Rutaecarpine Prevents High Glucose-Induced Endothelial Cell Senescence Through Transient Receptor Potential Vanilloid Subtype 1/ SIRT1 Pathway.

ABSTRACT: SIRT1 functions as a longevity factor to counteract vascular aging induced by high glucose. Our previous study revealed that rutaecarpine, the natural agonist of transient receptor potential vanilloid subtype 1 (TRPV1), prevented high glucose-induced endothelial dysfunction. The present study aims to evaluate the effects of rutaecarpine on endothelial cell senescence induced by high glucose, and focus on the regulatory effect on SIRT1 expression. In cultured human umbilical vein endothelial cell (HUVEC), exposure to 33 mM high glucose for 72 hours induced cellular senescence, demonstrated as cell cycle arrest at G0/G1 phase, decreased cell viability, and increased number of senescence-associated ß-galactosidase positive senescence cells and ROS production, which were effectively attenuated by treatment with rutaecarpine (0.3, 1, and 3 µM). Furthermore, rutaecarpine upregulated longevity protein SIRT1 expression in HUVECs, accompanied by decreased level of senescence marker p21. In addition, rutaecarpine increased intracellular calcium level in HUVECs, and pretreatment with TRPV1 antagonist capsazepine, intracellular Ca2+ chelator BAPTA-AM or CaM antagonist W-7 abolished the effects of rutaecarpine on SIRT1 expression. In summary, this study shows that rutaecarpine upregulates SIRT1 expression and prevents high glucose-induced endothelial cell senescence, which is related to activation of TRPV1/[Ca2+]i/CaM signal pathway. Our findings provide evidence that rutaecarpine may be a promising candidate with a novel mechanism in prevention vascular aging in diabetes.

Automatic Rate and Rate-Integrating Mode-Switchable Axisymmetric Gyroscope.

This paper describes a novel rate and rate-integrating mode-switchable axisymmetric gyroscope. A precession angle tracking algorithm is developed to enable the gyro to switch automatically between rate and rate-integrating modes at preset rate points through a digital control system within the gyro. We also propose a vibrating amplitude control method for the rate-integrating mode that directly extracts the angular rate output to ensure switching stability. In rate mode, the bias instability and angle random walk of the gyro reach 0.106°/h and 0.011°/√h, respectively. Additionally, an input range of over ±5000°/s is measured in rate-integrating mode. The scale factor nonlinearity reaches approximately 116 ppm over the full-scale range. The control system implements effective steering control of the gyroscope, with a switching delay of 10 ms from rate mode to rate-integrating mode and 100 ms from rate-integrating to rate mode. The proposed system actualizes a new type of gyroscope with high accuracy and a wide input range, which combines the benefits of rate and rate-integrating modes.

Synthesis and Bioactivity of Guanidinium-Functionalized Pillar[5]arene as a Biofilm Disruptor.

Due to the inherent resistance of bacterial biofilms to antibiotics and their serious threat to global public health, novel therapeutic agents and strategies to tackle biofilms are urgently needed. To this end, we designed and synthesized a novel guanidinium-functionalized pillar[5]arene (GP5) that exhibited high antibacterial potency against Gram-negative E. coli (BH101) and Gram-positive S. aureus (ATCC25904) strains. More importantly, GP5 effectively disrupted preformed E. coli biofilms by efficient penetration through biofilm barriers and subsequent destruction of biofilm-enclosed bacteria. Furthermore, host-guest complexation between GP5 and cefazolin sodium, a conventional antibiotic that otherwise shows negligible activity against biofilms, exhibited much enhanced, synergistic disruption activity against E. coli biofilms, thus providing a novel supramolecular platform to effectively disrupt biofilms.

Acupuncture as an Adjunctive Treatment for Angina Due to Coronary Artery Disease: A Meta-Analysis.

BACKGROUND In traditional Chinese medicine, acupuncture has been used to treat angina due to coronary artery disease (CAD). The aim of this systematic review of the literature and meta-analysis was to identify published randomized controlled trials (RCTs) that quantified the effectiveness of adjunctive acupuncture treatment in patients with angina due to CAD who were also treated with Western or Chinese medicine. MATERIAL AND METHODS A systematic review of the literature included a search of the PubMed, Embase, Cochrane library, and China National Knowledge Infrastructure (CNKI) databases, from their inception to September 2018. Published findings from RCTs were included that investigated the effectiveness of acupuncture as an adjunctive treatment for angina due to CAD in combination with Western or traditional Chinese medicine. The odds ratio (OR) and 95% confidence interval (CI) were calculated using the random-effects model to determine the outcomes of markedly and moderately effective rates for the use of acupuncture. RESULTS Twenty-four published RCTs were identified that included 1,916 patients with CAD. Patients who received adjunctive acupuncture treatment had a significantly increased markedly effective rate. However, the moderately effective rate between adjunctive acupuncture combined with standard treatment for angina and standard treatment alone was not statistically significant. Sensitivity analysis showed that the pooled results for the markedly and moderately effective rates were robust. Subgroup analysis in most subsets supported the main findings. CONCLUSIONS Meta-analysis supported a positive treatment effect for the use of acupuncture when used as adjunctive therapy in patients with angina due to CAD.

Yiqihuoxue decoction protects against post-myocardial infarction injury via activation of cardiomyocytes PGC-1α expression.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of ischemic heart disease, exacerbating cardiomyocytes injury in myocardial infarction (MI). Peroxisome proliferator-activated receptor gamma co-activator (PGC-1α) has been recognized as the key regulator of mitochondrial biogenesis and energy metabolism. Yiqihuoxue decoction (YQHX), a Traditional Chinese Medicine (TCM) prescription, can prevent and treat ischemic heart disease. However, the mechanisms of YQHX on PGC-1α expression in the ischemic heart have remained unclear. METHODS: Myocardial ischemia rat model and ischemia/hypoxia injury model in the cardiomyocytes were used to minic human cardiovascular disease. Rats were randomly assigned into 4 groups: Sham, Model, YQHX (8.2 g/kg) and Trimetazidine (10 mg/kg) group. 28 days after MI, cardiac functions and morphology were detected by echocardiography and HE staining, respectively. In vitro, the effects of YQHX on H9c2 cell viability, LDH and ROS were detected, respectively. PGC-1α relevant proteins were evaluated by Western blotting. RESULTS: In vivo, echocardiography and HE staining results showed that YQHX improved cardiac functions and modified pathological changes. YQHX enhanced PGC-1α expression and improved the mitochondrial ultrastructure and functions in rats MI model for 4 weeks. Further, we explored its potential mechanisms in cardiomyocytes. In vitro, YQHX significantly enhanced cell viability and reduced LDH release and ROS production induced by hypoxia in cardiomyocytes. Interestingly, exposure of cardiomyocytes to hypoxic conditions for 12 h induced the downregulation of PGC-1α expression, but the expression levels nearly returned to the normal state after hypoxia for 24 h. YQHX significantly enhanced PGC-1α expression between 12 h and 24 h induced by hypoxia through a mechanism associated with the activation of AMPK phosphorylation in H9c2 cells. In addition, YQHX upregulated the expression of Tfam and NRF-1, while NRF-1 expression was completely blocked by an AMPK inhibitor. YQHX largely restored the mitochondrial morphology and increased mitochondrial membrane potential in hypoxia-induced injury. Furthermore, the UHPLC-LTQ-Orbitrap-MSn analysis found that there were 87 chemical constituents in YQHX. CONCLUSIONS: These results suggest that the protective effect of YQHX on cardiomyocytes against hypoxia-induced injury may be attributed to activation of PGC-1α and maintenance of mitochondrial functions through a mechanism involving the activation of AMPK phosphorylation.

Highly Efficient Artificial Light-Harvesting Systems Constructed in Aqueous Solution Based on Supramolecular Self-Assembly.

Highly efficient light-harvesting systems were successfully fabricated in aqueous solution based on the supramolecular self-assembly of a water-soluble pillar[6]arene (WP6), a salicylaldehyde azine derivative (G), and two different fluorescence dyes, Nile Red (NiR) or Eosin Y (ESY). The WP6-G supramolecular assembly exhibits remarkably improved aggregation-induced emission enhancement and acts as a donor for the artificial light-harvesting system, and NiR or ESY, which are loaded within the WP6-G assembly, act as acceptors. An efficient energy-transfer process takes place from the WP6-G assembly not only to NiR but also to ESY for these two different systems. Furthermore, both of the WP6-G-NiR and WP6-G-ESY systems show an ultrahigh antenna effect at a high donor/acceptor ratio.

POTENTIAL APPROACHES FOR REDUCING AMYLOID ß PRODUCTION.

Alzheimer's disease (AD), a neurodegenerative disorder, is associated with the mitochondrial dysfunction, defective synapses, and impaired cognition in elderly patients. The accumulation of amyloid ß (Aß) in synapses and synaptic mitochondria is thought one of the critical pathological events of synaptic defect and impaired mitochondrial dynamics in AD neurons. In order to understand disease progression and designing therapeutic agents using available molecular targets, extensive research is in progress throughout the world. However, no drug has been reported, up to now, as effectively preventing and treating moiety for AD, due to hidden knowledge about exact mode of AD pathogenesis. However, some hypotheses based-drugs, possessing capability of regulating amyloid ß precursor protein, have been indicated for alleviation of psychological and behavioral symptoms of AD patients. This review article briefly describes the recent developments made for exploring the Aß induced-mitochondrial defects in AD and some treatment possibilities through Aß-targeting approaches for AD therapy.

Ultrasonography of lower limb vascular angiopathy and plaque formation in type 2 diabetes patients and finding its relevance to the carotid atherosclerotic formation.

OBJECTIVE: One of the major complications of diabetes is blood vessel disease, termed angiopathy, which is characterized by abnormal angiogenesis. The objective of this study was to discuss the characteristics of lower limb vascular angiopathy and plaque formation in type 2 diabetes patients and finding its relevance to the carotid atherosclerotic plaque formation, thus directing the clinical diagnosis and treatment. METHODS: The ultrasonography was used to monitor the patients with carotid artery and lower limb artery. RESULTS: Compared with the control group, decreased blood flow to lower limb and lower limb angiopathy occurred more obviously in dorsal artery of foot than in popliteal artery. The study revealed that the detection rate of the prevalence of carotid atherosclerosis plaque and lower limb arterial plaque and the combination of plaque both carotid and lower limb arteries in diabetic patients was 369:342:296 (about 1.25:1.15:1) and that the prevalence of carotid plaque and lower limb arterial plaque in all subjects with plaque was 71.3%. The risk of plaque formation also had positive correlation with patient's age. Color Doppler ultrasound had a clinical significance in the early diagnosis and curative effect observation in type 2 diabetes with lower limb angiopathy. The risk of simultaneous plaque formation in both carotid artery and lower extremity artery was greater in type 2 diabetes than that of control subjects, but they were not necessarily to occur simultaneously. The symptoms were inconspicuous in the early course of diabetes. CONCLUSION: The application of ultrasound monitoring in patients with carotid artery and lower limb artery might play a role in early warning, delaying the occurrence of macrovascular diseases, and slowing down the development of macroangiopathy such as cerebral infarction and diabetic foot and so on, thus providing a significant basis for clinical diagnosis and treatment.

Synthesis and Biological Evaluation of Fluorine-18 and Deuterium Labeled l-Fluoroalanines as Positron Emission Tomography Imaging Agents for Cancer Detection.

To fully explore the potential of 18F-labeled l-fluoroalanine for imaging cancer and other chronic diseases, a simple and mild radiosynthesis method has been established to produce optically pure l-3-[18F]fluoroalanine (l-[18F]FAla), using a serine-derivatized, five-membered-ring sulfamidate as the radiofluorination precursor. A deuterated analogue, l-3-[18F]fluoroalanine-d3 (l-[18F]FAla-d3), was also prepared to improve metabolic stability. Both l-[18F]FAla and l-[18F]FAla-d3 were rapidly taken up by 9L/lacZ, MIA PaCa-2, and U87MG cells and were shown to be substrates for the alanine-serine-cysteine (ASC) amino acid transporter. The ability of l-[18F]FAla, l-[18F]FAla-d3, and the d-enantiomer, d-[18F]FAla-d3, to image tumors was evaluated in U87MG tumor-bearing mice. Despite the significant bone uptake was observed for both l-[18F]FAla and l-[18F]FAla-d3, the latter had enhanced tumor uptake compared to l-[18F]FAla, and d-[18F]FAla-d3 was not specifically taken up by the tumors. The enhanced tumor uptake of l-[18F]FAla-d3 compared with its nondeuterated counterpart, l-[18F]FAla, warranted the further biological investigation of this radiotracer as a potential cancer imaging agent.

Melatonin decreases GSDME mediated mesothelial cell pyroptosis and prevents peritoneal fibrosis and ultrafiltration failure.

Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure. Mesothelial cell loss is an initiating event for peritoneal fibrosis. We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E, driving downstream inflammatory responses, including the activation of macrophages. Moreover, pyroptosis is associated with elevated vascular endothelial growth factor A and C, two key factors in vascular angiogenesis and lymphatic vessel formation. GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure. Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action, and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy. Mechanistically, melatonin treatment maintains mitochondrial integrity in mesothelial cells, meanwhile activating mTOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate. These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress. Thus, Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.

pH-Controlled reversible formation of a supramolecular hyperbranched polymer showing fluorescence switching.

A π-conjugated AB2 monomer 1 with a dibenzo[24]crown-8 (DB24C8) ring and two secondary amine centres has been synthesised. Treatment of a solution of 1 in dichloromethane with trifluoroacetic acid (TFA) leads to protonation of the amine groups, and then the DB24C8 rings are threaded by the dialkylammonium ion centres of other monomer molecules, leading to the formation of a supramolecular hyperbranched polymer, TFA-1. Rather strong π-π stacking interactions between the conjugated cores are evident in this polymer. The supramolecular hyperbranched polymer (SHP) can be completely depolymerised by adding a slight excess of N-tert-butyl-N',N',N'',N'',N''',N'''-hexamethylphosphorimidic triamide, tetrabutylammonium fluoride, or tetrabutylammonium acetate. The acid-base-controlled process induces a reversible change in the fluorescence intensities of the solutions due to the controllable presence of the π-π stacking interactions between the conjugated cores. This dynamic behaviour is significant with respect to "smart" supramolecular polymer materials.

Prediction of Acute Kidney Injury by Fibroblast Growth Factor 23 (FGF-23) in Adult Patients, A Meta-analysis Study.

INTRODUCTION: The aim of the current meta-analysis was to assess the predictive value of blood fibroblast growth factor 23 (FGF-23) for acute kidney injury (AKI) in adult patients. METHODS: We retrieved relative publications from electronic databases including the Cochrane Library, PubMed, Google Scholar, Scopus, web of science, and Wanfang Data from their inception to Aug 2022. RESULTS: This meta-analysis study included seven prospective cohort trials comprising 1,655 adult patients. The overall pooled area under the receiver operating characteristic curve (AUC) from seven studies was 0.83 (95% CI: 0.80 to 0.86). Significant heterogeneity was identified (Q = 9.82, P = .004, I2 = 80). Pooled sensitivity and specificity were 0.75 (95% CI: 0.59 to 0.87) and 0.77 (95% CI: 0.65 to 0.87), respectively. Pooled positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 3.3 (95% CI: 1.8 to 6.3), 0.32 (95% CI: 0.16 to 0.63), and 10 (95% CI: 3 to 38); respectively. Moreover, our sensitivity analysis showed that when a trial from Asia was excluded, the predictive value of FGF-23 was declined. CONCLUSION: Our results of meta-analysis of seven prospective cohort trials suggested that blood FGF-23 is a candidate indicator for the prediction of AKI in adult patients. Results of future large and well-designed clinical trials are still needed.  DOI: 10.52547/ijkd.7189.

Protection of H9c2 Myocardial Cells from Oxidative Stress by Crocetin via PINK1/Parkin Pathway-Mediated Mitophagy.

This study aimed to explore the oxidative stress-protective effect of crocetin on H2O2-mediated H9c2 myocardial cells through in vitro experiments, and further explore whether its mechanism is related to the impact of mitophagy. This study also aimed to demonstrate the therapeutic effect of safflower acid on oxidative stress in cardiomyocytes and explore whether its mechanism is related to the effect of mitophagy. Here, an H2O2-based oxidative stress model was constructed and assessed the degree of oxidative stress injury of cardiomyocytes by detecting the levels of lactate dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH Px). Reactive oxygen species (ROS)-detecting fluorescent dye DCFH-DA, JC-1 dye, and TUNEL dye were employed to assess mitochondrial damage and apoptosis. Autophagic flux was measured by transfecting Ad-mCherry-GFP-LC3B adenovirus. Mitophagy-related proteins were then detected via western blotting and immunofluorescence. However, crocetin (0.1-10 µM) could significantly improve cell viability and reduce apoptosis and oxidative stress damage caused by H2O2. In cells with excessive autophagic activation, crocetin could also reduce autophagy flow and the expression of mitophagy-related proteins PINK1 and Parkin, and reverse the transfer of Parkin to mitochondria. Crocetin could reduce H2O2-mediated oxidative stress damage and the apoptosis of H9c2 cells, and its mechanism was closely related to mitophagy.

Effect of Quadrature Control Mode on ZRO Drift of MEMS Gyroscope and Online Compensation Method.

The quadrature coupling error is an important factor that affects the detection output of microelectromechanical system (MEMS) gyroscopes. In this study, two quadrature error control methods, quadrature force-to-rebalance control (Mode I) and quadrature stiffness control (Mode II) were analyzed. We obtained the main factors affecting the zero-rate output (ZRO) under force-to-rebalance (FTR) closed-loop detection. The analysis results showed that the circuit phase delay in Mode I caused the quadrature channel to leak into the in-phase channel. However, in Mode II, the quadrature coupling stiffness was corrected in real time, which effectively improved the stability of the ZRO. The changes in the vibration displacement and Q-factor were the main factors for the ZRO drift in Mode II. Therefore, we propose an online compensation method for ZRO drift based on multiparameter fusion. The experimental results on a cobweb-like disk resonator gyroscope (CDRG) with a 340 k Q-factor showed that the bias instability (BI) of Mode II was significantly better than that of Mode I. After online compensation, the BI reached 0.23°/h, and the bias repeatability reached 3.15°/h at room temperature.

Combatting Antibiotic Resistance Using Supramolecular Assemblies.

Antibiotic resistance has posed a great threat to human health. The emergence of antibiotic resistance has always outpaced the development of new antibiotics, and the investment in the development of new antibiotics is diminishing. Supramolecular self-assembly of the conventional antibacterial agents has been proved to be a promising and versatile strategy to tackle the serious problem of antibiotic resistance. In this review, the recent development of antibacterial agents based on supramolecular self-assembly strategies will be introduced.

Capsaicin ameliorates intermittent high glucose-mediated endothelial senescence via the TRPV1/SIRT1 pathway.

BACKGROUND: Patients with diabetes have accelerated vascular aging when compared with healthy individuals. Hyperglycemia, especially intermittent high glucose (IHG), is the main cause of vascular endothelial senescence. Capsaicin, a major component of chili pepper is thought to contribute to cardiovascular protection by spicy food. OBJECTIVE: To investigate the pathway related with the effects of capsaicin on endothelial cell senescence induced by IHG. METHODS: HUVECs were exposed to IHG (5 mM or 33 mM glucose, alternating every 12 hours for 3 days) and treated with capsaicin at 0.3, 1 and 3 µM. To determine endothelial cell senescence, we examined the senescence-related ß-galactosidase staining, cell cycle arrest, cell viability, as well as production of reactive oxygen species (ROS). To evaluate the involvement of TRPV1/[Ca2+]i/CaMKII/AMPK/SIRT1 pathway in anti- senescence effects of capsaicin, HUVECs were treated with CAPZ (a TRPV1 antagonist), BAPTA-AM (an intracellular calcium chelator), KN62 (a CaMKII antagonist), compound C (an AMPK inhibitor), or EX527 (a SIRT1 inhibitor). To knockdown TRPV1, HUVECs were transfected with shRNA lentivirus targeting TRPV1. The levels of SIRT1, p21, TRPV1, AMPK and phospho-AMPK were evaluated by western blotting. RESULTS: IHG suppressed the levels of SIRT1 and enhanced endothelial senescence. Capsaicin upregulated SIRT1 expression and downregulated the senescence marker, p21, thereby protecting endothelial cells from IHG-induced senescence as indicated by relieved G0/G1 phase arrest, improved cell viabilities, and reduced counts of senescent cells and ROS production. Pre-treatment with CAPZ, BAPTA-AM, KN62 or compound C abrogated the anti-senescence effects of capsaicin. Capsaicin restored AMPK phosphorylation and IHG-inhibited TRPV1 expression. Moreover, TRPV1 silencing suppressed SIRT1 expression and abolished the anti-senescence effects of capsaicin. CONCLUSION: Capsaicin elevates SIRT1 levels through TRPV1/[Ca2+]i/CaMKII/AMPK pathway and suppresses IHG-mediated endothelial cell senescence. This study provides initial evidence that capsaicin is a potential candidate for the prevention of vascular aging in diabetes.

RNA modifications in aging-associated cardiovascular diseases.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide that bears an enormous healthcare burden and aging is a major contributing factor to CVDs. Functional gene expression network during aging is regulated by mRNAs transcriptionally and by non-coding RNAs epi-transcriptionally. RNA modifications alter the stability and function of both mRNAs and non-coding RNAs and are involved in differentiation, development, and diseases. Here we review major chemical RNA modifications on mRNAs and non-coding RNAs, including N6-adenosine methylation, N1-adenosine methylation, 5-methylcytidine, pseudouridylation, 2' -O-ribose-methylation, and N7-methylguanosine, in the aging process with an emphasis on cardiovascular aging. We also summarize the currently available methods to detect RNA modifications and the bioinformatic tools to study RNA modifications. More importantly, we discussed the specific implication of the RNA modifications on mRNAs and non-coding RNAs in the pathogenesis of aging-associated CVDs, including atherosclerosis, hypertension, coronary heart diseases, congestive heart failure, atrial fibrillation, peripheral artery disease, venous insufficiency, and stroke.

Near-Infrared Photo-controlled Permeability of a Biomimetic Polymersome with Sustained Drug Release and Efficient Tumor Therapy.

Synthetic polymersomes have structure similarity to bio-vesicles and could disassemble in response to stimuli for "on-demand" release of encapsulated cargos. Though widely applied as a drug delivery carrier, the burst release mode with structure complete destruction is usually taken for most responsive polymersomes, which would shorten the effective drug reaction time and impair the therapeutic effect. Inspired by the cell organelles' communication mode via regulating membrane permeability for transportation control, we highlight here a biomimetic polymersome with sustained drug release over a specific period of time via near-infrared (NIR) pre-activation. The polymersome is prepared by the self-assembling amphiphilic diblock copolymer P(OEGMA-co-EoS)-b-PNBOC and encapsulates the hypoxia-activated prodrug AQ4N and upconversion nanoparticle (PEG-UCNP) in its hydrophilic centric cavity. Thirty minutes of NIR pre-activation triggers cross-linking of NBOC and converts the permeability of the polymersome with sustained AQ4N release until 24 h after the NIR pre-activation. The photosensitizer EoS is activated and aggravates environmental hypoxic conditions during a sustained drug release period to boost the AQ4N therapeutic effect. The combination of sustained drug release with concurrent hypoxia intensification results in a highly efficient tumor therapeutic effect both intracellularly and in vivo. This biomimetic polymersome will provide an effective and universal tumor therapeutic approach.

NIR-II reinforced intracellular cyclic reaction to enhance chemodynamic therapy with abundant H2O2 supply.

Chemodynamic therapy (CDT) is an ideal therapeutic modality with endogenous H2O2 as stimulus. Most intracellular H2O2 supplement strategies for improving CDT efficiency are strongly rely on oxygen participation, and the hypoxia tumor microenvironment impairs their performance. Here we develop a self-assembled metal-organic coordinated nanoparticle Cu-OCNP/Lap with NIR-II reinforced intracellular cyclic reaction to enhance CDT efficiency. Cu-OCNP/Lap is synthesized using Cu2+ as nodes and 1,4,5,8-tetrahydroxyanthraquinone (THQ) and banoxantrone dihydrochloride (AQ4N) as ligands, with ß-lapachone (ß-Lap) loading to conduct intracellular cyclic reaction. Cu-OCNP/Lap has good photothermal effect at NIR-II window, and the corresponding local temperature increase speeds blood flow and supplies sufficient oxygen at tumor site to reinforce ß-Lap cyclic reaction with abundant H2O2 generation. Cu+ is released from Cu-OCNP/Lap in response to glutathione (GSH) and triggers CDT. Sufficient intracellular H2O2 supply enhances CDT effect and demonstrates good suppressions for tumor growth. This design offers a promising strategy to enhance CDT efficiency.

Conjugated Polymer-Ferrocence Nanoparticle as an NIR-II Light Powered Nanoamplifier to Enhance Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a promising therapeutic modality with transition metal ions and endogenous H2O2 as reagents, but its efficiency is impaired by low endogenous H2O2 levels and nonregeneration of metal ions. Most intracellular H2O2 supplement strategies use oxidases and are intensively dependent on oxygen participation. The hypoxia microenvironments of solid tumors weaken their performance. Here, we develop a near-infrared II light powered nanoamplifier to improve the local oxygen level and to enhance CDT. The nanoamplifier CPNP-Fc/Pt consists of ferrocene (Fc)- and cisplatin prodrug (Pt(IV))-modified conjugated polymer nanoparticles (CPNPs). CPNP has a donor-acceptor structure and demonstrates a good photothermal effect under 1064 nm light irradiation, which accelerates blood flow and efficiently elevates the local oxygen content. In response to intracellular glutathione, Pt(II) is released from CPNP-Fc/Pt and triggers enzymatic cascade reactions with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and superoxide dismutase to convert oxygen into H2O2. The enhanced oxygen level results in efficient intracellular H2O2 supply. Fc is reacted with H2O2 and converted to Fc+ via the Fenton reaction, with the generation of hydroxyl radicals for CDT. Unlike free metal ions, the Fe(III) in Fc+ is reduced to Fe(II) by intracellular NAD(P)H, which achieves the regeneration of Fc. The sufficient intracellular H2O2 supply and efficient Fc regeneration effectively enhance the Fenton reaction and demonstrate good in vivo CDT results with tumor growth suppression. This design offers a promising strategy to enhance CDT efficiency in the hypoxia microenvironment of solid tumors.