Mechanistic studies on the alleviation of ANIT-induced cholestatic liver injury by Polygala fallax Hemsl. polysaccharides.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl. polysaccharides (PFPs) are of interest for their potential health benefits. AIM OF THIS STUDY: This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. MATERIALS AND METHODS: A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. RESULTS: Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1ß, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. CONCLUSIONS: In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.

Dietary Supplementation of Ancientino Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress.

Ancientino, a complex dietary fiber supplement mimicking the ancient diet, has improved chronic heart failure, kidney function, and constipation. However, its effect on ulcerative colitis is unknown. This study explores the impact of Ancientino on colitis caused by dextran sulfate sodium (DSS) and its mechanisms. Data analyses showed that Ancientino alleviated bodyweight loss, colon shortening and injury, and disease activity index (DAI) score, regulated levels of inflammatory factors (tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-1 beta (IL-1ß), and interleukin 6 (IL-6)), reduced intestinal permeability (d-lactate and endotoxin), fluorescein isothiocyanate-dextran (FITC-dextran), and diamine oxidase (DAO), repaired colonic function (ZO-1 and occludin), and suppressed oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA)) in vivo and in vitro. In short, this study demonstrated that Ancientino alleviates colitis and exerts an anticolitis effect by reducing inflammatory response, suppressing oxidative stress, and repairing intestinal barrier function. Thus, Ancientino may be an effective therapeutic dietary resource for ulcerative colitis.

Overcoming Hypoxia-Induced Ferroptosis Resistance via a 19 F/1 H-MRI Traceable Core-Shell Nanostructure.

Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses the efficacy of ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia-induced ferroptosis resistance. Specifically, we synthesize a novel kind of perfluorocarbon (PFOB)@manganese oxide (MnOx) core-shell nanoparticles (PM-CS NPs). Owing to the good carrier of O2 as fuel, PM-CS NPs can induce higher level of ROS generation, lipid peroxidation and GSH depletion, as well as lower activity of GPX4, compared with MnOx NPs alone. Moreover, the supplement of O2 can relieve tumor hypoxia to break down the storage of intracellular lipid droplets and increase expression of ACSL4 (a symbol for ferroptosis sensitivity). Furthermore, upon stimulus of GSH or acidity, PM-CS NPs exhibit the "turn on" 19 F-MRI signal and activatable T1 /T2 -MRI contrast for correlating with the release of Mn. Finally, PM-CS NPs exert high cancer inhibition rate for ferroptosis based therapy via synergetic combination of O2 -mediated enhancement of key pathways of ferroptosis.

High-efficiency and safe sulfur-doped iron oxides for magnetic resonance imaging-guided photothermal/magnetic hyperthermia therapy.

Heat therapy is a promising therapeutic modality for cancer treatment due to the minimum adverse effects of selective local hyperthermia; however, the low heating efficiency of heat therapy under safe conditions is an issue for its bioapplication. Here, we report the synthesis of water-dispersible sulfur doped iron oxides (SDIOs) with different phase structures and the exploration of the relationships between the different SDIOs and their induction heating capacities as a guideline to obtain a photo-magnetic hyperthermia agent. The agent exhibits good biocompatibility, excellent photothermal conversion efficiency (55.8%) and great T2 weighted magnetic resonance imaging (63.7 mM-1 s-1). Significantly, the SDIOs effectively eliminate tumours in a biologically safe AC magnetic field range (H·f = 4.3 < 5.0 × 106 kA m-1 s-1) and with 808 nm laser irradiation at a safe density of 0.33 W cm-2; also, they can be mostly metabolized from the body after one month. The work presented here adopts anion-doped iron oxides to dramatically improve photo-magnetic hyperthermia effects and may enable further exploration in thermotherapeutic research.

A full-spectrum-absorption from nickel sulphide nanoparticles for efficient NIR-II window photothermal therapy.

Near-infrared (NIR) light has been widely applied in the field of photothermal therapy (PTT). Recent advances in the light wavelength for efficient cancer PTT have gradually shifted from the first NIR (NIR-I) biowindow (700-1000 nm) to the second NIR (NIR-II) biowindow (1000-1350 nm) owing to its intrinsic deeper tissue penetration ability and a higher maximum permissible exposure (MPE) value. Herein, we have prepared nickel sulphide (Ni9S8) nanoparticles (NPs) with a full-spectrum-absorption (400 nm-1100 nm) in the NIR region. By a fair comparison, it is found that the PTT using the NPs upon irradiation from an NIR-II (i.e., 1064 nm) laser is more efficient than that from an NIR-I (i.e., 808, 915, and 976 nm) laser. The large mass extinction coefficient value (22.18 L g-1 cm-1) and high photothermal conversion efficiency (46%) at 1064 nm make these NPs promising candidates for NIR-II photo-thermal therapy. This study will benefit future exploration and optimization of nickel-based photoabsorbers utilizing NIR-II light for photothermal applications.

New Strategy for Specific Eradication of Implant-Related Infections Based on Special and Selective Degradability of Rhenium Trioxide Nanocubes.

The greatest bottleneck for photothermal antibacterial therapy could be the difficulty in heating the infection site directly and specifically to evade the unwanted damage for surrounding healthy tissues. In recent years, infectious microenvironments (IMEs) have been increasingly recognized as a crucial contributor to bacterial infections. Here, based on the unique IMEs and rhenium trioxide (ReO3) nanocubes (NCs), a new specific photothermal antibacterial strategy is reported. These NCs synthesized by a rapid and straightforward space-confined on-substrate approach have good biocompatibility and exhibit efficient photothermal antibacterial ability. Especially when they are utilized in antibiofilm, the expression levels of biofilm-related genes (icaA, fnbA, atlE, and sarA for Staphylococcus aureus) can be effectively inhibited to block bacterial adhesion and formation of biofilm. Importantly, the ReO3 NCs can transform into hydrogen rhenium bronze (HxReO3) in an aqueous environment, making them relatively stable within the low pH of IMEs for photothermal therapy, while rapidly degradable within the surrounding healthy tissues to decrease photothermal damage. Note that under phosphate-buffered saline (PBS) at pH 7.4 without assistant conditions, these ReO3 NCs have the highest degradation rate among all known degradable inorganic photothermal nanoagents. This special and IME-sensitive selective degradability of the ReO3 NCs not only facilitates safe, efficient, and specific elimination of implant-related infections, but also enables effective body clearance after therapy. Solely containing the element (Re) whose atomic number is higher than clinic-applied iodine in all reported degradable inorganic photothermal nanoagents under the PBS (pH 7.4) without any assistant condition, the ReO3 NCs with high X-ray attenuation ability could be further applied to X-ray computed tomography imaging-guided therapy against implant-related infections. The present work described here is the first to adopt degradable inorganic photothermal nanoagents to achieve specific antibacterial therapy and inspires other therapies on this concept.

Porous cobalt sulfide hollow nanospheres with tunable optical property for magnetic resonance imaging-guided photothermal therapy.

Transition-metal chalcogenides with an imaging element and tunable optical property are strongly desired as ideal high-efficiency photothermal theranostic agents to diagnose and eliminate tumors. Herein, we report on a one-pot solvothermal strategy to synthesize various porous cobalt sulfide hollow nanospheres (PCSH NSs) and elucidate the relation between PCSH NSs and their optical absorption as a guide to obtain optimal photothermal therapy (PTT) agents. After PEG modification, PEG-PCSH NSs show superexcellent photothermal conversion efficiency (∼70.1%) which is higher than that of binary transition-metal chalcogenides materials reported to date. A low dose (100 µL, 25 ppm) could completely ablate tumors under an 808 nm laser power of 0.7 W cm-2, reducing in vivo long-term residual agent content and thus lowering the possibility of side effects. Additionally, they also exhibit excellent biocompatibility, good photostability and utility for magnetic resonance imaging. Our results indicate that PCSH NSs can be considered as an outstanding PTT agent and give guidance towards the design of other photothermal theranostic agents.

Degradable rhenium trioxide nanocubes with high localized surface plasmon resonance absorbance like gold for photothermal theranostics.

The applications of inorganic theranostic agents in clinical trials are generally limited to their innate non-biodegradability and potential long-term biotoxicity. To address this problem, herein via a straightforward and tailored space-confined on-substrate route, we obtained rhenium trioxide (ReO3) nanocubes (NCs) that display a good biocompatibility and biosafety. Importantly, their aqueous dispersion has high localized surface plasmon resonance (LSPR) absorbance in near-infrared (NIR) region different from previous report, which possibly associates with the charge transfer and structural distortion in hydrogen rhenium bronze (HxReO3), as well as ReO3's cubic shape. Such a high LSPR absorbance in the NIR region endows them with photoacoustic (PA)/infrared (IR) thermal imaging, and high photothermal conversion efficiency (∼57.0%) for efficient ablation of cancer cells. Also, ReO3 NCs show X-ray computed tomography (CT) imaging derived from the high-Z element Re. More attractively, those ReO3 NCs, with pH-dependent oxidized degradation behaviors, are revealed to be relatively stable in hypoxic and weakly acidic microenvironment of tumor for imaging and treatment whilst degradable in normal physiological environments of organs to enable effective clearance. In spite of their degradability, ReO3 NCs still possess tumor targeting capabilities. We thus develop a simple but powerful, safe and biodegradable inorganic theranostic platform to achieve PA/CT/IR imaging-guided cancer photothermal therapy (PTT) for improved therapeutic efficacy and decreased toxic side effects.

CuCo2S4 nanocrystals: a new platform for multimodal imaging guided photothermal therapy.

Multifunctional nanomaterials open an avenue for the integration of cancer treatment and diagnosis, trending towards the clinical application of nanomedicines in future. Herein, we synthesized biocompatible CuCo2S4 nanocrystals (NCs) via a simple reflux method and unitized them as a new theranostic platform, where an intense near-infrared (NIR) absorption offers the CuCo2S4 NCs a perfect photothermal performance and photoacoustic (PA) imaging ability; the magnetic characteristic of Co allows them to serve as an enhanced magnetic resonance (MR) contrast agent. The in vitro and in vivo experiments demonstrated their good biocompatibility, non-toxicity and perfect photothermal conversion performance and further confirmed that HeLa tumors could be effectively thermal-ablated upon the assistance of the CuCo2S4 NCs. This work introduces the first bioapplication of the CuCo2S4 NCs and promotes theranostics based on other ternary compounds.

Nicotine's attenuation of body weight involves the perifornical hypothalamus.

Previously we showed that intermittent administration of nicotine (NIC) in the dark phase decreased food intake and body weight and this could be blocked when the NIC receptor antagonist mecamylamine was infused into the fourth ventricle. Catecholaminergic neurons adjacent to the fourth ventricle contain NIC receptors and directly innervate the perifornical hypothalamus (PFH) which has been shown to be involved in regulation of feeding. This study explored whether NIC regulates feeding behavior by modulating catecholaminergic input to the PFH. Epinephrine and norepinephrine neuronal input was ablated within the PFH by infusion of 6-hydroxydopamine hydrobromide (6-OHDA), while bupropion was infused to protect dopaminergic neurons. After recovery of body weights to pre-surgery levels, food intake, meal size, meal number and body weight were measured after intermittent NIC injections. The results showed the PFH lesioned animals did not exhibit the typical prolonged drop in food intake, meal size and body weight normally associated with NIC administration. High performance liquid chromatography analyses demonstrated that compared to control rats, 6-OHDA administration significantly reduced PFH norepinephrine and epinephrine levels, but not dopamine levels. These results are consistent with NIC reducing food intake in part by acting through catecholaminergic neurons within or extending through the PFH.

Nicotine administration effects on feeding and cocaine-amphetamine-regulated transcript (CART) expression in the hypothalamus.

In previous studies food intake and meal size significantly decreased in rats two days after injecting 4 mg/kg/day nicotine tartrate. Food intake returned to normal after nine days of continued nicotine treatment, when reduced meal size is countered by an increase in meal number. Nicotine also reduced body weight after nicotine injection and body weight remained low after nine days. To begin characterizing the mechanism that modulates these changes in feeding behavior and/or body weight during nicotine exposure the transcript levels for agouti related protein (AGRP), cocaine-amphetamine-regulated transcript (CART), corticotropin releasing hormone receptor one (CRH-R1), melanocortin receptors three and four (MC3R/4R), neuropeptide Y (NPY), NPY Y1 and Y5 receptors and/or pro-opiomelanocortin (POMC) were analyzed in the arcuate (ARC), dorsomedial (DMN) and paraventricular (PVN)/periventricular (PE) hypothalamic nuclei on the second and ninth day of saline or nicotine treatment. Results show that the transcript levels of the anorexigenic molecule CART increased in the PVN and/or PE two days after nicotine treatment but after nine days CART levels equalize. In contrast, nine days of nicotine treatment reduced CART levels in the DMN as compared to saline controls. To investigate CART's role in regulating feeding, infusion of CART (55-102) into the third ventricle reduced food intake and meal size. These results are consistent with nicotine modulating feeding behavior and body weight, in part, by affecting CART transcript levels in the DMN, PVN and/or PE.