Unrestricted molecular motions enable mild photothermy for recurrence-resistant FLASH antitumor radiotherapy.

Ultrahigh dose-rate (FLASH) radiotherapy is an emerging technology with excellent therapeutic effects and low biological toxicity. However, tumor recurrence largely impede the effectiveness of FLASH therapy. Overcoming tumor recurrence is crucial for practical FLASH applications. Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839). Within nanoparticles, TPE-BBT exhibits aggregation-induced emission peaked at 900 nm, while the unrestricted molecular motions endow TPE-BBT with a mild photothermy generation ability. The balanced photothermal effect and photoluminescence are ideal for phototheranostics. Upon 660-nm laser irradiation, the temperature-rising effect softens and hydrolyzes the hydrogel to release TPE-BBT and CB-839 into the tumor site for concurrent mild photothermal therapy and chemotherapy, jointly inhibiting homologous recombination repair of DNA. The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects.

Glutathione-responsive Aggregation-induced Emission Photosensitizers for Enhanced Photodynamic Therapy of Lung Cancer.

Lung cancer, a highly prevalent and lethal form of cancer, is often associated with oxidative stress. Photodynamic therapy (PDT) has emerged as a promising alternative therapeutic tool in cancer treatments, but its efficacy is closely correlated to the photosensitizers generating reactive oxygen species (ROS) and the antioxidant capacity of tumor cells. In particular, glutathione (GSH) can reduce the ROS and thus compromise PDT efficacy. In this study, a GSH-responsive near-infrared photosensitizer (TBPPN) based on aggregation-induced emission for real-time monitoring of GSH levels and enhanced PDT for lung cancer treatment is developed. The strategic design of TBPPN, consisting of a donor-acceptor structure and incorporation of dinitrobenzene, enables dual functionality by not only the fluorescence being activated by GSH but also depleting GSH to enhance the cytotoxic effect of PDT. TBPPN demonstrates synergistic PDT efficacy in vitro against A549 lung cancer cells by specifically targeting different cellular compartments and depleting intracellular GSH. In vivo studies further confirm that TBPPN can effectively inhibit tumor growth in a mouse model with lung cancer, highlighting its potential as an integrated agent for the diagnosis and treatment of lung cancer. This approach enhances the effectiveness of PDT for lung cancer and deserves further exploration of its potential for clinical application.

Soap Film Transfer Printing for Ultrathin Electronics.

Flexible and stretchable electronics have attractive applications inaccessible to conventional rigid electronics. However, the mainstream transfer printing techniques have challenges for electronic films in terms of thickness and size and limitations for target substrates in terms of curvature, depth, and interfacial adhesion. Here a facile, damage-free, and contamination-free soap film transfer printing technique is reported that enables the wrinkle-free transfer of ultrathin electronic films, precise alignment in a transparent manner, and conformal and adhesion-independent printing onto various substrates, including those too topographically and adhesively challenging by existing methods. In principle, not only the pattern, resolution, and thickness of transferred films, but also the curvature, depth, and adhesion of target substrates are unlimited, while the size of transferred films can be as high as meter-scale. To demonstrate the capabilities of soap film transfer printing, pre-fabricated ultrathin electronics with multiple patterns, single micron resolution, sub-micron thickness, and centimeter size are conformably integrated onto the ultrathin web, ultra-soft cotton, DVD-R disk with the minimum radius of curvature of 131 nm, interior cavity of Klein bottle and dandelion with ultralow adhesion. The printed ultrathin sensors show superior conformabilities and robust adhesion, leading to engineering opportunities including electrocardiogram (ECG) signal acquisition and temperature measurement in aqueous environments.

NAD+ Protects against Hyperlipidemia-induced Kidney Injury in Apolipoprotein E-deficient Mice.

Background: Hyperlipidemia is an independent risk factor for kidney injury. Several studies have shown that nicotinamide adenine dinucleotide (NAD+) is an important coenzyme involved in normal body metabolism. Therefore, this study aimed to investigate the possible protective effects of NAD+ against hyperlipidemia-induced kidney injury in apolipoprotein Edeficient (ApoE-/-) mice.

Methods: Twenty-five eight-week-old male ApoE-/- mice were randomly assigned into four groups: normal diet (ND), ND supplemented with NAD+ (ND+NAD+), high-fat diet (HFD), and HFD supplemented with NAD+ (HFD+NAD+). The mice were subjected to their respective diets for a duration of 16 weeks. Blood samples were obtained from the inferior vena cava, collected in serum tubes, and stored at -80°C until use. Kidney tissues was fixed in 10% formalin and then embedded in paraffin for histological evaluation. The remainder of the kidney tissues was snapfrozen in liquid nitrogen for Western blot analysis.

Results: Metabolic parameters (total cholesterol, triglycerides, low-density lipoprotein-cholesterol, creatinine, and blood urea nitrogen) were significantly higher in the HFD group compared to the other groups. Histological analysis revealed prominent pathological manifestations in the kidneys of the HFD group. The HFD+NAD+ group showed increased levels of oxidative stress markers (NRF2 and SOD2) and decreased levels of NOX4 compared to the HFD group. Furthermore, the HFD group exhibited higher levels of TGF-ß, Smad3, Collagen I, Collagen III, Bax, and Bak compared to the other groups. NAD+ supplementation in the HFD+NAD+ group significantly increased the levels of SIRT3, HO-1, Bcl-2, and Bcl-xL compared to the HFD group. Additionally, NF-κB protein expression was higher in the HFD group than in the HFD+NAD+ group.

Conclusion: These findings demonstrated that NAD+ may hold potential as a clinical treatment for kidney injury caused by hyperlipidemia.

Powerful Synergy of Traditional Chinese Medicine and Aggregation-Induced Emission-Active Photosensitizer in Photodynamic Therapy.

Breast cancer (BC) remains a significant global health challenge for women despite advancements in early detection and treatment. Isoliquiritigenin (ISL), a compound derived from traditional Chinese medicine, has shown potential as an anti-BC therapy, but its low bioavailability and poor water solubility restrict its effectiveness. In this study, we created theranostic nanoparticles consisting of ISL and a near-infrared (NIR) photosensitizer, TBPI, which displays aggregation-induced emission (AIE), with the goal of providing combined chemo- and photodynamic therapies (PDT) for BC. Initially, we designed an asymmetric organic molecule, TBPI, featuring a rotorlike triphenylamine as the donor and 1-methylpyridinium iodide as the acceptor, which led to the production of reactive oxygen species in mitochondria. We then combined TBPI with ISL and encapsulated them in DSPE-PEG-RGD nanoparticles to produce IT-PEG-RGD nanoparticles, which showed high affinity for BC, better intersystem crossing (ISC) efficiency, and Förster resonance energy transfer (FRET) between TBPI and ISL. In both 4T1 BC cell line and a 4T1 tumor-bearing BC mouse model, the IT-PEG-RGD nanoparticles demonstrated excellent drug delivery, synergistic antitumor effects, enhanced tumor-killing efficacy, and reduced drug dosage and side effects. Furthermore, we exploited the optical properties of TBPI with ISL to reveal the release process and distribution of nanoparticles in cells. This study provides a valuable basis for further exploration of IT-PEG-RGD nanoparticles and their anticancer mechanisms, highlighting the potential of theranostic nanoparticles in BC treatment.

An Alkaline Phosphatase-Responsive Aggregation-Induced Emission Photosensitizer for Selective Imaging and Photodynamic Therapy of Cancer Cells.

Fluorescence-guided photodynamic therapy (PDT) has been considered as an emerging strategy for precise cancer treatment by making use of photosensitizers (PSs) with reactive oxygen species (ROS) generation. Some efficient PSs have been reported in recent years, but multifunctional PSs that are responsive to cancer-specific biomarkers are rarely reported. In this study, we introduced a phosphate group as a cancer-specific biomarker of alkaline phosphatase (ALP) on a PS with the features of aggregation-induced emission (AIE) for cancer cell imaging and therapy. In cancer cells with high ALP expression, the phosphate group on the AIE probe is selectively hydrolyzed by ALP. Consequently, the hydrophobic probe residue is aggregated in aqueous media and gives a "turn on" fluorescent response. Moreover, fluorescence-guided PDT was realized by the aggregates of probe residue with strong ROS generation efficiency under white light irradiation. Overall, this work presents a strategy of applying ALP-responsive AIE PS for specific imaging cancer cells and succeeding with specific PDT upon the cancer biomarker stimulated responsive reactions.

Dual Behavior Regulation: Tether-Free Deep-Brain Stimulation by Photothermal and Upconversion Hybrid Nanoparticles.

Optogenetics has been plagued by invasive brain implants and thermal effects during photo-modulation. Here, two upconversion hybrid nanoparticles modified with photothermal agents, named PT-UCNP-B/G, which can modulate neuronal activities via photostimulation and thermo-stimulation under near-infrared laser irradiation at 980 nm and 808 nm, respectively, are demonstrated. PT-UCNP-B/G emits visible light (410-500 nm or 500-570 nm) through the upconversion process at 980 nm, while they exhibit efficient photothermal effect at 808 nm with no visible emission and tissue damage. Intriguingly, PT-UCNP-B significantly activates extracellular sodium currents in neuro2a cells expressing light-gated channelrhodopsin-2 (ChR2) ion channels under 980-nm irradiation, and inhibits potassium currents in human embryonic kidney 293 cells expressing the voltage-gated potassium channels (KCNQ1) under 808-nm irradiation in vitro. Furthermore, deep-brain bidirectional modulation of feeding behavior is achieved under tether-free 980 or 808-nm illumination (0.8 W cm-2 ) in mice stereotactically injected with PT-UCNP-B in the ChR2-expressing lateral hypothalamus region. Thus, PT-UCNP-B/G creates new possibility of utilizing both light and heat to modulate neural activities and provides a viable strategy to overcome the limits of optogenetics.

Design of Smart Aggregates: Toward Rapid Clinical Diagnosis of Hyperlipidemia in Human Blood.

Molecular aggregates with environmental responsive properties are desired for their wide practical applications such as bioprobes. Here, a series of smart near-infrared (NIR) luminogens for hyperlipidemia (HLP) diagnosis is reported. The aggregates of these molecules exhibit a twisted intramolecular charge-transfer effect in aqueous media, but aggregation-induced emission in highly viscous media due to the restriction of the intramolecular motion. These aggregates, which can autonomously respond to different environments via switching the aggregation state without changing their chemical structures are described, as "smart aggregates". Intriguingly, these luminogens demonstrate NIR-II and NIR-III luminescence with ultralarge Stokes shifts (>950 nm). Both in vitro detection and in vivo imaging of HLP can be realized in a mouse model. Linear relationships exist between the emission intensity and multiple pathological parameters in blood samples of HLP patients. Thus, the design of smart aggregate facilitates rapid and accurate detection of HLP and provides a promising attempt in aggregate science.

Rational Design of NIR-II AIEgens with Ultrahigh Quantum Yields for Photo- and Chemiluminescence Imaging.

Fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) using small-molecule dyes has high potential for clinical use. However, many NIR-II dyes suffer from the emission quenching effect and extremely low quantum yields (QYs) in the practical usage forms. The AIE strategy has been successfully utilized to develop NIR-II dyes with donor-acceptor (D-A) structures with acceptable QYs in the aggregate state, but there is still large room for QY improvement. Here, we rationally designed a NIR-II emissive dye named TPE-BBT and its derivative (TPEO-BBT) by changing the electron-donating triphenylamine unit to tetraphenylethylene (TPE). Their nanoparticles exhibited ultrahigh relative QYs of 31.5% and 23.9% in water, respectively. By using an integrating sphere, the absolute QY of TPE-BBT nanoparticles was measured to be 1.8% in water. Its crystals showed an absolute QY of 10.4%, which is the highest value among organic small molecules reported so far. The optimized D-A interaction and the higher rigidity of TPE-BBT in the aggregate state are believed to be the two key factors for its ultrahigh QY. Finally, we utilized TPE-BBT for NIR-II photoluminescence (PL) and chemiluminescence (CL) bioimaging through successive CL resonance energy transfer and Förster resonance energy transfer processes. The ultrahigh QY of TPE-BBT realized an excellent PL imaging quality in mouse blood vessels and an excellent CL imaging quality in the local arthrosis inflammation in mice with a high signal-to-background ratio of 130. Thus, the design strategy presented here brings new possibilities for the development of bright NIR-II dyes and NIR-II bioimaging technologies.

Aggregation-Induced Emission Luminogens for Cell Death Research.

Cell death is closely related to various diseases, and monitoring and controlling cell death is a promising strategy to develop efficient therapy. Aggregation-induced emission luminogens (AIEgens) are ideal candidates for developing novel theranostic agents because of their intriguing properties in the aggregate state. The rational application of AIE materials in cell death-related research is still in its infancy but has shown great clinical potential. This review discussed the research frontier and our understanding of AIE materials in various subroutines of cell death, including apoptosis, necrosis, immunogenic cell death, pyroptosis, autophagy, lysosome-dependent cell death, and ferroptosis. We hope that the new insights can be offered to this growing field and attract more researchers to provide valuable contributions.

Metal-Based Aggregation-Induced Emission Theranostic Systems.

Efficient theranostic systems can realize better outcomes in disease treatment because of precise diagnosis and the concomitant effective therapy. Aggregation-induced emission luminogens (AIEgens) are a unique type of organic emitters with intriguing photophysical properties in the aggregate state. Among the AIEgens studied for biomedical applications, so far, metal-based AIE systems have shown great potential in theranostics due to the enhanced multimodal bioimaging ability and therapeutic effect. This research field has been growing rapidly, and many rationally designed systems with promising activities to cancer and other diseases have been reported recently. In this review, we summarized the recent progress of metal-based AIE materials in bioimaging and biological theranostics, and deciphered the pertinent design strategies. We hope that this review can offer new insights into the development of this growing field.

Pharmacologic Management of Neuropathic Pain.

This article aims to provide the practitioner with therapeutic options to treat a broad spectrum of acute and chronic orofacial pain syndromes. The focus will be nonsurgical that the oral health care physician can implement to treat this population of patients. The World Health Organization estimated that more than 1 in every 3 people suffers from acute or chronic pain. This article is primarily devoted to medication management once the diagnosis of neuropathic pain, a true trigeminal neuralgia, or a variant of trigeminal neuralgia often referred to as traumatic neuropathic pain or traumatic trigeminal neuralgia.

Management of Oroantral Communications.

Oroantral communication and fistula are commonly seen complications in the field of oral and maxillofacial surgery. Oral surgeons must be familiar with the diagnosis and proper management including multiple soft and hard tissue approaches to this surgical dilemma.

Regional brain network and behavioral alterations in EGR3 gene transfected rat model of schizophrenia.

Schizophrenia is a severe psychiatric disease while its etiology and effective treatment are not completely clear. A rat model of schizophrenia was previously established by transfecting EGR3 gene into the hippocampus of rats. This study aimed to investigate the behavioral and cerebral alterations of the schizophrenic model rats and the risperidone effects. Twenty-six rats were divided into 3 groups: schizophrenia model group (E group), risperidone treatment group (T group), and healthy control group (H group). Morris water maze and open field test were used as behavioral tests, resting-state functional magnetic resonance imaging (fMRI) was performed after EGR3 gene transfection and risperidone therapy. Graph analyses were used for examining cerebral alterations of the rats. Behavioral tests demonstrated reduced spatial working memory and exploring unfamiliar space ability in schizophrenic model rats. Graph analyses revealed reduced regional architectures in the olfactory bulb, nucleus accumbens, and pineal gland in group E compared to group H (p < 0.05), while group T showed increased regional architecture in pineal gland compared to group E (p < 0.05). Besides, the regional architectures in the olfactory bulb, nucleus accumbens were lower in group T than group H, while the hippocampus showed increased regional architecture in group T compared to group H (p < 0.05). Schizophrenia induced several regional alterations in the cerebrum while risperidone can reverse part of these alterations. This study lends support for future research on the pathology of schizophrenia and provides new insights on the role of risperidone in schizophrenia.

Influence of EGR3 Transfection on Imaging and Behavior in Rats and Therapeutic Effect of Risperidone in Schizophrenia Model.

Schizophrenia is a type of neurodevelopmental psychiatric disorder. However, to date, scientists have not discovered the etiology and effective treatment of this condition. We injected the early growth response gene (EGR3) into the bilateral hippocampus to build a schizophrenia rat model. Behavioral phenotyping and resting-state functional magnetic resonance imaging (rs-fMRI) were used to analyze the behavioral and cerebral alterations in the schizophrenia rat model. The efficacy of risperidone therapy was also evaluated. We divided 34 rats into four groups: schizophrenia model group (E group), sham-operation group (FE group), healthy control group (H group), and risperidone therapy group (T group). Open field test and Morris water maze were conducted as behavioral experiments. Next, we performed rs-fMRI after four weeks of EGR3 transfection and risperidone treatment and analyzed imaging data using regional homogeneity (ReHo), the amplitude of low-frequency fluctuations (ALFF), and functional connectivity (FC). We examined the difference in behavioral and neural activation among the four groups and considered the correlations between behavior and imaging results. EGR3 gene transfection decreased the total moved distance in the open field test and the duration in the Q5 zone of the Morris water maze. Risperidone treatment reversed the trend and improved the performance of rats in these behavioral tests. Schizophrenia induced several neural alterations in ALFF and ReHo metrics of the rat brain, and risperidone could partly reverse these alterations. The results suggest that similar research is required for schizophrenia and that risperidone may be a novel treatment for dysregulated neural activation in schizophrenia.

DR5 related autophagy can promote apoptosis in gliomas after irradiation.

As a cancer treatment strategy, irradiation therapy is widely used that can cause DNA breakage and increase free radicals, which leads to different types of cell death. Among them, apoptosis and autophagy are the most important and the most studied cell death processes. Although the exploration of the relationship between apoptosis and autophagy has been a major area of focus, still the molecular mechanisms of autophagy on apoptosis remain unclear. Here, we have revealed that apoptosis was enhanced by the death receptor 5 (DR5) pathway, and the effect of autophagy on apoptosis was promoted by DR5 interacting with LC3B as well as Caspase8 in gliomas after irradiation. Interestingly, we observed that the addition of four different autophagy inducers, rapamycin (RAP), CCI779, ABT737 and temozolomide (TMZ), induced the differences of DR5 expression and cell apoptosis after irradiation. Unlike RAP and CCI779, ABT737 and TMZ were able to increase DR5 expression and further induce cell death. Therefore, we have concluded that DR5 plays a novel and indispensable role in promoting cell apoptosis under irradiation and suggest a potential therapeutic approach for glioblastoma treatment.

A secret that underlies Parkinson's disease: The damaging cycle.

Parkinson's disease (PD) is a movement disorder, and its common characteristics include the loss of dopaminergic neurons and the accumulation of a special type of cytoplasmic inclusions called Lewy bodies in the substantia nigra pars compacta, which are more prevalent in the elderly. However, the pathophysiology of PD is still elusive. In this review, we summarized five common factors involved in PD, namely, (i) oxidative stress, (ii) mitochondrial dysfunction, (iii) inflammation, (iv) abnormal α-synuclein, and (v) endogenous neurotoxins, and proposed a hypothesis involving a damaging cycle. Oxidative stress-triggered aldehydes react with biogenic amines to produce endogenous neurotoxins. They cause mitochondrial dysfunction and the formation of inflammasomes, which induce the activation of neuroglial cells and the infiltration of T lymphocytes. The synergistic effect of these processes fosters chronic inflammation and α-synuclein aggregation and further exacerbates the impact of oxidative stress to establish a damaging cycle that eventually results in the degeneration of dopaminergic neurons. This damaging cycle provides an explanation of progressive neuronal death during the pathogenesis of PD and provides new potential targets beneficial for developing new drugs and approaches for clinical neuroprotection.

HPLC-ESI-MSn Identification and NMR Characterization of Glucosyloxybenzyl 2R-Benzylmalate Deriva-Tives from Arundina Graminifolia and Their Anti-Liver Fibrotic Effects In Vitro.

Four new glucosyloxybenzyl 2R-benzylmalate derivatives, named Arundinoside H (2), I (5), J (6), K (8) as well as four known compounds Arundinoside D (1), G (3), F (4), E (7) were isolated and characterized by a combination of chemical and spectroscopic methods, including HR-ESI-MS, 1D and 2D NMR experiments. Besides, 24 unreported compounds were inferred from ESI-MSn data. The anti-liver fibrotic activities of the isolates were determined as proliferation inhibition of lipopolysaccharide (LPS)-induced activation of rat hepatic stellate cells (HSC-T6). The result suggested Arundinosides D, H, F, I and K showed moderate inhibitory effects in vitro.

Changes in salsolinol production and salsolinol synthase activity in Parkinson's disease model.

Salsolinol is an endogenous neurotoxin derived from dopamine, and has been proved to cause the apoptosis of the dopaminergic neurons involved in the pathogenesis of Parkinson's disease (PD). Salsolinol synthase is the key enzyme in the biosynthesis of salsolinol, and its activity exists in most regions of rat brain. However, the activity distribution and its catalyzed function in vivo are still unknown. On the basis of the chromatographic assay established previously, we investigated the activity of salsolinol synthase and salsolinol production in both cell and rat model of PD induced by 6-hydroxydopamine (6-OHDA). The results show that the enzymatic activity increases in cell model and in the striatum region of PD rat brain. Nevertheless, there is a reduction of activity in hippocampus, cortex, and midbrain of PD model when compared with control. Conversely, the level of salsolinol was significantly increased in the midbrain region. Together, these results indicate the relationship between the oxidative stress induced by 6-OHDA and the activity of salsolinol synthase, suggesting the correlation of the endogenous neurotoxin and Parkinson's disease. Further research will provide more evidence and clarity on the function of Sal synthase.

Comparison between α-synuclein wild-type and A53T mutation in a progressive Parkinson's disease model.

BACKGROUND AND AIMS: Vector based over-expression of α-synuclein is a newly developed method to establish animal Parkinson's disease (PD) model. In this paper, we inject the rat brain with recombinant adeno-associated virus (rAAV) to express α-synuclein wild-type and A53T mutation, and compared the degeneration of dopaminergic neurons between them. METHOD AND RESULTS: The rAAV vectors were injected into the substantia nigra pars compacta (SNpc) of rat brain. In different time point, immunohistochemistry was used to detect the expression of α-synuclein. The expression level was lower in the 3rd and 6th week and increased from the 9th week. α-synuclein spread around the neurons in SNpc in the 12th week. The loss of dopaminergic neurons was increasing along the expression of α-synuclein, and damage extent was more serious in the A53T group than the WT group. In the A53T group, there were more insoluble inclusions can be detected, and the phosphorylation of α-synuclein was also higher. CONLUSION: The result of comparison between the two types of α-synuclein showed that A53T mutated α-synuclein was more effective to establish PD model, and the model based A53T mutated α-synuclein was a suitable model to early-onset PD.