficient mice were used. Mice were treated with WVOE for 7 days, and subjected to S. aureus infection by nasal administration on day 5 for 48 h. Lung and blood samples were collected for assessing lung damage and protein abundance. Lung bacterial load, wet/dry ratio, C-reactive protein (CRP) levels, inflammatory cytokines secretion, and lung histopathological injury were examined.

Results: WVOE effectively reduced lung bacterial load, wet/dry ratio, and CRP levels increased following S. aureus infection in mice. WVOE decreased the secretion of inflammatory cytokines (IL-6 and TNF-α) and lung histopathological injury, and suppressed the NF-κB pathway and NLRP3 inflammasome activation. NLRP3^-/- mice exhibited lower bacterial load, inflammatory cytokines levels and lung histopathological injury compared with mice in the model group. Autophagy was enhanced in S. aureus-infected mice, with higher levels of p-mTOR, Beclin-1, Atg 16L1, Atg7, p62, p-p62, and LC3II. WVOE administration restored the autophagy related protein levels. Autophagy was inhibited in NLRP3^-/- mice of the control and model groups, and WVOE lost its ability to regulate the autophagy-related proteins enhanced upon S. aureus infection. WVOE enhanced autophagy to alleviate lung injury by inhibiting NLRP3-targeted P62. Furthermore, compared with the 3MA + model group, WVOE reduced the bacterial load and CRP levels, pulmonary septa narrowing, and congestion. NLRP3 protein expression increased due to autophagy inhibition. WVOE exerted a pharmacological effect through the PI3K/AKT/mTOR pathway.

Conclusion: WVOE regulated the PI3K/AKT/mTOR pathway and enhanced autophagy, with NLRP3 playing a crucial role. WVOE exhibited protective effects against S. aureus-induced pneumonia by inhibiting NLRP3 inflammasome activation and enhancing autophagy. These findings expand the understanding of antibacterial properties of WVOE, and provide novel insights into the therapeutic potential of WVOE in managing S. aureus infections.

背景：本研究组曾从新鲜的 C. lansium (Lour.) Skeels（芸香科）（俗名 Wampee）叶中提取出挥发油，并用气相色谱-质谱对其成分进行了定性和定量分析。结果表明，兰西叶能改变金黄色葡萄球菌细胞膜的通透性，降低炎症因子的水平。假设/目的：评估万皮叶挥发油乳剂（WVOE）对金黄色葡萄球菌引起的肺炎的体内保护作用，并阐明其潜在的作用机制：方法：使用野生型小鼠和核苷酸寡聚化结构域样受体蛋白 3（NLRP3）缺陷小鼠。收集肺部和血液样本以评估肺部损伤和蛋白质丰度。对肺部细菌量、干湿比、C反应蛋白（CRP）水平、炎症细胞因子分泌和肺组织病理学损伤进行了检测：结果：WVOE 有效降低了小鼠肺部细菌量、干湿比和金黄色葡萄球菌感染后增加的 CRP 水平。WVOE 降低了炎性细胞因子（IL-6 和 TNF-α）的分泌和肺组织病理学损伤，抑制了 NF-κB 通路和 NLRP3 炎性体的激活。与模型组小鼠相比，NLRP3-/-小鼠的细菌负荷、炎症细胞因子水平和肺组织病理学损伤均较低。金黄色葡萄球菌感染小鼠的自噬作用增强，p-mTOR、Beclin-1、Atg 16L1、Atg7、p62、p-p62 和 LC3II 水平升高。服用 WVOE 可恢复自噬相关蛋白的水平。在对照组和模型组中，NLRP3-/-小鼠的自噬受到抑制，WVOE失去了调节金黄色葡萄球菌感染后自噬相关蛋白增强的能力。WVOE 通过抑制 NLRP3 靶向蛋白 P62 来增强自噬作用，从而减轻肺损伤。此外，与 3MA + 模型组相比，WVOE 降低了细菌负荷和 CRP 水平、肺隔狭窄和充血。自噬抑制导致 NLRP3 蛋白表达增加。WVOE通过PI3K/AKT/mTOR途径发挥药理作用：结论：WVOE能调节PI3K/AKT/mTOR通路并增强自噬，其中NLRP3起着关键作用。WVOE通过抑制NLRP3炎性体的激活和增强自噬作用，对金葡菌诱发的肺炎具有保护作用。这些发现拓展了人们对 WVOE 抗菌特性的认识，并为 WVOE 在控制金黄色葡萄球菌感染方面的治疗潜力提供了新的见解。

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引用次数: 0

A multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of Tongmai Yangxin pill on ventricular remodeling in acute anterior STEMI patients after primary PCI. 一项多中心、随机、双盲、安慰剂对照试验，评估通麦养心丸对初级 PCI 后急性前 STEMI 患者心室重构的影响。

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine

Pub Date : 2024-10-17 DOI: 10.1016/j.phymed.2024.156133

Yongxia Wang, Xinlu Wang, Jianru Wang, Chunjie Li, Guoan Zhao, Chaoyang Zheng, Xiaochi Shi, Xiaolong Wang, Ke Wang, Wei Wu, Zhenpeng Zhang, Hengliang Liu, Hao Zhou, Fei Lin, Xiaofen Ruan, Jia Zhao, Shichao Wang, Xingyuan Li, Shanshan Nie, Xiaohui Li, Jinyu Huang, Heng Sun, Linping Pian, Wei Xing, Bin Li, Rui Yu, Zuoying Xing, Yankun Song, Yutian Luo, Duolao Wang, Yanming Xie, Junhua Zhang, Mingjun Zhu

Background: Acute ST-segment elevation myocardial infarction (STEMI) is a severe form of coronary heart disease and a leading cause of mortality and morbidity. This can mainly be ascribed to adverse ventricular remodeling (VR). However, the efficacy of existing treatment strategies for STEMI is not entirely satisfactory. Tongmai Yangxin Pill (TMYX), a patented traditional Chinese medicine (TCM), has been approved for treating various cardiovascular diseases.

Purpose: The purpose was to assess the effect of TMYX on VR in acute STEMI patients undergoing primary percutaneous coronary intervention (PPCI).

Study design: A multicenter, randomized, double-blinded, and placebo-controlled trial conducted across 11 hospitals in China.

Method: A total of 270 patients with acute anterior STEMI, undergoing PPCI within 10 days of symptom onset were enrolled and randomly assigned to receive either a placebo or TMYX, in addition to guideline-directed treatments for STEMI. The primary endpoint was a change in left ventricular end-diastolic volume index (LVEDVI) at 12 weeks.

Result: Among the 270 randomized patients, 218 (TMYX: 109 and placebo: 109) were included in the per-protocol analysis. At 4 and 12 weeks, TXMY significantly improved LVEDVI than the placebo group ([-2.17(-9.24, 8.28) vs. 3.76(-2.38, 11.48), p < 0.05] and [-1.17 (-12.19, 12.88) vs. 4.46 (-2.89, 11.99), p < 0.05]). Changes in left ventricular end-diastolic volume (LVEDV) at 4 weeks were superior in the TMYX group than the placebo group (-4.37 (-17, 13.99) vs. 7.41 (-4.56, 21.79), p < 0.05). Cardiac magnetic resonance imaging (CMRI) showed that left ventricular ejection fraction (LVEF) was significantly greater in the TMYX group than in the placebo group at 4 weeks. There were no statistically significant differences between groups for left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), 6 min walking distance (6MWD), and major adverse cardiac and cerebrovascular events (MACCEs) (p > 0.05).

Conclusion: TMYX, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly delayed VR in patients with acute anterior STEMI undergoing PPCI within 10 days of symptom onset.

背景：急性 ST 段抬高型心肌梗死（STEMI）是冠心病的一种严重形式，也是导致死亡和发病的主要原因。这主要归因于不良的心室重塑（VR）。然而，现有的 STEMI 治疗策略的疗效并不完全令人满意。通脉养心丸（TMYX）是一种专利中药，已被批准用于治疗各种心血管疾病。研究目的：旨在评估通脉养心丸对接受经皮冠状动脉介入治疗（PPCI）的急性 STEMI 患者心室重构的影响：研究设计：一项在中国11家医院开展的多中心、随机、双盲和安慰剂对照试验：共纳入 270 名急性前 STEMI 患者，他们在症状出现后 10 天内接受了 PPCI，除了接受 STEMI 指南指导的治疗外，还被随机分配接受安慰剂或 TMYX。主要终点是12周时左心室舒张末期容积指数（LVEDVI）的变化：结果：在270名随机患者中，218名（TMYX：109名，安慰剂：109名）纳入了按协议分析。在4周和12周时，TXMY对LVEDVI的改善明显优于安慰剂组（[-2.17(-9.24, 8.28) vs. 3.76(-2.38, 11.48)，p < 0.05]和[-1.17 (-12.19, 12.88) vs. 4.46 (-2.89, 11.99)，p < 0.05]）。4周时左心室舒张末期容积（LVEDV）的变化，TMYX组优于安慰剂组（-4.37（-17，13.99）vs 7.41（-4.56，21.79），P <0.05）。心脏磁共振成像（CMRI）显示，4周时，TMYX组的左心室射血分数（LVEF）明显高于安慰剂组。在左心室收缩末期容积（LVESV）、左心室收缩末期容积指数（LVESVI）、6 分钟步行距离（6MWD）和主要心脑血管不良事件（MACCEs）方面，组间差异无统计学意义（P > 0.05）：结论：TMYX 作为 STEMI 指南指导疗法的辅助疗法，可显著延迟在症状出现后 10 天内接受 PPCI 的急性前 STEMI 患者的 VR。

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引用次数: 0