Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD‑1)/programmed death ligand 1 (PD‑L1) axis have achieved marked and durable efficacy in patients with different solid tumors and have improved their survival. However, the presence of primary or acquired resistance to immune checkpoint blockades results in only a small fraction of patients benefiting from the treatment. An increasing number of preclinical studies have reported that PD‑L1 expression in tumor cells is involved in a number of epigenetic changes, including histone modifications, non‑coding RNA regulation and DNA methylation. In addition, multiple epigenetic targeting drugs have been demonstrated to directly or indirectly interfere with PD‑L1 expression in various cancer models. This provides opportunities to better characterize the regulatory mechanisms of PD‑L1 expression and explore novel therapeutic strategies to improve immunosuppressant response rates and overcome drug resistance. The present review focuses on the latest findings and evidence on the epigenetic mechanism regulating PD‑L1 expression and discusses the biological and clinical implications of this regulatory mechanism in solid tumors. A rational combination of epigenetic regulation and PD‑1/PD‑L1 axis blockade may improve the prognosis of patients with solid tumors.
Radix Bupleuri has been used in traditional Chinese medicine for thousands of years, with confirmed curative effects. This plant is also used in healthy food and cosmetics. A recent increase in studies of Radix Bupleuri’s chemical constituents (mainly comprising flavonoids, lignins, phenyl propanol derivatives, triterpenoid saponins, and volatile oils) and pharmacological effects motivates the aim of the present study: to review the chemical components and pharmacological effects of Radix Bupleuri. Our review found that Radix Bupleuri exhibits diverse pharmacological effects. More than 281 components have been isolated from Radix Bupleuri, including 15 flavonoids, 430 lignins, 12 phenyl propanol derivatives, 66 triterpenoid saponins, and 158 volatile oils.
Neuroinflammation plays an important role in the pathogenesis of neurological disorders, and despite intensive research, treatment of neuroinflammation remains limited. BaiXiangDan capsule (BXD) is widely used in clinical practice. However, systematic studies on the direct role and mechanisms of BXD in neuroinflammation are still lacking. We systematically evaluated the potential pharmacological mechanisms of BXD on neuroinflammation using network pharmacological analysis combined with experimental validation. Multiple databases are used to mine potential targets for bioactive ingredients, drug targets and neuroinflammation. GO and KEGG pathway analysis was also performed. Interactions between active ingredients and pivotal targets were confirmed by molecular docking. An experimental model of neuroinflammation was used to evaluate possible therapeutic mechanisms for BXD. Network pharmacological analysis revealed that Chrysoeriol, Kaempferol and Luteolin in BXD exerted their anti-neuroinflammatory effects mainly by acting on targets such as NCOA2, PIK3CA and PTGS2. Molecular docking results showed that their average affinity was less than -5 kcal/mol, with an average affinity of -8.286 kcal/mol. Pathways in cancer was found to be a potentially important pathway, with involvement of PI3K/AKT signaling pathways. In addition, in vivo experiments showed that BXD treatment ameliorated neural damage and reduced neuronal cell death. Western blotting, RT-qPCR and ELISA analysis showed that BXD inhibited not only the expression of IL-1β, TNF-α and NO, but also NF-κB, MMP9 and PI3K/AKT signaling pathways. This study applied network pharmacology and in vivo experiments to explore the possible mechanisms of BXD against neuroinflammation, providing insight into the treatment of neuroinflammation.
Zhenlong Xingnao Capsule (ZXC) is a Tibetan medicine used to treat ischemic stroke. In this study, we determined the in vitro and in vivo effects of ZXC on reactive oxygen species (ROS) in a mouse BV-2 microglial cell hypoxia-reoxygenation and rat middle cerebral artery occlusion infarction models. We aimed to clarify the role of ZXC in cerebral ischemia protection; reveal amino acid neurotransmitter changes in the frontal cortex after drug intervention; determine mRNA and protein expression changes in Bcl-2, Bax, caspase-3, P38, and nuclear factor (NF)-кB in the frontal cortex and changes in antioxidant indices in the brain; and elucidate the mechanisms underlying ZXC action. After hypoxia-reoxygenation, ROS levels were significantly increased in BV-2 cells, and their levels decreased after treatment with ZXC. ZXC had protective effects on ischemic/anoxic injury in vitro and in vivo by downregulating the expressions of caspase-3 and NF-кB mRNA during ischemia and reperfusion and that of p38 and caspase-3 during acute ischemia and reperfusion as well as the steady-state levels of excitatory amino acids/inhibitory amino acids and by improving the total antioxidant capacity and total superoxide dismutase activities during ischemia. These findings provide new molecular evidence for the mechanisms underlying ZXC action.
Cryptotanshinone (IUPAC name: (R)-1,2,6,7,8,9-hexahydro-1,6,6-trimethyl-phenanthro(1,2-b)furan-10,11-dione), a biologically active constituent extracted from the roots and rhizomes of the plant Salvia miltiorrhiza, has been studied in depth as a medicinally active compound and shown to have efficacy in the treatment of numerous diseases and disorders. In this review, we describe in detail the current status of cryptotanshinone research, including findings relating to the structure, pharmacokinetics, pharmacological activity, and derivatives of this compound. Cryptotanshinoneh as a diverse range of pharmacological effects, including anti-cancer, anti-inflammatory, immune regulatory, neuroprotective, and anti-fibrosis activities. Studies on the molecular mechanisms underlying the activities of cryptotanshinone have established that the JAK2/STAT3, PI3K/AKT, NF-κB, AMPK, and cell cycle pathways are involved in the inhibitory and pro-apoptotic effects of cryptotanshinone on different tumor cell lines, these molecular pathways interact in a coordinated manner to inhibit cell proliferation, migration and invasion,and induce transformation, autophagy, necrosis, and cellular immunity. The anti-inflammatory mechanisms of cryptotanshinone have been found to be associated with the TLR4-MyD88/PI3K/Nrf2 and TLR4-MyD88/NF-κB/MAPK pathways, whereasthe Hedgehog, NF-κB, and Nrf-2/HO-1 pathways are regulated by cryptotanshinone to reduce organ fibrosis, and its inhibitory effects on the PI3K/AKT-eNOS pathway have been linked to neuroprotective effects. Given the potential medicinal utility of cryptotanshinone, further research is needed to verify the efficacy and safety of this compound in clinical use, evaluate its pharmacological activity, and identify molecular targets.
As one of the many breast cancer subtypes, human epidermal growth factor receptor 2 (Her2)-positive breast cancer has higher invasiveness and poor prognosis, although the advent of anti-Her2 drugs has brought good news to patients. However, the emergence of drug resistance still limits its clinical efficacy, so there is an urgent need to explore new targets and develop a risk scoring system to improve treatments and evaluate patient prognosis.Differentially expressed mRNAs associated with Her2-positive breast cancer were screened from a TCGA cohort. The prognostic risk scoring system was constructed according to univariate and Lasso Cox regression model analyses and combined with clinical factors (such as age and TNM) for univariate and multivariate analyses to verify the specificity and sensitivity of the risk scoring system. Finally, based on correlation and CNV mutation analyses, we explored the research value of the mRNAs involved in the system as key genes of the model.In this study, six mRNAs were screened and identified to construct a prognostic risk scoring system, including four up-regulated mRNA (RDH16, SPC25, SPC24, and SCUBE3) and two down-regulated mRNA (DGAT2 and CCDC69). The risk scoring system can divide Her2-positive breast cancer samples into high-risk and low-risk groups to evaluate patient prognosis. In addition, whether through the time-dependent receiver operating characteristics curve or compared with clinical factors, the risk scoring system showed high predictive sensitivity and specificity. Moreover, some CNV mutations in mRNA increase patient risk by influencing expression levels.The risk scoring system constructed in this study is helpful to improve the screening of high-risk patients with Her2-positive breast cancer and is beneficial for implementing early diagnosis and personalized treatment. It is suggested that these mRNAs may play an important role in the progression of Her2-positive breast cancer.
The treatment process of tumor is advanced with the development of immunotherapy. In clinical experience, immunotherapy has achieved very significant results. However, the application of immunotherapy is limited by a variety of immune microenvironment. For a long time in the past, polysaccharides such as lentinan and Ganoderma lucidum glycopeptide have been used in clinic as adjuvant drugs to widely improve the immunity of the body. However, their mechanism in tumor immunotherapy has not been deeply discussed. Studies have shown that natural polysaccharides can stimulate innate immunity by activating upstream immune cells so as to regulate adaptive immune pathways such as T cells and improve the effect of immunotherapy, suggesting that polysaccharides also have a promising future in cancer therapy. This review systematically discusses that polysaccharides can directly or indirectly activate macrophages, dendritic cells, natural killer cells etc., binding to their surface receptors, inducing PI3K/Akt, mitogen-activated protein kinase, Notch and other pathways, promote their proliferation and differentiation, increasing the secretion of cytokines, and improve the state of immune suppression. These results provide relevant basis for guiding polysaccharide to be used as adjuvants of cancer immunotherapy.
Correction for ‘Eliciting an immune hot tumor niche with biomimetic drug-based multi-functional nanohybrids augments immune checkpoint blockade-based breast cancer therapy’ by Wei Du et al. , Nanoscale , 2020, 12 , 3317–3329, https://doi.org/10.1039/C9NR09835F.
Lung squamous cell carcinoma (LUSC) is characterized by poor prognosis and obvious limitations of therapeutic methods. The molecular target and mechanism of quercetin (QR), a natural anticancer product with extensive pharmacological activities, on lung squamous cell carcinoma is still unclear.The effects of QR on LUSC were examined using cell proliferation, migration, and invasion tests. Key target genes were screened using The Cancer Genome Atlas (TCGA) database, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) database, STRING website, topology, and prognosis analysis, molecular docking, and other bioinformatics methods for further analysis. Finally, the effects of QR on the expression of key targets in LUSC cells were detected using a cell cycle assay and western blotting.Our study demonstrates that QR not only inhibits the proliferation of LUSC but also affects the invasion and metastasis of LUSC. After downloading and analyzing the TCGA database, 2150 differentially expressed genes were identified. PLK1, CDC20, and BUB1B were identified using enrichment analysis, topological network analysis, cluster analysis, and molecular docking screening. Subsequent experiments showed that QR could interfere with the cell cycle and downregulate the expression of the target gene PLK1 at the protein level.We found that QR not only inhibits the proliferation, migration, and invasion but also blocks the cell cycle progression of LUSC. QR downregulated the expression of the LUSC target gene PLK1 at the protein level.
Immune checkpoint blockade (ICB) has emerged as one of the breakthrough approaches for tumor immunotherapy. However, known as an immune "cold" tumor, breast cancer harbors an immunosuppressive tumor niche that compromises ICB-based therapy. Chemoimmunotherapy combines a chemotherapeutic with an immune-modulating agent, representing a promising tactic to combat cancers, while the lack of effectively targeted co-delivery strategy is one of the main obstacles to achieve the synergistic utilization. Herein, self-assembled PEGylated pure drug-based nanohybrids (DNH) were created, which could evoke immunogenic cell death (ICD), aiding ICB-based immunotherapy by controlling the spatiotemporal release of oxaliplatin (OXA) and small molecular inhibitor 1-methyl-d-tryptophan (1-MT). Furthermore, biomimetic functionalization was exploited by nature killer cell membrane camouflaging to target cancerous cells as well as by elicit immune response through inducing M1 macrophage polarization. The drug release profiles of the nanosystem were investigated in the presence of low pH and intracellular reductants. Systemic in vivo bio-behaviors were evaluated via pharmacokinetics and biodistribution. As an "all-in-one" pure drug-based codelivery system, our biomimetic nanoplatform possessed multiple immunomodulation functions, which markedly aided in increasing the frequency of immune responders and generate an immune "hot" breast tumor niche, and eventually allowed to boost breast cancer therapy.
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