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For its vital role in maintaining cellular activity and survival, mitochondrion is highly involved in various diseases, and several strategies to target mitochondria have been developed for specific imaging and treatment. Among these approaches, theranostic may realize both diagnosis and therapy with one integrated material, benefiting the simplification of treatment process and candidate drug evaluation. A variety of mitochondria-targeting theranostic agents have been designed based on the differential structure and composition of mitochondria, which enable more precise localization within cellular mitochondria at disease sites, facilitating the unveiling of pathological information while concurrently performing therapeutic interventions. Here, progress of mitochondria-targeting theranostic materials reported in recent years along with background information on mitochondria-targeting and therapy have been briefly summarized, determining to deliver updated status and design ideas in this field to readers.
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PURPOSE: Overexpression of Poly (ADP-ribose) polymerase (PARP) is associated with many diseases such as oncological diseases. Several PARP-targeting radiotracers have been developed to detect tumor in recent years. Two 18F labelled probes based on Olaparib and Rucaparib molecular scaffolds have been evaluated in clinical trials, but their slow hepatic clearance hinders their tumor imaging performance. Although a number of positron emission tomography (PET) probes with lower liver uptake have been designed, the tumor to background ratios remains to be low. Therefore, we designed a probe with low lipid-water partition coefficient to solve this problem. METHODS: A pyridine-containing quinazoline-2,4(1 H,3 H)-dione PARP-targeting group was rationally designed and used to conjugate with the chelator 2,2',2'',2'''-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) to prepare the lead compound named as SMIC-2001 for radiolabeling. In vitro experiments, the lipid-water partition coefficient, stability, binding affinity, and cellular uptake of [68Ga]Ga-SMIC-2001 were determined. In vivo experiments, the U87MG xenograft models were used to evaluate its tumor imaging properties. RESULTS: [68Ga]Ga-SMIC-2001 showed a low Log D7.4 (-3.82 ± 0.06) and high affinity for PARP-1 (48.13 nM). In vivo study revealed that it exhibited a high tumor-to-background contrast in the U87MG xenograft models and mainly renal clearance. And the ratios of tumor to main organs were high except for the kidney (e.g. tumor to liver ratio reached 2.20 ± 0.51) at 60 min p.i. CONCLUSION: In summary, pyridine-containing quinazoline-2,4(1 H,3 H)-dione is a novel PARP-targeting molecular scaffold for imaging probe development, and [68Ga]Ga-SMIC-2001 is a highly promising PET probe capable of imaging tumors with PARP overexpression.
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Due to the wide application of reporter gene-related visible/NIR-I bioluminescent imaging, multiplexed fluorescence imaging across visible/NIR-I/NIR-II has excellent potential in biomedical research. However, in vivo multiplexed imaging applications across those regions have rarely been reported due to the lack of proper fluorophores. Herein, nine squaraine dyes, which exhibit diverse adsorption and emission wavelengths, were synthesized. Among them, water-soluble SQ 710-5k and SQ 905 were found to have significant absorption differences, which allowed the tumor and lymph nodes to be identified. Then, for the first time, six-channel multiplexed fluorescence imaging across visible/NIR-I/II was achieved by coordination with reporter gene-related bioluminescent phosphors. Additional research revealed that SQ 710-5k exhibited higher-quality blood vessels and tumor imaging in NIR-II. H-aggregates SQ 905 demonstrated a high photothermal conversion efficiency for photothermal therapy. This study proposed an approach to creating small molecular dyes that coordinate with reporter gene-related bioluminescent phosphors for six-color fluorescence imaging.
Subject(s)
Cyclobutanes , Fluorescent Dyes , Optical Imaging , Phenols , Photothermal Therapy , Cyclobutanes/chemistry , Cyclobutanes/chemical synthesis , Animals , Fluorescent Dyes/chemistry , Humans , Mice , Phenols/chemistry , Photothermal Therapy/methods , Infrared Rays , Mice, Nude , Cell Line, Tumor , Female , Molecular Structure , Mice, Inbred BALB CABSTRACT
The purpose of this study is to explore the potential plasma metabolism biomarkers reflecting the maintenance status of growing pigs. The repeated measurement design was used in this experiment, and six barrows (28.6 ± 0.5 kg BW) were selected and kept in metabolism crates. The feeding level in growing pigs close to ad libitum was 2400 kJ ME/kg BW0.6 ·day-1 during Day 1 to Day 7, while a feeding level of 782 kJ ME/kg BW0.6 ·day-1 was provided as energy requirement for maintenance during Day 8 to Day 14. Plasma samples of each pig were collected from the anterior vena cava on the morning of Day 8 and Day 15. The metabolites of plasma were determined by high-resolution mass spectrometry using a metabolomics approach. Results showed that metabolomics analysis between ad libitum-fed state and maintained status revealed differences in 16 compounds. Identified compounds were enriched in metabolic pathways related to linoleic acid metabolism, tryptophan metabolism, and alanine, aspartate and glutamate metabolism. In conclusion, linoleic acid metabolism, tryptophan metabolism, alanine, aspartate and glutamic acid metabolism pathways played a major regulatory role in the maintenance status of growing pigs. The potential metabolism biomarkers of maintenance in growing pigs were linoleic acid, glutamine and tyrosine.
Subject(s)
Aspartic Acid , Linoleic Acid , Swine , Animals , Chromatography, High Pressure Liquid/veterinary , Chromatography, Liquid/veterinary , Tryptophan , Tandem Mass Spectrometry/veterinary , Energy Metabolism , Metabolomics , Alanine , Biomarkers , Animal Feed/analysisABSTRACT
Though the energy requirement for maintenance is an important part of net energy system, little is known of the metabolic characteristics of maintenance energy expenditure. This study was investigated the effect of feeding level at metabolizable energy requirement for maintenance (FLM) on plasma metabolites in growing pigs. Ten barrows (22.5 ± 0.5 kg BW) were kept in metabolism crates and catheterized in the precaval vein during adaptation period. Pigs were fed a corn-soybean meal diet at 782 kJ ME/kg BW0.6·d-1 during d 1 to 8 and then were refeeding at 2,400 kJ ME/kg BW0.6·d-1 on d 9. Plasma samples of each pig were collected by catheter on the morning of d 1, 3, 5, 7, 9, and 10, respectively, for metabolomics testing. Results showed that the concentration of plasma urea nitrogen decreased under FLM (p < 0.01) and increased significantly after refeeding (p < 0.01). The concentration of total cholesterol, high-density lipoprotein, low-density lipoprotein, and albumin in plasma were decreased significantly after refeeding (p < 0.01). Eleven identified compounds were up-regulated and six ones were down-regulated under FLM. In conclusion, the energy metabolism of growing pigs was relatively stable after 4 days of feeding at FLM.
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In this prospective study of an in-vivo cervical examination using optical coherence tomography (OCT), we evaluated the diagnostic value of non-invasive and real-time OCT in cervical precancerous lesions and cancer diagnosis, and determined the characteristics of OCT images. 733 patients from 5 Chinese hospitals were inspected with OCT and colposcopy-directed biopsy. The OCT images were compared with the histological sections to find out the characteristics of various categories of lesions. The OCT images were also interpreted by 3 investigators to make a 2-class classification, and the results were compared against the pathological results. Various structures of the cervical tissue were clearly observed in OCT images, which matched well with the corresponding histological sections. The OCT diagnosis results delivered a sensitivity of 87.0% (95% confidence interval, CI 82.2-90.7%), a specificity of 84.1% (95% CI 80.3-87.2%), and an overall accuracy of 85.1%. Both good consistency of OCT images and histological images and satisfactory diagnosis results were provided by OCT. Due to its features of non-invasion, real-time, and accuracy, OCT is valuable for the in-vivo evaluation of cervical lesions and has the potential to be one of the routine cervical diagnosis methods.
Subject(s)
Tomography, Optical Coherence , Uterine Cervical Neoplasms/diagnostic imaging , Uterine Cervical Neoplasms/diagnosis , Adult , Cervix Uteri/diagnostic imaging , Cervix Uteri/pathology , Colposcopy , Female , Humans , Image Processing, Computer-Assisted , Neoplasm Grading , Squamous Intraepithelial Lesions of the Cervix/diagnosis , Squamous Intraepithelial Lesions of the Cervix/diagnostic imaging , Squamous Intraepithelial Lesions of the Cervix/pathology , Statistics as Topic , Uterine Cervical Neoplasms/pathologyABSTRACT
BACKGROUND: Determination of the endogenous loss of fat (ELF) is used to adjust for the estimation of true total tract digestibility (TTTD) of fat in diets and ingredients. Any factor which affected ELF may further affect the digestibility of fat, including sources and concentrations of fat and fiber in the diet. There are some reports of determining the ELF using regression methods based on different levels of fat intake, while reports on effects of dietary fiber content and different fiber-rich ingredients in pig diets on ELF are very limited. Therefore, the objective of this study was to determine the effects of dietary fiber content and different fiber-rich ingredients on endogenous losses of fat and fatty acids at the end of ileum and throughout the entire intestinal tract in growing pigs. METHODS: In Exp. 1, the effect of fiber content on endogenous loss of fat was determined using six growing pigs (Duroc × Landrace × Yorkshire; 27.6 ± 2.4 kg), fitted with a T-cannula at the end of ileum. The experimental design was a 6 × 6 complete Latin square design with six periods of feeding and six diets. The six experimental fat-free diets were formulated to include graded levels of neutral detergent fiber (NDF) (0, 40, 80, 120, 160 and 200 g/kg) and soybean hull (SH) was the only fiber source, providing 0, 75, 150, 225, 300 and 375 g/kg, respectively. Chromic oxide was included at 4 g/kg in all diets as an indigestible marker. In Exp. 2, six crossbred growing barrows (27.6 ± 1.6 kg) were used and the experimental design was the same as for Exp. 1. The six fat-free diets were formulated to include six common fiber-rich ingredients and the concentration of NDF was 100 g/kg. The six fiber-rich ingredients were defatted rice bran (DRB), sugar beet pulp (SBP), rice hull (RH), corn germ meal (CGM), SH and wheat bran (WB) and they were fed at represented 250, 270, 145, 250, 170 and 280 g/kg in the diet, respectively. RESULTS: In Exp. 1, the endogenous loss of fatty acids profile did not change as dietary NDF increased in growing pigs. The endogenous losses of fat, C16:0, C18:0, C18:1, C18:2, total unsaturated fatty acids (UFA) and total saturated fatty acids (SFA) in growing pigs at the end of ileum and throughout the entire intestinal tract increased linearly as NDF content of diets increased. The endogenous losses of fat, as well as C16:0 and C18:0 throughout the entire intestinal tract also increased quadratically as NDF content of diets increased. The ELF increased from 0.71 to 3.14 g/kg of dry matter intake (DMI) and 0.56 to 8.21 g /kg DMI at the end of ileum and throughout the entire intestinal tract in growing pigs, respectively. The ELF occurred in the hindgut except for the growing pigs fed 0 and 4% NDF in their diets. The endogenous losses of C16:0 and UFA occurred primarily in the upper regions of the gut and the greatest endogenous losses of C18:0 occurred in the hindgut. The endogenous losses of fat, individual SFA and total SFA throughout the entire intestinal tract were much greater than that at the end of ileum. However, the endogenous losses of individual UFA and total UFA were less throughout the intestinal tract than at the end of ileum. In Exp. 2, the endogenous losses of fat at the end of ileum were greater in growing pigs fed CGM or WB diets. The endogenous loss of fatty acids profile changed to a slight degree at the end of ileum that the endogenous loss of UFA (particularly C18:1 and C18:2) in growing pigs fed CGM or WB diets were greater (P < 0.01) than that for the other four diets. The greatest (P < 0.01) endogenous loss of SFA (particularly C18:0) was in growing pigs fed the RH diet. The endogenous losses of fat, C16:0, C18:0 and SFA over the entire intestinal tract were much greater in growing pigs fed CGM or WB diets, whereas the lowest values were in growing pigs fed DRB diet. The ELF at the end of ileum in growing pigs fed CGM or WB diets were 3.50 or 4.17 g/kg DMI, respectively, and the ELF over the entire intestinal tract was 7.23 or 7.38 g/kg DMI. The contribution in percentage of ELF in the upper gut was greater than that in the hindgut of growing pigs fed DRB and RH diets, while the ELF in the upper gut and hindgut were equal in growing pigs fed SBP, CGM and WB diets. On the whole, the endogenous losses of C18:1 and C18:2 throughout the entire intestinal tract in growing pigs fed the six fiber-rich ingredients diets were less than losses at the end of ileum, whereas the endogenous loss of fat, C16:0, C18:0 and SFA were greater throughout the intestinal tract than at the end of ileum. CONCLUSION: The profile of loss in endogenous fatty acids did not change as dietary NDF increased in growing pigs and the endogenous losses of fatty acids (C16:0, C18:0, C18:1 and C18:2) fat, UFA and SFA increased linearly as NDF content increased in the diets of pigs. The endogenous losses of fat or fatty acids at the end of ileum were greater in growing pigs fed RH, CGM or WB diets. The endogenous losses of fat, fatty acids (C16:0 and C18:0) and SFA were greater over the entire intestinal tract in pigs fed CGM or WB diet, while these values were the lowest in growing pigs fed the DRB diet. The contribution in percentage losses of fat in the upper gut were greater than in the hindgut of growing pigs fed DRB and RH diets, while the contribution of losses of fat in the upper gut and hindgut were equal in growing pigs fed SBP, CGM and WB diets. In addition, the endogenous loss of individual or total UFA was less over the entire intestinal tract of growing pigs fed fiber diets than that at the end of ileum, and the greatest endogenous losses of fat, individual or total SFA were over the entire intestinal tract. Therefore, differences in fiber content and the nature of fiber-rich ingredients in diets of pigs have different effects to the endogenous losses of fat or fatty acids. Considering the requirement of fat or fatty acids of pigs, careful attention must be paid that the endogenous losses of fat and fatty acids when fiber ingredients are used in diets of pigs.
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A diet consumed by pigs provides the nutrients for the production of a large number of metabolites that, after first-pass metabolism in the liver, circulate systemically where they may exert diverse physiologic influences on pigs. So far, little is known of how feeding elicits changes in metabolic profiles for growing pigs. This study investigated differences in plasma metabolites in growing pigs at several intervals after feeding using the technique of metabolomics. Ten barrows (22.5 ± 0.5 kg BW) were fed a corn-soybean meal basal diet and were kept in metabolism crates for a period of 11 days. An indwelling catheter was inserted into the jugular vein of each pig before the experimental period. Plasmas before and 1, 4, and 8 hr after feeding were collected at day 11 and differential metabolites were determined using a metabolomics approach. Direct comparison at several intervals after feeding revealed differences in 14 compounds. Identified signatures were enriched in metabolic pathways related to linoleic acid metabolism, arginine and proline metabolism, lysine degradation, glycine, serine and threonine metabolism, and lysine biosynthesis. These results suggest that plasma metabolites of growing pigs after feeding were modulated through changes in linoleic acid metabolism and amino acid metabolism.