Sarcandra glabra (Thunb.) Nakai alleviates DSS-induced ulcerative colitis by promoting restitution, restoring barrier function, and modulating IL-17/Notch1/FoxP3 pathway in intestinal cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Sarcandra glabra is officially named Zhong Jie Feng as a traditional medicine. In the nationality of Yao and Zhuang, it has been used to treat digestive diseases like stomachache and dysentery. Similarly, in Dai nationality, it has been used to treat intestinal diseases like gastric ulcers. However, the effect and mechanism of S. glabra on experimental ulcerative colitis (UC) are known. AIM OF STUDY: The main objective of this study was to investigate the effect and mechanism of S. glabra on experimental UC. MATERIALS AND METHODS: The chemical components in the water extract of S. glabra (ZJF) were analyzed by UPLC-MS/MS method. The HCoEpiC cell line was used to assess the promotive effect on intestinal proliferation and restitution. RAW264.7 cells were used to assess the in vitro anti-inflammatory effect of ZJF. The 3% DSS-induced colitis model was used to evaluate the in vivo effect of ZJF (4.5 g/kg and 9.0 g/kg). Mesalazine (0.5 g/kg) was used as the positive drug. ELISA, RT-qPCR, Western blot, and multiplex immunohistochemical experiments were used to test gene levels in the colon tissue. The H&E staining method was used to monitor the pathological changes of colon tissue. TUNEL assay kit was used to detect apoptosis of epithelial colonic cells. RESULTS: ZJF could alleviate the DSS-caused colitis in colon tissues, showing a comparative effect to that of the positive drug mesalazine. Mechanism study indicated that ZJF could promote normal colonic HCoEpiC cell proliferation and restitution, inhibit overexpression of pro-inflammatory cytokines, restore the M1/M2 ratio, decrease epithelial colonic cell apoptosis, rescue tight junction protein levels, and modulate IL-17/Notch1/FoxP3 pathway to treat experimental UC. CONCLUSION: Our results indicated that S. glabra can promote intestinal cell restitution, balance immune response, and modulate IL-17/Notch1/FoxP3 pathway to treat experimental UC.

Impact of Drp1-regulated changes in T cell activity on the combined antitumor effects of PARPi and PD-1 inhibitors.

This study aimed to investigate the influence of dynamin-related protein 1 (Drp1)-regulated T cells on the antitumor effects of poly (ADP-ribose) polymerase inhibitors (PARPi) combined with programmed cell death protein 1 (PD-1) inhibitors to identify potential targets for enhancing immunotherapy efficacy. We found that T cells with high expression of Drp1 promoted the inhibitory and killing effects of the PARPi and PD-1 inhibitor combination on lung cancer cells in vivo and in vitro. This synergistic mechanism involves Drp1-regulated promotion of activation, migration, and intratumor infiltration of effector T cells; inhibition of negative immunomodulatory cells in the tumor microenvironment; and suppression of PARPi-induced upregulation of PD-L1 expression in tumor cells. These findings suggest that Drp1 could serve as a new target for comprehensively improving the tumor microenvironment, enhancing immunotherapy efficacy, and reversing immunotherapy resistance.

Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer.

BACKGROUND: Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays important roles in the activation, proliferation, and migration of T cells. METHODS: We investigated the synergistic effect of Drp1-mediated T cell antitumor activities and programmed cell death protein 1 (PD-1) blockade for treating lung cancer through in vitro co-culture experiments and an in vivo nude mouse xenograft model. RESULTS: High expression levels of Drp1 positively regulated T cell activation, enhanced T cell-induced suppression of lung cancer cells, promoted CD8+ T cell infiltration in the tumor and spleen, and significantly enhanced the antitumor immune response of the PD-1 inhibitor pembrolizumab. The mechanism of this synergistic antitumor effect involved the secretion of immune killing-related cytokines and the regulation of the PD-1-ERK/Drp1 pathway in T cells. CONCLUSIONS: Our findings suggest that modifying Drp1 expression in T cells could serve as a potential therapeutic target for enhancing the antitumor immune response in future immunotherapies.

Oridonin attenuated human PC-3 cell activity by modulating the Wnt/ß-catenin signaling.

BACKGROUND: Prostate cancer (PC) prevention is effectively achieved through its inhibition. Oridonin (ORD), an active diterpenoid isolated from Rabdosia rubescens, has been shown to have an inhibitory effect on PC cells, although its impact on PC is unknown. OBJECTIVES: The present work investigated the actions and probable mechanisms of ORD on cellular proliferation, apoptosis, PC, and the wingless-type MMTV integration site family member 2 (Wnt)/ß-catenin signaling pathway using the androgen-independent PC-3 cell line. MATERIAL AND METHODS: In this study, cell viability was analyzed with MTT assay method, apoptotic morphology determined using DAPI dye method, while protein (CD1333, OCT-4, Nanog, SOX-2 & Aldh1A1) and mRNA expressions were analyzed with western blotting and real time polymerase chain reaction (PCR). RESULTS: We demonstrated a concentration-dependent ORD inhibition of PC-3 cell proliferation and inhibition of induction apoptosis. Furthermore, ORD decreased PC-3 Wnt-2, phosphorylated glycogen synthase kinase-3 (p-GSK3), and ß-catenin protein levels and downregulated cyclin-D1 and c-myc messenger ribonucleic acid (mRNA). CONCLUSIONS: Oridonin inhibited proliferation and induced apoptosis in PC-3 cells, with the findings suggesting that it acted via the Wnt/ß-catenin pathway to exert its effects. This study demonstrates that ORD may impact PC.

Pirfenidone inhibits TGF-ß1-induced metabolic reprogramming during epithelial-mesenchymal transition in non-small cell lung cancer.

Metastasis is an important contributor to increased mortality rates in non-small cell lung cancer (NSCLC). The TGF-ß signalling pathway plays a crucial role in facilitating tumour metastasis through epithelial-mesenchymal transition (EMT). Glycolysis, a key metabolic process, is strongly correlated with NSCLC metastasis. Pirfenidone (PFD) has been shown to safely and effectively inhibit TGF-ß1 in patients with lung diseases. Furthermore, TGF-ß1 and glycolysis demonstrate an interdependent relationship within the tumour microenvironment. Our previous study demonstrated that PFD effectively inhibited glycolysis in NSCLC cells, prompting further investigation into its potential antitumour effects in this context. Therefore, the present study aims to investigate the potential antitumour effect of PFD in NSCLC and explore the relationship among TGF-ß1, glycolysis and EMT through further experimentation. The antitumour effects of PFD were evaluated using five different NSCLC cell lines and a xenograft tumour model. Notably, PFD demonstrated a significant antitumour effect specifically in highly glycolytic H1299 cells. To elucidate the underlying mechanism, we compared the efficacy of PFD after pretreatment with either TGF-ß1 or a TGF-ß receptor inhibitor (LY2109761). The energy metabolomics analysis of tumour tissue demonstrated that PFD, a chemosensitizing agent, reduced lactate and ATP production, thereby inhibiting glycolysis and exerting synergistic antineoplastic effects. Additionally, PFD combined with cisplatin targeted TGF-ß1 to inhibit glycolysis during EMT and enhanced the chemosensitization of A549 and H1299 cells. The magnitude of the anticancer effect exhibited by PFD was intricately linked to its metabolic properties.

In vitro and in vivo killing effects of methionine enkephalin on osteosarcoma.

OBJECTIVE: This study aimed to investigate the underlying regulatory effects of methionine enkephalin (MENK) on osteosarcoma. METHODS: The Cell Counting Kit-8 assay, clone formation, wound healing, transwell assay, and flow cytometry were performed to measure the effects of MENK on the proliferation, migration, invasion, and apoptosis of MG-63 and Saos-2 cells. Opiate growth factor receptor expression (OGFr) in cells was stably knocked down using siRNA. A tumor model was established by inoculating MG-63 cells into mice. Flow cytometry was performed to identify alterations in mice bone marrow, spleen, and tumor tissue immune cells. The phenotype of tumor-associated macrophages was determined using immunohistochemistry. After OGFr knockdown or/and treatment with MENK, Bax, Bcl-2, caspase 3, caspase 9, and PARP expression levels were characterized using qRT-PCR, western blot, and WES, respectively. RESULTS: MENK could significantly inhibit the proliferation, invasion, and migration of MG-63 and Saos-2, arrest the cell cycle in the G0/G1 phase, upregulate Bax, caspase 3, caspase 9, and PARP expression, and downregulate Bcl-2 expression. Tumor size and weight were lower in the MENK group than those in the control group. MENK-treated mice exhibited a reduced ratio of CD11b + Gr-1 + myeloid-derived suppressor cells. MENK increased the ratio of M1-type macrophages and decreased the proportion of M2-type macrophages in tumor tissue. Furthermore, the level of TNF-α significantly increased while that of IL-10 decreased in MENK-treated mice. The effect of MENK could be partly reversed by OGFr knockdown. CONCLUSION: MENK reduces the abundance of myeloid-derived suppressor cells, induces M1 polarization of macrophages, and exhibits an inhibitory effect on osteosarcoma.

Exploring the Molecular Mechanism of Niuxi-Mugua Formula in Treating Coronavirus Disease 2019 via Network Pharmacology, Computational Biology, and Surface Plasmon Resonance Verification.

BACKGROUND: In China, Niuxi-Mugua formula (NMF) has been widely used to prevent and treat coronavirus disease 2019 (COVID-19). However, the mechanism of NMF for treating COVID-19 is not yet fully understood. OBJECTIVE: This study aimed to explore the potential mechanism of NMF for treating COVID-19 by network pharmacology, computational biology, and surface plasmon resonance (SPR) verification. METHODS: The NMF-compound-target network was constructed to screen the key compounds, and the Molecular Complex Detection (MCODE) tool was used to screen the preliminary key genes. The overlapped genes (OGEs) and the preliminary key genes were further analyzed by enrichment analysis. Then, the correlation analysis of immune signatures and the preliminary key genes was performed. Molecular docking and molecular dynamic (MD) simulation assays were applied to clarify the interactions between key compounds and key genes. Moreover, the SPR interaction experiment was used for further affinity kinetic verification. RESULTS: Lipid and atherosclerosis, TNF, IL-17, and NF-kappa B signaling pathways were the main pathways of NMF in the treatment of COVID-19. There was a positive correlation between almost the majority of immune signatures and all preliminary key genes. The key compounds and the key genes were screened out, and they were involved in the main pathways of NMF for treating COVID-19. Moreover, the binding affinities of most key compounds binding to key genes were good, and IL1B-Quercetin had the best binding stability. SPR analysis further demonstrated that IL1B-Quercetin showed good binding affinity. CONCLUSION: Our findings provided theoretical grounds for NMF in the treatment of COVID19.

Rational application of EGFR-TKI adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant NSCLC: a systematic review and meta-analysis of 11 randomized controlled trials.

PURPOSE: To determine the role and rational application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant non-small-cell lung cancer (NSCLC). METHOD: Randomized controlled trials (RCTs) that compared the survival outcomes between adjuvant EGFR-TKIs and adjuvant chemotherapy or a placebo, or between different EGFR-TKI treatment durations for resected NSCLC, were eligible for inclusion. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated as effective measures using random-effect or fixed-effect models. Subgroup analysis was also performed. RESULTS: Eleven RCTs involving 2102 EGFR-mutant NSCLC patients with or without EGFR-TKI adjuvant therapy were included. For all stage IB-IIIA NSCLC patients, EGFR-TKIs adjuvant therapy could not only significantly improve DFS (HR 0.43, 95% CI 0.30-0.63, P < 0.001) and 2- and 3-year DFS rates, but also improve OS (HR 0.72, 95% CI, 0.54-0.96, P = 0.024), compared with chemotherapy or the placebo. Further subgroup analyses indicated prolonged OS from first-generation EGFR-TKI adjuvant therapy in stage III patients, compared with chemotherapy or the placebo (HR for OS, 0.34; 95% CI, 0.18-0.63; P = 0.001). Of note, osimertinib adjuvant therapy led to the OS benefit expanding from stage III to stage II-III patients, with significantly improved DFS and a lower risk of brain recurrence, compared with the placebo. A 2-year treatment duration with EGFR-TKI adjuvant therapy showed a significantly lower recurrence risk than a ≤ 1-year duration. CONCLUSION: The DFS advantage from first-generation EGFR-TKI adjuvant therapy can translate into an OS benefit in stage III NSCLC patients. Osimertinib might be more suitable for adjuvant therapy than first-generation EGFR-TKIs, because of the lower recurrence rate and the potential OS benefit even in early-stage patients. The optimal treatment duration for EGFR-TKIs at different stages of disease needs to be validated.

Effect of aerobic exercise on GRP78 and ATF6 expressions in mice with non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent medical condition with an ever-growing trend. Although multiple intracellular mechanisms are involved, endoplasmic reticulum (ER) stress has been demonstrated to play a significant role in the genesis and progression. Most of the research supports the advantages of exercise for NAFLD. However, little is known about the molecular mechanism(s) that underpin the effectiveness of exercise training in NAFLD. This study aimed to identify how aerobic exercise affected hepatic ER stress in a mouse NAFLD model. In this study, the mice were fed either a standard diet (SD) or a high-fat diet (HFD) for 17 weeks. HFD mice were trained on a treadmill during the last eight weeks. All animals were tested for serum levels of biochemical assays, protein expression, and gene expression. The hematoxylin and eosin, Oil red O, and immunohistochemistry staining were also performed. The results indicated that a high-fat diet generated NAFLD, with serum lipid disruption and hepatic function impairment, and increased GRP78 and ATF6 expressions. However, aerobic training reversed the majority of these alterations. It is concluded that NAFLD appears to be associated with hepatic ER stress response, and aerobic exercise mitigates NAFLD via lowering ER stress proteins GRP78 and ATF6.

Glycolate oxidase gene family identification and functional analyses in cotton resistance to Verticillium wilt.

Glycolate oxidase (GOX) plays an important role in the regulation of photorespiration and photosynthesis in plants. However, as one of the main enzymes to produce the second messenger hydrogen peroxide (H2O2), its functions in response to pathogens are still poorly understood. In this study, we carried out genome-wide identification, and 14 GOX genes were identified in Gossypium hirsutum. These GOX genes are located on 10 chromosomes and divided into hydroxyacid-oxidases (HAOX) and GOX groups. After infection with Verticillium dahliae Kleb., six GOX gene expression levels were changed. Moreover, H2O2, salicylic acid (SA), and the content and activity of GOX increased in cotton. GhHAOX2-D-silenced plants showed more wilting than control plants after infection with V. dahliae. Additionally, H2O2 accumulation and SA content were reduced in GhHAOX2-D-silenced plants. The expression levels of GhPAL, GhPAD4, and GhPR1 and the lignin content of the silenced plants were significantly lower than those of the control plants. These results indicate that GhHAOX2-D is a positive regulator of Verticillium wilt tolerance in cotton and may promote H2O2 accumulation via the synergistic effects of GOX genes and SA. Collectively, GOX genes play an important role in cotton resistance to Verticillium wilt.

Acute myeloid leukemia (AML)-derived mesenchymal stem cells induce chemoresistance and epithelial-mesenchymal transition-like program in AML through IL-6/JAK2/STAT3 signaling.

Acute myeloid leukemia (AML) has a high rate of treatment failure due to increased prevalence of therapy resistance. Mesenchymal stem cells (MSCs) in the leukemia microenvironment contribute to chemoresistance in AML, but the specific mechanism remains unclear. The critical role of the epithelial-mesenchymal transition (EMT)-like profile in AML chemoresistance has been gradually recognized. However, there is no research to suggest that the AML-derived bone marrow mesenchymal stem cells (AML-MSCs) induce the EMT program in AML thus far. We isolated AML-MSCs and cocultured them with AML cells. We found that AML-MSCs induced a significant mesenchymal-like morphology in drug-resistant AML cells, but it was scarce in parental AML cells. The AML-MSCs promoted growth of AML cells in the presence or absence of chemotherapeutics in vitro and in vivo. Acute myeloid leukemia MSCs also induced EMT marker expression in AML cells, especially in chemoresistant AML cells. Mechanistically, AML-MSCs secreted abundant interleukin-6 (IL-6) and upregulated IL-6 expression in AML cells. Acute myeloid leukemia cells upregulated IL-6 expression in AML-MSCs in turn. Meanwhile, AML-MSCs activated the JAK2/STAT3 pathway in AML cells. Two JAK/STAT pathway inhibitors counteracted the AML-MSCs induced morphology change and EMT marker expression in AML cells. In conclusion, AML-MSCs not only promote the emergence of chemoresistance but also enhance it once AML acquires chemoresistance. AML-MSCs induce EMT-like features in AML cells; this phenotypic change could be related to chemoresistance progression. AML-MSCs induce the EMT-like program in AML cells through IL-6/JAK2/STAT3 signaling, which provides a therapeutic target to reverse chemoresistance in AML.

The m6A modulator-mediated cytarabine sensitivity and immune cell infiltration signature in acute myeloid leukemia.

PURPOSE: The study aims to investigate the impact of m6A modulators on drug resistance and the immune microenvironment in acute myeloid leukemia (AML). The emergence of drug resistance is a significant factor that contributes to relapse and refractory AML, leading to a poor prognosis. METHODS: The AML transcriptome data were retrieved from the TCGA database. The "oncoPredict" R package was utilized to assess the sensitivity of each sample to cytarabine (Ara-C) and classify them into distinct groups. Differential expression analysis was performed to identify m6A modulators differentially expressed between the two groups. Select Random Forest (RF) to build a predictive model. Model performance was evaluated using calibration curve, clinical decision curve, and clinical impact curve. The impacts of METTL3 on Ara-C sensitivity and immune microenvironment in AML were examined using GO, KEGG, CIBERSORT, and GSEA analyses. RESULTS: Seventeen out of 26 m6A modulators exhibited differential expression between the Ara-C-sensitive and resistant groups, with a high degree of correlation. We selected the 5 genes with the highest scores in the RF model to build a reliable and accurate prediction model. METTL3 plays a vital role in m6A modification, and further analysis shows its impact on the sensitivity of AML cells to Ara-C through its interaction with 7 types of immune-infiltrating cells and autophagy. CONCLUSION: This study utilizes m6A modulators to develop a prediction model for the sensitivity of AML patients to Ara-C, which can assist in treating AML drug resistance by targeting mRNA methylation.

Drug combinations identified by high-throughput screening promote cell cycle transition and upregulate Smad pathways in myeloma.

Drug resistance and disease progression are common in multiple myeloma (MM) patients, underscoring the need for new therapeutic combinations. A high-throughput drug screen in 47 MM cell lines and in silico Huber robust regression analysis of drug responses revealed 43 potentially synergistic combinations. We hypothesized that effective combinations would reduce MYC expression and enhance p16 activity. Six combinations cooperatively reduced MYC protein, frequently over-expressed in MM and also cooperatively increased p16 expression, frequently downregulated in MM. Synergistic reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines, while sparing fibroblasts. Three combinations significantly prolonged survival in a transplantable Ras-driven allograft model of advanced MM closely recapitulating high-risk/refractory myeloma in humans and reduced viability of ex vivo treated patient cells. Common genetic pathways similarly downregulated by these combinations promoted cell cycle transition, whereas pathways most upregulated were involved in TGFß/SMAD signaling. These preclinical data identify potentially useful drug combinations for evaluation in drug-resistant MM and reveal potential mechanisms of combined drug sensitivity.

Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor.

Poly (ADP-ribose)-polymerases (PARPs) play an essential role in the maintenance of genome integrity, DNA repair, and apoptosis. PARP inhibitors (PARPi) exert antitumor effects via synthetic lethality and PARP trapping. PARPi impact the antitumor immune response by modulating the tumor microenvironment, and their effect has dual properties of promoting and inhibiting the antitumor immune response. PARPi promote M1 macrophage polarization, antigen presentation by dendritic cells, infiltration of B and T cells and their killing capacity and inhibit tumor angiogenesis. PARPi can also inhibit the activation and function of immune cells by upregulating PD-L1. In this review, we summarize the dual immunomodulatory effects and possible underlying mechanisms of PARPi, providing a basis for the design of combination regimens for clinical treatment and the identification of populations who may benefit from these therapies.

Intravoxel incoherent motion imaging used to assess tumor microvascular changes after transarterial chemoembolization in a rabbit VX2 liver tumor model.

Purpose: To evaluate the correlation between microvascular density (MVD) and intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) parameters and the effect of glycolytic flux after transarterial chemoembolization (TACE) in a rabbit VX2 liver tumor. Materials and methods: VX2 liver tumor allografts in 15 New Zealand white rabbits were treated with sterile saline (control group, n = 5) or lipiodol-doxorubicin emulsion (experimental group, n = 10). MRI was performed 2 weeks after the procedure to evaluate IVIM parameters, including apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (PF). All animal samples were taken of the tumor and surrounding liver. Immunostaining for CD31, CD34, CD105, and VEGF was used to evaluate MVD. The protein expression of Glut4, HK2, PKM2, LDHA, and MCT1 was determined using western blotting. Pearson correlation tests were used to analyze the relationship between MVD and IVIM parameters. Results: D* value in the peritumoral region was negatively correlated with CD34 (r = -0.71, P = 0.01). PF value positively correlated with CD34 (r = 0.68, P = 0.015), CD105 (r = 0.76, P = 0.004) and VEGF (r = 0.72, P = 0.008) in the peritumoral region. Glut4, HK2, PKM2, and MCT1 in the peritumoral regions were higher in the experimental group than in the control group (all P < 0.05). Conclusion: IVIM parameters were correlated with MVD in the intratumoral and peritumoral regions after TACE in a rabbit liver tumor model. The angiogenesis reflected by MVD may be related to changes of glycolytic flux.

The transcription factor GhWRKY70 from gossypium hirsutum enhances resistance to verticillium wilt via the jasmonic acid pathway.

BACKGROUND: The WRKY transcription factors play significant roles in plant growth, development, and defense responses. However, in cotton, the molecular mechanism of most WRKY proteins and their involvement in Verticillium wilt tolerance are not well understood. RESULTS: GhWRKY70 is greatly up-regulated in cotton by Verticillium dahliae. Subcellular localization suggests that GhWRKY70 is only located in the nucleus. Transcriptional activation of GhWRKY70 further demonstrates that GhWRKY70 function as a transcriptional activator. Transgenic Arabidopsis plants overexpressing GhWRKY70 exhibited better growth performance and higher lignin content, antioxidant enzyme activities and jasmonic acid (JA) levels than wild-type plants after infection with V. dahliae. In addition, the transgenic Arabidopsis resulted in an enhanced expression level of AtAOS1, a gene related to JA synthesis, further leading to a higher JA accumulation compared to the wild type. However, the disease index (DI) values of the VIGS-treated cotton plants with TRV:WRKY70 were also significantly higher than those of the VIGS-treated cotton plants with TRV:00. The chlorophyll and lignin contents of TRV:WRKY70 plants were significantly lower than those of TRV:00 plants. GhAOS1 expression and JA abundance in TRV:WRKY70 plants were decreased. The GhWRKY70 protein was confirmed to bind to the W-box element in the promoter region of GhAOS by yeast one-hybrid assay and transient expression. CONCLUSION: These results indicate that the GhWRKY70 transcription factor is a positive regulator in Verticillium wilt tolerance of cotton, and may promote the production of JA via regulation of GhAOS1 expression.

Methionine enkephalin suppresses lung cancer metastasis by regulating the polarization of tumor-associated macrophages and the distribution of myeloid-derived suppressor cells in the tumor microenvironment and inhibiting epithelial-mesenchymal transition.

Metastasis is one of the most difficult challenges for clinical lung cancer treatment. Epithelial-mesenchymal transition (EMT) is the crucial step of tumor metastasis. Immune cells in the tumor microenvironment (TME), such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), promote cancer cell EMT. In this study, we explored the effect of methionine enkephalin (MENK) on the EMT process in vitro and in vivo, and its influence on TAMs, MDSCs, and associated cytokines in vivo. The results showed that MENK suppressed growth, migration, and invasion of lung cancer cells and inhibited the EMT process by interacting with opioid growth factor receptor. MENK reduced the number of M2 macrophages and MDSC infiltration, and downregulated the expression of interleukin-10 and transforming growth factor-ß1 in both primary and metastatic tumors of nude mice. The present findings suggest that MENK is a potential target for suppressing metastasis in lung cancer treatment.

Absorption, metabolism, bioactivity, and biotransformation of epigallocatechin gallate.

Epigallocatechin gallate (EGCG), a typical flavone-3-ol polyphenol containing eight free hydroxyl groups, is associated with a variety of bioactivities, such as antioxidant, anti-inflammatory, anti-cancer, and antibacterial activities. However, the poor bioavailability of EGCG restricts its use. In this review, we discuss the processes involved in the absorption and metabolism of EGCG, with a focus on its metabolic interactions with the gut microbiota. Next, we summarize the bioactivities of some key metabolites, describe the biotransformation of EGCG by different microorganisms, and discuss its catabolism by specific bacteria. A deeper understanding of the absorption, metabolism, and biotransformation of EGCG may enable its disease-preventive and therapeutic properties to be better utilized. This review provides a theoretical basis for further development and utilization of EGCG and its metabolites for improving the gut microbiota and physiological health.

Pirfenidone suppressed triple-negative breast cancer metastasis by inhibiting the activity of the TGF-ß/SMAD pathway.

Among breast cancer patients, metastases are the leading cause of death. Despite decades of effort, little progress has been made to improve the treatment of breast cancer metastases, especially triple-negative breast cancer (TNBC). The extracellular matrix plays an important role in tumour growth and metastasis by causing its deposition, remodelling, and signalling. As we know, the process of fibrosis results in excessive amounts of extracellular matrix being deposited within the cells. So, it will be interesting to study if the use of anti-fibrotic drugs in combination with conventional chemotherapy drugs can produce synergistic antitumor effects. In this study, we assessed the efficacy of Pirfenidone (PFD), an FDA-approved medication for the treatment of idiopathic pulmonary fibrosis, on TNBC cells as well as its anti-tumour effects in xenograft tumour model. PFD inhibited in a dose-dependent manner breast cancer cell proliferation, migration, and invasion, while promoted their apoptosis in vitro. PFD also suppressed TGF-ß-induced activation of Smad signalling pathway and expression level of EMT-inducing transcription factors (e.g. SNAI2, TWIST1, ZEB1) as well as the mesenchymal genes such as VIMENTIN and N-Cadherin. On the contrary, the expression level of epithelial marker gene E-Cadherin was up-regulated in the presence of PFD. In vivo, PFD alone exerted a milder but significant anti-tumour effect than the chemotherapy drug nanoparticle albumin-bound paclitaxel (nab-PTX) did in the breast cancer xenograft mouse model. Interestingly, PFD synergistically boosted the cancer-killing effect of nab-PTX. Furthermore, Our data suggest that PFD suppressed breast cancer metastasis by inhibiting the activity of the TGFß/SMAD pathway.

Relationship between Antithrombin III Activity and Mortality in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

We aimed to explore the role of antithrombin III (AT-III) activity in diagnosing patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and chronic bronchitis, and its relationship with all-cause mortality of AECOPD patients. We performed univariate and multivariate Cox regression analyses of the factors determining all-cause mortality. We recruited 279 patients with AECOPD and 91 with chronic bronchitis. On admission, patients with AECOPD had lower AT-III activity (80.7 vs. 86.35%, p = 0.002) and higher neutrophil percentages (70.12 vs. 66.40%, p = 0.02) than those with chronic bronchitis. The patients who died were older (78 vs. 73 years, p < 0.001); had higher CRP (39.05 vs. 5.65 mg/L, p < 0.001), D-dimer (1.72 vs. 0.46 mg/L, p < 0.001), FIB (3.56 vs. 3.05 g/L, p = 0.01) levels; and exhibited lower AT-III activity (71.29 vs. 82.94%, p < 0.001) than the survivors. The AT-III area under the receiver operating characteristic curve for predicting COPD all-cause mortality was 0.75 (p < 0.001), optimal cutoff point 79.75%, sensitivity 86.8%, and specificity 57.1%. Multivariate Cox regression analyses showed that increased levels of CRP (HR = 1.005, p = 0.02), D-dimer (HR = 1.17, p = 0.01), WBC count (HR = 1.11, p = 0.002), and reduced AT-III activity (HR = 0.97, p = 0.02) were independent prognostic factors for all-cause mortality. Patients with AT-III ≤ 79.75% were 4.52 times (p = 0.001) more likely to die than those with AT-III > 79.75%. AT-III activity was lower in patients with AECOPD than in those with chronic bronchitis and is potentially useful as an independent predictor of all-cause mortality in patients with AECOPD: reduced AT-III activity and increased CRP and D-dimer levels indicate a higher risk of all-cause mortality.