Endothelial-mesenchymal transition (EndMT) is defined as an important process of cellular differentiation by which endothelial cells (ECs) are prone to lose their characteristics and transform into mesenchymal cells. During EndMT, reduced expression of endothelial adhesion molecules disrupts intercellular adhesion, triggering cytoskeletal reorganization and mesenchymal transition. Numerous studies have proved that EndMT is a multifaceted biological event driven primarily by cytokines such as TGF-β, TNF-α, and IL-1β, alongside signaling pathways like WNT, Smad, MEK-ERK, and Notch. Nevertheless, the exact roles of EndMT in complicated diseases have not been comprehensively reviewed. In this review, we summarize the predominant molecular regulatory mechanisms and signaling pathways that contribute to the development of EndMT, as well as highlight the contributions of a series of imperative non-coding RNAs in curbing the initiation of EndMT. Furthermore, we discuss the significant impact of EndMT on worsening vasculature-related diseases, including cancer, cardiovascular diseases, atherosclerosis, pulmonary vascular diseases, diabetes-associated fibrotic conditions, and cerebral cavernous malformation, providing the implications that targeting EndMT holds promise as a therapeutic strategy to mitigate disease progression.

At present, tumor metastasis still remains the leading contributor to high recurrence and mortality in cancer patients.There have been no clinically effective therapeutic strategies for treating patients with metastatic cancer.In recent years, a growing body of evidence has shown that the pre-metastatic niche (PMN) plays a crucial role in driving tumor metastasis.Nevertheless, a clear and detailed understanding of the formation of PMN is still lacking given the fact that PMN formation involves in a wealth of complicated communications and underlying mechanisms between primary tumors and metastatic target organs.Despite that the roles of numerous components including tumor exosomes and extracellular vesicles in influencing the evolution of PMN have been well documented, the involvement of cancer-associated fibroblasts (CAFs) in the tumor microenvironment for controlling PMN formation is frequently overlooked.It has been increasingly recognized that fibroblasts trigger the formation of PMN by virtue of modulating exosomes, metabolism and so on.In this review, we mainly summarize the underlying mechanisms of fibroblasts from diverse origins in exerting impacts on PMN evolution, and further highlight the prospective strategies for targeting fibroblasts to prevent PMN formation.

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors, and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor progression. Herein, we demonstrated that salvianic acid A (SAA) played a pivotal role in contributing to vascular normalization in the tumor-bearing mice, thereby improving delivery and effectiveness of the chemotherapeutic agent. SAA was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells (HUVECs) exposed to hypoxia. Mechanistically, SAA was inclined to directly bind to the glycolytic enzyme PKM2, leading to a dramatic decrease in endothelial glycolysis. More importantly, SAA improved the endothelial integrity via activating the β-Catenin/Claudin-5 signaling axis in a PKM2-dependent manner. Our findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

Ethnopharmacological relevance: Based on the notion of traditional Chinese medicine, the theory of invigorating the circulation of blood is a prominent treatment for cancer in clinic. Therefore, Salvia miltiorrhiza Bunge, as a representative of Chinese medicine of invigorating the circulation of blood, has been proved to be an effective medicinal herb for treating cancer.Aim of the study: To clarify the anti-cancer effect of Salvia miltiorrhiza Bunge aqueous extract (SMAE) on colo-rectal cancer (CRC) and investigate whether the therapeutic effect of SMAE was mediated by attenuating the infiltration of tumor-associated macrophages (TAMs) into the tumor microenvironment (TME). Materials and methods: High-performance liquid chromatography (HPLC) was used for determined the main compounds of SMAE. MC38 cells were subcutaneously injected into the mice to establish the mouse model of CRC. Tumor growth curve was detected by tumor volume measurement. The model group received distilled water irrigation once a day. SMAE-treated group received 5 g/kg or 10 g/kg SMAE once a day. Anti-PD-L1 treated group received 5 mg/kg anti-PD-L1 once every three days. Protein expression of Cox2 and PD-L1 was determined by Western blot assay. The secretion levels of PGE2, IL-1 & beta;, IL-6, MCP-1, and GM-CSF were evaluated through ELISA. The mRNA expression of CSF1, CCL2, CXCL1, CXCL2, and CXCL3 was measured by using RT-qPCR. Staining of Ki67, TUNEL and Caspase3 was used to investigate cell proliferation and apoptosis. Immu-nohistochemical staining was used to determine CD8+ T cell distribution. H & E staining was used to confirm histopathological changes. The expressions of F4/80 and CD68 were measured by flow cytometry to identify macrophages in tumors and lymph nodes. The number of CD8+ T cells and the expression of PD-1, IFN-& gamma;, and Granzyme B (GZMB) were determined by flow cytometry.Results: SMAE significantly retarded the growth of MC38 mouse colorectal cancer. SMAE strikingly inhibited the expression of Cox2 and impaired the secretion of PGE2 in tumors, contributing to the attenuated intra-tumoral infiltration of TAMs via Cox2/PGE2 cascade. Meanwhile, SMAE augmented anti-tumor immunity by the elevated proportion of IFN-& gamma;+ CD8+ T cells and GZMB+ CD8+ T cells, which decreased the tumor load. Furthermore, the combination of SMAE and anti-PD-L1 showed a higher therapeutic efficacy than either monotherapy in con-trolling tumor growth in MC38 xenograft model. Conclusions: SMAE attenuated the infiltration of TAMs into tumors and synergized with anti-PD-L1 to treat CRC via modulating Cox2/PGE2 cascade.

Numerous pharmacological effects of quercetin have been illustrated, including antiinflammation, antioxidation, and anticancer properties. In recent years, the antioxidant activity of quercetin has been extensively reported, in particular, its impacts on glutathione, enzyme activity, signaling transduction pathways, and reactive oxygen species (ROS). Quercetin has also been demonstrated to exert a striking antiinflammatory effect mainly by inhibiting the production of cytokines, reducing the expression of cyclooxygenase and lipoxygenase, and preserving the integrity of mast cells. By regulating oxidative stress and inflammation, which are regarded as two critical processes involved in the defense and regular physiological operation of biological systems, quercetin has been validated to be effective in treating a variety of disorders. Symptoms of these reactions have been linked to degenerative processes and metabolic disorders, including metabolic syndrome, cardiovascular, neurodegeneration, cancer, and nonalcoholic fatty liver disease. Despite that evidence demonstrates that antioxidants are employed to prevent excessive oxidative and inflammatory processes, there are still concerns regarding the expense, accessibility, and side effects of agents. Notably, natural products, especially those derived from plants, are widely accessible, affordable, and generally safe. In this review, the antioxidant and antiinflammatory abilities of the active ingredient quercetin and its application in oxidative stress-related disorders have been outlined in detail.

Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment (TME) through limiting immune cell infiltration into tumors. The defective vascular perfusion in tumors also impairs the delivery and efficacy of chemotherapeutic agents. Targeting abnormal tumor blood vessels has emerged as an effective therapeutic strategy to improve the outcome of chemotherapy and immunotherapy. In this study, we demonstrated that Salvianolic acid B (SalB), one of the major ingredients of Salvia miltiorriza elicited vascular normalization in the mouse models of breast cancer, contributing to improved delivery and response of chemotherapeutic agent cisplatin as well as attenuated metastasis. Moreover, SalB in combination with anti-PD-L1 blockade retarded tumor growth, which was mainly due to elevated infiltration of immune effector cells and boosted delivery of anti-PD-L1 into tumors. Mechanistically, tumor cell enhancer of zeste homolog 2 (Ezh2)-driven cytokines disrupted the endothelial junctions with diminished VE-cadherin expression, which could be rescued in the presence of SalB. The restored vascular integrity by SalB via modulating the interactions between tumor cells and endothelial cells (ECs) offered a principal route for achieving vascular normalization. Taken together, our data elucidated that SalB enhanced sensitivity of tumor cells to chemotherapy and immunotherapy through triggering tumor vascular normalization, providing a potential therapeutic strategy of combining SalB and chemotherapy or immunotherapy for patients with breast cancer.

目的 中医辨证中,丹参属活血化淤药,能够治疗瘀血症候,肿瘤作为癥积,属久瘀所致.基于丹参在心肌缺血、冠心病等疾病中发挥改善血管结构和促进血管灌注的作用,而肿瘤血管也存在结构异常和灌注不足的特征,本研究着眼于丹参主要活性成分丹酚酸B对于肿瘤微血管的调控,是否能促进肿瘤血管正常化.方法 选用健康雌性小鼠,注射乳腺癌细胞悬液,构建小鼠原位乳腺癌模型,分为模型组、丹酚酸B低剂量给药组、高剂量给药组.每3d测定肿瘤体积.实验周期结束,每组选择小鼠进行尾静脉注射TRITC-Dextran和Pimonidazole,考察肿瘤血管渗漏以及缺氧状况.利用扫描电子显微镜,观察不同组别内部血管内皮内衬.使用免疫荧光染色,测定CD31/α-SMA、CD31/NG2、CD31/VE-cadherin、CD31/claudin5等,分析肿瘤血管结构.使用小动物光声成像系统,考察肿瘤组织内部的血氧灌注情况,评判肿瘤血管功能.结果 与模型组相比,丹酚酸B低剂量和高剂量组均没有显著抑制肿瘤体积增长.免疫荧光结果显示,相比于模型组,丹酚酸B低剂量组和高剂量组能够显著的增加肿瘤血管成熟细胞覆盖率(P<0.05),并增强内皮细胞间的紧密连接(P<0.05).CD31/TRITC-Dextran结果显示,丹酚酸B能够显著降低肿瘤血管的渗漏,能够促进肿瘤血管结构的完整.Pimonidazole免疫荧光结果显示,丹酚酸B低剂量组和高剂量组的血管缺氧情况得到显著改善(P<0.05).活体成像系统结果显示一致结果,丹酚酸B能够促进肿瘤组织内部的血氧灌注.结论 丹酚酸B作为活血化瘀中药丹参中主要活性成分,能够通过促进肿瘤血管壁成熟细胞覆盖、加强肿瘤内皮细胞间紧密连接,从而改善血管渗漏,促进血管携氧功能.揭示其促进肿瘤血管正常化的作用.