Hypsochromic Shift Donor-Acceptor NIR-II Dye for High-Efficiency Tumor Imaging.

Nowadays, second near-infrared window (NIR-II) dyes' development focuses on pursuing a longer absorption/emission wavelength and higher quantum yield, which usually means an extended π conjugation system, resulting in an enormous molecular weight and poor druggability. Most researchers thought that the reduced π conjugation system would bring on a blueshift spectrum that causes dim imaging qualities. Little efforts have been made to study smaller NIR-II dyes with a reduced π conjugation system. Herein, we synthesized a reduced π conjugation system donor-acceptor (D-A) probe TQ-1006 (Em = 1006 nm). Compared with its counterpart donor-acceptor-donor (D-A-D) structure TQT-1048 (Em = 1048 nm), TQ-1006 exhibited comparable excellent blood vessels, lymphatic drainage imaging performance, and a higher tumor-to-normal tissue (T/N) ratio. An RGD conjugated probe TQ-RGD showed an extra high contrast tumor imaging (T/N ≥ 10), further proving D-A dyes' excellent NIR-II biomedical imaging applications. Overall, the D-A framework provides a promising approach to designing next-generation NIR-II fluorophores.

Design, Synthesis, and Antitumor Activities of Isomers of Artemisinin Dimer Derivatives.

In recent years, numerous studies have reported on the anti-tumor properties of artemisinin and its derivatives. However, the relationship between their artemisinin chirality and activity remains unknown. In this study, we synthesized a series of artemisinin dimer derivatives with three different chiral structures and tested their antiproliferative activity in MCF-7 and HepG2 cells using the CCK-8 assay. Interestingly, we discovered that artemisinin dimer derivatives with ß, ß and α, ß conformations at C-10 exhibited stronger anti-tumor activity than those with an α, α configuration in MCF-7 and HepG2 cells. Notably, compound 4 showed an activity of 0.06 µM in MCF-7 cells. This study demonstrates the relationship between the conformation and activity of artemisinin dimer derivatives, and these derivatives have the potential to be developed into anti-cancer drugs.

ROS-activatable nanocomposites for CT imaging tracking and antioxidative protection of mesenchymal stem cells in idiopathic pulmonary fibrosis therapy.

Mesenchymal stem cell (MSC) transplantation is emerging as a promising approach in the treatment of idiopathic pulmonary fibrosis (IPF), while it is still impeded by several challenges, including unsatisfactory treatment outcomes due to the poor survival of transplanted MSCs, and the lack of non-invasive and long-term imaging modality for tracking the behavior of MSCs. Herein, copper-based nanozyme (CuxO NPs) and gold nanoparticles (Au NPs) were encapsulated in oxidation-sensitive dextran (Oxi-Dex), a dextran derivative with reactive oxygen species (ROS)-responsiveness, forming a kind of novel nanocomposites (assigned as RSNPs) to act as ROS scavengers and computer tomography (CT) imaging tracers. After being internalized by MSCs, RSNPs enabled continuous CT imaging tracking of the transplanted MSCs for 21 days in IPF treatment, obtaining the location and distribution of the transplanted MSCs. Once MSCs were attacked by oxidative stress, the intracellular RSNPs could activate ROS clearance on demand by releasing CuxO NPs, thereby enhancing the therapeutic efficacy against IPF by improving cell survival. Taken together, a novel multifunctional RSNP was fabricated to label MSCs for CT imaging tracking and clearing superfluous ROS, presenting a promising high-efficient IPF therapy.

Early Infant Formula Feeding Impacts Urinary Metabolite Profile at 3 Months of Age.

There is a growing consensus that nutritional programming may persist and influence risk for several chronic diseases in adulthood. In the present study, we used urinary metabolic analysis in assessing diet effects on early-life metabolism. Urine samples from healthy three-month-old infants fed human milk (HM; n = 93), cow's milk-based infant formula [MF; n = 80], or soy protein-based infant formula (SF; n = 76) were analyzed with an untargeted metabolomics approach using GC-TOF MS. PLS-DA and ANOVA analyses were performed using MetaboAnalyst (v4.0). A total of 150 metabolites differed significantly among the feeding groups, including dietary-specific patterns of urinary metabolites of sugars, sugar alcohols, amino acids, and polyphenols. Urinary metabolites may mirror the infant's overall metabolism and serve as a noninvasive tool to examine the neonatal effects of diet on early-infant metabolism.

Fibroblast Growth Factor-21 to Adiponectin Ratio: A Potential Biomarker to Monitor Liver Fat in Children With Obesity.

Background: There is a pressing need for effective and non-invasive biomarkers to track intrahepatic triglyceride (IHTG) in children at-risk for non-alcoholic fatty liver disease (NAFLD), as standard-of-care reference tools, liver biopsy and magnetic resonance imaging (MRI), are impractical to monitor the course disease. Objective: We aimed to examine the association between serum fibroblast growth factor (FGF)-21 to adiponectin ratio (FAR) and IHTG as assessed by MRI in children with obesity. Methods: Serum FGF21 and adiponectin levels and IHTG were measured at two time points (baseline, 6 months) in obese children enrolled in a clinical weight loss program. The association between percent change in FAR and IHTG at final visit was examined using a multiple linear regression model. Results: At baseline, FAR was higher in the subjects with NAFLD (n = 23, 35.8 ± 41.9 pg/ng) than without NAFLD (n = 35, 19.8 ± 13.7 pg/ng; p = 0.042). Forty-eight subjects completed both visits and were divided into IHTG loss (≥1% reduction than baseline), no change (within ±1% change), and gain (≥1% increase than baseline) groups. At 6 months, the percent change in FAR was different among the three groups (p = 0.005). Multiple linear regression showed a positive relationship between percent change in FAR and the final liver fat percent in sex and pubertal stage-similar subjects with NAFLD at baseline (slope coefficient 6.18, 95% CI 1.90-10.47, P = 0.007), but not in those without NAFLD. Conclusions: Higher value in percent increase in FAR is positively associated with higher level of IHTG percent value at 6 months in children with baseline NAFLD. FAR could be a potential biomarker to monitor the changes in IHTG in children with NAFLD.

Synthesis and biological activity of C-7, C-9 and C-10 modified taxane analogues from 1-deoxybaccatin VI.

A series of C-7, C-9 and C-10 modified taxane analogues were synthesized and their in vitro anticancer activities against three human cancer cell lines: A-549 (human lung cancer cell line), MDA-MB-231 (human breast cancer cell line), A-549/T (human lung cancer resistant cell line) were studied. The novel 1-deoxybaccatin VI derivatives modified with carbonate group at C-9 and C-10 positions enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the three cell lines, especially in drug-resistant cell line, showed by the newly synthesized taxane analogues indicated them as potential lead compounds for anticancer drug design.

Design, synthesis of novel C-3'-N-sulfonyl modified taxane analogues from 1-deoxybaccatin VI and their impact on anti-HCC activity.

A new series of C-3'-N-sulfonyl paclitaxel analogs were designed and synthesized from 1-deoxybaccatin VI and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. The synthesized compounds were evaluated for their in vitro anti-Hepatocellular carcinoma (HCC) activity against human hepatoma (HepG2) cell line. Bioassay results showed that compounds 17c, 17d and 17f exhibited more potent inhibitory activity against HepG2 cell line in comparison with paclitaxel. It is suggested that paclitaxel analogs containing the C-3'-N-sulfonyl could be considered as a precursor structure for further synthesis of more potent analogues.

Infant Formula Feeding Changes the Proliferative Status in Piglet Neonatal Mammary Glands Independently of Estrogen Signaling.

BACKGROUND: Soy infant formula contains isoflavones, which are able to bind to and activate estrogen receptor (ER) pathways. The mammary gland is sensitive to estrogens, raising concern that the use of soy formulas may promote premature development. OBJECTIVE: We aimed to determine if soy formula feeding increases mammary gland proliferation and differentiation in comparison to other infant postnatal diets. METHODS: White-Dutch Landrace piglets aged 2 d received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17-beta-estradiol (2 mg/(kg·d); M + E2), or milk formula supplemented with genistein (84 mg/L of diet; M + G) until day 21. Mammary gland proliferation and differentiation was assessed by histology, and real-time RT-PCR confirmation of differentially expressed genes identified by microarray analysis. RESULTS: Mammary terminal end bud numbers were 19-31% greater in the Milk, Soy, and M + G groups relative to the Sow and M + E2, P <0.05. Microarray analysis identified differentially expressed genes between each formula-fed group relative to the Sow (±1.7-fold, P <0.05). Real-time RT-PCR confirmed 2- to 4-fold increases in mRNA transcripts of genes involved in cell proliferation, insulin-like growth factor 1 (IGF1), fibroblast growth factor 10 (FGF10), and fibroblast growth factor 18 (FGF18), in all groups relative to the Sow, P <0.05. In contrast, genes involved in cell differentiation and ductal morphogenesis, angiotensin II receptor type 2 (AGTR2), microtubule associated protein 1b (MAP1B), and kinesin family member 26b (KIF26B), were significantly upregulated by 2-, 4-, and 13-fold, respectively, in the M + E2 group. Additionally, mRNA expression of ER-specific gene targets, progesterone receptor (PGR), was increased by 12-fold, and amphiregulin (AREG) and Ras-like estrogen regulated growth inhibitor (RERG) expression by 1.5-fold in the M + E2 group, P <0.05. In the soy and M + G groups, mRNA expressions of fatty acid synthesis genes were increased 2- to 4-fold. CONCLUSIONS: Our data indicate soy formula feeding does not promote ER-signaling in the piglet mammary gland. Infant formula feeding (milk- or soy-based) may initiate proliferative pathways independently of estrogenic signaling.

Synthesis and biological evaluation of C-13, C-14 modified taxane analogues from 1-deoxybaccatin VI.

Four C-13, C-14 side chain modified 9(R)-hydroxy-1-deoxy-taxane analogues 15, 16, 19 and 22 were semi-synthesized from 1-deoxybaccatin VI. The in vitro antitumor activity of these compounds was evaluated against A549 and A2780 cell lines. The preliminary SAR analysis showed that introduction of oxygen-containing group on C-14 could improve the cytotoxic activities.

Experimental Characterization of the Binding Affinities between Proapoptotic BH3 Peptides and Antiapoptotic Bcl-2 Proteins.

The Bcl-2 family proteins are key regulators of the intrinsic apoptotic pathway and are among the validated targets for developing anticancer drugs. Protein-protein interactions between the pro- and antiapoptotic members of this family determine mitochondrial outer-membrane permeabilization. Elucidating such protein-protein interactions in a quantitative way is helpful for network pharmacology studies on the Bcl-2 family, which, in turn, will provide valuable guidance for developing new anticancer therapies. In this study, the binding affinities of the BH3 peptides derived from eight proapoptotic BH3-only proteins (i.e., Bid, Bim, Puma, Noxa, Bad, Bmf, Bik, Hrk) against five well-studied antiapoptotic proteins (i.e., Bcl-xL , Bcl-2, Mcl-1, Bcl-w, Bfl-1) in the Bcl-2 family have been measured. Three different types of binding assay (i.e., surface plasmon resonance, fluorescence polarization, and homogeneous time-resolved fluorescence) were employed for cross-validation. The results confirmed that each proapoptotic BH3 peptide exhibited a distinct binding profile against the five antiapoptotic proteins. The binding data obtained herein serve as a fresh update or correction to existing knowledge. It is expected that such binding data will be helpful for building more accurate mathematical network models for depicting the complex protein-protein interactions within the Bcl-2 family.

Cell-assembled nanoclusters of MSC-targeting Gd-DOTA-peptide as a T2 contrast agent for MRI cell tracking.

A cyclic peptide CC9 that targets cell membrane of mesenchymal stem cells (MSCs) is coupled with Gd-DOTA to yield a Gd-DOTA-CC9 complex as MRI contrast agent. It is used to label human MSCs (hMSCs) via electroporation. Electroporation-labeling of hMSCs with Gd-DOTA-CC9 induces cell-assembly of Gd-DOTA-CC9 nanoclusters in the cytoplasm, significantly promotes cell-labeling efficacy and intracellular retention time of the agent. In vitro MRI of labeled hMSCs exhibits significant signal reduction under T2 -weighted MRI, which can allow long-term tracking of labeled cell transplants in in vivo migration. The labeling strategy is safe in cytotoxicity and differentiation potential.

Acridone suppresses the proliferation of human breast cancer cells in vitro via ATP-binding cassette subfamily G member 2.

In the past decades, the tricyclic acridone ring system has become a focus of major research by medicinal chemists due to the biological significance of this moiety in drug design and discovery. Acridone has substantial bio-potential since it performs crucial functions, including antibacterial, antimalarial, antiviral and anti-neoplastic activities. However, the anticancer effect and the underlying mechanisms of acridone on breast cancer cells remains unclear. In the present study, the anti-tumor function and the underlying mechanisms of acridone were evaluated in vitro. Firstly, an MTT assay was used to evaluate the inhibitory effect of acridone. Subsequently, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to investigate whether ATP binding cassette subfamily G member 2 (ABCG2) was associated with the function of acridone. Finally, western blotting was used to confirm the results of RT-qPCR. The present study demonstrated that acridone may decrease the proliferation of MDA-MB-231 cells dose-dependently. Further experiments revealed that acridone may downregulate the mRNA and protein expression levels of ABCG2, supporting the potential application of acridone in breast cancer treatment. These findings suggested that acridone is a potential agent in the treatment of human breast cancer.

Design of diversified self-assembly systems based on a natural rosin-based tertiary amine for doxorubicin delivery and excellent emulsification.

A novel rosin-based ester tertiary amine (RETA) with three hydrophilic groups and a rigid hydrophobic group was synthesized from rosin by Diels-Alder addition, acylation and esterification reactions. RETA was characterized by infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance spectroscopy (13C NMR). Results from testing surface tension, zeta potential, and transmission electron spectroscopy showed that RETA had unique pH responsiveness. RETA self-assembled into worm-like micelles, spherical micelles 130 nm in diameter and big spherical worm-like aggregates with diameter of 2 µm at pH = 5.76, 8.04 and 9.38, respectively. The critical micelle concentration (CMC) of RETA was 0.42 mmol/L, and the surface tension at CMC (γcmc) was 38.73 mN/m when pH was 8.04. The RETA had a potential application in delivering doxorubicin hydrochloride (DOX) due to the pH responsiveness. Self-assembly mixed systems of RETA and rosin-based phosphoric acid (DDPD) were designed to improve emulsification. The mixed systems had obvious synergistic effects and unexpected emulsification. The γcmc and CMC of mixtures were 41.74 mN/m and 0.20 mmol/L, the size of mixture micelles increased up to 300 nm in the optimum molar ratio of RETA/DDPD (7:3) by TEM and cryo-TEM. It was worth noting that the mixture system formed vesicles in the RETA/DDPD molar ratio of 5:5. The stability time of emulsion with RETA and DDPD as emulsifier were only 63 s and 52 s respectively, but the stability time increased to 234 s in the optimum molar ratio. In addition, the formation mechanisms of micelles at different pH and in various mixtures were discussed in detail. What's more, cytotoxicity results showed that the toxicity of RETA was lower significantly than that of lecithin, a food ingredient in egg yolk and soybean. The cell viability was more than 83% in the high concentration of RETA (4000 µg/ml).

Synthesis and biological evaluation of novel A-seco-taxoids derived from 1-deoxybaccatin VI.

Three novel nor-seco-taxoids 13, 15, 23 in which the A rings are cleaved but the B, C, and D rings are retained were prepared from 1-deoxybaccatin VI via its nor-dioxo derivative and their structures were confirmed by 1H NMR, 13C NMR and high resolution MS. Oxidative introduction of C-1 hydroxyl to 1-deoxybaccatin VI with oxidising agent KBrO3 and catalyst RuCl3 led to the dioxo derivative 6 and its structure is determined by X-ray crystallographic analysis. A-seco taxoids 13, 15, 23 with a C-13 ester linkage were tested for cytotoxic activity and all compounds showed no measurable cytotoxic activity against HCT-116 cell line. However, 1-deoxy-9a-dihydrotaxane analogue 4 semi-synthesised from 1-deoxybaccatin VI is 10-fold less cytotoxic than paclitaxel, indicating the indispensible nature of the A ring double bond for the bioactivity of paclitaxel.

Dose-response analysis of epigenetic, metabolic, and apical endpoints after short-term exposure to experimental hepatotoxicants.

Identification of sensitive and novel biomarkers or endpoints associated with toxicity and carcinogenesis is of a high priority. There is increasing interest in the incorporation of epigenetic and metabolic biomarkers to complement apical data; however, a number of questions, including the tissue specificity, dose-response patterns, early detection of those endpoints, and the added value need to be addressed. In this study, we investigated the dose-response relationship between apical, epigenetic, and metabolomics endpoints following short-term exposure to experimental hepatotoxicants, clofibrate (CF) and phenobarbital (PB). Male F344 rats were exposed to PB (0, 5, 25, and 100 mg/kg/day) or CF (0, 10, 50, and 250 mg/kg/day) for seven days. Exposure to PB or CF resulted in dose-dependent increases in relative liver weights, hepatocellular hypertrophy and proliferation, and increases in Cyp2b1 and Cyp4a1 transcripts. These changes were associated with altered histone modifications within the regulatory units of cytochrome genes, LINE-1 DNA hypomethylation, and altered microRNA profiles. Metabolomics data indicated alterations in the metabolism of bile acids. This study provides the first comprehensive analysis of the apical, epigenetic and metabolic alterations, and suggests that the latter two occur within or near the dose response curve of apical endpoint alterations following exposure to experimental hepatotoxicants.

Risk factors of progressive IgA nephropathy which progress to end stage renal disease within ten years: a case-control study.

BACKGROUND: There were few related studies aiming to severe IgA nephropathy (IgAN) which could progress rapidly to end stage renal disease (ESRD) within ten years. To find valuable clinical or pathological factors and promising precautions is essential. METHODS: A single center case-control study was performed. Fifty ESRD patients with the primary cause of IgAN and a short renal survival time of less than ten years after diagnose were enrolled in the case group. One hundred IgAN patients with a renal survival time of more than ten years were enrolled in the control group. IgA Oxford classification scores, clinical data at baseline and during the follow-up were collected. Multivariate logistic regression was used to investigate factors associated with the development of ESRD. RESULTS: There were significant differences in baseline clinical data between these two groups, as well as the constituent ratio of Oxford MEST-score. Distinct differences were observed in time-average uric acid(TA-UA), time-average hemoglobin(TA-Hb), time-average albumin(TA-Alb), time-average total cholesterol(TA-TC) and time-average urinary protein(TA-P) during the follow-up. In multivariate logistic models, IgA Oxford score M1(OR = 5.10, P = 0.018) and eGFR(OR = 0.97, P = 0.039) at biopsy, TA-UA (OR = 2.06, P = 0.026) and TA-Hb (OR = 0.53, P = 0.022) during the follow-up were identified independent factors for developing ESRD. CONCLUSION: IgAN patients with pathological assessment of M1, low baseline eGFR, TA-Hb and high TA-UA were more likely to progress to ESRD, and should be paid more attention. Appropriate regulations of UA, Hb and urine protein after diagnose may be a promising treatment.

Synthesis and anti-inflammatory evaluation of novel paclitaxel analogs.

A series of paclitaxel analogs modified at C-3'-N and C-7 positions were synthesized from baccatin III and their structures were confirmed by 1H-NMR, 13C-NMR, HR-MS. Compound 7e exhibited potent ability to decrease TNFα (tumor necrosis factor α) in the LPS-activated RAW264.7 murine macrophage-like cell line. The preliminary data indicated that the anti-inflammatory effects may be related to MD-2 and Toll-like receptor 4 (TLR4), rather than Toll-like receptor 2 (TLR2).

Syntheses and biological evaluation of C-3'-N-acyl modified taxane analogues from 1-deoxybaccatin-VI.

A series of side-chain modified taxane analogues were synthesized and their in vitro anticancer activities against four human cancer cell lines: MDA-MB-231 (human breast cancer), PC-3 (human prostatic cancer), HepG2 and H460 (human hepatoma) were studied. The three hydroxyl groups at C-7, C-9 and C-10 enable the behavior of these compounds to be evidently distinct from other similar compounds. The strong cytotoxicity in the four cell lines showed by the newly synthesized taxane analogues 13a and 13d indicated them as potential lead compounds for anticancer drug design.

Tight junction disruption by cadmium in an in vitro human airway tissue model.

BACKGROUND: The cadmium (Cd) present in air pollutants and cigarette smoke has the potential of causing multiple adverse health outcomes involving damage to pulmonary and cardiovascular tissue. Injury to pulmonary epithelium may include alterations in tight junction (TJ) integrity, resulting in impaired epithelial barrier function and enhanced penetration of chemicals and biomolecules. Herein, we investigated mechanisms involved in the disruption of TJ integrity by Cd exposure using an in vitro human air-liquid-interface (ALI) airway tissue model derived from normal primary human bronchial epithelial cells. METHODS: ALI cultures were exposed to noncytotoxic doses of CdCl2 basolaterally and TJ integrity was measured by Trans-Epithelial Electrical Resistance (TEER) and immunofluorescence staining with TJ markers. PCR array analysis was used to identify genes involved with TJ collapse. To explore the involvement of kinase signaling pathways, cultures were treated with CdCl2 in the presence of kinase inhibitors specific for cellular Src or Protein Kinase C (PKC). RESULTS: Noncytotoxic doses of CdCl2 resulted in the collapse of barrier function, as demonstrated by TEER measurements and Zonula occludens-1 (ZO-1) and occludin staining. CdCl2 exposure altered the expression of several groups of genes encoding proteins involved in TJ homeostasis. In particular, down-regulation of select junction-interacting proteins suggested that a possible mechanism for Cd toxicity involves disruption of the peripheral junctional complexes implicated in connecting membrane-bound TJ components to the actin cytoskeleton. Inhibition of kinase signaling using inhibitors specific for cellular Src or PKC preserved the integrity of TJs, possibly by preventing occludin tyrosine hyperphosphorylation, rather than reversing the down-regulation of the junction-interacting proteins. CONCLUSIONS: Our findings indicate that acute doses of Cd likely disrupt TJ integrity in human ALI airway cultures both through occludin hyperphosphorylation via kinase activation and by direct disruption of the junction-interacting complex.

Mechanistic evaluation of Ginkgo biloba leaf extract-induced genotoxicity in L5178Y cells.

Ginkgo biloba has been used for many thousand years as a traditional herbal remedy and its extract has been consumed for many decades as a dietary supplement. Ginkgo biloba leaf extract is a complex mixture with many constituents, including flavonol glycosides and terpene lactones. The National Toxicology Program 2-year cancer bioassay found that G. biloba leaf extract targets the liver, thyroid gland, and nose of rodents; however, the mechanism of G. biloba leaf extract-associated carcinogenicity remains unclear. In the current study, the in vitro genotoxicity of G. biloba leaf extract and its eight constituents was evaluated using the mouse lymphoma assay (MLA) and Comet assay. The underlying mechanisms of G. biloba leaf extract-associated genotoxicity were explored. Ginkgo biloba leaf extract, quercetin, and kaempferol resulted in a dose-dependent increase in the mutant frequency and DNA double-strand breaks (DSBs). Western blot analysis confirmed that G. biloba leaf extract, quercetin, and kaempferol activated the DNA damage signaling pathway with increased expression of γ-H2AX and phosphorylated Chk2 and Chk1. In addition, G. biloba leaf extract produced reactive oxygen species and decreased glutathione levels in L5178Y cells. Loss of heterozygosity analysis of mutants indicated that G. biloba leaf extract, quercetin, and kaempferol treatments resulted in extensive chromosomal damage. These results indicate that G. biloba leaf extract and its two constituents, quercetin and kaempferol, are mutagenic to the mouse L5178Y cells and induce DSBs. Quercetin and kaempferol likely are major contributors to G. biloba leaf extract-induced genotoxicity.