ABSTRACT
Immune checkpoints (ICs) are immunosuppressive molecules expressed on immune cells, which can regulate immune cells' activation. Immune checkpoint inhibitors (ICIs) which can block the interaction of immune checkpoints and their ligands, improve the cytotoxic effect of the immune system on tumor cells. Immunotherapy such as employing ICIs has gradually become a conventional therapeutic strategy for cancer treatment. However, the low response rate and the emergence of drug resistance have seriously affected the clinical efficacy of ICIs. Reactive oxygen species (ROS) are electronic reduction products of active oxygen, as well as natural by-products of cell metabolism, which can be used as regulators of intercellular signals. Tumor microenvironment (TME) is often in the state of oxidative stress (OS), which is the imbalance between oxidative system and antioxidant system. ROS can affect the interaction with its ligands by regulating the expression and activity of immune checkpoints in TME, thus affecting the anti-tumor effect of immune cells. Accumulating studies have shown that ROS could regulate tumor immune checkpoints through several pathways. Due to different types and stages of tumor, it would be clinical beneficial to understand the mechanistic link of ROS on tumor immune checkpoint, and choose appropriate ROS regulators combined with immune checkpoint inhibitors to maximize anti-tumor effects. This article reviews the common metabolic sources and characteristics of ROS, the regulatory effect and mechanism of ROS on tumor immune checkpoints and its therapeutic application.
ABSTRACT
OBJECTIVE Our previous studies demonstrated that various ingredients from the traditional Chinese medicine (TCM) for promoting blood circulation and removing blood stasis, as exemplified by cryptotanshinone and salvi?anolic acid B, exerted striking effects on modulating angiogenesis and vascular permeability, which suggests that they may be effective in treating vascular leak-driven diseases (e.g. tumor, cerebral cavernous malformation and diabetic reti?nopathy). However, the lack of reliable and advanced technologies and models sets up difficult hurdles for better under?standing the role of TCM for promoting blood circulation and removing blood stasis. To this end, this study is to outline numerous cutting-edge platforms that can be utilized for exploring the function of TCM for promoting blood circulation and removing blood stasis in vascular leak-driven diseases. METHODS Two-photon laser scanning fluorescence micros?copy was used to observe the interactions between neutrophils and blood vessels in a real-time manner. Dynamic flow system was employed to mimic the in vivo behaviors of neutrophils. RIP1-Tag5 spontaneous pancreatic cancer model was used to study the function of tumor blood vessels. CCM2ECKO (deletion of CCM2 in endothelial cells) mice were employed to establish the cerebral cavernous malformation (CCM) animal model. Micro-computed tomography (micro-CT) was utilized to assess the CCM lesion. Müller cell-knockout mouse model was used to study the progression of dia?betic retinopathy. Vascular permeability in this model was assessed by fluorescein angiography. RESULTS The interac?tions between neutrophils and endothelial cells involve a series of complicated processes, including rolling, adhesion, intraluminal crawling and transmigration, which were all monitored in vivo by two-photon laser scanning fluorescence microscopy in a real-time manner. Dynamic flow system was capable of recapitulating the biological behaviors of neutro?phils in vitro. Tumor vascular function in particular vascular perfusion could be assessed in the RIP1-Tag5 spontaneous pancreatic cancer model. In terms of CCM studies, specific deletion of CCM2 in endothelial cells resulted in the initiation of CCM lesion. The size and number of CCM lesions could be visualized and quantified by micro-CT. Furthermore, the Müller cell-knockout mouse model was able to precisely reflect the clinical symptoms of diabetic retinopathy. Vascular leak could be monitored at different time points using fluorescein angiography. CONCLUSION An array of high technol?ogies and animal models can be used in investigating the occurrence and progression of multiple vascular leak-driven diseases. The pre-clinical and clinical studies of TCM for promoting blood circulation and removing blood stasis provide fundamental support for the application of the above-mentioned platforms, with the purpose of uncovering the scientific basis of TCM for promoting blood circulation and removing blood stasis.
ABSTRACT
The tumor contains abundant new vessels, which are unevenly distributed, irregular, and branch-disordered. Angiopoietin (Ang) and tyrosine kinase receptor Tie mediate stable maturation of angiogenesis. Ang1 mainly plays a role in promoting vascular stabilization, and Ang2 is highly expressed in vessels, which makes the structure and function of vessels abnormal. Leaked vessels provide opportunities for invasion and metastasis of circulating tumor cells. Targeting the Ang/Tie axis to correct the abnormal state of vessels and promote its normalization, combined with chemotherapy drugs or immunotherapy, play a synergistic effect against tumors. This article summarizes the role of Ang/Tie axis in tumor angiogenesis and metastasis, and it aims to provide new ideas and strategies for clinical treatment of tumors.
ABSTRACT
Objective:To investigate the mechanism of immunomodulatory effect of extracts from Salviae Miltiorrhizae Radix et Rhizoma and Sophorae Flavescentis Radix on immunodeficiency mice by immunosuppressive mouse model induced by cyclophosphamide. Method:An immunosuppressive animal model was established by cyclophosphamide. The blank group, the model group, the low,medium and high dose group of Salvia miltiorrhiza and Sophora extract groups (25,50,100 mg·kg-1), using mouse organs organ evaluation index using a mouse model to evaluate the carbon clearance phagocytic cell function using luminex to detect levels of relevant cytokines in serum and using flow to detect the number of helper T cells. Mouse mononuclear macrophage leukemia cells (RAW264.7) were cultured in vitro, and the effect of Salvia miltiorrhiza extracts on the proliferation of RAW264.7 cells were detected by methylthiazolyldiphenyl-tetrazolium bromide(MTT)assay. The proliferation was induced by Real-time PCR. The impact and its possible mechanisms are explored. Result:Compared with blank group, cyclophosphamide significantly inhibited liver index (PPPP-1 cyclophosphamide significantly inhibited the proliferation of mononuclear macrophage RAW264.7 (PPPPPPPP1 gene (CCND1) plays an anti-apoptotic role. Conclusion:The extracts from Salviae Miltiorrhizae Radix et Rhizoma and Sophorae Flavescentis Radix can counteract the immunosuppression caused by cyclophosphamide and enhance the immune function of animals.
ABSTRACT
Metastasis is the leading cause of cancer-related death. Pre-metastatic niche formation is the contributing factor of tumor metastasis. Traditional Chinese medicine (TCM) has a curative effect on metastasis and cancer recurrence in clinic. Modern pharmacological studies have shown that China meteria medica (CMM) can inhibit tumor metastasis by affecting tumor secretion, preventing recruitment of immune suppressive cells, and influencing anti-inflammatory polarization of matrix components in certain tissues. The regulation of CMM has the characteristics of multi-target, minor effect, and bidirection, It may play a integrate role with multi-factor and minor effect in regulating tumor-related gene expression or gene-gene combination by influencing regulating tumor-related functional gene networks. This is consistent with the research strategy of taking signal transduction dynamic network as drug target. Therefore, the prevention and treatment of pre-metastatic niche formation via TCM is an effective research strategy. This review summarizes the current research progress on regulating pre-metastasis niche by CMM, and provides a theoretical basis for the future research of TCM to prevent tumor metastasis.
ABSTRACT
Recently,research on microbes has been explored ex-plosively. Microbial-related studies have become the forefront of anti-cancer research. A large number of microorganisms are uni-versal in the viscera, skin, nose, mouth and reproductive sys-tem. Probiotics is a kind of microorganisms beneficial to human health. Although most studies have proven the tumor-promoting effects of bacterial flora,antitumor effects of probiotics have also been observed. Studies have confirmed that probiotics can pre-vent the onset of early stage colon cancer as well as non-colorec-tal cancer mainly via several mechanisms,such as adjustment of intestinal flora,regulation of immune response,anti-inflammato-inactivation of metabolic carcinogen, antioxidant and induction of tumor cell apoptosis. However,the specific underlying molecular mechanism still needs to be further studied. The latest studies on human have shown that intestinal microbiota combining with diet can alter the risk of special colorectal cancer. As a cancer chemoprevention strategy, more pre-clinical and clinical research are in need for the study of the effects of probiotics on cancer prevention and treatment.
ABSTRACT
In recent years,a large number of studies have shown that myeloid cells in tumor microenvironment play an important role in tumorigenesis and tumor progression.On one hand,myeloid cells can regulate human immune system;on the other hand,myeloid cells can influence tumor progression,metastasis and clinical treatments.In this review,we summarize the interaction between myeloid cells and tumors,discuss the effects of myeloid cells after recruited to tumor sites and its mechanisms,try to put forward clinical therapy targeting myeloid cells and provide references for the following research and clinical treatments.
ABSTRACT
Accumulative evidences have underpinned the nature candidates from Chinese medicine (CM), particularly CM served as blood activating and stasis resolving (BASR, Huoxue Huayu in Chinese) by targeting tumor-associated angiogenesis. However, recent experiment research on the therapeutic angiogenesis by BASR-CM attracts wide attention and discussion. This opinion review focused on the underlying link between two indications and anticipated that (1) BASR-CM might emphasize on a balanced multi-cytokines network interaction; (2) BASR-CM might address on the nature of diseases prior to differently affecting physiological and pathological angiogenesis; (3) BASR-CM might mainly act on perivascular cells, either promotes arteriogenesis by increasing arteriogenic factors in ischemic diseases, or simultaneously keep a quiescent vasculature to impede angiogenesis in tumor context.
Subject(s)
Animals , Humans , Angiogenesis Inhibitors , Chemistry , Therapeutic Uses , Antineoplastic Agents , Therapeutic Uses , Drugs, Chinese Herbal , Chemistry , Therapeutic Uses , Models, Biological , Neovascularization, Pathologic , Blood , Drug TherapyABSTRACT
Diseases with excessive angiogenesis such as tumors need to be treated with anti-angiogenesis agents, while ischemic diseases need to be treated with pro-angiogenesis agents. Salviae Miltiorrhizae Radix et Rhizoma, the representative drug which promotes circulation and resolves clots, was widely used in treating tumors and ischemic diseases. This review focused on the current research on the angiogenic effect of Salviae Miltiorrhizae Radix et Rhizoma and its water-soluble or fat-soluble components. It was found that there are some controversy reports. Both pro-angiogenic and anti-angiogenic effects of Salviae Miltiorrhizae Radix et Rhizoma and its components have been reported. The major difference between tumor and ischemia is the maturity and stability of vessels. Angiogenesis is a complex process involving many signaling molecules. Therefore, the components of Salviae Miltiorrhizae Radix et Rhizoma will regulate the levels and functions of angiogenesis, and then vessels produce different maturity and stability. Overall, such controversy may be caused by differences in experimental conditions, the diversity of Salviae Miltiorrhizae Radix et Rhizoma components, the complexity of the angiogenic process, and the differences of drug distribution under different pathological states in vivo.
ABSTRACT
<p><b>OBJECTIVE</b>To study the effect of aqueous extract of several kinds of herbs on human platelet aggregation and expression of P-selectin in vitro.</p><p><b>METHODS</b>Blood was collected from volunteers. Effects of the prepared water extracts of herbs on platelet aggregation were monitored on a Packs-4 aggregometer. The fluorescence intensity of water extracts of Caulis Spatholobi, Flos Carthami and Rhizoma Curcumae on the expression of P-selectin in human platelets of healthy persons was measured with flow cytometry.</p><p><b>RESULTS</b>Out of several herbs investigated, Flos Carthami and Rhizoma Curcumae potently inhibited platelet aggregation after incubation with platelet-rich plasma (PRP) for 15 min. Caulis Spatholobi Flos Carthami and Rhizoma Curcumae inhibited adenosine-5'-diphosphate (ADP) or platelet activating factor (PAF)-induced platelet aggregation in PRP in a dose-dependent manner. In contrast to Flos Carthami and Rhizoma Curcumae, Caulis Spatholobi could not inhibit thrombin-induced platelet aggregation. Despite its inability to inhibit thrombin-induced platelet aggregation in PRP, Caulis Spatholobi had a greater anti-aggregating activity in PRP induced by ADP or PAF. Caulis Spatholobi and Flos Carthami showed significant inhibitory effects on the expression of P-selectin.</p><p><b>CONCLUSIONS</b>Caulis Spatholobi, Flos Carthami and Rhizoma Curcumae have potent anti-platelet properties, and their inhibitory actions are mediated via different mechanisms. Caulis Spatholobi inhibited ADP-induced platelet aggregation but not by thrombin, indicating that its mechanism of action might be independent of the thromboxane pathway. The effect of Caulis Spatholobi and Flos Carthami were associated with suppressing the expression of P-selectin.</p>