Dual Roles of the Photooxidation of Organic Amines for Enhanced Triplet-Triplet Annihilation Upconversion in Nanoparticles.

Oxygen-mediated triplet-triplet annihilation upconversion (TTA-UC) quenching limits the application of such organic upconversion materials. Here, we report that the photooxidation of organic amines is an effective and versatile strategy to suppress oxygen-mediated upconversion quenching in both organic solvents and aqueous solutions. The strategy is based on the dual role of organic amines in photooxidation, i.e., as singlet oxygen scavengers and electron donors. Under photoexcitation, the photosensitizer sensitizes oxygen to produce singlet oxygen for the oxidation of alkylamine, reducing the oxygen concentration. However, photoinduced electron transfer among photosensitizers, organic amines, and oxygen leads to the production of superoxide anions that suppress TTA-UC. To observe oxygen-tolerating TTA-UC, we find that alkyl secondary amines can balance the production of singlet oxygen and superoxide anions. We then utilize polyethyleneimine (PEI) to synthesize amphiphilic polymers to encapsulate TTA-UC pairs for the formation of water-dispersible, ultrasmall, and multicolor-emitting TTA-UC nanoparticles.

A deep semantic network-based image segmentation of soybean rust pathogens.

Introduction: Asian soybean rust is a highly aggressive leaf-based disease triggered by the obligate biotrophic fungus Phakopsora pachyrhizi which can cause up to 80% yield loss in soybean. The precise image segmentation of fungus can characterize fungal phenotype transitions during growth and help to discover new medicines and agricultural biocides using large-scale phenotypic screens. Methods: The improved Mask R-CNN method is proposed to accomplish the segmentation of densely distributed, overlapping and intersecting microimages. First, Res2net is utilized to layer the residual connections in a single residual block to replace the backbone of the original Mask R-CNN, which is then combined with FPG to enhance the feature extraction capability of the network model. Secondly, the loss function is optimized and the CIoU loss function is adopted as the loss function for boundary box regression prediction, which accelerates the convergence speed of the model and meets the accurate classification of high-density spore images. Results: The experimental results show that the mAP for detection and segmentation, accuracy of the improved algorithm is improved by 6.4%, 12.3% and 2.2% respectively over the original Mask R-CNN algorithm. Discussion: This method is more suitable for the segmentation of fungi images and provide an effective tool for large-scale phenotypic screens of plant fungal pathogens.

New Type Annihilator of π-Expanded Diketopyrrolopyrrole for Robust Photostable NIR-Excitable Triplet-Triplet Annihilation Upconversion.

Near-infrared light excitable triplet-triplet annihilation upconversion (NIR TTA-UC) materials have attracted interest in a variety of emerging applications such as photoredox catalysis, optogenetics, and stereoscopic 3D printing. Currently, the practical application of NIR TTA-UC materials requires substantial improvement in photostability. Here, we found that the new annihilator of π-expanded diketopyrrolopyrrole (π-DPP) cannot activate oxygen to generate superoxide anion via photoinduced electron transfer, and its electron-deficient characteristics prevent the singlet oxygen-mediated [2 + 2] cycloaddition reaction; thus, π-DPP exhibited superior resistance to photobleaching. In conjunction with the NIR photosensitizer PdTNP, the upconversion efficiency of π-DPP is as high as 8.9%, which is eight times of the previously reported PdPc/Furan-DPP. Importantly, after polystyrene film encapsulation, less than 10% photobleaching was observed for this PdTNP/π-DPP-based NIR TTA-UC material after four hours of intensive NIR light exposure. These findings provide a type of annihilator with extraordinary photostability, facilitating the development of NIR TTA-UC materials for practical photonics.

Targeting Nanomotor with Near-Infrared/Ultrasound Triggered-Transformation for Polystage-Propelled Cascade Thrombolysis and Multimodal Imaging Diagnosis.

Nowadays, cardiovascular and cerebrovascular diseases caused by venous thromboembolism become main causes of mortality around the world. The current thrombolytic strategies in clinics are confined primarily due to poor penetration of nanoplatforms, limited thrombolytic efficiency, and extremely-low imaging accuracy. Herein, a novel nanomotor (NM) is engineered by combining iron oxide/perfluorohexane (PFH)/urokinase (UK) into liposome nanovesicle, which exhibits near-infrared/ultrasound (NIR/US) triggered transformation, achieves non-invasive vein thrombolysis, and realizes multimodal imaging diagnosis altogether. Interestingly, a three-step propelled cascade thrombolytic therapy is revealed from such intelligent NM. First, the NM is effectively herded at the thrombus site under guidance of a magnetic field. Afterwards, stimulations of NIR/US propel phase transition of PFH, which intensifies penetration of the NM toward deep thrombus dependent on cavitation effect. Ultimately, UK is released from the collapsed NM and achieves pharmaceutical thrombolysis in a synergistic way. After an intravenous injection of NM in vivo, the whole thrombolytic process is monitored in real-time through multimodal photoacoustic, ultrasonic, and color Doppler ultrasonic imagings. Overall, such advanced nanoplatform provides a brand-new strategy for time-critical vein thrombolytic therapy through efficient thrombolysis and multimodal imaging diagnosis.

Effects of extracellular enzymes secreted by wild edible fungi mycelia on the surface properties of local soil colloids.

The extracellular enzymes secreted by wild edible fungi mycelia participate in a series of physiochemical reactions in soil, thereby changing the surface properties of local soil colloids irreversibly. However, the reaction process and mechanism were generally ignored, leading to a misunderstanding of local soil functions. In this work, the soil samples collected from areas where growing wild edible fungi were selected as model substances, and the effects of extracellular enzymes (α-amylase, ß-glucosidase, and peroxidase) secreted by wild edible fungi mycelia on the physicochemical properties of soil colloids were explored. After adding extracellular enzymes, the pores and fissures between the lamellar sheets were observed more obviously and the surface heights decreased significantly, especially after adding α-amylase. The addition of extracellular enzymes increased the electronegativity and the suspension stability of soil colloids owing to the decrease in their polarity and water solubility. The added extracellular enzymes might be adsorbed on the organic and inorganic components in soil colloids and could promote the decomposition of soil organic matter, thereby changing the physicochemical properties of soil colloids and improving the soil quality. The results will lay a theoretical foundation for understanding the soil function in the areas where growing wild edible fungi.

Spatiotemporally Controlled Formation and Rotation of Magnetic Nanochains In Vivo for Precise Mechanotherapy of Tumors.

Systemic cancer therapy is always accompanied with toxicity to normal tissue, which has prompted concerted efforts to develop precise treatment strategies. Herein, we firstly develop an approach that enables spatiotemporally controlled formation and rotation of magnetic nanochains in vivo, allowing for precise mechanotherapy of tumor. The nanochain comprised nanocomposites of pheophorbide-A (PP) modified iron oxide nanoparticle (IONP) and lanthanide-doped down-conversion NP (DCNP). In a permanent magnetic field, the nanocomposites would be aligned to form nanochain. Next, MnO2 NPs were subsequently administered to accumulate in tumor as suppliers of Mn2+ , which coordinates with PP to immobilize the nanochain. In a rotating magnetic field, the nanochain would rapidly rotate, leading to apoptosis/necrosis of tumor cell. The nanochain showed high T2 -MR and NIR-II fluorescence imaging signals, which facilitated guided therapy. The strategy has great potential in practical applications.

Efficiency improvement of GaN-based micro-light-emitting diodes embedded with Ag NPs into a periodic arrangement of nano-hole channel structure by ultra close range localized surface plasmon coupling.

NH-µLED, namely a micro light-emitting diode structure with nano-holes dug all the way through the active region, is designed to make silver nanoparticles in extremely close contact with the quantum wells for improving the coupling between the localized surface plasmon and the quantum wells (LSP-QWs coupling) and thus enhancing the optical properties of theµLED. The experimental results show that, thanks to this deep nanohole structure, the LSP-QWs coupling can be realized effectively, which ultimately increases the optical performance of theµLED. The internal quantum efficiency of the NH-µLED filled with silver nanoparticles is increased by 12%, and the final optical output power is also enhanced. We have further carried out a comparison study which measures the transient lifetime of two different types ofµLEDs, and the results provide convincing evidence for the existence of the ultra close range LSP-QWs coupling effect.

Activatable Nanoprobe with Aggregation-Induced Dual Fluorescence and Photoacoustic Signal Enhancement for Tumor Precision Imaging and Radiotherapy.

Owing to the high sensitivity and high spatial resolution, fluorescence (FL) imaging has been widely applied for visualizing biological processes. To gain insight into molecular events on deeper tissues, photoacoustic (PA) imaging with better deep-tissue imaging capability can be incorporated to provide complementary visualization and quantitative information on the pathological status. However, the development of activatable imaging probes to achieve both FL and PA signal amplification remains challenging because the enhancement of light absorption in PA imaging often caused the quenching of FL signal. Herein, we first developed a caspase-3 enzyme activatable nanoprobe of a nanogapped gold nanoparticle coated with AIE molecule INT20 and DEVD peptides (AuNNP@DEVD-INT20) for tumor FL and PA imaging and subsequent imaging-guided radiotherapy. The nanoprobe could interact with GSH and caspase-3 enzyme to liberate INT20 molecules, leading to AIE. Simultaneously, the in situ self-assembly of AuNPs was achieved through the cross-linking reaction between the sulfhydryl and the maleimide, resulting in ratiometric PA imaging in tumor. Remarkably, the nanoprobe can generate richful ROS for cancer radiotherapy under X-ray irradiation. The platform not only achieves the aggregation-induced FL and PA signal enhancement but also provides a general strategy for imaging of various biomarkers, eventually benefiting precise cancer therapy.

Neutrophil-to-lymphocyte ratio is associated with malnutrition risk estimated by the Royal Free Hospital-Nutritional Prioritizing Tool in hospitalized cirrhosis.

BACKGROUND: Liver cirrhosis is characterized by immune dysfunction, contributing to malnutrition. We previously revealed neutrophil-to-lymphocyte ratio (NLR) as an indicator of disordered immune system. Herein we aimed to (1) determine the optimal NLR cutoff that best predicts malnutrition risk and (2) clarify the association between NLR and nutrition status. METHODS: A total of 135 hospitalized patients with cirrhosis were included. Immune dysfunction was evaluated by levels of serum C-reactive protein (CRP), NLR, and other parameters. Malnutrition was screened by a risk score referring to the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT). Receiver operating characteristic (ROC) curve was implemented to determine the best NLR cutoff that predicts malnutrition risk. Correlation between NLR and indicators of hepatic and physical function (handgrip strength) were also examined. Multivariable logistic regression was used to assess the association between NLR and malnutrition risk. RESULTS: ROC curve revealed that the optimum cutoff to predict malnutrition risk was NLR > 4.2, with a sensitivity of 47.2%, specificity of 81.0%, negative predictive value of 58.0%, and positive predictive value of 74.5%, respectively. Patients with NLR > 4.2 exhibited a higher RFH-NPT score, serum platelet-to-lymphocyte ratio, and CRP. A positive correlation was found between NLR values and Child-Turcotte-Pugh (r = 0.22; P = .010), model for end-stage liver disease (r = 0.36; P < .001), and RFH-NPT scores (r = 0.31; P < .001). NLR was a risk factor for malnutrition independently of alcoholic liver disease and presence of ascites. CONCLUSIONS: Immune dysfunction measured by NLR was associated with malnutrition risk estimated by RFH-NPT in cirrhosis.

An Activatable Hybrid Organic-Inorganic Nanocomposite as Early Evaluation System of Therapy Effect.

Delays in evaluating cancer response to radiotherapy (RT) usually reduce therapy effect or miss the right time for treatment optimization. Hence, exploring timely and accurate methods enabling one to gain insights of RT response are highly desirable. In this study, we have developed an apoptosis enzyme (caspase-3) activated nanoprobe for early evaluation of RT efficacy. The nanoprobe bridged the nanogapped gold nanoparticles (AuNNPs) and the second near-infrared window (NIR-II) fluorescent (FL) molecules (IR-1048) through a caspase-3 specific peptide sequence (DEVD) (AuNNP@DEVD-IR1048). After X-ray irradiation, caspase-3 was activated to cut DEVD, turning on both NIR-II FL and PA imaging signals. The increased NIR-II FL/PA signals exhibited a positive correlation with the content of caspase-3. Moreover, the amount of the activated caspase-3 was negatively correlated with the tumor size. The results underscore the role of the caspase-3 activated by X-ray irradiation in bridging the imaging signals variation and tumor inhibition rate. Overall, activatable NIR-II FL/PA imaging was successfully used to timely predict and evaluate the RT efficacy. The evaluation system based on biomarker-triggered living imaging has the capacity to guide treatment decisions for numerous cancer types.

Relationship Between Sleep-Wake Disturbance and Risk of Malnutrition in Hospitalized Patients With Cirrhosis.

Both sleep-wake disturbance and malnutrition are common in cirrhosis and might be associated with similar adverse outcomes, such as impaired health-related quality of life, hepatic encephalopathy, and sarcopenia, but there is no study investigating the relationship between these two. We aimed to explore the relationship between sleep-wake disturbance [estimated by the Pittsburgh Sleep Quality Index (PSQI)] and malnutrition risk [estimated by the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT)]. About 150 patients with cirrhosis were prospectively recruited. The nutritional risk is classified as low (0 points), moderate (1 point), and high (2-7 points) according to the RFH-NPT score. A global PSQI >5 indicated poor sleepers. Furthermore, multivariate linear regression analyses were performed to determine the relationship between sleep-wake disturbance and malnutrition. The median PSQI was seven, and RFH-NPT was two in the entire cohort, with 60.67 and 56.67% rated as poor sleep quality and high malnutrition risk, respectively. Patients with cirrhosis with poor sleep quality had significantly higher RFH-NPT score (3 vs. 1, P = 0.007). Our multivariate analyses indicated that male patients (ß = 0.279, P < 0.001), ascites (ß = 0.210, P = 0.016), and PSQI (ß = 0.262, P = 0.001) were independent predictors of malnutrition. In addition, the differences regarding PSQI score were more significant in male patients, as well as those >65 years or with Child-Turcotte-Pugh class A/B (CTP-A/B) or the median model for end-stage liver disease (MELD) <15. Taken together, the sleep-wake disturbance is strongly correlated with high malnutrition risk in patients with cirrhosis. Given sleep-wake disturbance is remediable, it is tempting to incorporate therapies to reverse poor sleep quality for improving nutritional status in patients with cirrhosis.

Relationship between sarcopenia/myosteatosis and frailty in hospitalized patients with cirrhosis: a sex-stratified analysis.

BACKGROUND: Previous studies have shown that sarcopenia appears to be a significant contributor to physical frailty among outpatients with cirrhosis. However, the evidence is scant regarding the relationship between sarcopenia and multi-dimensional frailty among inpatients. We aimed to investigate the potential contribution of sarcopenia to frailty in hospitalized patients with cirrhosis in a sex-dependent manner. METHODS: This cohort enrolled consecutive cirrhotics. Muscle quantity and quality were assessed using the computed tomography-based skeletal muscle index (SMI) and intramuscular adipose tissue content, respectively. Frailty phenotype was clarified by a self-reported Frailty Index. Multiple linear regression determined the association between sarcopenia and frailty phenotype. RESULTS: A total of 202 cirrhotic patients with 48.5% male were included. The median Frailty Index was 0.13, rendering 17.3% subjects as frail. Among the 16 frail men, 68.8% had sarcopenia and 62.5% exhibited myosteatosis. In contrast, among the 19 frail women, 26.3% had sarcopenia and 15.8% exhibited myosteatosis. Frail patients had a significantly lower median SMI (42.80 cm2/m2) compared with those with pre-frailty (48.23 cm2/m2) and with robust status (50.82 cm2/m2) in the male but not the female group. In male patients, multivariate linear regression implicated age (ß = 0.330, p < 0.001), SMI (ß = -0.260, p < 0.001), albumin (ß = -0.245, p = 0.005), and sodium (ß = -0.179, p = 0.037) as independent risk factors for frailty. CONCLUSION: Sarcopenia is associated with multi-dimensional frailty in male patients with cirrhosis. It is tempting to incorporate sex-specific intervention with the purpose of mitigating frailty among inpatients.

In Situ Activatable Ratiometric NIR-II Fluorescence Nanoprobe for Quantitative Detection of H2S in Colon Cancer.

As key characteristic molecules, several H2S-activated probes have been explored for colon cancer studies. However, a few ratiometric fluorescence (FL) probes with NIR-II emissions have been reported for the quantitative detection of H2S in colon cancer in vivo. Here, we developed an in situ H2S-activatable ratiometric nanoprobe with two NIR-II emission signals for the detection of H2S and intelligently lighting up colon cancer. The nanoprobe comprised a down conversion nanoparticle (DCNP), which emitted NIR-II FL at 1550 nm on irradiation with a 980 nm laser (F1550Em, 980Ex). Further, human serum albumin (HSA) was combined with Ag+ on the surface of DCNP to form a DCNP@HSA-Ag+ nanoprobe. In the presence of H2S, Ag2S quantum dots (QDs) were formed in coated HSA, which emitted FL at approximately 1050 nm on irradiation with an 808 nm laser (F1050Em, 808Ex) through an H2S-induced chemical reaction between H2S and Ag+; however, the FL signal of DCNP was stable at 1550 nm (F1550Em, 980Ex), generating a H2S concentration-dependent ratiometric F1050Em, 808Ex/F1550Em, 980Ex signal. The NIR-II ratiometric nanoprobe was successfully used for the accurate quantitative detection of H2S and the detection of the precise location of colon cancer through an endogenous H2S-induced in situ reduction reaction to form Ag2S QDs. Thus, these findings provide a new strategy for the specific detection of targeted molecules and diagnosis of disease based on the in situ-activatable NIR-II ratiometric FL nanoprobe.

Association between sleep disturbance and multidimensional frailty assessed by Frailty Index in hospitalized cirrhosis.

OBJECTIVES: Both sleep disturbance and frailty are common in patients with cirrhosis, but their correlation remains elusive. We aimed to investigate whether dysregulated sleep [as estimated by Pittsburgh Sleep Quality Index (PSQI)] is independently associated with frailty and their relationship in distinct subgroups. METHODS: In total 105 adult cirrhotic patients were recruited. The frailty phenotype was identified by a self-reported scale (Frailty Index) which demonstrates good validity and moderate performance based on our previous publication. Patients were categorized into frailty and nonfrailty groups according to a cut-point of 0.38 by Frailty Index. Multiple linear regression was performed to determine independent factors associated with frailty. RESULTS: The median PSQI was 6.0 in the entire cohort and sleep disturbance was observed in 61 patients with cirrhosis (58.1%). Poor sleepers had a significantly higher Frailty Index than that in good sleepers (0.11 vs. 0.08; P = 0.025). In univariate analysis, PSQI score was markedly associated with the Frailty Index (ß = 0.012; 95% CI, 0.006-0.018; P < 0.001), and remained significantly associated with frailty phenotype in multivariate adjustment (ß = 0.010; 95% CI, 0.004-0.015; P = 0.001). The escalating PSQI scores were more prominent in frail patients, with female gender or aged 65 years and over. CONCLUSIONS: Poor sleep quality is strongly associated with frailty in patients with cirrhosis. Given that sleep disturbance is modifiable, our data suggest that efficient interventions to mitigate frailty should incorporate strategies by reversing sleep dysfunction in cirrhotics with poor sleep quality.

NIR-II Photoacoustic Reporter for Biopsy-Free and Real-Time Assessment of Wilson's Disease.

Wilson's disease (WD) is a rare inherited disorder of copper metabolism with pathological copper hyperaccumulation in some vital organs. However, the clinical diagnosis technique of WD is complicated, aggressive, and time-consuming. In this work, a novel ratiometric photoacoustic (PA) imaging nanoprobe in the NIR-II window is developed to achieve noninvasive, rapid, and accurate Cu2+ quantitative detection in vitro and in vivo. The nanoprobe consists of Cu2+ -responsive IR970 dye and a nonresponsive palladium-coated gold nanorod (AuNR-Pd), achieving a concentration-dependent ratiometric PA970 /PA1260 signal change. The urinary Cu2+ content is detectable within minutes down to a detection limit of 76 × 10-9 m. This report acquisition time is several orders of magnitude shorter than those of existing detection approaches requiring complex procedure. Moreover, utilizing the ratiometric PA nanoprobe, PA imaging enables biopsy-free measurement of the liver Cu2+ content and visualization of the liver Cu2+ biodistribution of WD patient, which avoid the body injury during the clinical Cu2+ test using liver biopsy method. The NIR-II ratiometric PA detection method is simple and noninvasive with super precision, celerity, and simplification, which holds great promise as an alternative to liver biopsy for clinical diagnosis of WD.

Highly Controlled Janus Organic-Inorganic Nanocomposite as a Versatile Photoacoustic Platform.

Controlling the structural order of nanoparticles (NPs), morphology, and composition is of paramount significance in tailoring the physical properties of nanoassembly. However, the commonly reported symmetrical nanocomposites often suffer an interference or sacrifice of the photophysical properties of the original components. To address this challenge, we developed a novel type of organic-inorganic Janus nanocomposite (JNCP) with an asymmetric architecture, offering unique features such as the precisely controlled localization of components, combined modular optical properties, and independent stimuli. As a proof of concept, JNCPs were prepared by incorporating two photoacoustic (PA) imaging agents, namely an organic semiconducting dye and responsive gold nanoparticles (AuNP) assembly in separate compartments of JNCP. Theoretical simulation results confirmed that the formation mechanism of JNCPs arises from the entropy equilibrium in the system. The AuNP assembly generated a PA images with the variation of pH, while the semiconducting molecule served as an internal PA standard agent, leading to ratiometric PA imaging of pH. JNCP based probe holds great potential for real-time and accurate detection of diverse biological targets in living systems.

A predictive nomogram incorporating gait speed for all-cause mortality in hospitalized cirrhotics.

OBJECTIVES: No tailored model incorporating physical frailty for 2-year mortality in cirrhosis is available for practitioners in general practice. Thus we aimed to develop a model based on laboratory results and physical frailty allowing clinicians for stratifying cirrhotics by using individual estimate. METHODS: One hundred and thirteen cases were assigned to the primary cohort, and all other 76 patients were regarded as the validation cohort. Multivariate Cox regression was performed, and a nomogram including five-meter gait speed (5MGS) were generated. The performance of the proposed model was assessed by C-index, calibration curve, and decision curve analysis (DCA). RESULTS: On multivariate analysis, the Model for End-Stage Liver Disease-Sodium, albumin and 5MGS were independent predictors for 2-year mortality in cirrhosis. A nomogram incorporating all these parameters achieved a C-index of 0.804 (95%CI, 0.731-0.877). The calibration curve implied optimal correspondence between the predicted survival and actual outcomes. Our model is useful in the clinical settings based on DCA. Similar results were observed in the validation cohort with a C-index of 0.796 (95%CI, 0.689-0.899). Moreover, 5MGS, as a surrogate of physical performance, significantly correlated with multiple domains of general frailty according to Frailty Index (our published data), including instrumental activities of daily living, self-reported health, social activity and falls. CONCLUSION: In conclusion, the nomogram incorporating 5MGS may represent an individualized tool for predicting mortality in cirrhosis for primary care physicians.

Asymmetric Core-Shell Gold Nanoparticles and Controllable Assemblies for SERS Ratiometric Detection of MicroRNA.

Janus nanogap gold nanoparticles (JAuNNPs) with varying proportions of Au shell coverage of (ca. 100/75/50/25 %) are presented. The internal nanogap between the partial Au shell and core caused asymmetric optical behavior; tunability depends on the degree of Au shell coverage and structural asymmetry. The shell-to-shell or core-to-core JAuNNDs(50 %) were self-assembled from amphiphilic JAuNNPs(50 %) by tuning the hydrophilic and hydrophobic polymer brushes on the Au core or shell. The positions of electromagnetic field enhancement of JAuNNDs varied with geometrical configurations because of hybridized plasmonic coupling effects. Furthermore, DNA linkers were utilized to form JAuNND12 (50 %). By combining with Raman molecules, ratiometric SERS signals could be generated, enabling JAuNND12 (50 %) to image the distribution of miR-21 in living cells and tumors. Asymmetric JAuNNPs allowed facile conjugation of various linkage molecules to fabricate dimeric nanostructures.

Quantitative Assessment of Copper(II) in Wilson's Disease Based on Photoacoustic Imaging and Ratiometric Surface-Enhanced Raman Scattering.

Cu2+ is closely related to the occurrence and development of Wilson's disease (WD), and quantitative detection of various copper indicators (especially liver Cu2 and urinary Cu2+) is the key step for the early diagnosis of WD in the clinic. However, the clinic Cu2+ detection approach was mainly based on testing the liver tissue through combined invasive liver biopsy and the ICP-MS method, which is painful for the patient and limited in determining WD status in real-time. Herein, we rationally designed a type of Cu2+-activated nanoprobe based on nanogapped gold nanoparticles (AuNNP) and poly(N-isopropylacrylamide) (PNIPAM) to simultaneously quantify the liver Cu2+ content and urinary Cu2+ in WD by photoacoustic (PA) imaging and ratiometric surface-enhanced Raman scattering (SERS), respectively. In the nanoprobe, one Raman molecule of 2-naphthylthiol (NAT) was placed in the nanogap of AuNNP. PNIPAM and the other Raman molecule mercaptobenzonitrile (MBN) were coated on the AuNNP surface, named AuNNP-NAT@MBN/PNIPAM. Cu2+ can efficiently coordinate with the chelator PNIPAM and lead to aggregation of the nanoprobe, resulting in the absorption red-shift and increased PA performance of the nanoprobe in the NIR-II window. Meanwhile, the SERS signal at 2223 cm-1 of MBN is amplified, while the SERS signal at 1378 cm-1 of NAT remains stable, generating a ratiometric SERS I2223/I1378 signal. Both NIR-II PA1250 nm and SERS I2223/I1378 signals of the nanoprobe show a linear relationship with the concentration of Cu2+. The nanoprobe was successfully applied for in vivo quantitative detection of liver Cu2+ of WD mice through NIR-II PA imaging and accurate quantification of urinary Cu2+ of WD patients by ratiometric SERS. We anticipate that the activatable nanoprobe might be applied for assisting an early, precise diagnosis of WD in the clinic in the future.

Therapeutic potential of bicyclol in liver diseases: Lessons from a synthetic drug based on herbal derivative in traditional Chinese medicine.

Bicyclol, an innovative chemical drug with proprietary intellectual property rights in China, is based on derivative of traditional Chinese medicine (TCM) Schisandra chinensis (Wuweizi) of North. Mounting data has proved that bicyclol has therapeutic potential in various pathological conditions in liver. In this narrative review, we provide the first summary of pharmacological activities, pharmacokinetic characteristics and toxicity of bicyclol, and discuss future research perspectives. Our results imply that bicyclol has a wide spectrum of pharmacological properties, including anti-viral, anti-inflammatory, immuno-regulatory, anti-oxidative, antisteatotic, anti-fibrotic, antitumor, cell death regulatory effects and modulation of heat shock proteins. Pharmacokinetic studies have indicated that bicyclol is the main substrate of CYP3A/2E1. Additionally, no obvious drug interactions have been found when bicyclol is administered simultaneously with other prescriptions. Furthermore, the results of chronic toxicity have strongly addressed that bicyclol has no noticeable toxic effects on all biochemical indices and pathological examinations of the main organs. In view of good pharmacological actions and safety, bicyclol is anticipated to be a potential candidate for various liver diseases, including acute liver injury, fulminant hepatitis, non-alcoholic fatty liver disease, fibrosis and hepatocellular carcinoma. Further studies are therefore required to delineate its molecular mechanisms and targets to confer this well-designed drug a far greater potency. We hope that bicyclol-based therapeutics for liver diseases might be broadly used in clinical practice worldwide.