Gastric cancer (GC) is a common cancer and causes severe deaths worldwide, while the current treatment cannot meet its medical needs. Timosaponin AIII (Timo AIII) is an active component isolated from Anemarrhena asphodeloides Bunge, which is a well-known Chinese Materia Medica and has multiple pharmacological activities, particularly anti-cancer activities. In this study, zebrafish and human GC cell models are utilized for the evaluation of the anti-GC activity of Timo AIII by integrating bioinformatics analysis and classical pharmacological approaches. We found that Timo AIII significantly decreased the GC growth in zebrafish. In human GC cell BGC-823, Timo AIII suppressed the cell viability, proliferation and migration in concentration- and time-dependent manners. Timo AIII blocked cell-cycle progression and promoted cell apoptosis. Moreover, Timo AIII activated programmed cell death (PCD), including apoptosis, ferroptosis, necroptosis and autophagy. The pharmacological inhibition of these processes and PI3K/Akt/MAPKs signaling by their specific inhibitors could partially abolish the anti-GC effect of Timo AIII. For the mechanistic study, the bioinformatics analysis revealed that p53 might be the central downstream effector of Timo AIII, promoting PCD. Timo AIII increased the intracellular protein levels of MEK, acetyl-p53 and p300 and the phosphorylation levels of Akt and MEK in BGC-823 cells, while it decreased the protein levels of p53 and Akt and the phosphorylation levels of ERK. In conclusion, Timo AIII presents anti-GC activity and the underlying mechanism is likely to be the activation of PCD via p300/acetyl-p53 and Akt/MEK/ERK signaling.

Cancer cachexia, which is characterized by weight loss and muscle wasting with or without fat depletion, is a complex syndrome that commonly seen in patients with advanced cancer. The underlying pathophysiological mechanisms of cancer cachexia are involved in systemic inflammation, abnormal metabolism and multiple organs dysfunction. Cancer cachexia greatly impacts the outcomes of the cancer patients while there is still lack specific and satisfied diagnosis and treatment approach yet. Apart from early diagnosis and novel biomarker discovery, patient-centered tailored multimodal intervention might be useful for improvement of quality of life and treatment efficacy. The natural products, which present multiple ingredients and pharmacological activities, are promising, in particular these derived from traditional medicines, for the treatment of cancer cachexia combined with current multimodal interventions. However, most of the evidence are from pre-clinical studies, high-quality clinical investigations are still needed for further validation.

Angiogenesis is a crucial process in ischemia diseases like coronary heart disease, stroke and wound healing. Panasenoside (PSS) is a flavonoid glycoside ioslated from Chinese Materia Medica GINSENG RADIX ET RHIZOMA which has been demonstrated with multiple biological activities. However, the pharmacological activity of PSS and the underlying mechanism are still unclear. We found that PSS promoted sub-intestinal vessel plexus (SIVs) growth in zebrafish. PSS ameliorated vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor II (VRI)-induced deficiency of intersegmental vessels (ISVs) in a concentration dependent manner by downregulation of mRNA expression of VEGF receptors, including Kdr/VEGFR-2 (kdr), VEGFR-1 (flt1), and Kdr-like/VEGFR-2 (kdrl), and up-regulation of VEGF (vegfaa). The angiogenesis effect of PSS on VRI-induced ISVs deficiency was suppressed by PI3K, AKT, MEK, ERK, P38, Sirtuin 1 (SIRT1), Nuclear factor erythroid-2-related factor 2 (NRF2) and Nicotinamide N-methyl transferase (NNMT) inhibitors. Activation of NRF2, SIRT1 and MNA significantly restored VRI-induced ISVs insufficiency. In addition, PSS protected against VRI-induced tube formation deficiency in human umbilical vascular endothelial cells (HUVECs). SIRT1, NRF2 and NNMT inhibitors or siRNA eliminated PSS promoting vascular endothelial cell tube formation. PSS also prevented SIRT1, NRF2 and NNMT inhibitors-induced vascular endothelial cell senescence. Furthermore, PSS upregulated the protein expression level of SIRT1 and downregulated its downstreams P53 and PGC-1α in HUVECs with high potence of activating SIRT1 by binding with its active domine. In conclusion, PSS presented pro-angiogenesis effect by mitigating vascular endothelial cell ageing and the underlying mechanisms were involved in the PI3K/AKT/MAPKs, SIRT1/NRF2 and NNMT/MNA signaling pathway with SIRT1 acting as a key regulator. We identified the pro-angiogenesis and anti-vascular endothelial cell ageing effects of PSS for the first time, and PSS is a promising drug candidate for treating vascular deficiency associated diseases.

BACKGROUND:Doxorubicin (DOX) is an effective first-line chemotherapeutic agent used to treat various kinds of cancers. The most serious side effect of DOX is its irreversible cardiotoxicity. Salviae Miltiorrhizae Radix et Rhizoma, which is the dry root of the natural plant Salvia miltiorrhiza and is named "Danshen" in Chinese, is a widely used Chinese Materia Medica for the treatment of cardiovascular and cerebrovascular disorders in traditional Chinese medicine. OBJECTIVE:This study aims to review the potential protective effect of Danshen against DOX-induced cardiotoxicity (DIC). METHODS:A comprehensive systematic search was performed in various electronic databases, including Web of Science, PubMed and Scopus up to July 2025 according to the PRISMA guideline. Two hundred and sixty studies were screened in accordance with a predefined set of inclusion and exclusion criteria. Thirty-five eligible articles were finally included in the current systematic review. All the characteristics and underlying mechanisms of Danshen protecting against DIC were summarized. Additionally, all the Danshen-related clinical trials evaluating their treatment effects for cardiovascular and cerebrovascular diseases were extracted and summarized from the registration databases of clinical trials. RESULTS:Danshen ameliorated DOX-caused pathological alterations of cardiac cells/tissue, decrease of surviving cardiomyocytes, body weight, heart weight and the ratio of heart to body weight, and increase of mortality. Eleven active ingredients and derivatives of Danshen including tanshinone IIA, sodium tanshinone IIA sulfonate, tanshinone I, salvianolic acid A, salvianolic acid B, salvianolic acid C, cryptotanshinone, ferulic acid, danshensu, dihydrotanshinone I and diethyl blechnic, were identified with potential protective effects against DIC in vitro and in vivo as well as the eight extracts and formulas of S. miltiorrhiza including salvianolic acids, S. miltiorrhiza aqueous extract, Compound DanShen Dripping Pill, Danhong injection, Qiliqiangxin, herbal formula B307, Qishen granule and Ershen Zhenwu Decoction. The underlying mechanisms were associated with the Danshen's multiple pharmacological activities, such as anti-apoptosis, anti-oxidative stress, anti-inflammation, anti-mitochondrial dysfunction, maintenance of intracellular Ca2+ homeostasis and regulating autophagy by targeting PI3K/Akt/JNK/GSK-3β/mPTP, MAPKs, Bax/Bcl-xL/Caspases, Keap1-Nrf2/NQO1/GPX4, SIRT3/Ac-SOD2, NF-κB, TGF-β/Smads, RhoA/ROCK, AMPK/PGC-1α/NRF-1/TFAM, miR-30a/Beclin1/LAMP1 signaling pathways. Moreover, Danshen-related clinical trials mainly focused on the treatment of cardiovascular and cerebrovascular diseases without clinical trials specifically for the evaluation of Danshen-related agents for the treatment of DIC. CONCLUSION:Danshen significantly alleviates DIC according to the previous experimental studies. But no previous study is implemented under cancer condition. A well-designed clinical study that targets certain cancer is an urgent requirement for the verification of Danshen's clinical efficacy in the future, in particular clarifying without affecting the anti-cancer efficacy of DOX.

Background/Objectives: Homocysteine (Hcy) and iron are factors co-related with the progression of cardiovascular diseases. The vascular endothelium is an important barrier for physiological homeostasis, and its impairment initiates cardiovascular injury. However, the mechanism underlying Hcy-caused vascular endothelial cell injury and the participation of iron are not fully elucidated. This study aims to investigate the Hcy-induced vascular endothelial injury and iron metabolism dysfunction as well as the underlying molecular mechanism. Methods: Human umbilical vein endothelial cells (HUVECs) were employed as the experimental model to examine the Hcy-induced endothelial injury and its underlying mechanism via various biochemical assays. Results: Hcy suppressed the cell viability and proliferation and caused cell death in a concentration-dependent manner. Hcy induced cell cycle arrest, apoptosis, and autophagy as well as impairment of intracellular energy metabolism. Hcy disrupted the intracellular antioxidant system and mitochondrial function by increasing intracellular ROS, MDA and mitochondrial content, and decreasing the SOD activity and mitochondrial membrane potential. Hcy significantly reduced the GSH-Px activity along with the accumulation of intracellular GSH in a concentration-dependent manner. Ferroptosis inhibitors, Ferrostatin-1 (Fer-1), and Deferoxamine (DFO) significantly decreased the Hcy-caused cytotoxicity accompanied by a reduction in dysregulated mitochondria content, but only DFO ameliorated the elevation of intracellular ROS, and neither Fer-1 nor DFO affected the Hcy-caused reduction in intracellular ATP. In addition, Hcy decreased the intracellular concentration of iron, and supplementing Hcy with various concentrations of Fe3+ increased the cell viability and decreased the LDH release in a concentration-dependent manner. Hcy dramatically decreased the mRNA expression level of transferrin receptor while increasing the mRNA expression levels of transferrin, ferritin light chain, ferritin heavy chain, ferroportin, and SLC7A11. Moreover, Hcy suppressed the protein expression of phospho-Akt, phospho-mTOR, Beclin-1, LC3A/B, Nrf2, HO-1, phospho-MEK1/2, phospho-ERK1/2, and Caspase-3 in concentration- and time-dependent manners. Conclusions: Hcy-induced vascular endothelial injury is likely to be associated with apoptosis and autophagy, but not ferroptosis. The key underlying mechanisms are involved in the disruption of the intracellular antioxidant system and iron metabolism via regulation of PI3K/Akt/mTOR, MAPKs, Nrf2/HO-1, and iron metabolism.

Heart failure is a life-threatening cardiovascular disease and characterized by cardiac hypertrophy, inflammation and fibrosis. The traditional Chinese medicine formula Qiangxinyin (QXY) is effective for the treatment of heart failure while the underlying mechanism is not clear. This study aims to identify the active ingredients of QXY and explore its mechanisms protecting against cardiac hypertrophy. We found that QXY significantly protected against isoproterenol (ISO)-induced cardiac hypertrophy and dysfunction in zebrafish. Eight compounds, including benzoylmesaconine (BMA), atractylenolide I (ATL I), icariin (ICA), quercitrin (QUE), psoralen (PRN), kaempferol (KMP), ferulic acid (FA) and protocatechuic acid (PCA) were identified from QXY. PRN, KMP and icaritin (ICT). an active pharmaceutical ingredient of ICA, prevented ISO-induced cardiac hypertrophy and dysfunction in zebrafish. In H9c2 cardiomyocyte treated with ISO, QXY significantly blocked the calcium influx, reduced intracellular lipid peroxidative product MDA, stimulated ATP production and increased mitochondrial membrane potential. QXY also inhibited ISO-induced cardiomyocyte hypertrophy and cytoskeleton reorganization. Mechanistically, QXY enhanced the phosphorylation of Smad family member 2 (SMAD2) and myosin phosphatase target subunit-1 (MYPT1), and suppressed the phosphorylation of myosin light chain (MLC). In conclusion, PRN, KMP and ICA are the main active ingredients of QXY that protect against ISO-induced cardiac hypertrophy and dysfunction largely via the blockage of calcium influx and inhibition of mitochondrial dysfunction as well as cytoskeleton reorganization.

肿瘤与抑郁是严重困扰人类的两大类疾病,临床上肿瘤和抑郁常相伴发生,两者存在复杂的相互促进关系,二者共病造成了巨大的社会和经济负担,但目前尚缺乏系统的肿瘤抑郁共病研究平台.田建辉"调神治癌"课题组通过联合上海市精神卫生中心开展肿瘤相关精神心理问题的临床与基础研究探索,成功构建了"调神治癌"的临床和基础实验综合研究平台,以期通过专业详实的研究,丰富心理社会肿瘤学科内容,从神经-内分泌-免疫环路系统探索肿瘤防治的"生物-心理-社会"医学模式.

Homocysteine (Hcy) is one of the independent risk factors of cardiovascular disease. Sodium tanshinone IIA sulfonate (STS) is a hydrophilic derivate of tanshinone IIA which is the main active constitute of Chinese Materia Medica Salviae Miltiorrhizae Radix et Rhizoma, and exhibits multiple pharmacological activities. However, whether STS could prevent from Hcy-induced endothelial cell injury is unknown.We found that STS dramatically reversed Hcy-induced cell death concentration dependently in human umbilical vascular endothelial cells (HUVECs). STS ameliorated the endothelial cell cycle progression, proliferation and cell migratory function impaired by Hcy, which might be co-related to the inhibition of intracellular oxidative stress and mitochondrial dysfunction. STS also elevated the phosphorylation of AKT and MAPKs and protein expression of sirtuin1 (SIRT1), NRF2 and HO-1 which were suppressed by Hcy. The protective effect of STS against Hcy-induced endothelial cell toxicity was partially attenuated by PI3K, AKT, MEK, ERK, SIRT1, NRF2 and HO-1 inhibitors. Besides, knockdown of SIRT1 by its siRNA dramatically decreased the endothelial protective effect of STS accompanied with suppression of SIRT1, NRF2, HO-1 and phosphorylated AKT. The activation of AKT or NRF2 partially reversed SIRT1-knockdown impaired cyto-protective effect of STS against Hcy-induced cell injury. Furthermore, STS prevented from Hcy-induced intracellular nicotinamide N-methyltransferase (NNMT) reduction along with elevation of intracellular methylnicotinamide (MNA), and MNA enhanced STS protecting against Hcy induced endothelial death. Knockdown of NNMT reduced the protective effect of STS against Hcy induced endothelial cell injury.Collectively, STS presented potent endothelial protective effect against Hcy and the underlying molecular mechanisms were involved in the suppression of intracellular oxidative stress and mitochondria dysfunction by activation of AKT/MAPKs, SIRT1/NRF2/HO-1 and NNMT/MNA signaling pathways.

研究显示约40％因胸痛行冠脉造影术的患者未见明显狭窄,其心绞痛症状可能由于冠状动脉微血管病变引起,冠状动脉微血管疾病(Coronary microvascular disease,CMVD)主要由微血管系统的结构异常、血管舒缩功能障碍及自主神经功能紊乱导致心肌缺血心绞痛.同时,CMVD对糖尿病、肾脏疾病、风湿免疫性疾病等诸多疾病的临床表现及预后有重要的影响.尽管已了解到CMVD在多种情况下的病理生理机制,但到目前为止,还没有针对性的特殊治疗方法,因此,加强对CMVD的研究,并为此类患者制定相关的个性化治疗,应是未来缺血性疾病治疗的趋势.

目的 建立一种简单易行、重复性好的斑马鱼缓慢性心律失常模型及其评价体系.方法 选用24 hpf的野生型和心脏标记绿色荧光蛋白的转基因斑马鱼,分别用不同浓度的维拉帕米、普罗帕酮、美托洛尔、胺碘酮、美西律干预48 h,检测斑马鱼生存率、心率、心博量、心输出量、射血分数、心室舒张期和收缩期面积差值、静脉窦与动脉球(SV-BA)间距等心脏功能和心脏毒性评价指标.结果 药物毒性的评价中,半数致死浓度(IC50)排序为普罗帕酮

CYP17 (17α-hydroxylase-17,20-lyase; also P450c17 or P45017α) catalyses the17α-hydroxylation of progestogens and the subsequent acyl-carbon cleavage of the 17α-hydroxylated products (lyase activity) in the biosynthesis of androgens. The enzyme also catalyses another type of acyl-carbon cleavage (direct cleavage activity) in which the 17α-hydroxylation reaction is by-passed. Human CYP17 is heavily dependent on the presence of the membrane form of cytochrome b5 for both its lyase and direct cleavage activities. In the present study it was found that substitution of human CYP17 amino acids, Arg347, Arg358 and Arg449, with non-cationic residues, yielded variants that were impaired in the two acyl-carbon bond cleavage activities, quantitatively to the same extent and these were reduced to between 3 and 4% of the wild-type protein. When the arginines were replaced by lysines, the sensitivity to cytochrome b5 was restored and the acyl-carbon cleavage activities were recovered. All of the human mutant CYP17 proteins displayed wild-type hydroxylase activity, in the absence of cytochrome b5. The results suggest that the bifurcated cationic charges at Arg347, Arg358 and Arg449 make important contributions to the formation of catalytically competent CYP17·cytochrome b5 complex. The results support our original proposal that the main role of cytochrome b5 is to promote protein conformational changes which allow the iron-peroxo anion to form a tetrahedral adduct that fragments to produce the acyl-carbon cleavage products.

目的 构建经中医药治疗的非小细胞肺癌(NSCLC)患者预后的多因素评估模型.方法 回顾性收集至少经过6个月中医药治疗的NSCLC患者的临床资料,包括性别、年龄、免疫功能、TNM分期、治疗方式、无进展生存期(PFS)、是否发生复发或转移等.根据制定的外周免疫评分标准评价患者的免疫功能,并对患者外周免疫评分、性别、年龄、临床分期与是否复发或转移进行相关性分析;采用单因素Cox回归分析外周免疫评分与PFS之间的关系.将纳入病例分为建模组和验证组,分别采用单因素与多因素Cox回归分析年龄、性别、外周免疫评分、TNM分期、治疗方式与患者是否发生复发或转移的关系,据此建立列线图预测模型,分析其一致性系数(C-index),并以受试者工作特征曲线(ROC)下面积(AUC)和校准图来验证模型的准确性.结果 共纳入175例患者,根据外周免疫评分将患者分为3组,其中免疫低下(＜0分)组123例(70.29％)、免疫正常(=O分)组24例(13.71％)、免疫亢进(＞0分)组28例(16.00％).相关性分析显示,外周免疫评分与患者是否复发或转移呈负相关(P=0.008,r=-0.201),而临床分期、性别、年龄等因素与患者是否复发或转移无相关性;免疫正常组的PFS最长,免疫低下组的PFS最短.单因素分析显示,性别、治疗方式、TNM分期、外周免疫评分是影响患者是否复发或转移的潜在预测因素(P＜0.1);多因素分析显示,性别、治疗方式、TNM分期、外周免疫评分是影响患者是否复发或转移的独立因素(P＜0.05).建立列线图预测模型,建模组、验证组的C-index分别为0.779、0.718,建模组ROC曲线显示1年、3年AUC分别为0.831、0.798,验证组ROC曲线显示1年、3年AUC分别为0.542、0.649.结论 以性别、TNM分期、外周免疫评分、治疗方式为因素建立的模型可以预测经中医药治疗后的NSCLC患者的预后,其中外周免疫评分可作为评估预后的独立因素.

目的 观察山海丹颗粒对气虚血瘀型老年高血压患者的临床研究.方法 本次临床试验共选取60例老年高血压(气虚血瘀证)患者,按1:1的比例随机分为治疗组和对照组.对照组予口服长效二氢吡啶类钙拮抗剂和安慰剂,治疗组予口服长效二氢吡啶类钙拮抗剂和山海丹颗粒,12周后观察动态血压(ABPM)指标、动态心电图指标、中医症候积分、血脂四项.结果 治疗12周后,治疗组的24h动态收缩压、脉压、收缩压负荷、SDNN及中医证候积分与治疗前比较,差异有统计学意义(P<0.05),治疗组疗效优于对照组(P<0.05).在血脂方面,治疗组与对照组治疗前后比较,差异均无统计学意义(P>0.05).结论 山海丹颗粒对气虚血瘀型老年高血压患者的治疗,能够降低收缩压、脉压、收缩压血压负荷、心率变异性指标,改善临床症状,且安全可行.

肝癌与抑郁可分别归属于肝积与郁证,二者病位均以肝为主,常相互影响.原发性肝癌患者常并发不同程度的抑郁.肝积病机主要为肝气郁结,邪毒瘀滞;郁证病机主要为气机不畅,气血郁滞.二者均可影响全身气血通畅,导致枢机不利.临证治疗肝癌不应只立足于消癥散结、攻毒扶正,而忽略肝癌患者常伴发抑郁,当以少阳为枢,调理全身气机,方可气血和顺、解郁安神、形神并调,提高疗效.

Inflammation response is a regulated cellular process and excessive inflammation has been recognized in numerous diseases, such as cardiovascular disease, neurodegenerative disease, inflammatory bowel disease, and cancer. Tribulus terrestris L. (TT), also known as Bai Jili in Chinese, has been applied in traditional Chinese medicine for thousands of years while its anti-inflammatory activity and underlying mechanism are not fully elucidated. Here, we hypothesize Tribulus terrestris L. extract (BJL) which presents anti-inflammatory effect, and the action mechanism was also investigated. We employed the transgenic zebrafish line Tg(MPO:GFP), which expresses green fluorescence protein (GFP) in neutrophils, and mice macrophage RAW 264.7 cells as the in vivo and in vitro model to evaluate the anti-inflammatory effect of BJL, respectively. The production of nitric oxide (NO) was measured by Griess reagent. The mRNA expression levels of inflammatory cytokines and inducible nitric oxide synthase (iNOS) were measured by real-time PCR, and the intracellular total or phosphorylated protein levels of NF-κB, Akt, and MAPKs including MEK, ERK, p38, and JNK were detected by western blot. We found that BJL significantly inhibited fin transection or lipopolysaccharide- (LPS-) induced neutrophil migration and aggregation in zebrafish in vivo. In mice macrophage RAW 264.7 cells, BJL ameliorated LPS-triggered excessive release of NO and transcription of inflammatory cytokine genes including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β). BJL also reduced the LPS-induced elevations of intracellular iNOS and nuclear factor kappa B (NF-κB) which mediate the cellular NO and inflammatory cytokine productions, respectively. Moreover, LPS dramatically increased the phosphorylation of Akt and MAPKs including MEK, ERK, p38, and JNK in RAW 264.7 cells, while cotreatment BJL with LPS suppressed their phosphorylation. Taken together, our data suggested that BJL presented potent anti-inflammatory effect and the underlying mechanism was closely related to the inhibition of Akt/MAPKs and NF-κB/iNOS-NO signaling pathways.

平滑肌细胞增殖是动脉粥样硬化(AS)早期的一个重要环节,许多内源性和外源性因素,包括脂质、葡萄糖、同型半胱氨酸、各种炎症趋化因子和细胞生长因子等,使得血管平滑肌细胞发生表型转换,加快细胞周期,从而导致血管平滑肌细胞的异常增殖.中医药在调节平滑肌细胞增殖疗效显著,从而能更好地延缓AS的发生和发展.文章主要综述平滑肌细胞增殖在AS中的作用,总结中医药调节平滑肌细胞增殖的分子作用机制,为中医药防治AS提供重要思路.

铁死亡是近年发现的一种细胞程序性死亡方式,以铁依赖性脂质活性氧增多为主要特点,与铁代谢异常及脂质过氧化等密切相关,其细胞死亡特征不同于传统的坏死、凋亡、自噬等细胞死亡形式,形态学上主要表现为线粒体缩小,细胞膜密度增大,但细胞核形态不变.该文介绍谷氨酸-胱氨酸转运受阻、氧化应激、铁代谢异常、脂质过氧化与铁死亡的关系,及铁死亡对心血管疾病(包括心肌梗死和动脉粥样硬化)的影响.

Hemorrhage stroke is a severe vascular disease of the brain with a high mortality rate in humans. Salvia miltiorrhiza Bunge (Danshen) is a well-known Chinese Materia Medica for treating cerebral vascular and cardiovascular diseases in traditional Chinese medicine. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, which is the main active ingredient of Danshen. In our previous study, we established a zebrafish model of cerebral hemorrhage and found that STS dramatically decreased both the hemorrhage rate and hemorrhage area, although the underlying mechanism was not fully elucidated. We conducted a transcriptome analysis of the protective effect of STS against atorvastatin (Ator)-induced cerebral hemorrhage in zebrafish using RNA-seq technology. RNA-seq revealed 207 DEGs between the Ator-treated group and control group; the expression levels of 53 DEGs between the Ator-treated group and control group were reversed between the STS + Ator-treated group and Ator-treated group. GO enrichment analysis indicated that these 53 DEGs encode proteins with roles in hemoglobin complexes, oxygen carrier activity and oxygen binding, etc. KEGG analysis suggested that these 53 DEGs were most enriched in three items, namely, porphyrin and chlorophyll metabolism, ferroptosis, and the HIF-1 signaling pathway. The PPI network analysis identified 12 hub genes, and we further verified that Ator elevated the mRNA expression levels of hemoglobin (hbae1.3, hbae3, hbae5, hbbe2, and hbbe3), carbonic anhydrase (cahz), HIF-1 (hif1al2) and Na+/H+ exchanger (slc4a1a and slc9a1) genes, while STS significantly suppressed these genes. In addition, we found that pharmacological inhibition of PI3K/Akt, MAPKs, and mTOR signaling pathways by specific inhibitors partially attenuated the protective effect of STS against Ator-induced cerebral hemorrhage in zebrafish, regardless of mTOR inhibition. We concluded that hemoglobin, carbonic anhydrase, Na+/H+ exchanger and HIF-1 genes might be potential biomarkers of Ator-induced cerebral hemorrhage in zebrafish, as well as pharmacological targets of STS. Moreover, HIF-1 and its regulators, i.e., the PI3K/Akt and MAPK signaling pathways, were involved in the protective effect of STS against Ator-induced cerebral hemorrhage. This study also provided evidence of biomarkers involved in hemorrhage stroke and improved understanding of the effects of HMG-COA reductase inhibition on vascular permeability and cerebral hemorrhage.

免疫检查点抑制剂(ICIs)显著改善恶性肿瘤患者生存时间,其产生的免疫相关不良反应发生率高,尤其心脏毒性因致死率高而被临床广泛关注.ICIs引起的心脏损伤贯穿肿瘤免疫治疗全程,临床表现为复杂多样,目前并无针对防治心脏损伤的特异性治疗,早期筛查和预防是防治关键,早期预测生物标记物的研发应用及新型免疫解毒剂的研发,可能为ICIs引起的心脏毒性防治提供更多新的思路.