First insights into the bioaccumulation, biotransformation and trophic transfer of typical tetrabromobisphenol A (TBBPA) analogues along a simulated aquatic food chain.

Tetrabromobisphenol A (TBBPA) analogues have been investigated for their prevalent occurrence in environments and potential hazardous effects to humans and wildlife; however, there is still limited knowledge regarding their toxicokinetics and trophic transfer in aquatic food chains. Using a developed toxicokinetic model framework, we quantified the bioaccumulation, biotransformation and trophic transfer of tetrabromobisphenol S (TBBPS) and tetrabromobisphenol A di(allyl ether) (TBBPA-DAE) during trophic transfer from brine shrimp (Artemia salina) to zebrafish (Danio rerio). The results showed that the two TBBPA analogues could be readily accumulated by brine shrimp, and the estimated bioconcentration factor (BCF) value of TBBPS (5.68 L kg-1 ww) was higher than that of TBBPA-DAE (1.04 L kg-1 ww). The assimilation efficiency (AE) of TBBPA-DAE in zebrafish fed brine shrimp was calculated to be 16.3%, resulting in a low whole-body biomagnification factor (BMF) in fish (0.684 g g-1 ww). Based on the transformation products screened using ultra-high-performance liquid chromatograph-high resolution mass spectrometry (UPLC-HRMS), oxidative debromination and hydrolysis were identified as the major transformation pathways of TBBPS, while the biotransformation of TBBPA-DAE mainly took place through ether bond breaking and phase-II metabolism. Lower accumulation of TBBPA as a metabolite than its parent chemical was observed in both brine shrimp and zebrafish, with metabolite parent concentration factors (MPCFs) < 1. The investigated BCFs for shrimp of the two TBBPA analogues were only 3.77 × 10-10 - 5.59 × 10-3 times of the theoretical Kshrimp-water based on the polyparameter linear free energy relationships (pp-LFERs) model, and the BMF of TBBPA-DAE for fish was 0.299 times of the predicted Kshrimp-fish. Overall, these results indicated the potential of the trophic transfer in bioaccumulation of specific TBBPA analogues in higher trophic-level aquatic organisms and pointed out biotransformation as an important mechanism in regulating their bioaccumulation processes. ENVIRONMENTAL IMPLICATION: The internal concentration of a pollutant in the body determines its toxicity to organisms, while bioaccumulation and trophic transfer play important roles in elucidating its risks to ecosystems. Tetrabromobisphenol A (TBBPA) analogues have been extensively investigated for their adverse effects on humans and wildlife; however, there is still limited knowledge regarding their toxicokinetics and trophic transfer in aquatic food chains. This study investigated the bioaccumulation, biotransformation and trophic transfer of TBBPS and TBBPA-DAE in a simulated di-trophic food chain. This state-of-art study will provide a reference for further research on this kind of emerging pollutant in aquatic environments.

A Novel Ageladine A Derivative Acts as a STAT3 Inhibitor and Exhibits Potential Antitumor Effects.

The Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway controls multiple biological processes, including cell survival, proliferation, and differentiation. Abnormally activated STAT3 signaling promotes tumor cell growth, proliferation, and survival, as well as tumor invasion, angiogenesis, and immunosuppression. Hence, JAK/STAT3 signaling has been considered a promising target for antitumor therapy. In this study, a number of ageladine A derivative compounds were synthesized. The most effective of these was found to be compound 25. Our results indicated that compound 25 had the greatest inhibitory effect on the STAT3 luciferase gene reporter. Molecular docking results showed that compound 25 could dock into the STAT3 SH2 structural domain. Western blot assays demonstrated that compound 25 selectively inhibited the phosphorylation of STAT3 on the Tyr705 residue, thereby reducing STAT3 downstream gene expression without affecting the expression of the upstream proteins, p-STAT1 and p-STAT5. Compound 25 also suppressed the proliferation and migration of A549 and DU145 cells. Finally, in vivo research revealed that 10 mg/kg of compound 25 effectively inhibited the growth of A549 xenograft tumors with persistent STAT3 activation without causing significant weight loss. These results clearly indicate that compound 25 could be a potential antitumor agent by inhibiting STAT3 activation.

APOBEC3B expression has prognostic significance in cervical cancer.

OBJECTIVE: Cervical cancer is one of the leading fatal diseases in women, and the role of Apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) in cervical cancer is uncertain. METHODS: Four Gene Expression Omnibus (GEO) mRNA microarray datasets were analyzed to identify differentially expressed genes (DEGs) between cervical cancer and normal cervical tissues. The results were validated using a The Cancer Genome Atlas (TCGA)-cervical cancer (CESC) dataset. Expression profiles and patients' clinical data were used to investigate the relationship between APOBEC3B expression and cervical cancer survival. APOBEC3B co-expressed genes were subjected to enrichment analyses, and correlations between APOBEC3B expression and immunologic infiltrates were investigated using Tumor Immune Estimation Resource (TIMER). We generated receiver operating characteristic curve (ROC) curves to evaluate the performance of APOBEC3B expression in predicting cervical cancer prognosis. RESULTS: Fourteen overlapping DEGs were obtained, and APOBEC3B was chosen as a candidate gene. TCGA data further confirmed that APOBEC3B was significantly increased in cervical cancer, relative to normal adjacent tissues, and this expression was associated with poor clinical outcome. Results from quantitative real time polymerase chain reaction (RT-qPCR) and immunohistochemical staining of cervical carcinoma tissues supported these findings. Enrichment analysis showed that APOBEC3B co-expressed genes were mainly enriched in cell cycle, DNA replication and chromosomal region. Moreover, APOBEC3B expression was significantly associated with T stage, M stage, primary therapy outcome and poor clinical prognosis in cervical cancer. Similarly, APOBEC3B was closely correlated with gene markers of diverse immune cells. APOBEC3B expression was an independent indicator of cervical cancer prognosis, according to univariate Cox and ROC analyses. CONCLUSION: High APOBEC3B expression is strongly related to a poor prognosis in cervical cancer patients.

[Self-Aggregating Porphyrin-Based Photosensitizer Nano Micelles for Photodynamic Therapy].

Objective: To prepare supramolecular photosensitizer that can be retained at the site of tumors and that has high light conversion efficiency so as to improve the efficacy of tumor photodynamic therapy (PDT). Methods: A covalent organic framework material based on amino tetraphenyl porphyrin (Tapp), henceforth referred to as Tapp-COF, was synthesized. The spectral characteristics, energy gap characteristics and singlet oxygen generation ability of the material were characterized. Then, Tapp-COF was processed by thin film hydration method to derive T-C@PP, a nano micelle unstable in physiological environment. The same method was used to process Tapp in order to make T@PP micelles, which were used as the controls. The particle size, potential, surface morphology and stability were examined. B16F10 mouse melanoma cells were injected subcutaneously into C57 mice and T-C@PP or T@PP were injected intratumorally, followed by light exposure or no light exposure. We assessed the in vitro photodynamic killing efficiency of the nano micelles and the status of tumor cells co-cultured with the photosensitizer micelles and validated the tumor retention ability and killing efficiency of the micelles . Results: Compared with Tapp, Tapp-COF displayed higher photodynamic conversion efficiency, and could produce more ROS. The T-C@PP micelles were unstable in physiological environment, and adsorptive aggregation would occur after co-culturing with tumor cells for a period of time. T-C@PP showed low cytotoxicity when there was no light exposure, but could kill tumor cells at relatively low concentration under 660 nm laser irradiation. T-C@PP could be retained in tumor tissue, and had better in vivo killing efficiency that that of T@PP. Conclusion: In this study, highly efficient TPP-COF based T-C@PP micelles were prepared. Under physiological conditions, these micelles could achieve tumor retention through self-aggregation. Possessing sound safety, the nano micelles showed promise for potential application in tumor PDT.

Astragaloside trigger autophagy: Implication a potential therapeutic strategy for pulmonary fibrosis.

Pulmonary fibrosis is an abnormal wound-healing response to repeated alveolar injury, characterized by continuous inflammation and abnormal collagen deposition. Its treatment is problematic. Astragaloside (AST) is an active component of Astragalus membranaceus with anti-inflammatory and anti-tumor properties. Although the underlying mechanisms are unknown, AST is also used to treat fibrotic diseases. This study aimed to investigate the mechanisms of action of AST in pulmonary fibrosis treatment. We found that AST significantly improved restrictive ventilatory impairment, compliance, total lung capacity, and functional residual capacity. In mice with pulmonary fibrosis, extracellular matrix deposition in the pulmonary parenchyma and intemperate inflammation were reversed. This therapeutic effect can be attributed to autophagy, activating the genes for autophagy flux and autophagic vacuoles. Impaired autophagy increased susceptibility to pulmonary fibrosis by exacerbating collagen deposition in vitro and in vivo. Using a combination of molecular docking and network pharmacology, the Ras/Raf/MEK/ERK signaling pathway was identified as a possible candidate for the pharmacologic target of AST. Functional dephosphorylation of MEK and ERK inhibited the Ras/Raf/MEK/ERK signaling pathway, which converges at the rapamycin switch to initiate autophagy. Inhibitors of Ras and MEK regulated autophagy. These findings suggest that AST might treat pulmonary fibrosis by modulating the Ras/Raf/MEK/ERK signaling pathway mediated by depression.

Construction of an Integrated Device of a Self-Powered Biosensor and Matching Capacitor Based on Graphdiyne and Multiple Signal Amplification: Ultrasensitive Method for MicroRNA Detection.

The detection of microRNA (miRNA) in human serum has great significance for cancer prevention. Herein, a novel self-powered biosensing platform is developed, which effectively integrates an enzymatic biofuel cell (EBFC)-based self-powered biosensor with a matching capacitor for miRNA detection. A catalytic hairpin assembly and hybrid chain reaction are used to improve the analytical performance of EBFC. Furthermore, the matching capacitor is selected as an auxiliary signal amplifying device, and graphdiyne is applied as substrate material for EBFC. The results confirm that the developed method obviously increases the output current of EBFC, and the sensitivity can reach 2.75 µA/pM, which is 786% of pure EBFC. MiRNA can be detected in an expanded linear range of 0.1-100000 fM with a detection limit of 0.034 fM (S/N = 3). It can offer a selective and sensitive platform for nucleotide sequence detection with great potential in clinical diagnostics.

Gastrodia remodels intestinal microflora to suppress inflammation in mice with early atherosclerosis.

Atherosclsis is a critical actuator causing cardiac-cerebral vascular disease with a complicated pathogeneon, refered to the disorders of intestinal flora and persistent inflammation. Gastrodin (4-(hydroxymethyl) phenyl-ß-D- Glucopyranoside) is the most abundant glucoside extracted from the Gastrodiaelata, which is a traditional Chinese herbal medicine for cardiac-cerebral vascular disease, yet its mechanisms remain little known. In the present study, the gastrodia extract and gastrodin attenuate the lipid deposition and foam cells on the inner membrane of the inner membrane of the thoracic aorta in the early atherosclerosis mice. Blood lipid detection tips that TC and LDL-C were reduced in peripheral blood after treatment with the gastrodia extract and gastrodin. Furthermore, unordered gut microbes are remodeled in terms of bacterial diversity and abundance at family and genus level. Also, the intestinal mucosa damage and permeability were reversed, accompaniedwith the reducing of inflammatory cytokines. Our findings revealed that the functions of gastrodia extract and gastrodin in cardiac-cerebral vascular disease involved to rescued gut microbes and anti-inflammation may be the mechanismof remission lipid accumulation.

Induction of autophagy via the TLR4/NF-κB signaling pathway by astragaloside â £ contributes to the amelioration of inflammation in RAW264.7 cells.

Cigarette smoking-related lung injury is one of the most common and fatal etiologies of many respiratory diseases, for which no effective interventions are available. Astragaloside Ⅳ (ASⅣ) is an active component extracted from Astragalus membranaceus. It is prescribed as a treatment for upper respiratory tract infections. Here, we report the potential anti-inflammatory effects and mechanisms of ASⅣ on cigarette smoking extract- (CSE)-exposed RAW264.7 cells. Murine macrophages were exposed to CSE, followed by administration of ASⅣ at 25-100 µg/mL for 24 h. ASⅣ significantly rescued CSE-induced cell death by inhibition of release pro-inflammatory cytokines. We measured autophagy as an intracellular scavenger by analyzing autophagic flux using tandem mRFP-GFP-LC3 fluorescence microscopy. Following administration with ASⅣ in CSE-exposed RAW264.7 cells, there was a notable increase in autophagosomes and a range of autophagic vacuoles were generated, as seen with transmission electron microscopy. Loss of autophagy following transfection siRNA aggravated inflammatory injury and release of inflammatory cytokines. Mechanistically, ASⅣ-triggered autophagy is mediated by the TLR4/NF-κB signaling pathway to reduce inflammation. Taken together, our findings suggest that ASⅣ acts stimulates autophagy, and that ASⅣ induces autophagy by inhibiting the TLR4/NF-κB signaling pathway, contributing to alleviation of inflammation.

Computer modeling and in vitro experimental study of water-cooled microwave ablation array.

INTRODUCTION: Microwaves (MWs) quickly deliver relatively high temperatures into tumors and cover a large ablation zone. We present a research protocol for using water-cooled double-needle MW ablation arrays for tumor ablation here. MATERIAL AND METHODS: Our research program includes computer modeling, tissue-mimicking phantom experiments, and in vitro swine liver experiments. The computer modeling is based on the finite element method (FEM) to evaluate ablation temperature distributions. In tissue-mimicking phantom and in vitro swine liver ablation experiments, the performances of the new device and the single-needle MW device currently used in clinical practice are compared. RESULTS: FEM shows that the maximum transverse ablation diameter (MTAD) is 4.2 cm at 100 W output and 300 s (assessed at the 50 °C isotherm). In the tissue-mimicking phantom, the MTDA is 2.6 cm at 50 W and 300 s in single-needle MW ablation, and 4 cm in double needle MW ablation array. In in vitro swine liver experiments, the MTAD is 2.820 ± 0.127 cm at 100 W and 300 s in single-needle MW ablation, and 3.847 ± 0.103 cm in MW ablation array. CONCLUSION: A new type of water-cooled MW ablation array is designed and tested, and has potential advantages over currently used devices.

pH-Sensitive Near-IR Emitting Dinuclear Ruthenium Complex for Recognition, Two-Photon Luminescent Imaging, and Subcellular Localization of Cancer Cells.

A dinuclear Ru(II) complex of [(bpy)2Ru(Hdip)Ru(H2bip)](ClO4)4 {bpy is 2,2'-bipyridine, Hdip is 2-(2,6-di(pyridin-2-yl)-pyridin-4-yl)-1H-imidazo[4,5-f]-[1,10]phenanthroline, and H2bip is 2,6-bis(imidazole-2-yl)-pyridine} was synthesized and characterized by elemental analysis, mass spectrometry, and 1H NMR spectroscopy. Spectrophotometric pH titrations in aqueous buffer and in vitro cell experiments indicated the response ability of the complex to pH fluctuations in the physiological pH range (6.0-8.0). The complex was found to be capable of differentiating live HeLa cells from healthy HEK293 cells by selectively accumulating in lysosomes of the HeLa cells. The low cytotoxicity (IC50 > 100 µM), a large Stokes shift (∼200 nm), strong near-IR emission at ∼700 nm, a relatively long excited state lifetime, high photostability, and solubility make this complex considerably promising in real-time tracking and visualization of lysosomes in live cells. More interestingly, the tumor cell-specific two-photon luminescent imaging properties also endow this Ru complex with potential for applications in high-resolution tumor imaging and luminescence-guided tumor resection.

Recent Progress in Polynuclear Ruthenium Complex-Based DNA Binders/Structural Probes and Anticancer Agents.

Ruthenium complexes have stood out by several mononuclear complexes which have entered into clinical trials, such as imidazolium [trans-RuCl4(1H-imidazole)(DMSO-S)] (NAMI-A) and ([Ru(II)(4,4'-dimethyl-2,2'-bipyridine)2-(2(2'-,2'':5'',2'''-terthiophene)-imidazo[4,5-f] [1,10]phenanthroline)] 2+) (TLD-1433), opening a new avenue for developing promising ruthenium-based anticancer drugs alternative to Cisplatin. Polynuclear ruthenium complexes were reported to exhibit synergistic and/or complementary effects: the enhanced DNA structural recognition and DNA binding as well as in vitro anticancer activities. This review overviews some representative polynuclear ruthenium complexes acting as DNA structural probes, DNA binders and in vitro anticancer agents, which were developed during last decades. These complexes are reviewed according to two main categories of homo-polynuclear and hetero-polynuclear complexes, each of which is further clarified into the metal centers linked by rigid and flexible bridging ligands. The perspective, challenges and future efforts for investigations into these exciting complexes are pointed out or suggested.

Near-IR/Visible-Emitting Thiophenyl-Based Ru(II) Complexes: Efficient Photodynamic Therapy, Cellular Uptake, and DNA Binding.

Near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes that hold great application potentials as photodynamic therapy and/or photodetection agents for cancers have been poorly explored. In this paper, the solvatochromism, calf thymus DNA binding, and singlet oxygen generation properties of a known ruthenium(II) complex of visible-emitting [Ru(bpy)2(dtdpq)](ClO4)2 (Ru1) and a new homoleptic complex of near-IR-emitting [Ru(dtdpq)3](ClO4)2 (Ru2) (bpy = 2,2'-bipyridine, dtdpq = 2,3-bis(thiophen-2-yl)pyrazino[2,3-f][1,10]phenanothroline) in water are reported. Moreover, DNA photocleavage, singlet oxygen generation in HeLa cells, cellular uptake/localization, and in vitro photodynamic therapy for cancer cells of water-soluble Ru1 are described in detail. The results show that Ru1 acted as potent photodynamic cancer therapy and mitochondrial imaging agents. Ru2 exhibited very strong solvatochromism from a visible emission maximum at 588 nm in CH2Cl2 to the near-IR region at 700 nm in water and singlet oxygen generation yield in water (23%) and DNA binding properties (intercalative DNA binding constant on the order of 106 M-1) comparable to those of Ru1, which should make Ru2 attractive for the aforementioned applications of Ru1 if the water solubility of Ru2 can be improved enough for the studies above.

Photodynamic therapy as salvage therapy for residual microscopic cancer after ultra-low anterior resection: A case report.

BACKGROUND: The rate of positive resection margins (R1) in patients with low rectal cancer is substantial. Recommended remedies such as extended resection or chemoradiotherapy have their own serious drawbacks. It has been reported that photodynamic therapy (PDT) as a remedial treatment for esophageal cancer. Colorectal cancer and esophageal cancer has many similarities, however, PDT as a salvage therapy for rectal cancer is rare. CASE SUMMARY: Here, we describe a 56-year-old man who was admitted to the hospital due to a 6-mo history of hemafecia, which had been aggravated for 1 mo. Colonoscopy revealed a 3 cm × 4 cm ulcerated mass in the rectum 4 cm from the anus. Preoperative pathological examination showed villous adenoma, moderate-to-high-grade dysplasia, good differentiation, and invasion of the mucosal muscle. The patient had R1 after ultra-low anterior resection, but he refused extended resection and experienced severe liver function impairment after 3 cycles of chemotherapy. Ultimately, the patient underwent PDT to remove R1. After five years of follow-up, there was no liver function impairment, recurrence, metastasis, sexual dysfunction, or abnormal defecation function. CONCLUSION: This is the first case worldwide in which R1 of rectal cancer were successfully treated by PDT.

The tumor suppressor gene RhoBTB1 is a novel target of miR-31 in human colon cancer.

miRNAs are a class of endogenous non-coding RNA, which can regulate downstream target genes through binding to the 3'UTR of those genes. Numerous studies have indicated that abnormal expression of miRNAs is implicated in tumor development. Aberrant expression of miR-31 has been found in various cancers, including colorectal cancer. Here, we show that miR-31 is upregulated in human colon cancer tissues and cell lines, and that repression of miR-31 inhibited colon cancer cell proliferation and colony formation in soft agarose. To further elucidate the mechanism underlying the role of miR-31 in promoting colon cancer, we used online miRNA target prediction databases and found that the tumor suppressor RhoTBT1 may be a target of miR-31. Imunohistochemistry assay revealed that RhoBTB1 was significantly decreased in HT29 cells. In addition, ectopic expression of miR-31 reduced RhoBTB1 in the colon cancer cell line HT29. The results suggested that suppression of RhoBTB1 may be responsible for colon tumorigenesis, which was inhibited directly by miR-31. The results of MTT and soft agarose colony-formation assays showed that knockdown of RhoBTB1 by RNAi induced cell proliferation, and colony formation in soft agarose, which mimicked the function of miR-31. This further suggested that suppression of RhoBTB1 was responsible for colon tumorigenesis. In conclusion, we found that miR-31 acts as an oncogene in colon cancer and identified RhoBTB1 as a new target of miR-31 further study demonstrated that miR-31 contributed to the development of colon cancer at least partly by targeting RhoBTB1.

Prevalence and etiology of abnormal liver tests in an adult population in Jilin, China.

BACKGROUND: Serum biochemical liver tests (LTs) (alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase) and platelet counts are often used to screen for chronic liver disease. We determined the prevalence and etiologies of abnormal LTs in an adult population in Jilin, China. METHODS: A total of 3791 individuals between the ages of 18 and 79 years were interviewed and then underwent ultrasonography and blood tests. RESULTS: The prevalence of abnormal LTs was 14.77% (560 out of 3791 subjects). The risk factors for abnormal LTs were non-alcoholic fatty liver disease (NAFLD) alone, which accounted for 11.61%, metabolic syndrome alone for 25%, or both for 22.14%. Abnormal LTs were more common in male than in female subjects. The development of abnormal LTs was correlated with older age males, increased daily alcohol intake, poor quality of sleep, smoking, fasting plasma glucose, body mass index, triglyceridemia, and low-density lipoprotein. Abnormal LTs in patients with metabolic syndrome and NAFLD were associated with high fasting plasma glucose, triglycerides, body mass index, low density lipoprotein, male, young age, poor sleep quality, smoking, and alcohol intake. However, abnormal LTs in patients with hepatitis B virus were associated with gender and increased age. CONCLUSIONS: The results from the current study demonstrated that the prevalence of abnormal LTs is high in the population (14.77%). Metabolic syndrome, NAFLD, and alcohol intake appear to be potentially important causes of the observed abnormal LTs.