Identification of a metabolic reprogramming-related signature associated with prognosis and immune microenvironment of head and neck squamous cell carcinoma by in silico analysis.

BACKGROUND: Metabolic reprogramming is one of the essential features of tumorigenesis. Herein, this study aimed to develop a novel metabolism-related gene signature for head and neck squamous cell carcinoma (HNSCC) patients. METHODS: The transcriptomic and clinical data of HNSCC samples were collected from The Cancer Genome Atlas (TCGA) and GSE65858 datasets. The metabolism-related gene-based prognostic signature (MRGPS) was constructed by the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. The time-dependent receiver operating characteristic (ROC) and Kaplan-Meier (K-M) survival curves were plotted for evaluating its predicting performance. At the same time, univariate along with multivariate analysis was carried out to explore its correlation with clinicopathologic factors. Furthermore, GSEA analysis was performed to explore the signaling pathways affected by MRGPS. We also analyzed the associations of MRGPS with the tumor immune microenvironment (TIME), as well as identified potential compounds via Connectivity Map (CMap) and molecular docking. RESULTS: A total of 12 differentially expressed metabolism-related genes were identified and selected to construct the MRGPS. Notably, this signature performed well in predicting HNSCC patients' survival and could serve as an independent prognostic factor in multiple datasets. In addition to the metabolism-related pathway, this signature could also affect some immune-related pathways. The results indicated that MRGPS is correlated with immune cells infiltration and anti-cancer immune response. Furthermore, we identified cephaeline as a potential therapeutic compound for HNSCC. CONCLUSION: Taken together, we established an MRGs-based signature that has the potential to predict the clinical outcome and immune microenvironment, which help to search for potential combination immunotherapy compounds and provide a promising therapeutic strategy for treating HNSCC patients.

Identification and validation of a prognostic signature and combination drug therapy for immunotherapy of head and neck squamous cell carcinoma.

Immunotherapy has become a promising therapeutic option for Head and neck squamous cell carcinoma (HNSC). However, only a small percentage of patients could benefit from it, and the overall prognosis was far from satisfactory. In this study, by comprehensively computational analyses of hundreds of HNSC samples, a prognostic signature composed of 13 immune-related genes (IRGs) was constructed. The results of the analyses in multiple datasets indicated that our signature had high predictive accuracy and could serve as an independent prognostic predictor. Based on this signature and multiple clinical variables, we also established a prognostic nomogram to quantitatively predict the survival risk of individual patients. Moreover, this signature could accurately predict survival, reflect the immune microenvironment, and predict immunotherapy efficacy among HNSC patients. Two potential drugs (doxorubicin and daunorubicin) were also identified via Connectivity Map and molecular docking, which could be used for HNSC combination therapy. Taken together, we developed and validated a robust IRG-based prognostic signature to monitor the prognosis of HNSC, which could provide a solid foundation for individualized cancer immunotherapy.

A large-scale transcriptional study reveals inhibition of COVID-19 related cytokine storm by traditional Chinese medicines.

Coronavirus disease-2019 (COVID-19) has become a major global epidemic. Facilitated by HTS2 technology, we evaluated the effects of 578 herbs and all 338 reported anti-COVID-19 TCM formulae on cytokine storm-related signaling pathways, and identified the key targets of the relevant pathways and potential active ingredients in these herbs. This large-scale transcriptional study innovatively combines HTS2 technology with bioinformatics methods and computer-aided drug design. For the first time, it systematically explores the molecular mechanism of TCM in regulating the COVID-19-related cytokine storm, providing an important scientific basis for elucidating the mechanism of action of TCM in treating COVID-19.

An immune-related gene signature for predicting survival and immunotherapy efficacy in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) ranks the fourth in terms of cancer-related mortality globally. Herein, in this research, we attempted to develop a novel immune-related gene signature that could predict survival and efficacy of immunotherapy for HCC patients. METHODS: The transcriptomic and clinical data of HCC samples were downloaded from The Cancer Genome Atlas (TCGA) and GSE14520 datasets, followed by acquiring immune-related genes from the ImmPort database. Afterwards, an immune-related gene-based prognostic index (IRGPI) was constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression model. Kaplan-Meier survival curves as well as time-dependent receiver operating characteristic (ROC) curve were performed to evaluate its predictive capability. Besides, both univariate and multivariate analyses on overall survival for the IRGPI and multiple clinicopathologic factors were carried out, followed by the construction of a nomogram. Finally, we explored the possible correlation of IRGPI with immune cell infiltration or immunotherapy efficacy. RESULTS: Analysis of 365 HCC samples identified 11 differentially expressed immune-related genes, which were selected to establish the IRGPI. Notably, it can predict the survival of HCC patients more accurately than published biomarkers. Furthermore, IRGPI can predict the infiltration of immune cells in the tumor microenvironment of HCC, as well as the response of immunotherapy. CONCLUSION: Collectively, the currently established IRGPI can accurately predict survival, reflect the immune microenvironment, and predict the efficacy of immunotherapy among HCC patients.

Guizhi Fuling Decoction inhibiting the PI3K and MAPK pathways in breast cancer cells revealed by HTS2 technology and systems pharmacology.

As one of the classical traditional Chinese medicine (TCM) prescriptions in treating gynecological tumors, Guizhi Fuling Decoction (GFD) has been used to treat breast cancer (BRCA). Nonetheless, the potential molecular mechanism remains unclear so far. Therefore, systems pharmacology was used in combination with high throughput sequencing-based high throughput screening (HTS2) assay and bioinformatic technologies in this study to investigate the molecular mechanisms of GFD in treating BRCA. By computationally analyzing 76 active ingredients in GFD, 38 potential therapeutic targets were predicted and significantly enriched in the "pathways in cancer". Meanwhile, experimental analysis was carried out to examine changes in the expression levels of 308 genes involved in the "pathways in cancer" in BRCA cells treated by five herbs of GFD utilizing HTS2 platform, and 5 key therapeutic targets, including HRAS, EGFR, PTK2, SOS1, and ITGB1, were identified. The binding mode of active compounds to these five targets was analyzed by molecular docking and molecular dynamics simulation. It was found after integrating the computational and experimental data that, GFD possessed the anti-proliferation, pro-apoptosis, and anti-angiogenesis activities mainly through regulating the PI3K and the MAPK signaling pathways to inhibit BRCA. Besides, consistent with the TCM theory about the synergy of Cinnamomi Ramulus (Guizhi) by Cortex Moutan (Mudanpi) in GFD, both of these two herbs acted on the same targets and pathways. Taken together, the combined application of computational systems pharmacology techniques and experimental HTS2 platform provides a practical research strategy to investigate the functional and biological mechanisms of the complicated TCM prescriptions.

Development of a prognostic index of colon adenocarcinoma based on immunogenomic landscape analysis.

BACKGROUND: Colon adenocarcinoma (COAD) is one of the most commonly diagnosed cancers, and it is closely related to the immune microenvironment. Considering that immunotherapy is not effective for all COAD patients, it is necessary to identify the effective population before administering treatment. In this study, we established an independent prognostic index based on immune-related genes (IRGs), in order to evaluate the clinical outcome of COAD. METHODS: The gene expression profiles and IRGs taken from The Cancer Genome Atlas (TCGA) and Immunology Database and Analysis Portal (ImmPort), respectively, were integrated in order to identify the differentially expressed IRGs. Functional enrichment analysis was conducted and the prognostic value of survival-related IRGs was determined. Based on Cox regression analysis, the IRG-based prognostic index (IRGPI) was established, and the model was evaluated and applied. RESULTS: A total of 51 differentially expressed survival-related IRGs were identified. The most significant signaling pathway was "cytokine-cytokine receptor interaction". The index established herein was based on 12 survival-related IRGs, and it was highly accurate in monitoring prognosis. Moreover, the IRGPI was significantly correlated with multiple clinicopathologic factors, as well as with the infiltration of immune cells. CONCLUSIONS: An independent IRGPI was established in order to assess the immune status and tumor prognosis in COAD patients. This index can serve as a robust biomarker in clinical prognosis applications, including cancer immunotherapy.

Jinbei Oral Liquid ameliorates bleomycin-induced idiopathic pulmonary fibrosis in rats via reversion of Th1/Th2 shift.

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal interstitial lung disease with high mortality. The pivotal role of Th1/Th2 immunological balance in the development and progression of IPF has been demonstrated previously. This study aimed to evaluate the effect of Jinbei Oral Liquid (JBOL) on IPF and its relationship with Th1/Th2 shift. Methods: Rats were divided into six groups: control group, model group (bleomycin), pirfenidone group (positive group, 54 mg/kg, i.g.) and JBOL (5.4, 10.8 and 21.6 mL/kg, i.g.) groups. The rat model was established by an intratracheal instillation of bleomycin (BLM, 5 mg/kg). One day after injection of BLM, pirfenidone or JBOL was given to rats once daily within 28 consecutive days, respectively. Positron emission tomography/computed tomography (PET/CT) was performed on the treated rats. The extent of alveolitis and fibrosis was observed by H&E and Masson trichrome staining. The contents of TGF-ß1, TNF-α, IL-4 and IFN-γ were further quantified by ELISA assay. Results: PET/CT and histopathological evidence showed the ability of JBOL to attenuate bleomycin-induced alveolitis and fibrosis extent, and the alveolitis lesion score was markedly decreased compared with the model group. The increased expression of inflammatory cytokines TGF-ß1 and TNF-α induced by bleomycin was also suppressed by JBOL. The Th1 response was limited by the reduced IFN-γ after BLM administration, and the Th2 response predominated significantly marked by the increased IL-4. JBOL could increase the level of IFN-γ and markedly increased the ratio of IFN-γ/IL-4. Conclusion: These findings suggested that JBOL may attenuate BLM-induced idiopathic pulmonary fibrosis via reducing inflammatory cell infiltration, pro-inflammatory cytokine release and excessive collagen deposition in rats. One of the mechanisms is the reversion of Th1/Th2 shift caused by BLM.

Artemisinin B Improves Learning and Memory Impairment in AD Dementia Mice by Suppressing Neuroinflammation.

Alzheimer's disease is a chronic neurological ailment that seriously threatens human health and imposes a huge burden on families and the society at large. Emerging evidence suggests that neuroinflammation is an important pathological manifestation of neurodegenerative diseases, and currently considered a new research target. We previously found that artemisinin B from Artemisia annua Linn. has strong anti-inflammatory and immunological activities. In the present study, we assessed the anti-neuroinflammatory effects of artemisinin B in vitro and in vivo, exploring the underlying mechanisms. The results demonstrated that artemisinin B inhibited NO secretion from LPS-induced BV2 cells and significantly reduced the expression levels of the inflammatory cytokines IL-1ß, IL-6 and TNF-α. This was accompanied by reduced gene expression levels of MyD88 and NF-κB as well as TLR4 and MyD88 protein levels. These inhibitory effects were further confirmed in AD model mice. This study also showed that artemisinin B improved spatial memory in dementia mice in the water maze and step-through tests, and altered the pathological features and the levels of inflammatory cytokines in the hippocampus and the cortex. These results suggested that artemisinin B might inhibit neuroinflammation and exert neuroprotective effects on cognitive functions by modulating the TLR4-MyD88-NF-κB signaling pathway. This study provides direct evidence for the potential application of artemisinin B in the treatment of neuroinflammatory diseases.

A New Strategy to Uncover the Anticancer Mechanism of Chinese Compound Formula by Integrating Systems Pharmacology and Bioinformatics.

Currently, cancer has become one of the major refractory diseases threatening human health. Complementary and alternative medicine (CAM) has gradually become an alternative choice for patients, which can be attributed to the high cost of leading cancer treatments (including surgery, radiotherapy, and chemotherapy) and the severe related adverse effects. As a critical component of CAM, traditional Chinese medicine (TCM) has increasing application in preventing and treating cancer over the past few decades. Huanglian Jiedu Decoction (HJD), a classical Chinese compound formula, has been recognized to exert a beneficial effect on cancer treatment, with few adverse effects reported. Nevertheless, the precise molecular mechanism remains unclear yet. In this study, we had integrated systems pharmacology and bioinformatics to explore the major active ingredients against cancer, targets for cancer treatment, and the related mechanisms of action. These targets were scrutinized using web-based Gene SeT Analysis Toolkit (WebGestalt), and 10 KEGG pathways were identified by enrichment analysis. Refined analysis of the KEGG pathways indicated that the anticancer effect of HJD showed a functional correlation with the p53 signaling pathway; moreover, HJD had potential therapeutic effect on prostate cancer (PCa) and small cell lung cancer (SCLC). Afterwards, genetic alterations and survival analysis of key targets for cancer treatment were examined in both PCa and SCLC. Our results suggested that such integrated research strategy might serve as a new paradigm to guide future research on Chinese compound formula. Importantly, such strategy contributes to studying the anticancer effect and the mechanisms of action of Chinese compound formula, which has also laid down the foundation for clinical application.

Wuji Wan Formula Ameliorates Diarrhea and Disordered Colonic Motility in Post-inflammation Irritable Bowel Syndrome Rats by Modulating the Gut Microbiota.

Emerging evidence suggests that gut microbiota contribute to the treatment of post-inflammatory irritable bowel syndrome (PI-IBS). Our previous studies have demonstrated that a Chinese formula, Wuji Wan, has the ability to mitigate abdominal pain and diarrhea in PI-IBS rats. However, little is known about the underlying mechanism and whether the gut microbiota mediate the effect of Wuji Wan on PI-IBS. Thus, the aim of this study was to determine whether Wuji Wan mitigated PI-IBS by modifying the gut microbiota. PI-IBS was induced in Sprague-Dawley rats by enema using 4% acetic acid and restraint stress. Rats were fed water, Wuji Wan extract (630 mg/kg) or pinaverium bromide (13.5 mg/kg). Our data showed that Wuji Wan effectively ameliorated abdominal pain, colonic motility abnormality and visceral hypersensitivity. Analysis of the fecal microbiota showed that Wuji Wan could reverse the reduction in richness of the gut microbiota and significantly increase the relative abundances of Akkermansia, Bacteroides, and Parasutterella; however, Lactobacillus and Prevotella were markedly decreased in the PI-IBS rats. Moreover, Wuji Wan promoted goblet cell proliferation in the colonic mucosa by increasing the release of mucin, up-regulating the distribution of tight junction proteins Occludin and ZO-1 and down-regulating the expression of MLCK in colonic epithelial cells. These findings suggest that Wuji Wan may remit IBS by modulating the gut microbiota and stabilizing the gut mucosal barrier, indicating that the use of a classical formula of Traditional Chinese Medicine (TCM) that exhibits a prebiotic effect may be a promising strategy for PI-IBS treatment.

Herb-herb interaction in traditional Chinese medicine:a review of pharmacokinetics-based interaction in Herb-Pairs / 中国药理学与毒理学杂志

″Herb-Pairs″, also known as pair drugs, refers to a prescription consisted of two relatively fixed traditional Chinese medicine, is the most basic, most simple and most common form of medication prescription in traditional Chinese medicine compound compatibility. It is not a random combination of two herbs, nor is the simple accumulation of efficacy, but the simple and delicate experience of ancient Chinese medicine practitioners. As a bridge between single drug and prescriptions, it is the embodiment of the regular and dialectical connotation. Therefore, research on Herb-Pairs has always been the most basic and most important entry point for compound compatibility studies. However, the interaction between herbs and herbs is an effect with a downside as well as benefits. The beneficial herb-herb interaction in Herb-Pairs include mutual promotion, mutual enhancement, mutual restraint between two drugs and counteract toxicity of another drug. And the harmful herb- herb interaction in Herb- Pairs includes mutual inhibition and antagonism. All of these interactions areby means of affecting the metabolism of components to play a therapeutic effect. Using the pharmacokinetic-pharmacodynamic (PK-PD) binding model, the combination of drug metabolism and pharmacodynamics can further elucidate the influence on effect caused by drug concentration and metabolism, which can help elucidate the mechanism of drug action. Consequently, in this review, the herb-herb interactions in terms of pharmacokinetic were summarized to elucidate rule of TCM compatibility.