Search

Photodynamic therapy (PDT) is a promising antitumor treatment that is based on the photosensitizers that inhibit cancer cells by yielding reactive oxygen species (ROS) after irradiation of light with specific wavelengths. As a potential photosensitizer, titanium dioxide (TiO2) exhibits minimal dark cytotoxicity and excellent ultraviolet (UV) light triggered cytotoxicity, but is challenged by the limited tissue penetration of UV light. Herein, a novel near-infrared (NIR) light activated photosensitizer for PDT based on TiO2-coated upconversion nanoparticle (UCNP) core/shell nanocomposites (UCNPs@TiO2 NCs) is designed. NaYF4:Yb(3+),Tm(3+)@NaGdF4:Yb(3+) core/shell UCNPs can efficiently convert NIR light to UV emission that matches well with the absorption of TiO2 shells. The UCNPs@TiO2 NCs endocytosed by cancer cells are able to generate intracellular ROS under NIR irradiation, decreasing the mitochondrial membrane potential to release cytochrome c into the cytosol and then activating caspase 3 to induce cancer cell apoptosis. NIR light triggered PDT of tumor-bearing mice with UCNPs@TiO2 as photosensitizers can suppress tumor growth efficiently due to the better tissue penetration than UV irradiation. On the basis of the evidence of in vitro and in vivo results, UCNPs@TiO2 NCs could serve as an effective photosensitizer for NIR light mediated PDT in antitumor therapy.

Despite being a powerful weapon against cancer cells, cisplatin's therapeutic potential is hampered by numerous adverse reactions, including acute kidney injury (AKI). Compound 5 has 3-SH fragments at the end of the vertical short alkyl side chain, which is an ROS scavenger synthesized. In this study, we evaluated the protective effect of compound 5 on the kidney after cisplatin administration and its mechanism. The results founded that compound 5 can alleviate serum urea nitrogen and serum creatinine induced by cisplatin administration in vivo. In addition, histopathological analysis of the kidneys showed that compound 5 significantly reduced cisplatin-induced (Cis -induced) renal toxicity compared with the cisplatin group. A mechanism study showed that compound 5 significantly reduces NOX4 levels, improves the activity of antioxidant enzymes (SOD and GSH-Px), reduces Malondialdehyde (MDA) levels, increases the total antioxidant level, reduces oxidative stress, and thus reduces kidney tissue damage. At the same time, compound 5 activated the Nrf2 signaling pathway. In addition, it can increase the expression of Bax, reduce the expression of Bcl-2 and caspase-3, a marker of apoptosis, which is beneficial to the survival of kidney cells. Additionally, compound 5 did not interfere with the antitumor effects of cisplatin in in vivo xenotransplantation models. • Compound 5, a free radical scavenger, mitigates kidney damage caused by cisplatin. • It suppressed renal MDA, NOX4, Nrf2, boosted SOD and GSH-Px, thus improving T-AOC. • It augmented Bax, downregulated Bcl-2 and caspase3, ultimately inhibiting apoptosis. • It does not affect the antitumor effect of cisplatin. [ABSTRACT FROM AUTHOR]

In liver transplantation (LT), although various immunosuppressants have been used in clinical practice, acute rejection remains a common complication that significantly shortens recipient survival. In recent years, manipulating immune tolerance has been regarded as one of the promising solutions to rejection. Autophagy, an evolutionarily conserved protein degradation system, has been reported to be involved in immune rejection and may be a target to establish immune tolerance. However, the role of autophagy in acute rejection reaction after LT has not been elucidated. Here, we showed that the autophagy of CD8+ T cells was strongly enhanced in patients with graft rejection and that the autophagy level was positively correlated with the severity of rejection. Similar findings were observed in a rat acute hepatic rejection model. Furthermore, administration of the autophagy inhibitor 3-methyladenine (3-MA) largely decreased the viability and function of CD8+ T cells through inhibiting autophagy, which significantly prolonged graft survival in rats. In addition, inhibiting the autophagy of activated CD8+ T cells in vitro considerably suppressed mitochondria mediated survival and downregulated T cell function. Conclusions: We first showed that the inhibition of autophagy significantly prolongs liver allograft survival by promoting the apoptosis of CD8+ T cells, which may provide a novel strategy for immune tolerance induction. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of global cancer-related mortality. Dioscin-6'-O-acetate (DA), a novel natural steroidal saponin, was firstly isolated from the rhizomes of Dioscorea althaeoides R. Knuth. Until now, there were no studies on its pharmacological activities.Purpose: Here, we investigated the growth inhibitory effect and explored the underlying molecular mechanisms of DA against lung cancer cells.Methods/study Designs: NSCLC H460, H1299, H520 cells and SCLC H446 cells were treated with DA. To display the cytotoxic effects and possible mechanism of DA on these cells, MTT assay, flow cytometry and western blot analysis were carried out.Results: Our results showed that DA exerted strong anti-proliferative activity against lung cancer cells in a concentration- and time-dependent manner. Flow cytometry demonstrated DA induced the cell cycle arrest at S-phase (NCI-H460, NCI-H1299, NCI-H520) or G1-phase (NCI-H446), caused cellular apoptosis, generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Western blotting analysis showed DA treatment increased the levels of caspase 3, 8, 9, Bax, p21, p53, phosphorylated JNK and p38 MAPK and markedly decreased the expression of Bcl-2, p-ERK, p-PI3K, p-AKT and NF-κB. Blockade of caspases with Z-VAD-FMK converted apoptosis-related proteins. Suppression of p53 with pifithrin-α (PFT) attenuated cell cycle-related protein. Inhibition of ROS with N-acetyl-cysteine (NAC) adjusted apoptosis-related proteins and phosphorylated MAPK and PI3K, as well as NF-κB.Conclusion: Overall, our study indicated that DA suppressed lung cancer cells proliferation via inducing cell-cycle arrest and enhancing caspase-dependent apoptosis, at least partly, through ROS-mediated PI3K/AKT, MAPK and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]

This study was conducted to obtain the optimal dietary lipid requirement and evaluate the differential regulatory effects of optimal or excessive dietary lipid levels on growth performance, lipid metabolism and physiological responses including oxidative stress (OS) and endoplasmic reticulum stress (ERS) of juvenile black seabream (Acanthopagrus schlegelii) (initial weight 2.08 ± 0.01 g). Six isonitrogenous experimental diets were formulated with graded levels of lipid: 6.87% (D1), 11.17% (D2), 14.35% (D3), 18.89% (D4), 23.93% (D5) and 26.94% (D6), respectively. Results indicated that fish fed with the D2 diet showed significantly higher values of final weight (FW), weight gain (WG) and specific growth rate (SGR) than those fed with the other diets, except for D3 group. In fish fed with the diets containing 11.17% and 14.35% (D2 and D3 groups) had the significantly higher contents of high density lipoprotein cholesterol (HDL-C) than other treatments, but showed markedly low concentrations of low density lipoprotein cholesterol (LDL-C). The contents of cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST) and alanine transaminase (ALT) in serum increased with the increasing of dietary lipid levels, except for the contents of AST and ALT in D1 group. Likewise, the results of hepatic paraffin section indicated that fish fed the dietary lipid levels of 18.89% or beyond (D4, D5 and D6) increased vacuolar fat drops and induced hepatic fat pathological changes. The mRNA expression level and protein concentration of sterol regulatory element-binding protein-1(srebp-1) were significantly up-regulated with the increasing of dietary lipid levels. However, the mRNA expression levels and protein concentrations of peroxisome proliferator-activated receptor alpha (pparα) and silent information regulator 1 (sirt1) significantly activated by fish fed with the D2 diet. Additionally, when fish fed with excessive dietary lipid (over 18.89%) could result in various responses related to OS and ERS. The key marker of OS malonaldehyde (MDA) was significantly increased with the increasing of dietary lipid levels being highest in the D6 group. A contrary pattern was found for total antioxidant capacity, which showed significantly higher activity in the D2 group. All parameters related to ERS increased with the increasing of dietary lipid levels and, hence, triggering inflammation and apoptosis by up-regulating the expression levels of key genes including nuclear factor kappa B (nf-κb) and c-Jun N-terminal kinase (jnk). Overall, based on WG, the optimal dietary lipid requirement of juvenile A. schlegelii is 12.82% by quadratic curve model analysis. When dietary lipid level exceeded 18.89%, excessive lipid could reduce growth performance, cause hepatic fat pathological changes, induce lipid deposition by modulating Sirt1/Srebp-1/Pparɑ pathways, lead to OS and ERS and, hence, triggering hepatic inflammation and apoptosis. These findings provide further insight and understanding of the regulatory effects on growth, lipid metabolism, physiological stress response (including OS and ERS) of A. schlegelii fed with optimal or excessive dietary lipid levels • The optimal dietary lipid requirement of juvenile A. schlegelii is 12.82%. • Optimal lipid diet could maintain normal physiological functions of A. schlegelii. • Dietary lipid levels containing 18.89% or beyond had adverse effect on growth. • Excessive lipid diet induced lipid deposition by modulating Sirt1/Pparα/Srebp1pathway. • Excessive lipid diet caused stress responses including OS and ERS. [ABSTRACT FROM AUTHOR]

The physiological metabolism of marine animals farmed in coastal areas is influenced greatly by extreme weather and frequent aqueous layer exchange, with short or long periods of heavy rain reducing seawater salinity. Black seabream (Acanthopagrus schlegelii) is a euryhaline fish, that are farmed in China under both normal/ambient salinity in seawater cages and low salinity conditions in pond culture. To explore the effects of an acute change in salinity on physiological metabolism, juvenile black seabream (weight 19.80 ± 0.37 g) was subjected to low salinity (4–5 psu) over five time points including 1 h (H1), 6 h (H6), 12 h (H12), 24 h (H24) and one week (W), with 0 h (initial, natural salinity of 22 psu) as control group. Results indicated that acute exposure to low-salinity resulted in various responses related to oxidative stress (OS) and endoplasmic reticulum stress (ERS). The key markers of OS including reactive oxygen species and malonaldehyde were significantly increased with acute salinity stress up to 6 h, then decreased to return to normal levels. A similar pattern was recorded for total antioxidant capacity, which showed significantly higher activity in the H6 group. All parameters related to ERS increased with duration of the low-salinity stress, which stimulated expression of key genes including nuclear factor kappa B (nf-κb) and c-Jun N-terminal kinase (jnk), triggering inflammation and apoptosis. However, total apoptotic cell rate decreased markedly as the duration of salinity stress increased up to one week. Gill expression of genes of long-chain polyunsaturated fatty acid (LC-PUFA) biosynthesis was up-regulated by low salinity stress with levels of docosahexaenoic (DHA), eicosapentaenoic (EPA) and arachidonic acids (ARA) being highest in the H12 group, which positively contributed to enhanced ability of osmoregulation. In conclusion, acute low-salinity stress stimulated various stress responses but, as the duration of salinity stress increased, the fish showed signs of physiological adaptation to the environmental change. During the adaptive process to maintain hemolymph osmotic pressure regulation, LC-PUFA were rapidly enriched in gill, which might be a crucial strategy allowing A. schlegelii to adapt to low-salinity stress. These findings provided further insight and understanding of the physiological responses and underlying adaptive strategy of euryhaline fish to salinity stress, and confirmed time-dependent effects. [Display omitted] • A. schlegelii showed time-dependent responses to low-salinity stress (22 to 4 psu). • LC-PUFA were enriched in gill with acute low-salinity stress. • Low-salinity caused stress responses including OS and ERS. • nf-κb and jnk were stimulated by ERS triggering inflammation and apoptosis. • A. schlegelii showed physiological adaptation to low-salinity stress. [ABSTRACT FROM AUTHOR]