LDHA contributes to nicotine induced cardiac fibrosis through autophagy flux impairment.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis.

Unnatural Direct Interspecies Electron Transfer Enabled by Living Cell-Cell Click Chemistry.

Direct interspecies electron transfer (DIET) is essential for maintaining the function and stability of anaerobic microbial consortia. However, only limited natural DIET modes have been identified and DIET engineering remains highly challenging. Here, an unnatural DIET between Shewanella oneidensis MR-1 (SO, electron donating partner) and Rhodopseudomonas palustris (RP, electron accepting partner) was artificially established by a facile living cell-cell click chemistry strategy. By introducing alkyne- or azide-modified monosaccharides onto the cell outer surface of the target species, precise covalent connections between different species in high proximity were realized via a fast click chemistry reaction. Remarkably, upon covalent connection, outer cell surface C-type cytochromes mediated DIET between SO and RP was achieved and identified, although this was never realized naturally. Moreover, this connection directly shifted the natural H2 mediated interspecies electron transfer (MIET) to DIET between SO and RP, which delivered superior interspecies electron exchange efficiency. Therefore, this work demonstrated a naturally unachievable DIET and an unprecedented MIET shift to DIET accomplished by cell-cell distance engineering, offering an efficient and versatile solution for DIET engineering, which would extend our understanding of DIET and open up new avenue for DIET exploration and applications.

Revealing Hydrogen Bond Effect in Rechargeable Aqueous Zinc-Organic Batteries.

The surrounding hydrogen bond (H-bond) interaction around the active sites plays indispensable functions in enabling the organic electrode materials (OEMs) to fulfill their roles as ion reservoirs in aqueous zinc-organic batteries (ZOBs). Despite important, there are still no works could fully shed its real effects light on. Herein, quinone-based small molecules with a H-bond evolution model has been rationally selected to disclose the regulation and equilibration of H-bond interaction between OEMs, and OEM and the electrolyte. It has been found that only a suitable H-bond interaction could make the OEMs fully liberate their potential performance. Accordingly, the 2,5-diaminocyclohexa-2,5-diene-1,4-dione (DABQ) with elaborately designed H-bond structure exhibits a capacity of 193.3 mA h g-1 at a record-high mass loading of 66.2 mg cm-2 and 100% capacity retention after 1500 cycles at 5 A g-1. In addition, the DABQ//Zn battery also possesses air-rechargeable ability by utilizing the chemistry redox of proton. Our results put forward a specific pathway to precise utilization of H-bond to liberate the performance of OEMs.

The Brassinosteroid Receptor StBRI1 Promotes Tuber Development by Enhancing Plasma Membrane H+-ATPase Activity in Potato.

The brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) plays a critical role in plant growth and development. Although much is known about how BR signaling regulates growth and development in many crop species, the role of StBRI1 in regulating potato (Solanum tuberosum) tuber development is not well understood. To address this question, a series of comprehensive genetic and biochemical methods were applied in this investigation. It was determined that StBRI1 and Solanum tuberosum PLASMA MEMBRANE (PM) PROTON ATPASE2 (PHA2), a PM-localized proton ATPase, play important roles in potato tuber development. The individual overexpression of StBRI1 and PHA2 led to a 22% and 25% increase in tuber yield per plant, respectively. Consistent with the genetic evidence, in vivo interaction analysis using double transgenic lines and PM H+-ATPase activity assays indicated that StBRI1 interacts with the C-terminus of PHA2, which restrains the intramolecular interaction of the PHA2 C-terminus with the PHA2 central loop to attenuate autoinhibition of PM H+-ATPase activity, resulting in increased PHA2 activity. Furthermore, the extent of PM H+-ATPase autoinhibition involving phosphorylation-dependent mechanisms corresponds to phosphorylation of the penultimate Thr residue (Thr-951) in PHA2. These results suggest that StBRI1 phosphorylates PHA2 and enhances its activity, which subsequently promotes tuber development. Altogether, our results uncover a BR-StBRI1-PHA2 module that regulates tuber development and suggest a prospective strategy for improving tuberous crop growth and increasing yield via the cell surface-based BR signaling pathway.

Reconfiguring the Hydrogen Networks of Aqueous Electrolyte to Stabilize Iron Hexacyanoferrate for High-Voltage Decoupled Cell.

Prussian blue analogs (PBAs) as insertion-type cathodes have attracted significant attention in various aqueous batteries to accommodate metal or non-metal ions while suffering from serious dissolution and consequent inferior lifespan. Herein, we reveal that the dissolution of PBAs primarily originates from the locally elevated pH of electrolytes that are caused by proton co-insertion during discharge. To address this issue, a water-locking electrolyte (WLE) has been strategically implemented, which interrupts the generation and Grotthuss diffusion of protons by breaking the well-connected hydrogen bonding network in aqueous electrolytes. As a result, the WLE enables the iron hexacyanoferrate to endure over 1000 cycles at a 1C rate and supports a high-voltage decoupled cell with an average voltage of 1.95 V. These findings provide insights for mitigating dissolution problems in electrode materials, thereby enhancing the viability and performance of aqueous batteries.

Ganonorsterone A, a norsteroid from the medicinal fungus Ganoderma lingzhi.

Phytochemical investigation on the fruiting bodies of the medicinal fungus Ganoderma lingzhi led to the isolation of a new norsteroid, namely ganonorsterone A (1), together with one known steroid, cyathisterol (2). The structure and absolute configuration of compound 1 were assigned by extensive analysis of MS, NMR data, and quantum-chemical calculations including electronic circular dichroism (ECD) and calculated 13C NMR-DP4+ analysis. Bioassay results showed that compound 1 displayed moderate inhibition on NO production in RAW 264.7 macrophages.

Simultaneous Electrochemical Detection of Cu2+ and Zn2+ in Pig Farm Wastewater.

In recent years, the rapid development of pig farming has led to a large quantity of heavy metal-polluted wastewater. Thus, it was desirable to develop a simple heavy metal detection method for fast monitoring of the wastewater from the pig farms. Therefore, there was an urgent need to develop a simple method for rapidly detecting heavy metal ions in pig farm wastewater. Herein, a simple electrochemical method for simultaneous detection of Cu2+ and Zn2+ was developed and applied to pig farm wastewater. With a glassy carbon electrode and anodic stripping voltammetry, simultaneous detection of Cu2+ and Zn2+ in water was achieved without the need for complicated electrode modification. Furthermore, it was found that the addition of Cd2+ can enhance the response current of the electrode to Zn2+, which increased the signal by eight times. After systematic optimization, the limit of detection (LOD) of 9.3 µg/L for Cu2+ and 45.3 µg/L for Zn2+ was obtained. Finally, it was successfully applied for the quantification of Cu2+ and Zn2+ with high accuracy in pig farm wastewater. This work provided a new and simple solution for fast monitoring of the wastewater from pig farms and demonstrated the potential of electrochemical measurement for application in modern animal husbandry.

Transcranial alternating current stimulation improves quality of life in Parkinson's disease: study protocol for a randomized, double-blind, controlled trial.

BACKGROUND: The neural cells in the brains of patients with Parkinson's disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson's disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson's disease based on the central-peripheral-central theory. METHODS: The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson's disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes. DISCUSSION: The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023.

Melanoma differentiation-associated protein 5 prevents cardiac hypertrophy via apoptosis signal-regulating kinase 1-c-Jun N-terminal kinase/p38 signaling.

Pathological cardiac hypertrophy (CH) is driven by maladaptive changes in myocardial cells in response to pressure overload or other stimuli. CH has been identified as a significant risk factor for the development of various cardiovascular diseases, ultimately resulting in heart failure. Melanoma differentiation-associated protein 5 (MDA5), encoded by interferon-induced with helicase C domain 1 (IFIH1), is a cytoplasmic sensor that primarily functions as a detector of double-stranded ribonucleic acid (dsRNA) viruses in innate immune responses; however, its role in CH pathogenesis remains unclear. Thus, the aim of this study was to examine the relationship between MDA5 and CH using cellular and animal models generated by stimulating neonatal rat cardiomyocytes with phenylephrine and by performing transverse aortic constriction on mice, respectively. MDA5 expression was upregulated in all models. MDA5 deficiency exacerbated myocardial pachynsis, fibrosis, and inflammation in vivo, whereas its overexpression hindered CH development in vitro. In terms of the underlying molecular mechanism, MDA5 inhibited CH development by promoting apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, thereby suppressing c-Jun N-terminal kinase/p38 signaling pathway activation. Rescue experiments using an ASK1 activation inhibitor confirmed that ASK1 phosphorylation was essential for MDA5-mediated cell death. Thus, MDA5 protects against CH and is a potential therapeutic target.

Uptake and detection rate of colorectal cancer screening with colonoscopy in China: A population-based, prospective cohort study.

BACKGROUND: Colorectal cancer is the leading cause of cancer-related death worldwide. Colonoscopy is widely used as a screening test for detecting colorectal cancer in many countries. However, there is little evidence regarding the uptake and diagnostic yields of colonoscopy in population-based screening programs in countries with limited medical resources. OBJECTIVE: We reported the uptake of colonoscopy and the detection of colorectal lesions and explored related factors based on a colorectal cancer screening program in China. DESIGN: Individuals aged 45-74 years who were asymptomatic for colorectal cancer and had no history of colorectal cancer were recruited. An established risk score system was used to identify individuals at high risk for colorectal cancer, and they were subsequently recommended for colonoscopy. SETTING: A population-based, prospective cohort study was implemented in 169 communities, 14 districts of Chongqing, Southwest China. PARTICIPANTS: A total of 288,150 eligible participants were recruited from November 2013 to June 2021, and 41,315 participants were identified to be at high risk of colorectal cancer. METHODS: Generalized linear mixed model was used to explore the individual and community structural characteristics associated with uptake of colonoscopy. Additionally, the detection rate of colorectal lesions under colonoscopy screening was also reported, and their associated factors were explored. RESULTS: 7859 subjects underwent colonoscopy, with an uptake rate of 19.02 % (95 % CI 18.64 %-19.40 %). Lower uptake rates were associated with older age, lower education, more physical activity, and structural characteristics, including residing in developing areas (OR 0.73, 95 % CI 0.69-0.78), residing more than 5 km from screening hospital (5-10 km: OR 0.85, 95 % CI 0.79-0.91; >10 km: OR 0.85, 95 % CI 0.80-0.91), and not being exposed to social media publicity (OR 0.63, 95 % CI 0.53-0.75). Overall, 8 colorectal cancers (0.10 %), 423 advanced adenomas (5.38 %), 820 nonadvanced adenomas (10.43 %), and 684 hyperplastic polyps (8.70 %) were detected, with an adenoma detection rate of 15.92 %. Several factors, including older age, male, current smoking and a family history of colorectal cancer, were positively related to colorectal neoplasms. CONCLUSIONS: The uptake of colonoscopy for colorectal cancer screening was not optimal among a socioeconomically diverse high-risk population. The screening strategy should attempt to ensure equitable access to screening according to regional characteristics, and enhance the uptake of colonoscopy by recommended multifaceted interventions, which focus on individuals with poor compliance, select a closer screening hospital, and strengthen social media publicity at the structural level.

Modulating band structure through introducing Cu0/CuxO composites for the improved visible light driven ammonia synthesis.

The photocatalytic performance of ceria-based materials can be tuned by adjusting the surface structures with decorating the transition-metal, which are considered as the important active sites. Herein, cuprous oxide-metallic copper composite-doped ceria nanorods were assembled through a simple hydrothermal reduction method. The photocatalytic ammonia synthesis rates exhibit an inverted "V-shaped" trend with increasing Cu0/CuxO mole ratio. The best ammonia production rate, approximately 900 or 521 µmol·gcal-1·h-1 under full-spectra or visible light, can be achieved when the Cu0/CuxO ratio is approximately 0.16, and this value is 8 times greater than that of the original sample. The absorption edge of the as-prepared samples shifted towards visible wavelengths, and they also had appropriate ammonia synthesis levels. This research provides a strategy for designing noble metal-free photocatalysts through introducing the metal/metallic oxide compositesto the catalysts.

Spatial Structure Design of Thioether-Linked Naphthoquinone Cathodes for High-Performance Aqueous Zinc-Organic Batteries.

Organic electrode materials (OEMs) have gathered extensive attention for aqueous zinc-ion batteries (AZIBs) due to their structural diversity and molecular designability. However, the reported research mainly focuses on the design of the planar configuration of OEMs and does not take into account the important influence of the spatial structure on the electrochemical properties, which seriously hamper the further performance liberation of OEMs. Herein, this work has designed a series of thioether-linked naphthoquinone-derived isomers with tunable spatial structures and applied them as the cathodes in AZIBs. The incomplete conjugated structure of the elaborately engineered isomers can guarantee the independence of the redox reaction of active groups, which contributes to the full utilization of active sites and high redox reversibility. In addition, the position isomerization of naphthoquinones on the benzene rings changes the zincophilic activity and redox kinetics of the isomers, signifying the importance of spatial structure on the electrochemical performance. As a result, the 2,2'-(1,4-phenylenedithio) bis(1,4-naphthoquinone) (p-PNQ) with the smallest steric hindrance and the most independent redox of active sites exhibits a high specific capacity (279 mAh g-1), an outstanding rate capability (167 mAh g-1 at 100 A g-1), and a long-term cycling lifetime (over 2800 h at 0.05 A g-1).

Phenanthroline-Decorated Covalent Organic Framework for Catalytic Synthesis of 2-Aminobenzothiazoles in Water.

2-Aminobenzothiazoles are widely used in the fields of pharmaceuticals and pesticides. Herein, we report a metal-free protocol for the preparation of 2-aminobenzothiazoles by a covalent organic framework (COF) catalyzed tandem reaction. In the presence of catalytic amount of phenanthroline-decorated COF (Phen-COF), a variety of 2-aminobenzothiazoles are obtained in excellent yields by the cross-coupling of 2-iodoanilines with isothiocyanates at room temperature in water. In addition, the COF-catalyst is very stable and can be reused at least seven times without loss of its catalytic activity.

Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance.

Microtubule-targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule-targeting agents without such limitations are urgently needed. By employing a gene expression-based drug repositioning strategy, this study identifies VU-0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU-0365114 exhibits a broad-spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU-0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU-0365114 is not related to its original target, M5 mAChR. In addition, VU-0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus, it can overcome MDR. Furthermore, a kinome analysis shows that VU-0365114 did not exhibit other significant off-target effects. Taken together, our study suggests that VU-0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development.

Construction of Multifunctional Covalent Organic Frameworks for Photocatalysis.

Covalent organic frameworks (COFs) have recently drawn intense attention due to their potential applications in photocatalysis. Herein, we report a multifunctional COF which consists of triphenylamine (TPA) and 2,2'-bipyridine (2, 2'-bipy) entities. The obtained TAPA-BPy-COF is a heterogeneous photocatalyst and can efficiently catalyze the oxidative coupling of thiols to disulfides. In addition, TAPA-BPy-COF can be further metalated by Pd(II) via 2,2'-bipy-metal coordination. The generated Pd@TAPA-BPy-COF can highly promote photocatalytic synthesis of 3-cyanopyridines via cascade addition/cyclization of arylboronic acids with γ-ketodinitriles in heterogeneous way. This work has demonstrated the way for the rational design and preparation of more efficient photoactive COFs for photocatalysis.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

Facile Construction of Advanced 1D Metal-Organic Coordination Polymer for Efficient Lithium Storage.

Recently, coordination polymers (CPs) have been frequently reported in the field of energy storage as electrode materials for lithium-ion batteries (LIBs) due to their highly adjustable architectures, which have a variety of active sites and obviously defined lithium transport routes. A well-designed redox-active organic linker with potential active sites for storing lithium ions, pyrazine-2,3-dicarboxylate (H2PDA), was applied for generating CPs by a simple hydrothermal method. When employed as anode materials in LIBs, those two one-dimensional (1D) CPs with an isomorphic composition, [M(PDA)(H2O)2]n (M = Co for Co-PDA and Ni for Ni-PDA), produced outstanding reversible capacities and stable cycling performance. The Co-PDA displays a substantial reversible capacity of 936 mAh g-1 at 200 mA g-1 after 200 cycles, as well as an excellent cycling life at high currents. According to the ex situ characterizations, the high reversible specific capacity of the post-cycled electrodes was found to be a result of both the transition metal ions and the organic ligands, and Co-PDA and Ni-PDA electrode materials show reversible insertion/extraction processes that are accompanied by crystallization to an amorphous state.

Longitudinal multi-functional analysis identified responses of T cells, B cells, and monocytes as hallmarks of immunotherapy tolerance in patients with merkel cell carcinoma.

PURPOSE: Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma originating in the skin. Studies are needed to determine the mechanisms of immune escape in patients with MCC, and malignant cell conditions that promote immune evasion. METHODS: We used Single-cell RNA sequencing (scRNA-seq) to determine cellular features associated with MCC disease trajectory. A longitudinal multi-omics study was performed using scRNA-seq data of peripheral blood harvested from four-time points. Six major cell types and fifteen cell subgroups were identified and confirmed their presence by expression of characteristic markers. The expression patterns and specific changes of different cells at different time points were investigated. Subsequently, bulk RNA data was used to validate key findings. RESULTS: The dynamic characteristics of the cells were identified during the critical period between benign improvement and acquisition of resistance. Combined with the results of the validation cohort, the resistance program expressed in the relapse stage is mainly associated with T cell exhaustion and immune cell crosstalk disorder. Coinciding with immune escape, we also identified a decrease non-classical monocytes and an expansion of classical monocytes with features of high inflammation and immune deficiency. CONCLUSION: Changes in cellular status, such as depletion of T cells and dysregulation of B cell proliferation and differentiation, may lead to drug resistance in MCC patients. Meanwhile, the widespread decreased antigen presentation ability and immune disorders caused by deletion of MHC class II gene expression should not be ignored.

The more the better: on the formation of single-phase high entropy alloy nanoparticles as catalysts for the oxygen reduction reaction.

High entropy alloys (HEAs) are an important new material class with significant application potential in catalysis and electrocatalysis. The entropy-driven formation of HEA materials requires high temperatures and controlled cooling rates. However, catalysts in general also require highly dispersed materials, i.e., nanoparticles. Only then a favorable utilization of the expensive raw materials can be achieved. Several recently reported HEA nanoparticle synthesis strategies, therefore, avoid the high-temperature regime to prevent particle growth. In our work, we investigate a system of five noble metal single-source precursors with superior catalytic activity for the oxygen reduction reaction. Combining in situ X-ray powder diffraction with multi-edge X-ray absorption spectroscopy, we address the fundamental question of how single-phase HEA nanoparticles can form at low temperatures. It is demonstrated that the formation of HEA nanoparticles is governed by stochastic principles and the inhibition of precursor mobility during the formation process favors the formation of a single phase. The proposed formation principle is supported by simulations of the nanoparticle formation in a randomized process, rationalizing the experimentally found differences between two-element and multi-element metal precursor mixtures.

Endogenous H2O2 Self-Replenishment and Sustainable Cascades Enhance the Efficacy of Sonodynamic Therapy.

Purpose: Sonodynamic therapy (SDT), with its high tissue penetration and noninvasive advantages, represents an emerging approach to eradicating solid tumors. However, the outcomes of SDT are typically hampered by the low oxygen content and immunosuppression in the tumor microenvironment (TME). Accordingly, we constructed a cascade nanoplatform to regulate the TME and improve the anti-tumor efficiency of SDT. Methods: In this study, we rationally design cascade nanoplatform by incorporating immunostimulant hyaluronic acid (HA) and sonosensitizer chlorin e6 (Ce6) on the polydopamine nanocarrier that is pre-doped with platinum nanozymes (designated Ce6/Pt@PDA-HA, PPCH). Results: The cascade reactions of PPCH are evidenced by the results that HA exhibits reversing immunosuppressive that converts M2 macrophages into M1 macrophages in situ, while producing H2O2, and then platinum nanozymes further catalyze the H2O2 to produce O2, and O2 produces abundant singlet oxygen (1O2) under the action of Ce6 and low-intensity focused ultrasound (LIFU), resulting in a domino effect and further amplifying the efficacy of SDT. Due to its pH responsiveness and mitochondrial targeting, PPCH effectively accumulates in tumor cells. Under LIFU irradiation, PPCH effectively reverses immunosuppression, alleviates hypoxia in the TME, enhances reactive oxygen species (ROS) generation, and enhances SDT efficacy for eliminating tumor cells in vivo and in vitro. Meanwhile, an in vivo dual-modal imaging including fluorescence and photoacoustic imaging achieves precise tumor diagnosis. Conclusion: This cascade nanoplatform will provide a promising strategy for enhancing SDT eradication against tumors by modulating immunosuppression and relieving hypoxia.