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.

Value of pretreatment 18F-FDG PET/CT in prognosis and the reflection of tumor burden: a study in pediatric patients with newly diagnosed neuroblastoma.

Fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT has been commonly used in pediatric patients with newly diagnosed neuroblastoma (NB) for diagnosis. We retrospectively reviewed 40 pediatric patients with newly diagnosed NB who underwent 18F-FDG PET/CT. Clinicopathological factors and metabolic parameters including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on PET/CT were evaluated as predictive factors for progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Spearman rank correlation analyses were used to estimate the correlations between clinical factors and PET findings. The mean follow-up after 18F-FDG-PET/CT was 32.9 months. During the follow-up period 15 (37.5%) patients experienced progression, and 9 (22.5%) died. MTV (P=0.001) and TLG (p=0.004) remained significant predictive factors for tumor progression, along with lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and bone metastasis. Univariate analysis showed that bone metastasis, LDH (>1064 IU/L), NSE (>364.4 ug/L), MTV (>191 cm3) and TLG (>341.41 g) correlated with PFS, and LDH (>1064 IU/L), NSE (>364.4 ug/L) and MTV (>191 cm3) correlated with OS (p<0.05). In multivariate analysis, MTV and bone metastasis were independent prognostic factors for PFS (p=0.001 and 0.023, respectively), and MTV remained the only independent prognostic factor for OS (p= 0.004). We also found that there were correlations between semiquantitative PET/CT parameters and clinical features in NB. Our results suggested that 18F-FDG PET/CT was a useful tool to predictive progression and to reflect tumor burden for patients with NB.

Design, synthesis and biological evaluation of 1-Aryl-5-(4-arylpiperazine-1-carbonyl)-1H-tetrazols as novel microtubule destabilizers.

A series of 1-aryl-5-(4-arylpiperazine-1-carbonyl)-1H-tetrazols as microtubule destabilizers were designed, synthesised and evaluated for anticancer activity. Based on bioisosterism, we introduced the tetrazole moiety containing the hydrogen-bond acceptors as B-ring of XRP44X analogues. The key intermediates ethyl 1-aryl-1H-tetrazole-5-carboxylates 10 can be simply and efficiently prepared via a microwave-assisted continuous operation process. Among the compounds synthesised, compound 6-31 showed noteworthy potency against SGC-7901, A549 and HeLa cell lines. In mechanism studies, compound 6-31 inhibited tubulin polymerisation and disorganised microtubule in SGC-7901 cells by binding to tubulin. Moreover, compound 6-31 arrested SGC-7901cells in G2/M phase. This study provided a new perspective for development of antitumor agents that target tubulin.

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.

Design, synthesis and bio-evaluation of novel 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazoles as the tubulin polymerization inhibitors.

A series of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-5-substituted-1,2,3-triazoles were designed, synthesized and evaluated for the anticancer activities. Based on the model of DMAM-colchicine-tubulin complex interactions, various saturated nitrogen-containing heterocycles were introduced to the C5-position of 1,2,3-triazol to interact with a tolerant region at the entrance of the binding-pocket and increase the aqueous solubility of the compounds. All designed compounds were concisely synthesized by one-pot oxidative cyclization. Most compounds exhibited moderate antiproliferative activity with IC50 values in the micromolar to sub-micromolar range. Among them, 5g posed N-acyl-piperazine moiety at the C5-position of B-ring showed most potent against cancer cells, with IC50 values of 0.084-0.221 µM 5g potently disrupted microtubule/tubulin dynamics, induced cell cycle arrest at G2/M phase in SGC-7901 cells. In addition, molecular modeling studies suggested that 5g probably binds to the colchicine site of tubulin.

Machine Learning Assisted MRI Characterization for Diagnosis of Neonatal Acute Bilirubin Encephalopathy.

Background: The use of magnetic resonance imaging (MRI) in diagnosis of neonatal acute bilirubin encephalopathy (ABE) in newborns has been limited by its difficulty in differentiating confounding image contrast changes associated with normal myelination. This study aims to demonstrate the feasibility of building a machine learning prediction model based on radiomics features derived from MRI to better characterize and distinguish ABE from normal myelination. Methods: In this retrospective study, we included 32 neonates with clinically confirmed ABE and 29 age-matched controls with normal myelination. Radiomics features were extracted from the manually segmented region of interest (ROI) on T1-weighted spin echo images, followed by the feature selection using two-sample independent t-test, least absolute shrinkage and selection operator (Lasso) regression, and Pearson's correlation matrix. Additional feature quantifying the relative mean intensity of ROI was defined and calculated. A prediction model based on the selected features was built to classify ABE and normal myelination using multiple machine learning classifiers and a leave-one-out cross-validation scheme. Receiver operating characteristics (ROC) analysis was used to evaluate the prediction performance with the area under the curve (AUC) and feature importance ranked based on the Fisher score. Results: Among 1319 radiomics features, one radiologist-defined intensity-based feature and 12 texture features were selected as the most discriminative features. Based on these features, decision trees had the best classification performance with the largest AUC of 0.946, followed by support vector machine (SVM), tree-bagger, logistic regression, Naïve Bayes, discriminant analysis, and k-nearest neighborhood (KNN), which have an AUC of 0.931, 0.925, 0.905, 0.891, 0.883, and 0.817, respectively. The relative mean intensity outperformed other 12 texture features in differentiating ABE from controls. Conclusions: The results from this study demonstrated a new strategy of characterizing ABE-induced intensity and morphological changes in MRI, which are difficult to be recognized, interpreted, or quantified by the routine experience and visual-based reading strategy. With more quantitative and objective measurements, the reported machine learning assisted radiomics features-based approach can improve the diagnosis and support clinical decision-making.

Design, synthesis and biological evaluation of 3,4-diaryl-1,2,5-oxadiazole-2/5-oxides as highly potent inhibitors of tubulin polymerization.

Structure-activity relationships for rigid analogues of combretastatin A-4 (CA-4) were investigated, leading to the discovery of a series of 3,4-diaryl-1,2,5-oxadiazole-N-oxides. Among them, 7n' and 7n'' showed remarkable antiproliferative activities against three cancer cell lines in nanomolar concentrations. Interestingly, 7n' inhibited tubulin polymerization much more efficiently than CA-4. Cellular mechanism investigation elucidated 7n' disrupted the cellular microtubule structure, arrested cell cycle at G2/M phase and induces apoptosis. Molecular modeling study revealed 1,2,5-oxadiazole-N-oxide ring could increase a hydrogen bond interaction with the binding site. These results provide impetus and further guidance for the development of new CA-4 analogues.

Metastasis manners and the underlying mechanisms of ALK and ROS1 rearrangement lung cancer and current possible therapeutic strategies.

The rearrangements of anaplastic lymphoma kinase (ALK) and the c-ros oncogene 1 (ROS1) have both been important driving factors in non-small-cell lung cancer (NSCLC). They have already been defined in 3-5% of NSCLC patients. ALK and ROS1 rearrangements are associated with unique clinical and pathological features, especially patients are usually younger, with milder or never smoking history, and adenocarcinoma histology. Also, they have both been found to contribute to the metastasis of NSCLC by cell migration and invasion. It has recently been recognized that the brain can be considered as a primary site for metastasis in cancers with ALK or ROS1 rearrangements. The present review summarizes the current status of NSCLC metastasis and possible mechanisms based on available evidence, and then we list possible therapeutic strategies so that an increase in control of ALK and ROS1 rearrangement of NSCLC metastases by combination therapy can be translated in an increase in overall survival and prognosis.

Artificial trans-encoded small non-coding RNAs specifically silence the selected gene expression in bacteria.

Recently, many small non-coding RNAs (sRNAs) with important regulatory roles have been identified in bacteria. As their eukaryotic counterparts, a major class of bacterial trans-encoded sRNAs acts by basepairing with target mRNAs, resulting in changes in translation and stability of the mRNA. RNA interference (RNAi) has become a powerful gene silencing tool in eukaryotes. However, such an effective RNA silencing tool remains to be developed for prokaryotes. In this study, we described first the use of artificial trans-encoded sRNAs (atsRNAs) for specific gene silencing in bacteria. Based on the common structural characteristics of natural sRNAs in Gram-negative bacteria, we developed the designing principle of atsRNA. Most of the atsRNAs effectively suppressed the expression of exogenous EGFP gene and endogenous uidA gene in Escherichia coli. Further studies demonstrated that the mRNA base pairing region and AU rich Hfq binding site were crucial for the activity of atsRNA. The atsRNA-mediated gene silencing was Hfq dependent. The atsRNAs led to gene silencing and RNase E dependent degradation of target mRNA. We also designed a series of atsRNAs which targeted the toxic genes in Staphyloccocus aureus, but found no significant interfering effect. We established an effective method for specific gene silencing in Gram-negative bacteria.