Evaluating the efficacy and mechanisms of Hua-Zhuo-Ning-Fu-Decoction on psoriasis using integrated bioinformatics analysis and metabolomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Hua Zhuo Ning Fu Decoction (HZD) is an empirical prescription from traditional Chinese medicine that shows excellent clinical results for psoriasis patients. Uncertainty lingered over HZD's potential anti-psoriasis mechanisms. AIM OF THE STUDY: The study's objective is to investigate the pharmacological processes and therapeutic effects of HZD on psoriasis. MATERIALS AND METHODS: In the initial phase of the study, an investigation was conducted to assess the effects of HZD on psoriasis-afflicted mice using an imiquimod (IMQ)-induced murine model. The experimental mice were randomly allocated to different groups, including the IMQ-induced model group, the control group, the HZD therapy groups with varying dosage levels (low, medium, and high), and Dexamethasone (DEX, the positive control medicine) group. Bioinformatics analysis and molecular docking were subsequently employed to identify the primary components and molecular targets associated with the therapeutic action of HZD in the context of psoriasis. Additionally, to find the impacts on metabolite regulation, plasma metabolomics based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was used. It's interesting to note that the combined mechanisms from metabolomics were examined in tandem with the targets. In vivo tests were the last step in validating the potential mechanism. Throughout the trial, the following data were recorded: body weight, psoriasis area and severity index (PASI). The molecular targets connected to HZD's anti-psoriasis activities were revealed using histological examination, western blot (WB), and ELISA investigation. RESULTS: In mice induced with IMQ, HZD shown good anti-psoriasis effects in terms of PASI score and epidermal acanthosis. 95 HZD targets and 77 bioactive chemicals connected to psoriasis were found by bioinformatics research; of these, 7 key targets (EPHX2, PLA2G2A, TBXAS1, MAOA, ALDH1A3, ADH1A, and ADH1B) were linked to the mechanisms of HZD, the combination degree of which was finally expressed by the score of docking. In addition, HZD regulated nine metabolites. In line with this, HZD modified three metabolic pathways. Additionally, a combined examination of 7 key targets and 9 metabolites suggested that the metabolism of arachidonic acid might be the key metabolic route, which was identified by ELISA analysis. The in vivo investigation shown that HZD could control cytokines associated to inflammation (IL-10, TGF-ß, IL-17A, and IL-23), as well as important antioxidant system markers (ROS, GSH, and MDA). Moreover, HZD controlled iron levels and the expression of ferroptosis-related proteins (ACSL4 and GPX4), suggesting that ferroptosis played a crucial role in this process. CONCLUSIONS: Our findings demonstrated the whole mechanism and anti-psoriasis effectiveness of HZD, which will promote its clinical application and aid in the investigation of new bioactive components of HZD against psoriasis.

The role of angiogenesis in melanoma: Clinical treatments and future expectations.

The incidence of melanoma has increased rapidly over the past few decades, with mortality accounting for more than 75% of all skin cancers. The high metastatic potential of Melanoma is an essential factor in its high mortality. Vascular angiogenic system has been proved to be crucial for the metastasis of melanoma. An in-depth understanding of angiogenesis will be of great benefit to melanoma treatment and may promote the development of melanoma therapies. This review summarizes the recent advances and challenges of anti-angiogenic agents, including monoclonal antibodies, tyrosine kinase inhibitors, human recombinant Endostatin, and traditional Chinese herbal medicine. We hope to provide a better understanding of the mechanisms, clinical research progress, and future research directions of melanoma.

W436, a novel SMART derivative, exhibits anti-hepatocarcinoma activity by inducing apoptosis and G2/M cell cycle arrest in vitro and in vivo and induces protective autophagy.

Hepatocellular carcinoma (HCC) is considered one of the most common primary liver cancers and the second leading cause of cancer-associated mortality around the world annually. Therefore, it is urgent to develop novel drugs for HCC therapy. We synthesized a novel 4-substituted-methoxybenzoyl-aryl-thiazole (SMART) analog, (5-(4-aminopiperidin-1-yl)-2-phenyl-2H-1,2,3-triazol-4-yl) (3,4,5-trimethoxyphenyl) methanone (W436), with higher solubility, stability, and antitumor activity than SMART against HCC cells in vivo. The purpose of this study was to investigate the mechanisms by which W436 inhibited cell growth in HCC cells. We observed that W436 inhibited the proliferation of HepG2 and Hep3B cells in a dose-dependent manner. Importantly, the anticancer activity of W436 against HCC cells was even higher than that of SMART in vivo. In addition, the antiproliferative effects of W436 on HCC cells were associated with G2/M cell cycle arrest and apoptosis via the activation of reactive oxygen species-mediated mitochondrial apoptotic pathway. W436 also induced protective autophagy by inhibiting the protein kinase B/mammalian target of rapamycin pathway. At the same time, W436 treatment inhibited the cell adhesion and invasion as well as the process of epithelial-to-mesenchymal transition Taken together, our results showed that W436 had the promising potential for the therapeutic treatment of HCC with improved solubility, stability, and bioavailability.

The novel ALK inhibitor ZX-29 induces apoptosis through inhibiting ALK and inducing ROS-mediated endoplasmic reticulum stress in Karpas299 cells.

It is a well-known fact that 60%-85% of anaplastic large cell lymphoma (ALCL) is mainly driven by the anaplastic lymphoma kinase (ALK) fusion protein. Although ALK-positive ALCL patients respond significantly to ALK inhibitors, the development of resistance is inevitable, which requires the development of new therapeutic strategies for ALK-positive ALCL. Here, we investigated the anticancer activities of N-(2((5-chloro-2-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide (ZX-29), a newly synthesized ALK inhibitor, against nucleophosmin-ALK-positive cell line Karpas299. We demonstrated that ZX-29 decreased Karpas299 cells growth and had better cytotoxicity than ceritinib, which was mediated through downregulating the expression of ALK and related proteins, inducing cell cycle arrest, and promoting cell apoptosis. Moreover, ZX-29-induced cell apoptosis by inducing endoplasmic reticulum stress (ERS). In addition, ZX-29 increased the generation of reactive oxygen species (ROS), and cells pretreatment with N-acetyl- l-cysteine could attenuate ZX-29-induced cell apoptosis and ERS. Taken together, ZX-29 inhibited Karpas299 cell proliferation and induced apoptosis through inhibiting ALK and its downstream protein expression and inducing ROS-mediated ERS. Therefore, our results provide evidence for a novel antitumor candidate for the further investigation.

2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ) inhibits cancer cell metastasis behavior of TNBC via suppressing EMT and VEGF.

Triple-negative breast cancer (TNBC) is highly metastatic and lacks effective therapeutic targets among several subtypes of breast cancer. Cancer metastasis promotes the malignancy of TNBC and is closely related to the poor prognosis of the TNBC patients. We aim to explore novel agents that effectively inhibit cancer metastasis to treat TNBC. In our study, 2-Methoxy-5((3,4,5-trimethosyphenyl)seleninyl) phenol (SQ), a CA-4 analogue, could inhibit cell motility and invasion in MDA-MB-231 cells, and the mechanism is closely associated to the inhibition of epithelial-to-mesenchymal transition (EMT). Meanwhile, SQ significantly inhibited the expression and secretion of vascular endothelial growth factor (VEGF) in MDA-MB-231 cells. Moreover, the conditioned medium from SQ-treated MDA-MB-231 cells significantly inhibited the motility and invasion of human umbilical vein endothelial cells (HUVECs), which was correlated with the inhibition of EMT process in HUVECs. In addition, exogenous application of VEGF reversed the occurrence of EMT in HUVECs which stimulated by conditioned medium from SQ-treated cells. Furthermore, SQ inhibited vasculogenic mimicry (VM) formation in MDA-MB-231 cells, which was associated with VE-cadherin and EphA2 down-regulation. This study indicates that SQ inhibits MDA-MB-231 cell metastasis through suppressing EMT and VEGF, thereby implicating this compound might be a potential therapeutic agent against metastatic TNBC.

Recent advances and challenges of immune checkpoint inhibitors in immunotherapy of non-small cell lung cancer.

Chemotherapy and targeted therapy have significantly improved the progression of non-small cell lung cancer (NSCLC), but patients are inevitably suffering from drug resistance and relapse. With this background, the immunotherapy brings a turnaround for a subset of cancer patients. Over two decades, with the development of immunotherapy, immune checkpoint inhibitors (ICIs) have made a breakthrough in NSCLC patients. ICIs targeting the programmed death 1 receptor (PD-1), programmed cell death receptor ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) showed significantly antitumor efficacy, produced durable clinical responses, and prolonged survival by regulating T cell-mediated immunologic responses in patients with advanced/refractory and metastatic NSCLC in clinical trials. This review aims to summarize the recent advances and challenges of ICIs including nivolumab, pembrolizumab, PF-06801591, MEDI0680, atezolizumab, durvalumab, ipilimumab, tremelimumab, and other new PD-1/PD-L1 and CTLA-4 inhibitors in immunotherapy of NSCLC. We hope to provide a better understanding of the mechanisms, clinical research progress and future research directions of NSCLC immunotherapy.