Search

Imidazoline I 1 receptor (I 1 R) has been recognized as a promising target in the treatment of many diseases, but little is known about its function in liver fibrogenesis. This study aimed to investigate the effect of I 1 R activation on the development and progression of liver fibrosis. The results showed that I 1 R expression was decreased in the livers of both patients and mice with liver fibrosis, and in TGF-β-treated hepatic stellate cells (HSCs). Activation of I 1 R by moxonidine (MOX) significantly inhibited the progression of liver fibrosis in carbon tetrachloride-induced mice and attenuated the activation of HSCs and kupffer cells. MOX also suppressed the activation of TLR4/NF-κB and TGF-β/Smad signaling, however, knockdown of I 1 R abrogated the inhibitory effects of MOX. Additionally, MOX activated Nrf2 signaling in vivo and in vitro , but knockout or knockdown of Nrf2 ameliorated the anti-inflammatory and anti-fibrotic effects of MOX. Taken together, activation of I 1 R negatively regulates the progression of liver fibrosis in the Nrf2-dependent pathway, which suggests that specifically targeting I 1 R may be a potential therapeutic strategy for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

This study aims to explore the protective effects of nobiletin against hepatic ischemia–reperfusion (IR) injury after liver transplantation. Kupffer cells (KCs) were activated and co-cultured with different concentration of nobiletin for 24 h in vitro, inflammatory products and activity of TLR4/NF-κB signaling pathway were detected. Sprague–Dawley rats were selected and underwent orthotopic liver transplantation. Donors were injected intravenously with nobiletin (50 mg/kg) or saline solution, once a day for 1 week before the surgery. Recipients were randomly paired and sacrificed at the indicated time points (3, 6, and 24 h after the surgery), the graft liver tissues and blood samples were collected for analysis. Hepatic function, inflammatory mediators, apoptosis of hepatocytes, histological changes, KCs and CD4+ T-lymphocyte infiltration were assessed. Results showed nobiletin dose-dependently suppressed the expression of inflammatory mediators and the activity of TLR4/NF-κB signaling pathway in activated KCs. Furthermore, nobiletin alleviated liver damage induced by IR in vivo, significantly decreased the serum levels of alanine aminotransferase, aspartate transaminase, inflammatory cytokines and alleviated the histopathology changes. Moreover, liver in the nobiletin treated group exhibited less KCs and CD4+ lymphocyte infiltration and lower hepatocyte apoptosis after operation. In addition, activity of TLR4/NF-κB signaling pathway in KCs was also suppressed, consistent with the results in vitro. Collectively, Nobiletin can ameliorate IR injury after liver transplantation and may be a promising new strategy to protect against liver IR injury. [ABSTRACT FROM AUTHOR]

Objective We have evaluated the protective mechanism of tanshinone IIA in ischemia/reperfusion injury (IRI) induced by liver grafts, revealing novel supplementary immunotherapy for liver transplantation. Methods The tanshinone IIA preconditioning group (TP group) was pretreated with tanshinone IIA via intraperitoneal injection for 1 week before receiving orthotopic liver transplantation with hepatic arterial ischemia for 30 min. The sham-operation group (SO group), control graft group (CG group) and IRI group were pretreated with an equivalent volume of normal saline. The IRI group and CG group received orthotopic liver transplantation with or without hepatic arterial ischemia. Rats were sacrificed at each time point, serum was collected for ELISA detection, and Kupffer cells (KCs) were isolated to extract total protein and RNA for western blotting and real-time PCR, respectively. Results The levels of TNF-α and IL-4 in the TP group were significantly lower than those of in the IRI group; meanwhile the IL-10 and TGF-β levels were significantly higher than in the IRI group. The protein and mRNA expression levels of HMGB1 were significantly lower in TP group than in the IRI group at each time point. The TLR-4, Myd88, NLRP3 and p-NF-κb p65 expression levels in the TP groups were significantly lower than those in the IRI group, while the PTEN, PI3K and AKT phosphorylation levels in the TP groups were significantly higher than those in the IRI group. Conclusions Tanshinone IIA attenuates IRI caused by liver grafts via down-regulation of the HMGB1-TLR-4/NF-κb pathway in KCs and activation of PTEN/PI3K/AKT pathway, suggesting a potential role for prevention of liver cell IRI during liver transplantation. [ABSTRACT FROM AUTHOR]

During tumor development, the tumor itself must continuously generate new blood vessels to meet their growth needs while also allowing for tumor invasion and metastasis. One of the most common features of tumors is hypoxia, which drives the process of tumor angiogenesis by regulating the tumor microenvironment, thus adversely affecting the prognosis of patients. In addition, to overcome unsuitable environments for growth, such as hypoxia, nutrient deficiency, hyperacidity, and immunosuppression, the tumor microenvironment (TME) coordinates angiogenesis in several ways to restore the supply of oxygen and nutrients and to remove metabolic wastes. A growing body of research suggests that tumor angiogenesis and hypoxia interact through a complex interplay of crosstalk, which is inextricably linked to the TME. Here, we review the TME's positive contribution to angiogenesis from an angiogenesis-centric perspective while considering the objective impact of hypoxic phenotypes and the status and limitations of current angiogenic therapies. [Display omitted] • A close interactive link exists between tumor angiogenesis, hypoxia, and TME, collectively promoting tumorigenesis and progression. • Growth factors in the tumor microenvironment are secreted and regulated by various cell types, and a significant correlation exists between their expression levels and hypoxia. • The development of anti-angiogenic therapy is hampered by the lack of accurate biomarkers, the uncertain time window of medication, and the widespread problem of drug resistance. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME), the "soil" on which tumor cells grow, has an important role in regulating the proliferation and metastasis of tumor cells as well as their response to treatment. Cancer-associated fibroblasts (CAFs), as the most abundant stromal cells of the TME, can not only directly alter the immunosuppressive effect of the TME through their own metabolism, but also influence the aggregation and function of immune cells by secreting a large number of cytokines and chemokines, reducing the body's immune surveillance of tumor cells and making them more prone to immune escape. Our study provides a comprehensive review of fibroblast chemotaxis, malignant transformation, metabolic characteristics, and interactions with immune cells. In addition, the current small molecule drugs targeting CAFs have been summarized, including both natural small molecules and targeted drugs for current clinical therapeutic applications. A complete review of the role of fibroblasts in TME from an immune perspective is presented, which has important implications in improving the efficiency of immunotherapy by targeting fibroblasts. [Display omitted] • Complex regulatory relationships between fibroblasts and immune cells during metabolism, chemotaxis, and malignant transformation. • Fibroblasts regulate immune cell activity in an environmentally dependent manner. • Natural small molecules targeting CAFs and targeted drugs for current clinical therapeutic applications. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are the most critical effector cells of innate immunity and the most abundant tumor-infiltrating immune cells. They play a key role in the clearance of apoptotic bodies, regulation of inflammation, and tissue repair to maintain homeostasis in vivo. With the progression of triple-negative breast cancer（TNBC）, TAMs are "subverted" from tumor-promoting immune cells to tumor-promoting immune suppressor cells, which play a significant role in tumor development and are considered potential targets for cancer therapy. Here, we explored how macrophages, as the most important part of the TNBC ecosystem, are "subverted" to drive cancer evolution and the uniqueness of TAMs in TNBC progression and metastasis. Similarly, we discuss the rationale and available evidence for TAMs as potential targets for TNBC therapy. [Display omitted] • An exploration of how macrophages are gradually being "subverted" to drive cancer evolution. • The uniqueness of TAMs in TNBC progression and metastasis was elucidated. • The rationale and available evidence for TAMs as potential targets for TNBC treatment are detailed. • The co-dependence of TAMs on tumor evolution was explored from the perspective of co-evolution of TAMs and TNBC ecosystem. • It is helpful to optimize the current treatment plan of TNBC. [ABSTRACT FROM AUTHOR]

With the rapid development of next-generation sequencing technology, several studies have shown that ncRNAs can act as competitive endogenous RNAs (ceRNAs) and are involved in various biological processes, such as proliferation, differentiation, apoptosis, and migration of breast cancer (BC) cells, and plays an important role in BC progression as a molecular target for its diagnosis, treatment, prognosis, and differentiation of subtypes and age groups of BC patients. Based on the description of ceRNA-related biological functions, this study screened and sorted the sequencing analysis and experimental verification conclusions of BC-related ceRNAs and found that the ncRNAs mediated ceRNA networks can promote the development of BC by promoting the expression of genes related to BC proliferation, drug resistance, and apoptosis, inducing the production of epithelial-mesenchymal transition (EMT) to promote metastasis and activating cancer-related signaling pathways. [Display omitted] • ncRNA-mediated ceRNA networks is involved in various biological processes of breast cancer. • ncRNA-mediated ceRNA networks play a crucial role in diagnosis of breast cancer. • ncRNA-mediated ceRNA networks may facilitate the development of new anti-tumor drugs and clinical interventions of breast cancer. [ABSTRACT FROM AUTHOR]

The rise of cancer immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has significantly changed the clinical treatment paradigm for patients with cancer. The programmed death ligand 1 (PD-L1) protein in the tumor microenvironment (TME) binds to programmed cell death protein 1 (PD-1) on the surface of T cells and initiates the PD-1 / PD-L1 immunosuppressive program, which is currently one of the most promising target pathways for immunotherapy. However, problems such as low response rates, single targets, and high immunotoxicity have limited their clinical application. The upregulation or downregulation of PD-L1 expression in the TME can enhance the therapeutic efficacy of anti-PD-(L)1 inhibitors, and their combination with immunotherapy drugs may represent a novel anti-cancer treatment approach. The diverse immunomodulatory potential of polyphenolic compounds of plant origin offers a new direction for tumor immunotherapy. This review summarizes recent advances in research investigating the PD-L1 modulatory function of polyphenolic compounds and their combination with anti-PD-1/PD-L1 immunotherapy. In addition, we provide new insights into the advantages of polyphenolic compounds in macroscopic regulation in the tumor microenvironment and deeply explore the clinical application prospects and challenges of their immunotherapeutic potential. This study covers the most comprehensive understanding to date of polyphenolic compounds interfering with the PD-1/PD-L1 pathway in TME, intending to provide a comprehensive and valuable source of information regarding the development of polyphenolic phytochemicals as combinatorial adjuvant candidates for experimental studies, clinical applications, and their synergy with immune checkpoint blockade therapy. [Display omitted] • PD-1/PD-L1 pathway is a key pathway for tumor immune evasion. • Polyphenolic compounds have immune checkpoint protein PD-L1 regulatory function. • Polyphenols enhance the immunotherapeutic effect of anti-PD-1/PD-L1 antibodies. [ABSTRACT FROM AUTHOR]

With the development in tumor immunology, people are gradually understanding the complexity and diversity of the tumor microenvironment immune status and its important effect on tumors. Tumor-associated macrophages (TAMs), an important part of the tumor immune microenvironment, have a double effect on tumor growth and metastasis. Many studies have focused on lung cancer, especially non-small cell lung cancer and other "hot tumors" with typical inflammatory characteristics. The polarization and infiltration of TAMs is an important mechanism in the occurrence and development of malignant tumors, such as lung cancer, and in the tumor immune microenvironment. Therapeutic drugs designed for these reasons are key to targeting TAMs in the treatment of lung cancer. A large number of reports have suggested that natural compounds have a strong potential of affecting immunity by targeting the polarization and infiltration of TAMs to improve the immune microenvironment of lung cancer and exert a natural antitumor effect. This paper discusses the infiltration and polarization effects of natural compounds on lung cancer TAMs, provides a detailed classification and systematic review of natural compounds, and summarizes the bias of different kinds of natural compounds by affecting their antitumor mechanism of TAMs, with the aim of providing new perspectives and potential therapeutic drugs for targeted macrophages in the treatment of lung cancer. [Display omitted] • The dual effect of TAMs on lung cancer is related to polarization and infiltration. • Different kinds of natural compounds have obvious tendency to improve TAMs. • Natural compounds can modulate TAMs as an adjuvant therapy for lung cancer. [ABSTRACT FROM AUTHOR]