Investigating the efficacy and mechanisms of Jinfu'an decoction in treating non-small cell lung cancer using network pharmacology and in vitro and in vivo experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinfu'an Decoction (JFAD) is a traditional Chinese decoction used in lung cancer treatment to improve patient quality of life and survival. Previous research has established that JFAD has a significant therapeutic effect on non-small cell lung cancer (NSCLC), although the underlying molecular mechanisms have not been largely underexplored. AIM OF THE STUDY: We used network pharmacology to identify the putative active ingredients of JFAD and conducted experimental studies to determine the potential molecular mechanism of JFAD in NSCLC treatment. MATERIALS AND METHODS: The herbal components in JFAD-containing serum were identified by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS), and targets associated with the anti-lung cancer metastasis effects of JFAD were retrieved from various databases. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Next, the protein-protein interactions network and the "JFAD-Chemical Component-Target-KEGG Pathway" network were constructed. The network pharmacology findings were confirmed by in vitro and in vivo experiments. In vitro experiments were conducted to assess cell viability by CCK8 assay, cell cycle analysis by propidium iodide (PI) assay, and migration and invasion ability of cells by the transwell assay. In vivo experiments were performed to assess the efficacy of JFAD on the tumor by observing the growth of transplanted tumor models in nude mice and evaluated by in vivo bioluminescence imaging. Moreover, we assessed the effect of JFAD on the PI3K/Akt signaling pathway and proteins of Lumican, p120ctn, and specific RhoGTP enzyme family members (RhoA, Rac1, and RhoC) by Western Blot and immunohistochemistry. RESULTS: 32 herbal components were identified in the JFAD-containing serum, which potentially acted on 229 targets related to lung cancer metastasis. Network pharmacology results suggested that JFAD may treat lung cancer metastasis by targeting the PI3K/Akt pathway via regulating multiple core targets. Our experiments showed that JFAD suppressed the proliferation of A549 cells in vitro, induced cell cycle arrest, and reduced the migration and invasion ability of A549 cells. Our in vivo study revealed that JFAD inhibited tumor growth in a nude mouse model. Additionally, we found that JFAD could downregulate the expression of the PI3K/Akt pathway and affect the expression of Lumican, p120ctn, and specific RhoGTPase family members. CONCLUSIONS: In conclusion, through network pharmacology, we have unveiled the underlying mechanisms that link the various components, targets, and pathways influenced by JFAD in the context of lung cancer metastasis. Our experimental results suggest that the oncostatic effects of JFAD may be achieved by upregulating the expression of Lumican/p120ctn and downregulating the levels of specific RhoGTPase family members, which in turn block the PI3K/Akt signaling pathway.

The effectiveness of blood-activating and stasis-transforming traditional Chinese medicines (BAST) in lung cancer progression-a comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Blood-activating and stasis-transforming traditional Chinese medicines (BAST) are a class of herbs that have the effect of dilating blood vessels and dispersing stagnation. Modern pharmaceutical research has demonstrated that they are capable of improving hemodynamics and micro-flow, resist thrombosis and promote blood flow. BAST contain numerous active ingredients, which can theoretically regulate multiple targets at the same time and have a wide range of pharmacological effects in the treatment of diseases including human cancers. Clinically, BAST have minimal side effects and can be used in combination with Western medicine to improve patients' quality of life, lessen adverse effects and minimize the risk of recurrence and metastasis of cancers. AIM OF THE REVIEW: We aimed to summarize the research progression of BAST on lung cancer in the past five years and present a prospect for the future. Particularly, this review further analyzes the effects and molecular mechanisms that BAST inhibit the invasion and metastasis of lung cancer. MATERIALS AND METHODS: Relevant studies about BSAT were collected from PubMed and Web of science. RESULTS: Lung cancer is one of the malignant tumors with the highest mortality rate. Most patients with lung cancer are diagnosed at an advanced stage and are highly susceptible to metastasis. Recent studies have shown that BAST, a class of traditional Chinese medicine (TCM) with the function of opening veins and dispersing blood stasis, significantly improve hemodynamics and microcirculation, prevent thrombosis and promote blood flow, and thereby inhibiting the invasion and metastasis of lung cancer. In the current review, we analyzed 51 active ingredients extracted from BAST. It was found that BAST and their active ingredients contribute to the prevention of invasion and metastasis of lung cancer through multiple mechanisms, such as regulation of EMT process, specific signaling pathway and metastasis-related genes, tumor blood vessel formation, immune microenvironment and inflammatory response of tumors. CONCLUSIONS: BSAT and its active ingredients have showed promising anticancer activity and significantly inhibit the invasion and metastasis of lung cancer. A growing number of studies have realized their potential clinical significance in the therapy of lung cancer, which will provide substantial evidences for the development of new TCM for lung cancer therapy.

Development and validation of an immune-related gene signature for prognosis in Lung adenocarcinoma.

The most common type of lung cancer tissue is lung adenocarcinoma. The TCGA-LUAD cohort retrieved from the TCGA dataset was considered the internal training cohort, while GSE68465 and GSE13213 datasets from the GEO database were used as the external test cohort. The TCGA-LUAD cohort was classified into two immune subtypes using single-sample gene set enrichment analysis of the immune gene set and unsupervised clustering analysis. The ESTIMATE algorithm, the CIBERSORT algorithm, and HLA family expression levels again validated the reliability of this typing. We performed Venn analysis using immune-related genes from the immport dataset and differentially expressed genes from the subtypes to retrieve differentially expressed immune genes (DEIGs). In addition, DEIGs were used to construct a prognostic model with the least absolute shrinkage and selection operator regression analysis. A reliable risk model consisting of 11 DEIGs, including S100P, INHA, SEMA7A, INSL4, CD40LG, AGER, SERPIND1, CD1D, CX3CR1, SFTPD, and CD79A, was then built, and its reliability was further confirmed by ROC curve and calibration plot analysis. The high-risk score subgroup had a poor prognosis and a lower tumour immune dysfunction and exclusion score, indicating a greater likelihood of anti-PD-1/cytotoxic T lymphocyte antigen 4 benefit.

Plasma omega-3 polyunsaturated fatty acids and recurrence of endometrial cancer.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) were proposed to have potential effects against inflammation and cancer. However, results from epidemiology studies remain inconsistent. We aimed to explore the associations of plasma PUFAs with EC recurrence and all-cause mortality. METHOD: Women diagnosed with endometrial cancer (EC) between 2008 and 2013 and underwent surgery at Fudan University Shanghai Cancer Center of China were recruited. Survival status was followed up through September 2017. EC recurrence and total cause deaths were identified through medical record and telephone interview. In total, 202 patients with enough plasma samples at time of surgery were included. There were 195 patients who provided baseline plasma and survival information included in the current study. Plasma omega-3 PUFAs were measured by GC-FID. Cox Proportional Hazard model adjusted for potential cofounders was used to estimate HRs and 95% CIs. RESULTS: Median follow-up time for patients was 58 months after surgery. A total of 13 recurrences and 11 all-cause deaths, of which, 2 deaths from EC, were identified. Level of plasma EPA was higher in recurrent patients than total patients (0.78% vs 0.51%, P = 0.015). Higher plasma eicosapentaenoic acid (EPA) level trended to have positive association with EC recurrence (P-trend = 0.04), although comparing to the lowest tertile, the highest tertile of EPA level was not significantly associated with increased risk of EC recurrence (HRT3vsT1 = 6.02; 95%CI = 0.7-52.06). The association between total omega-3 PUFA and EC recurrence tended to be stronger among patients with deeper myometrial invasion (OR = 3.41; 95%CI = 1.06-10.95; P-interaction = 0.04). CONCLUSIONS: Higher plasma EPA level was significantly associated with EC recurrence. Further studies are warranted to confirm these findings. TRIAL REGISTRATION: ChiCTR1900025418; Retrospectively registered (26 August 2019); Chinses Clinical Trial Registry.

Dietary Fiber Intake and Endometrial Cancer Risk: A Systematic Review and Meta-Analysis.

Epidemiological studies are inconclusive regarding the association between dietary fiber intake and endometrial cancer risk. Thus, we aimed to conduct a meta-analysis to clarify the association between dietary fiber and endometrial cancer risk. We searched the PubMed and ISI Web databases for relevant studies through March 2018. The association between dietary fiber and endometrial cancer risk was evaluated by conducting a meta-analysis including 3 cohort and 12 case⁻control studies. A significant negative association was observed between total dietary fiber intake and endometrial cancer risk in 11 case⁻control studies (odds ratios (OR) 0.76, 95% confidence interval (CI): 0.64⁻0.89, I² = 35.2%, p = 0.117), but a marginal positive association was observed in three cohort studies (relative risk (RR) 1.22, 95% CI: 1.00⁻1.49, I² = 0.0%, p = 0.995). Particularly, a negative association was observed in North America (OR = 0.70, 95% CI: 0.59⁻0.83, I² = 8.9%, p = 0.362). In addition, a positive association was observed in cereal fiber (RR = 1.26, 95% CI: 1.03⁻1.52, I² = 0.0%, p = 0.530, 3 cohort studies) and a negative association was observed in vegetable fiber (OR = 0.74, 95% CI: 0.58⁻0.94, I² = 0.0%, p = 0.445, 3 case⁻control studies). In conclusion, negative associations with endometrial cancer risk were observed for higher total dietary fiber intake and higher vegetable fiber intake in the case⁻control studies. However, results from the cohort studies suggested positive relationships of higher total fiber intake and higher cereal fiber intake with endometrial cancer risk.

Dairy Products Intake and Endometrial Cancer Risk: A Meta-Analysis of Observational Studies.

Observational studies have suggested inconsistent findings on the relationship between dairy products intake and endometrial cancer risk. This study aimed to conduct a meta-analysis to evaluate this correlation; moreover, databases including PubMed, ISI Web of Science, and Embase were screened for relevant studies up to 26 February 2017. The inverse variance weighting method and random effects models were used to calculate the overall OR (odds ratio) values and 95% confidence interval (CI). A total of 2 cohort study and 16 case-control studies were included in the current analysis. No significant association was observed between endometrial cancer risk and the intake of total dairy products, milk, or cheese for the highest versus the lowest exposure category (total dairy products (14 studies): OR 1.04, 95% CI: 0.97-1.11, I² = 73%, p = 0.000; milk (6 studies): 0.99, 95% CI: 0.89-1.10, I² = 0.0%, p = 0.43; cheese (5 studies): 0.89, 95% CI: 0.76-1.05, I² = 39%, p = 0.16). The only cohort study with a total of 456,513 participants reported a positive association of butter intake with endometrial cancer risk (OR = 1.14; 95% CI = 1.03-1.26, I² = 2.6%, p = 0.31). There was a significant negative association of dairy products intake and endometrial cancer risk among women with a higher body mass index (BMI) (5 studies, OR 0.66, 95% CI = 0.46-0.96, I² = 75.8%, p = 0.002). Stratifying the analyses by risk factors including BMI should be taken into account when exploring the association of dairy products intake with endometrial cancer risk. Further well-designed studies are needed.

The Effect and Action Mechanisms of Oligochitosan on Control of Stem Dry Rot of Zanthoxylum bungeanum.

In this report, the effects of two oligochitosans, i.e., oligochitosan A (OCHA) and oligochitosan B (OCHB), on control of dry rot of Zanthoxylum bungeanum (Z. bungeanum) caused by Fusarium sambucinum (F. sambucinum) were evaluated. First, both oligochitosans show desirable ability to decrease the infection of F. sambucinum. Second, the oligochitosans strongly inhibit the radial colony and submerged biomass growth of F. sambucinum. Lastly, these oligochitosans are capable of increasing the activities of phenylalanine ammonia lyase (PAL), polyphenoloxidase (PPO) and peroxidase (POD) significantly, as well as enhancing the content of total phenolics in Z. bungeanum stems. These findings indicate that the protective effects of OCHA and OCHB on Z. bungeanum stems against dry rot may be associated with the direct fungitoxic function against pathogen and the elicitation of biochemical defensive responses in Z. bungeanum stems. The outcome of this report suggests that oligochitosans may serve as a promising natural fungicide to substitute, at least partially, for synthetic fungicides in the disease management of Z. bungeanum.

[Expression of circadian gene NPAS2 in colorectal cancer and its prognostic significance].

OBJECTIVE: To study the expression of NPAS2 in colorectal cancer (CRC) and analyze its relationship with the clinicopathological parameters and prognosis of the patients. METHODS: Real-time q-PCR was used to detect the expression of NPAS2 mRNA in 40 fresh CRC tissues and paired adjacent tissues; immunohistochemistry was used to detect the expression of NPAS2 protein in 120 paraffin-embedded tumor and adjacent tissues. The relationship between NPAS2 expression level and the 5-year survival rate of 78 CRC patients with follow-up data were analyzed with Kaplan-Meier survival analysis. RESULTS: Compared with the adjacent tissues, fresh CRC tissue expressed significantly lower NPAS2 mRNA levels (P<0.01). Among the paraffin-embedded CRC tissues, 19.2% were positive for NPAS2 expression, as compared to a much higher rate of 62.5% in the adjacent tissues (P<0.05). The expression of NPAS2 was correlated with the tumor size, lymph node metastasis and TNM stages (P<0.05) but not with the patients' gender, age, distant tumor metastasis, differentiation, or invasion. Patients with high NPAS2 expression levels had a significantly higher 5-year survival rate than those with low NPAS2 expressions (P=0.0001). CONCLUSION: NPAS2 is down-regulated in CRC and closely correlated with the malignant biological behavior of the tumor and 5-year survival of the patients, suggesting its value in predicting the prognosis of the CRC patients.

Betaine prevented fructose-induced NAFLD by regulating LXRα/PPARα pathway and alleviating ER stress in rats.

Betaine has been proven effective in treating nonalcoholic fatty liver disease (NAFLD) in animal models, however, its molecular mechanisms remain elusive. The aims of this study were to explore the mechanisms mediating the anti-inflammatory and anti-lipogenic actions of betaine in fructose-fed rats. In this study, betaine improved insulin resistance, reduced body weight gain and serum lipid levels, and prevented hepatic lipid accumulation in fructose-fed rats. It up-regulated hepatic expression of liver X receptor-alpha (LXRα) and peroxisome proliferator-activated receptor-alpha (PPARα), with the attenuation of the changes of their target genes, including hepatic carnitine palmitoyl transferase (CPT) 1α, glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1, apolipoprotein B, sterol regulatory element-binding protein 1c and adipocyte differentiation-related protein, involved in fatty acid oxidation and lipid storage in these model rats. Furthermore, betaine alleviated ER stress and inhibited acetyl-CoA carboxylase α, CPT II, stearoyl-CoA desaturase 1 and fatty acid synthase expression involved in fatty acid synthesis in the liver of fructose-fed rats. Betaine suppressed hepatic gluconeogenesis in fructose-fed rats by moderating protein kinase B -forkhead box protein O1 pathway, as well as p38 mitogen-activated protein kinase and mammalian target of rapamycin activity. Moreover, betaine inhibited hepatic nuclear factor kappa B /nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome activation-mediated inflammation in this animal model. These results demonstrated that betaine ameliorated hepatic lipid accumulation, gluconeogenesis, and inflammation through restoring LXRα and PPARα expression and alleviating ER stress in fructose-fed rats. This study provides the potential mechanisms of betaine involved in the treatment of NAFLD.

Effects of oligosaccharides from endophytic Fusarium oxysporum Dzf17 on activities of defense-related enzymes in Dioscorea zingiberensis suspension cell and seedling cultures

Background Three oligosaccharides (EOS, WOS and SOS) were respectively prepared from the corresponding polysaccharides, namely exopolysaccharide (EPS), water-extracted mycelial polysaccharide (WPS) and sodium hydroxide-extracted mycelial polysaccharides (SPS) from the endophytic fungus Fusarium oxysporum Dzf17. In this study, the effects of EOS, WOS and SOS on the activities of the defense-related enzymes, namely phenylalanine ammonia lyase (PAL), polyphenoloxidase (PPO) and peroxidase (POD) in its host plant Dioscorea zingiberensis cultures were investigated. Results For the suspension cell cultures of D. zingiberensis, the highest PAL activity was induced by 0.5 mg/mL of WOS at 48 h after treatment, which was 4.55-fold as that of control. Both PPO and POD activities were increased to the maximum values by 0.25 mg/mL of WOS at 48 h after treatment, which were respectively 3.74 and 3.45-fold as those of control. For the seedling cultures, the highest PAL activity was elicited by 2.5 mg/mL of EOS at 48 h after treatment, which was 3.62-fold as that of control. Both PPO and POD reached their maximum values treated with 2.5 mg/mL of WOS at 48 h after treatment, which were 4.61 and 4.19-fold as those of control, separately. Conclusions Both EOS and WOS significantly increased the activities of PAL, PPO and POD in the suspension cell and seedling cultures of D. zingiberensis. The results suggested that the oligosaccharides from the endophytic fungus F. oxysporum Dzf17 may be related to the activation and enhancement of the defensive mechanisms of D. zingiberensis suspension cell and seedling cultures.