In-situ TiO2-x decoration of titanium carbide MXene for photo/sono-responsive antitumor theranostics.

BACKGROUND: Sonodynamic therapy (SDT) has emerged as a noninvasive therapeutic modality that involves sonosensitizers and low-intensity ultrasound. However, owing to the rapid recombination of charge carriers, most of the sonosensitizers triggered poor reactive oxygen species (ROS) generation, resulting in unsatisfactory sonodynamic therapeutic effects. RESULTS: Herein, a photo/sono-responsive nanoplatform was developed through the in-situ systhesis of TiO2-x on the surface of two-dimensional MXene (titanium carbide, Ti3C2) for photoacoustic/photothermal bimodal imaging-guided near-infrared II (NIR-II) photothermal enhanced SDT of tumor. Because of several oxygen vacancies and smaller size (~ 10 nm), the in-situ formed TiO2-x nanoparticles possessed narrow band gap (2.65 eV) and high surface area, and thus served as a charge trap to restrict charge recombination under ultrasound (US) activation, resulting in enhanced sonodynamic ROS generation. Moreover, Ti3C2 nanosheets induced extensive localized hyperthermia relieves tumor hypoxia by accelerating intratumoral blood flow and tumor oxygenation, and thus further strengthened the efficacy of SDT. Upon US/NIR-II laser dual-stimuli, Ti3C2@TiO2-x nanoplatform triggered substantial cellular killing in vitro and complete tumor eradication in vivo, without any tumor recurrence and systemic toxicity. CONCLUSION: Our work presents the promising design of photo/sono-responsive nanoplatform for cancer nanotheranostics.

Evaluation of the Chemical Composition and Antioxidant Activity of Mulberry (Morus alba L.) Fruits from Different Varieties in China.

Mulberry (Morus alba L.) fruit is a fruit with nutritional and medicinal value. It is widely cultivated in different regions of China, which may result in differences in its chemical composition. In this research, 25 mulberry fruit samples from six provinces in China were investigated. The contents of anthocyanins were evaluated by high-performance liquid chromatography (HPLC). The contents of two main anthocyanins, cyanidin-3-O-glucoside (C3G) and cyanidin-3-O-rutinoside (C3R), ranged from 0.656 ± 0.006 mg/g to 4.367 ± 0.243 mg/g and from 0.226 ± 0.007 mg/g to 1.649 ± 0.013 mg/g, respectively. Additionally, the contents of total phenolic, total flavonoid, vitamin C, titratable acids, reducing sugars and antioxidant capacity (FRAP, DPPH, scavenging and hydroxyl radical scavenging activity) were also assessed. The results and principal component analysis showed that the Zhongsang 5801 variety from Sichuan, Dechang had the greatest health value with the highest active compound contents. Based on our analysis, the variety from Sichuan, Dechang is a high-quality plant source for mulberry fruit cultivation. This research provides a basis for the rational development and utilization of mulberry fruit resources in China.

Biodegradable Self-Assembled Ultrasmall Nanodots as Reactive Oxygen/Nitrogen Species Scavengers for Theranostic Application in Acute Kidney Injury.

Acute kidney injury (AKI) is frequently triggered by abundant reactive oxygen/nitrogen species (RONS) and leads to high morbidity and mortality in clinic. Unfortunately, the current clinical treatment options are only limited to supportive care, and hence, the development of nano-antioxidants with high kidney enrichment is an attractive novel strategy for AKI management. Herein, self-assembled ultrasmall nanodots are reported that consist of iron ion, gallic acid, and polyvinylpyrrolidone (denoted as FGP nanodots) as broad-spectrum RONS scavengers to alleviate both glycerinum- and cis-platinum- induced AKI in mice. Ultrasmall FGP nanodots (≈3.5 nm) offer efficient protection in vitro and reduce cellular apoptosis after H2 O2 stimulation by eliminating various RONS including hydroxyl radical (·OH), superoxide anion (·O2- ), nitric oxide (NO), and peroxynitrite (ONOO- ), etc. In vivo duplex magnetic resonance/fluorescence imaging demonstrates preferential accumulation of FGP nanodots in the kidneys with rapid renal clearance through urine. Importantly, FGP nanodots exhibit remarkable RONS consumption in vivo with enhanced biocompatibility and biodegradability, resulting in superior therapeutic effect than small molecule drug (Amifostine) in two AKI mouse models. This study presents the promising potential of ultrasmall self-assembled FGP nanodots as imaging contrast agent and broad-spectrum antioxidant nanomedicine for AKI theranotics.

Regulating Tumor N6 -Methyladenosine Methylation Landscape using Hypoxia-Modulating OsSx Nanoparticles.

The epigenetic dysregulation and hypoxia are two important factors that drive tumor malignancy, and N6 -methyladenosine (m6 A) in mRNA is involved in the regulation of gene expression. Herein, a nanocatalyst OsSx -PEG (PEG = poly(ethylene glycol)) nanoparticles (NPs) as O2 modulator is developed to improve tumor hypoxia. OsSx -PEG NPs can significantly downregulate genes involved in hypoxia pathway. Interestingly, OsSx -PEG NPs elevate RNA m6 A methylation levels to cause the m6 A-dependent mRNA degradation of the hypoxia-related genes. Moreover, OsSx -PEG NPs can regulate the expression of RNA m6 A methyltransferases and demethylases. Finally, DOX@OsSx -PEG (DOX = doxorubicin; utilized as a model drug) NPs modulate tumor hypoxia and regulate mRNA m6 A methylation of hypoxia-related genes in vivo. As the first report about relationship between catalytic nanomaterials and RNA modifications, the research opens a new avenue for unveiling the underlying action mechanisms of hypoxia-modulating nanomaterials and shows potential of regulating RNA modification to overcome chemoresistance.

Prussian blue-based theranostics for ameliorating acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) with high mortality rates is associated with an excess of reactive oxygen/nitrogen species (RONS) within kidney tissues. Recently, nanomedicine antioxidant therapy has been used to alleviate AKI. Herein, we synthesized ultrasmall Prussian blue nanozymes (PB NZs, 4.5 nm) as theranostic agents for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided AKI treatment. RESULTS: PB NZs exhibited multi-enzyme mimetic abilities, promoting the effective elimination of RONS both in vitro and in vivo. Moreover, benefiting from their imaging contrast properties, the rapid renal accumulation of PB NZs was verified by in vivo PA/MR dual-modal imaging. Due to their excellent enrichment in the kidney and unique multi-enzyme mimetic abilities, ultrasmall PB NZs displayed superior AKI treatment efficacy compared with that of amifostine in two clinically relevant types of AKI induced murine models (either by rhabdomyolysis or cisplatin). CONCLUSION: Our findings suggested ultrasmall PB NZs, as nanozyme theranostics, have great potential for AKI management.

Corrigendum to "Ultrasmall platinum nanozymes as broad-spectrum antioxidants for theranostic application in acute kidney injury" [Chem. Eng. J. 409 (2020) 127371].

[This corrects the article DOI: 10.1016/j.cej.2020.127371.].

Delivery of Platinum(IV) Prodrugs via Bi2Te3 Nanoparticles for Photothermal-Chemotherapy and Photothermal/Photoacoustic Imaging.

Combinational administration of photothermal therapy (PTT) and chemotherapy (CT) shows great potential in improving the efficiency of tumor treatment. Herein, we designed a novel nanocomposite Pt@Bi2Te3 composed of bismuth telluride (Bi2Te3) nanoparticles and platinum(IV) prodrugs (Pt) for PTT-CT combination therapy. The obtained Bi2Te3 was synthesized by a simple solvothermal method and modified by polyethylene glycol, which exhibited excellent photothermal (PT) efficiency and stability and could also serve as a bimodal bioimaging contrast agent in PT and photoacoustic (PA) imaging. In vitro experiment results showed that the nanocomposite Pt@Bi2Te3 could effectively increase the uptake of platinum in cancer cells, which could kill tumor cells through the combined effect of PTT and CT. Furthermore, combination therapy of cancer in vivo was achieved with obvious tumor-growth inhibition without inducing observed side effects. We revealed the great potential of Bi2Te3 nanocomposites in increasing therapeutic efficiency by PTT-CT therapy and PA-PT imaging.

Anticancer IrIII -Aspirin Conjugates for Enhanced Metabolic Immuno-Modulation and Mitochondrial Lifetime Imaging.

The chemo-anti-inflammatory strategy is attracting ever more attention for the treatment of cancer. Here, two cyclometalated IrIII complexes Ir2 and Ir3 formed by conjugation of Ir1 with two antiphlogistics (aspirin and salicylic acid) have been designed. Ir2 and Ir3 exhibit higher antitumor and anti-inflammatory potencies than a mixture of Ir1 and aspirin/salicylic acid. We show that they can be hydrolyzed, accumulate in mitochondria, and induce mitochondrial dysfunction. Due to their intense long-lived phosphorescence, Ir2 and Ir3 can track mitochondrial morphological changes. Phosphorescence lifetime imaging shows that Ir2 and Ir3 can aggregate during mitochondrial dysfunction. As expected, Ir2 and Ir3 exhibit immunomodulatory properties by regulating the activity of immune factors. Both Ir2 and Ir3 can induce caspase-dependent apoptosis and caspase-independent paraptosis and inhibit several events related to metastasis. Moreover, Ir2 and Ir3 show potent tumor growth inhibition in vivo. Our study demonstrates that the combination of mitochondrial-targeting and immunomodulatory activities is feasible to develop multifunctional metal-based anticancer agents.

"Four-Step Procedure" of laparoscopic exploration for gastric cancer in West China Hospital: a retrospective observational analysis from a high-volume institution in China.

BACKGROUND: The preoperative work-up has limitations on finding peritoneal dissemination (PD) in gastric cancer patients. Laparoscopic exploration (LE) can discover radiographically occult PD, obtain accurate stage and avert futile laparotomy. The aim of our study was to introduce "Four-Step Procedure" LE in West China Hospital and further evaluate its safety and feasibility. METHODS: We conducted a retrospective analysis on 165 patients from July 2016 to December 2017 who underwent "Four-Step Procedure" LE in gastrointestinal surgery department of West China Hospital. All the patients were diagnosed with gastric adenocarcinoma without explicit distant metastasis through Computed Tomography and/or Gastrointestinal Ultrasonography. Peritoneal lavage cytological examination (CY) was routinely performed during LE in our research. The "Four-Step" technical process of LE was introduced comprehensively. The clinicopathologic features and the presence of PD or CY at LE were analyzed, and the stratified analysis by cT and cN stages on the proportion of P1 and/or CY1 was also reported in this study. RESULTS: Total of 165 patients accepted LE in our study, among these patients: 27 (16.4%) patients with P1 and/or CY1: 19 (11.5%) patients were found PD (P1), 17 (10.3%) patients with positive cytological examination (CY1) and 9 (3.6%) patients with P1Cy1. The stratified analysis by cT stage indicated that there was no P1 and/or Cy1 in cT1-cT2 stages, 1 (2.7%) patient with P1 and 1 (2.7%) with Cy1 in cT3 stage, 18 (20.0%) patients with P1 and 16 (17.8%) with Cy1 in cT4 stage. After LE, there were 74 (44.8%) patients underwent laparoscopic assistant gastrectomy, 25 (15.2%) patients with open gastrectomy, 50 (30.3%) patients with neoadjuvant chemotherapy and 16 (9.7%) patients with palliative chemotherapy and/or conversion therapy. CONCLUSION: "Four-Step Procedure" LE is reliable and feasible for gastric cancer. From our study, LE has unique superiority on ascertaining PD and cytological examination and LE should be recommended in cT4 stage gastric cancer before resection.

Organoiodine-Catalyzed Enantioselective Alkoxylation/Oxidative Rearrangement of Allylic Alcohols.

An enantioselective catalytic alkoxylation/oxidative rearrangement of allylic alcohols has been established by using a Brønsted acid and chiral organoiodine. The presence of 20 mol % of an (S)-proline-derived C2 -symmetric chiral iodine led to enantioenriched α-arylated ß-alkoxylated ketones in good yields and with high levels of enantioselectivity (84-94 % ee).

Sirtuin3 protects aged human mesenchymal stem cells against oxidative stress and enhances efficacy of cell therapy for ischaemic heart diseases.

Sirtuin3 (SIRT3) is associated with oxidative stress and lifespan. However, the possible mechanisms underlying its influence are unknown. We hypothesized that SIRT3 increases the antioxidant capacity of aged cells and improves the efficacy of human mesenchymal stem cell (hMSC) therapy for ischaemic heart diseases in aged patients. In vitro, the antioxidant capacity of old hMSCs (O-hMSCs) was increased after SIRT3 overexpression using a gene transfection technique, while the antioxidant capacity of young hMSCs (Y-hMSCs) was decreased by SIRT3 silencing. The levels of forkhead box O3a (FoxO3a) in the nucleus, and antioxidant enzymes Mn-superoxide dismutase (MnSOD) and catalase (CAT) increased in SIRT3-overexpressed O-hMSCs while they decreased in SIRT3-silenced Y-hMSCs after oxidative stress. Following myocardial infarction in adult rats in vivo, infarct size decreased and cardiac function was significantly enhanced after cell transplantation with SIRT3 overexpressed O-hMSCs. The number of apoptotic cells decreased and the survival rate of transplanted cells increased following SIRT3 overexpression in O-hMSCs. SIRT3 protects aged hMSCs against oxidative stress by positively regulating antioxidant enzymes (MnSOD and CAT) via increasing the expression of FoxO3a in the nucleus. The efficacy of aged hMSC transplantation therapy for ischaemic heart diseases can be improved by SIRT3 overexpression.

Efficient and Versatile Pipet Microextraction Device Based on a Light-Heatable Sorbent.

Miniaturized sample pretreatment platforms have simplified analytical tasks in diverse disciplines. Herein, a novel pipet microextraction (PME) device is reported by making use of the photothermal property of a light-heatable sorbent (LHS) for the first time. Efficient and staining-free heating treatment of small volumes of liquids confined in the PME device is now enabled through light illumination. The light-induced heating treatment is capable of dramatically accelerating solvent elution rates, effectively unlocking bound toxin from its antibody, and rapidly quenching enzymatic activities, thus, provides PME with higher efficiencies and enables its new applications in antibody-intermediated sampling of targeted toxin from stained food surfaces and powders, as well as in accurate revelation of enzymatic reaction kinetics. This study offers a new perspective of designing efficient and versatile microextraction platforms and demonstrates their potential applications in different fields including public security, new drug development, and environmental protection.

Photodamaging of Mitochondrial DNA to Overcome Cisplatin Resistance by a RuII -PtII Bimetallic Complex.

Emerging studies have shown that mitochondrial DNA (mtDNA) is an attractive target for anticancer therapeutics. Herein, a heterobimetallic complex [Ru(dip)2 (µ-bpm)PtCl2 ]Cl2 (RuPt; dip=4,7-diphenyl-1,10-phenanthroline; bpm=2,2'-bipyrimidine) and the corresponding mononuclear complex [Ru(dip)2 (bpm)]Cl2 (Ru) have been designed and synthesized. RuPt can bind to mtDNA and damage it both in the dark and upon visible light irradiation. By using a variety of methods, it was demonstrated that RuPt can interfere with the function of mtDNA by decreasing the amplification and copy number of mtDNA, and affecting the transcriptional level of mitochondria-encoded genes. Furthermore, RuPt can disturb the physiological processes of mitochondria and induce caspase-dependent apoptosis in the presence of light. In addition, RuPt shows low systemic toxicity and potent in vivo anticancer potency upon light irradiation. This study provides strong evidence that mtDNA is an important molecular target of RuPt, and photodamaging mtDNA is an effective strategy to overcome cisplatin resistance.

Chiral Iodine-Catalyzed Dearomatizative Spirocyclization for the Enantioselective Construction of an All-Carbon Stereogenic Center.

The first enantioselective dearomatizative spirocyclization of 1-hydroxy-N-aryl-2-naphthamide derivatives has been accomplished by chiral organoiodine catalysis to stereoselectively create an all-carbon stereogenic center, providing a straightforward approach to access spirooxindole derivatives in good yields and with high to excellent levels of enantioselectivity. Chiral hypervalent phenyl-λ(3) -iodanes generated in situ from the oxidation of the chiral phenyl iodine actually participate in the asymmetric oxidative dearomatizative spirocyclization reaction.

Decreased SIRT3 in aged human mesenchymal stromal/stem cells increases cellular susceptibility to oxidative stress.

Sirtuin3 (SIRT3) is an important member of the sirtuin family of protein deacetylases that is localized to mitochondria and linked to lifespan extension in organisms ranging from yeast to humans. As aged cells have less regenerative capacity and are more susceptible to oxidative stress, we investigated the effect of ageing on SIRT3 levels and its correlation with antioxidant enzyme activities. Here, we show that severe oxidative stress reduces SIRT3 levels in young human mesenchymal stromal/stem cells (hMSCs). Overexpression of SIRT3 improved hMSCs resistance to the detrimental effects of oxidative stress. By activating manganese superoxide dismutase (MnSOD) and catalase (CAT), SIRT3 protects hMSCs from apoptosis under stress. SIRT3 expression, levels of MnSOD and CAT, as well as cell survival showed little difference in old versus young hMSCs under normal growth conditions, whereas older cells had a significantly reduced capacity to withstand oxidative stress compared to their younger counterparts. Expression of the short 28 kD SIRT3 isoform was higher, while the long 44 kD isoform expression was lower in young myocardial tissues compared with older ones. These results suggest that the active short isoform of SIRT3 protects hMSCs from oxidative injury by increasing the expression and activity of antioxidant enzymes. The expression of this short isoform decreases in cardiac tissue during ageing, leading to a reduced capacity for the heart to withstand oxidative stress.

Asymmetric organocatalytic direct C(sp²)-H/C(sp³)-H oxidative cross-coupling by chiral iodine reagents.

An asymmetric organocatalytic direct C-H/C-H oxidative coupling reaction of N(1),N(3)-diphenylmalonamides has been well established by using chiral organoiodine compounds as catalysts, wherein four C-H bonds were stereoselectively functionalized to give structurally diverse spirooxindoles with high levels of enantioselectivity. More importantly, the findings indicated that chiral hypervalent organoiodine reagents can serve as alternative catalysts for the creation of enantioselective functionalization of inactive C-H bonds.

Reactive oxygen/nitrogen species scavenging and inflammatory regulation by renal-targeted bio-inspired rhodium nanozymes for acute kidney injury theranostics.

Acute kidney injury (AKI) results from the rapid deterioration of renal function, which is mainly treated by transplantation and dialysis, and has a high mortality rate. Inflammation induced by excess reactive oxygen/nitrogen species (RONS) plays a crucial role in AKI. Although small molecule antioxidants have been utilized to alleviate AKI, low bioavailability and side-effect of these drugs tremendously limit their clinical use. Hence, we successfully construct ultra-small (2-4 nm) rhodium nanoparticles modified with l-serine (denoted as Rh-Ser). Our results show that Rh-Ser with multiple enzyme-mimicking activities, allows remove various RONS to protect damaged kidney cells. Additionally, the ultrasmall size of Rh-Ser is conducive to enrichment in the renal tubules, and the modification of l-serine enables Rh-Ser to bind to kidney injury molecule-1, which is highly expressed on the surface of damaged renal cells, thereby targeting the damaged kidney and increasing the retention time. Moreover, Rh-Ser allows the production of oxygen at the inflammatory site, thus further improving hypoxia and inhibiting pro-inflammatory macrophages to relieve inflammation, and increasing the survival rate of AKI mice from 0 to 80%, which exhibits a better therapeutic effect than that of small molecule drug. Photoacoustic and fluorescence imaging can effectively monitor and evaluate the enrichment and therapeutic effect of Rh-Ser. Our study provides a promising strategy for the targeted treatment of AKI via RONS scavenging and inflammatory regulation.

Biodegradable Osmium Nanoantidotes for Photothermal-/Chemo- Combined Treatment and to Prevent Chemotherapy-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a common adverse event in chemotherapy patients. AKI is accompanied by the generation of reactive oxygen species (ROS) and inflammation. Therefore, the management of ROS and inflammation is a potential strategy for AKI mitigation. Herein, polyethylene glycol-coated osmium nanozyme-based antidotes (Os) are developed for imaging-guided photothermal therapy (PTT) in combination with cisplatin (Pt); while, avoiding AKI induced by high-dose Pt. Os nanoantidotes can enhance the efficiency of tumor treatment during combined PTT and chemotherapy and inhibit tumor metastasis by improving the hypoxic and inflammatory tumor microenvironment. Os nanoantidotes preferentially accumulate in the kidney because of their 2-nm size distribution; and then, regulate inflammation by scavenging ROS and generating oxygen to alleviate Pt-induced AKI. Os nanoantidotes can be cleared from the kidneys by urine excretion but can be degraded under hydrogen peroxide stimulation, reducing the bio-retention of these compounds. By integrating PTT with inflammatory regulation, Os nanoantidotes have the potential to reduce the side effects of chemotherapy, offering an alternative route for the clinical management of cancer patients with chemotherapy-induced AKI.

An effective negative pressure cavitation-microwave assisted extraction for determination of phenolic compounds in P. calliantha H. Andr.

A novel negative pressure and microwave assisted extraction technique (NMAE) was first proposed and applied for extraction of phenolic compounds from pyrola. [C4MIM]BF4 aqueous solution was selected as extraction solvent. Optimal extraction conditions were microwave power 700 W, negative pressure -0.07 MPa, temperature 40 °C, liquid-solid ratio 20 : 1, ionic liquid (IL) concentration 0.5 M, extraction time 15 min. The predominance of NMAE was investigated by comparing with microwave-assisted extraction (MAE) and negative pressure cavitation extraction (NPCE) using a first-order kinetics equation. The C∞ values of the target compounds by NMAE were from 0.406 to 5.977 mg g⁻¹ higher than these by MAE and NPCE, which indicated that NMAE had higher extraction yields. The K values of NMAE were also the highest; it was testified that the target compounds could be transferred from matrix into solvent much more effectively by NMAE than by MAE and NPCE. In addition, the NMAE method was validated in terms of repeatability and reproducibility, the relative standard deviation for relative recovery was lower than 5.43 and 8.78%, respectively. Therefore, NMAE was a developed extraction technique for analytical sample preparation. The RP-HPLC-UV method was also successfully applied for the quantification of six target compounds in pyrola.

Tantalum Nitride-Based Theranostic Agent for Photoacoustic Imaging-Guided Photothermal Therapy in the Second NIR Window.

Metal nitrides show excellent photothermal stability and conversion properties, which have the potential for photothermal therapy (PTT) for cancer. Photoacoustic imaging (PAI) is a new non-invasive and non-ionizing biomedical imaging method that can provide real-time guidance for precise cancer treatment. In this work, we develop polyvinylpyrrolidone-functionalized tantalum nitride nanoparticles (defined as TaN-PVP NPs) for PAI-guided PTT of cancer in the second near-infrared (NIR-II) window. The TaN-PVP NPs are obtained by ultrasonic crushing of massive tantalum nitride and further modification by PVP to obtain good dispersion in water. Due to their good absorbance in the NIR-II window, TaN-PVP NPs with good biocompatibility have obvious photothermal conversion performance, realizing efficient tumor elimination by PTT in the NIR-II window. Meanwhile, the excellent PAI and photothermal imaging (PTI) capabilities of TaN-PVP NPs are able to provide monitoring and guidance for the treatment process. These results indicate that TaN-PVP NPs are qualified for cancer photothermal theranostics.