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Aim To elucidate the mechanism by which Rg3 regulates the function of CD8
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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.
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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.
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A large number of genetic mutations occur in the development of tumors, but only driver mutations determine the evolutionary direction of tumors. A variety of algorithmic tools and stationary analysis processes are available to search for driver genes with driver mutations. AS driver genes are different in different times and spaces, they are not the same in different stages of the development of breast cancer, leading to the different sensitivity of breast cancer patients to targeted therapy, which has become a major challenge for targeted therapy of breast cancer. This article reviews the progress and challenges of precision therapy for breast cancer from the perspective of driver genes.
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Tumor metastasis is an important cause of death in tumor patients. Once metastasis occurs, cancer will become more difficult to treat. Many studies have observed circulating tumor cells (CTCs) in the circulatory system of patients with metastasis. CTCs may occasionally appear in the form of clusters during the process of hematogenous metastasis. These aggregated tumor cell clusters have higher efficacy than the single CTC. The development of circulating tumor cell cluster capture technology provides new insights into tumor metastasis. The molecular mechanism of CTC clusters formation and their role in tumor hematogenous metastasis are discussed here, and their use as biomarkers and target in therapy is evaluated.
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; β-adrenergic receptors (β-ARs) are widely found in organs of the human body and play an important role in regulating heart function, blood vessel dilation, energy metabolism, etc. Studies have shown that β-ARs are abnormally high in breast cancer cells, which can promote the occurrence and development of breast cancer by affecting the growth and metabolism of breast cancer, invasive metastasis, and angiogenesis. Clinical studies have shown that blocking β-ARs signaling improves the prognosis of breast cancer patients, so β-ARs may be a potential treatment target for breast cancer. This paper summarizes the role of β-ARs in the development of breast cancer, with a view to providing some reference for follow-up research and clinical treatment.
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Aim To predict the potential targets of Salvia miltiorrhiza- Kushen herb pairs extracts (SK) and explore its anti-inflammatory effect on modelsbased on network pharmacology, so as to provide the research foundation of both new drugs and anti-inflammatory mechanism. Methods Network pharmacology was used to predict the potential anti-inflammatory targets of SK. Ear edema model was used to study the anti-in- flammatoiy effects of SK. Luminex liquid-phase chip analysis technology was used to observethe changes in secretion of pro-inflammatory cytokines in peripheral serumafter transdermal administration in mice by SK. Intraperitoneal injection of Evans blue experiment was used to simulate the exudation of inflammatory factors, and the effect of SK on capillary permeability in mice- was explored. Results Network pharmacology was used to predict that the anti-inflammatory effect of SK- was mainly related to immune-related processes and VEGF signaling pathways, unravelingthe relationship between the anti-inflammatory mechanismand the decrease of pro-inflammatory factors and vascular permea- bility. Conclusions The experiments verify that the results are the same as the prediction by network pharmacology. The anti-inflammatory effect involves decline the IL-6 levels, granulocyte colony-stimulating factor( G-CSF) levels and vascular permeability in the STAT3 pathway. Asthemain components of SK, tanshi- none, matrine and oxymatrine are linked to anti-in- flammatory effects.
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Aim To explore the effect of THPA1 in the metasta- sis of gastric cancer and the underlying mechanism. Methods The correlation between TRPA1 and the survival time of gastric cancer patients was analyzed using Kaplan-Meier plotter data base. The expressions of TRPA1 in different cells were detected by Western blot. Docking was used to explore the binding poten tial between cardamonin and TRPA1. Long-term dynamic cell imaging, CCK-8 and Transwell were used to evaluate the effects of HC-030031 and cardamonin on the proliferation and migration of MKN-45 cells. The differential metabolites between normal gastric epithelial cells and gastric cancer cells were studied by GC-MS. Results The expression of TRPA1 in gastric cancer patients was significantly negatively correlated with their surviv al. TRPA1 was overexpressed in gastric cancer cells. And the migration of gastric cancer cells was positively correlated with the expression and activation of TRPA1. Cardamonin had similar pharmacological effects with HC-030031, both of which could reduce the migration of gastric cancer cells. The metabolic path ways of asparagine and myo-inositol were found to be different between gastric cancer cells and normal gastric epithelial cells by cell metabolomics analysis. Conclusions TRPAI may be an indicator for detecting gastric cancer metastasis. Cardamonin in hibits metastasis by binding to TRPAI, meanwhile restrains the activation of TRPAI. Cardamonin may inhibit the function of TRPAI by binding to TRPAI, playing a role in inhibiting gastric cancer metastasis.
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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.
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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.
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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.
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To investigate the antiemetic effect of the active extract (ginger ether extract, GEE) and its bioactive compounds in ginger, the pica vomiting model in rats and the gastric emptying model in mice were used to observe the antiemetic effect of GEE in cisplatin-induced pica and gastric emptying, and the main components in GEE were detected by RP-HPLC; in vitro, the antagonist effect of GEE and the four components in it were explored by the contraction of guinea-pig ileum induced by SR57227A and carbachol. The results showed that the amount of Kaolin ingested by rats were declined significantly in all the three groups of GEE (25,50,100 mg•kg⁻¹) (P<0.01), while cisplatin-induced gastric emptying in mice was also suppressed in all the three groups (P<0.01), and 6-gingerol, 8-gingerol,10-gingerol and 6-shogaol were found mainly in GEE by RP-HPLC; the maximum contraction of isolated guinea-pig ileum could be reduced by addition of GEE (2.3, 4.6, 11.5 mg•L⁻¹), 6-gingerol,8-gingerol,10-gingerol or 6-shogaol (1, 2, 5 μmol•L⁻¹) when the concentration of SR5727A was 1×10⁻⁵ mol•L⁻¹ and that of carbachol was 1×10⁻⁴ mol•L⁻¹ (P<0.05, P<0.01). In conclusion, 5-HT3 and M3 receptors could be antagonized by GEE and its bioactive compounds 6-gingerol, 8-gingerol, 10-gingerol and 6-shogaol, which may be correlated with the antiemetic mechanism of ginger maybe related to it.
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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.