NIR Fluorescent/Photoacoustic Bimodal Imaging of Ferroptosis in Pancreatic Cancer Using Biothiols-Activable Probes.

Ferroptosis modulation is a powerful therapeutic option for pancreatic ductal adenocarcinoma (PDAC) with a low 5-year survival rate and lack of effective treatment methods. However, due to the dual role of ferroptosis in promoting and inhibiting pancreatic tumorigenesis, regulating the degree of ferroptosis is very important to obtain the best therapeutic effect of PDAC. Biothiols are suitable as biomarkers of imaging ferroptosis due to the dramatic decreases of biothiol levels in ferroptosis caused by the inhibited synthesis pathway of glutathione (GSH) and the depletion of biothiol by reactive oxygen species. Moreover, a very recent study reported that cysteine (Cys) depletion can lead to pancreatic tumor ferroptosis in mice and may be employed as an effective therapeutic strategy for PDAC. Therefore, visualization of biothiols in ferroptosis of PDAC will be helpful for regulating the degree of ferroptosis, understanding the mechanism of Cys depletion-induced pancreatic tumor ferroptosis, and further promoting the study and treatment of PDAC. Herein, two biothiol-activable near-infrared (NIR) fluorescent/photoacoustic bimodal imaging probes (HYD-BX and HYD-DX) for imaging of pancreatic tumor ferroptosis were reported. These two probes show excellent bimodal response performances for biothiols in solution, cells, and tumors. Subsequently, they have been employed successfully for real-time visualization of changes in concentration levels of biothiols during the ferroptosis process in PDAC cells and HepG2 cells. Most importantly, they have been further applied for bimodal imaging of ferroptosis in pancreatic cancer in mice, with satisfactory results. The development of these two probes provides new tools for monitoring changes in concentration levels of biothiols in ferroptosis and will have a positive impact on understanding the mechanism of Cys depletion-induced pancreatic tumor ferroptosis and further promoting the study and treatment of PDAC.

Recent Advances of Aminopeptidases-Responsive Small-Molecular Probes for Bioimaging.

Aminopeptidases, enzymes with critical roles in human body, are emerging as vital biomarkers for metabolic processes and diseases. Aberrant aminopeptidase levels are often associated with diseases, particularly cancer. Small-molecule probes, such as fluorescent, fluorescent/photoacoustics, bioluminescent, and chemiluminescent probes, are essential tools in the study of aminopeptidases-related diseases. The fluorescent probes provide real-time insights into protein activities, offering high sensitivity in specific locations, and precise spatiotemporal results. Additionally, photoacoustic probes offer signals that are able to penetrate deeper tissues. Bioluminescent and chemiluminescent probes can enhance in vivo imaging abilities by reducing the background. This comprehensive review is focused on small-molecule probes that respond to four key aminopeptidases: aminopeptidase N, leucine aminopeptidase, Pyroglutamate aminopeptidase 1, and Prolyl Aminopeptidase, and their utilization in imaging tumors and afflicted regions. In this review, the design strategy of small-molecule probes, the variety of designs from previous studies, and the opportunities of future bioimaging applications are discussed, serving as a roadmap for future research, sparking innovations in aminopeptidase-responsive probe development, and enhancing our understanding of these enzymes in disease diagnostics and treatment.

JS-K Combined with a Melanin-Based Theranostic Agent: A Novel Sequential Delivery Strategy to Enhance the Near-Infrared Fluorescence Imaging of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a 5 year survival rate less than 12%. This malignancy is closely related to the unique tumor microenvironment (TME), which is characterized by a hypovascular and hyperdense extracellular matrix, making it difficult for drugs to permeate the tumor center. Near-infrared fluorescence (NIRF) imaging, which has high sensitivity and resolution, may improve the survival rate of PDAC patients. In this study, we first used JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazine-1-yl] diazene-1-ium-1,2-diolate) to specifically dilate blood vessels within the TME of PDAC patients and subsequently injected IR820-PEG-MNPs (IPM NPs) to diagnose and treat orthotopic PDAC. We found that JS-K promoted the accumulation of IPM NPs in orthotopic Pan02 tumor-bearing mice and was able to increase the tumor signal-to-background ratio (SBR) in the orthotopic PDAC area by 41.5%. In addition, surgical navigation in orthotopic Pan02 tumor-bearing mice and complete tumor resection based on fluorescence imaging were achieved with a detection sensitivity of 81.0%. Moreover, we verified the feasibility of the combination of laparoscopy and photothermal ablation (PTA) for the treatment of PDAC. Finally, we demonstrated that IPM NPs had greater affinity for human PDAC tissues than for normal pancreatic tissues ex vivo, preliminarily highlighting the potential for clinical translation of these NPs. In conclusion, we developed and validated a novel sequential delivery strategy that promotes the accumulation of nanoagents in the tumor area and can be used for the diagnosis and treatment of PDAC.

Satellite Cell-Derived Exosomes: A Novel Approach to Alleviate Skeletal Muscle Atrophy and Fibrosis.

Skeletal muscle atrophy coincides with extensive fibrous tissue hyperplasia in muscle-atrophied patients, and fibrous tissue plays a vital role in skeletal muscle function and hinders muscle fiber regeneration. However, effective drugs to manage skeletal muscle atrophy and fibrosis remain elusive. This study isolated and characterized exosomes derived from skeletal muscle satellite cells (MuSC-Exo). The study investigated their effects on denervated skeletal muscle atrophy and fibrosis in Sprague Dawley (SD) rats via intramuscular injection. MuSC-Exo demonstrated the potential to alleviate skeletal muscle atrophy and fibrosis. The underlying mechanism using single-cell RNA sequencing data and functional analysis are analyzed. Mechanistic studies reveal close associations between fibroblasts and myoblasts, with the transforming growth factor ß1 (TGF-ß1)-Smad3-Pax7 axis governing fibroblast activation in atrophic skeletal muscle. MuSC-Exo intervention inhibited the TGF-ß1/Smad3 pathway and improved muscle atrophy and fibrosis. In conclusion, MuSC-Exo-based therapy may represent a novel strategy to alleviate skeletal muscle atrophy and reduce excessive fibrotic tissue by targeting Pax7 through the TGF-ß1/Smad3 pathway.

Telmisartan loading thermosensitive hydrogel repairs gut epithelial barrier for alleviating inflammatory bowel disease.

Inflammatory bowel disease (IBD) remains a global health concern with a complex and incompletely understood pathogenesis. In the course of IBD development, damage to intestinal epithelial cells and a reduction in the expression of tight junction (TJ) proteins compromise the integrity of the intestinal barrier, exacerbating inflammation. Notably, the renin-angiotensin system and angiotensin II receptor type 1 (AT1R) play a crucial role in regulating the pathological progression including vascular permeability, and immune microenvironment. Thus, Telmisartan (Tel), an AT1R inhibitor, loading thermosensitive hydrogel was constructed to investigate the potential of alleviating inflammatory bowel disease through rectal administration. The constructed hydrogel exhibits an advantageous property of rapid transformation from a solution to a gel state at 37°C, facilitating prolonged drug retention within the gut while mitigating irritation associated with rectal administration. Results indicate that Tel also exhibits a beneficial effect in ameliorating colon shortening, colon wall thickening, cup cell lacking, crypt disappearance, and inflammatory cell infiltration into the mucosa in colitis mice. Moreover, it significantly upregulates the expression of TJ proteins in colonic tissues thereby repairing the intestinal barrier damage and alleviating the ulcerative colitis (UC) disease process. In conclusion, Tel-loaded hydrogel demonstrates substantial promise as a potential treatment modality for IBD.

A review of metallurgical slags as catalysts in advanced oxidation processes for removal of refractory organic pollutants in wastewater.

With the rapid growth of the metallurgical industry, there is a significant increase in the production of metallurgical slags. The waste slags pose significant challenges for their disposal because of complex compositions, low utilization rates, and environmental toxicity. One promising approach is to utilize metallurgical slags as catalysts for treatment of refractory organic pollutants in wastewater through advanced oxidation processes (AOPs), achieving the objective of "treating waste with waste". This work provides a literature review of the source, production, and chemical composition of metallurgical slags, including steel slag, copper slag, electrolytic manganese residue, and red mud. It emphasizes the modification methods of metallurgical slags as catalysts and the application in AOPs for degradation of refractory organic pollutants. The reaction conditions, catalytic performance, and degradation mechanisms of organic pollutants using metallurgical slags are summarized. Studies have proved the feasibility of using metallurgical slags as catalysts for removing various pollutants by AOPs. The catalytic performance was significantly influenced by slags-derived catalysts, catalyst modification, and process factors. Future research should focus on addressing the safety and stability of catalysts, developing green and efficient modification methods, enhancing degradation efficiency, and implementing large-scale treatment of real wastewater. This work offers insights into the resource utilization of metallurgical slags and pollutant degradation in wastewater.

Reaction-Activated Disassembly of the NIR-II Probe Enables Fast Detection and Ratiometric Photoacoustic Imaging of Glutathione In Vivo.

Glutathione (GSH), the most abundant nonprotein biothiol, is a significant endogenous molecule that plays a key role in redox equilibrium in vivo and is regarded as a critical biomarker of cancer. Currently, various fluorescent probes have been designed and synthesized for imaging GSH at the cellular level in the visible range and the first near-infrared window (NIR-I, 750-900 nm). However, the application of these fluorescent probes for bioimaging and biosensing in vivo has been extremely hindered by the high biobackground and low tissue penetration. Herein, based on the self-assembly and disassembly of J-aggregation, we designed and synthesized a GSH-activatable probe MC-PSE for second near-infrared window (NIR-II) fluorescence and ratiometric photoacoustic imaging of GSH in vivo. The anionic cyanine-based MC-PSE tends to form stable J-aggregates in an aqueous solution. Upon the reaction with GSH, the J-aggregates of MC-PSE disassembled, the emission peak intensity of MC-PSE at 940 nm significantly increased by about 20 times, and the PA900/PA980 ratio increased by 4 times within 15 min in vitro. Notably, we used MC-PSE to visualize GSH in tumor-bearing mice and to distinguish normal and tumor areas successfully by virtue of NIR-II FL and PA dual-modal imaging. The design strategy of MC-PSE provides a novel method for ratiometric photoacoustic imaging, and MC-PSE is expected to be a powerful tool for the accurate detection of GSH in cancer diagnosis.

Endoscopically guided interventional photodynamic therapy for orthotopic pancreatic ductal adenocarcinoma based on NIR-II fluorescent nanoparticles.

Rationale: Pancreatic cancer, comprising mostly pancreatic ductal adenocarcinoma (PDAC), is a highly malignant disease, typically known as a hypoxic tumor microenvironment. The application of PDT in pancreatic cancer in clinic is still hampered by several shortcomings, including the (i) deep location of pancreatic cancer, (ii) tissue damage induced by optical fibers, (iii) hypoxic microenvironment, (iv) short excitation wavelengths of traditional photosensitizers, and (v) poor delivery efficiency of photosensitizers. Methods: We designed an organic nanoparticle as photosensitizer for near-infrared II (NIR-II) fluorescent (FL) imaging that exerts a type I PDT effect on deep orthotopic pancreatic tumors under excitation by a NIR (808 nm) laser. Results: This novel photosensitizer exhibits enhanced accumulation in orthotopic pancreatic cancer in mice and could be used to effectively detect pancreatic cancer and guide subsequent laser irradiation for accurate PDT of deep pancreatic cancer. In addition, we built an endoscopic platform monitored by NIR-II FL imaging to achieve minimally invasive endoscopically guided interventional photodynamic therapy (EG-iPDT) with efficient inhibition of orthotopic pancreatic cancer, which prolonged overall survival up to 78 days compared to PBS + EG-iPDT group (*p < 0.05) in a mouse model. Conclusions: Minimally invasive EG-iPDT has promise as an intraoperative treatment for early-stage or unresectable or metastatic pancreatic cancer.

Chinese herbal medicine Buyang Huanwu Decoction in treatment of peripheral nerve injury: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Peripheral nerve injuries (PNI) resulting from trauma can be severe and permanently disabling, approximately one-third of PNIs demonstrate incomplete recovery and poor functional restoration. However, despite extensive research on this aspect, complete functional recovery remains a challenge. In East Asian countries, Chinese herbal Buyang Huanwu Decoction (BHD) has been used to treat PNI for more than 200 years, and the studies of BHD to treat PNI have been increasing in recent years based on positive clinical outcomes. The purpose of this meta-analysis was to scientifically evaluate the safety and clinical efficacy of BHD in patients with PNI. METHOD: A literature search was conducted on PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, VIP, and Sinomed databases for randomized controlled clinical trials that evaluated the safety and effects of BHD alone or combination treatment on PNI. RESULTS: A total of 14 studies involving 1415 participants were included in this study. Each trial did not show significant heterogeneity or publication bias. The results showed that significant improvements of the total clinical effective rate (odds ratio = 3.55; 95% confidence interval [CI] = [2.62, 4.81]; P < .0001), radial nerve function score (standardized mean difference [SMD] = 1.28; 95% CI = [1.09, 1.47]; P = .007), motor nerve conduction velocity (SMD = 1.59; 95% CI = [1.40, 1.78]; P < .0001), sensory nerve conduction velocity (SMD = 1.69; 95% CI = [1.34, 2.05]; P < .0001), and electromyography amplitude (SMD = 2.67; 95% CI = [1.27, 4.06]; P = .0002), and significantly reduce of the visual analog scale scores (SMD = -3.85; 95% CI = [-7.55, -0.15]; P = .04) in the BHD group compared with the control group. In addition, there were no serious and permanent adverse effects in the 2 groups, the difference was not significant (odds ratio = 1.00; 95% CI = [0.40, 2.50]; P = 1.00). CONCLUSION: Current evidence suggests that BHD is an effective and safe treatment for PNI and could be treated as a complementary and alternative option with few side effects compared to a single treatment with neurotrophic drugs or electrical stimulation. However, considering the low methodological quality of the included studies, further rigorous studies are required.

Biochar/layered double hydroxides composites as catalysts for treatment of organic wastewater by advanced oxidation processes: A review.

Heterogeneous advanced oxidation process has been widely studied as an effective method for removing organic pollutants in wastewater, but the development of efficient catalysts is still challenging. This review summaries the present status of researches on biochar/layered double hydroxides composites (BLDHCs) as catalysts for treatment of organic wastewater. The synthesis methods of layered double hydroxides, the characterizations of BLDHCs, the impacts of process factors influencing catalytic performance, and research advances in various advanced oxidation processes are discussed in this work. The integration of layered double hydroxides and biochar provides synthetic effects for improving pollutant removal. The enhanced pollutant degradation in heterogeneous Fenton, sulfate radical-based, sono-assisted, and photo-assisted processes using BLDHCs have been verified. Pollutant degradation in heterogeneous advanced oxidation processes using BLDHCs is influenced by process factors such as catalyst dosage, oxidant addition, solution pH, reaction time, temperature, and co-existing substances. BLDHCs are promising catalysts due to the unique features including easy preparation, distinct structure, adjustable metal ions, and high stability. Currently, catalytic degradation of organic pollutants using BLDHCs is still in its infancy. More researches should be conducted on the controllable synthesis of BLDHCs, the in-depth understanding of catalytic mechanism, the improvement of catalytic performance, and large-scale application of treating real wastewater.

Harnessing the power of natural minerals: A comprehensive review of their application as heterogeneous catalysts in advanced oxidation processes for organic pollutant degradation.

The release of untreated wastewater into water bodies has become a significant environmental concern, resulting in the accumulation of refractory organic pollutants that pose risks to human health and ecosystems. Wastewater treatment methods, including biological, physical, and chemical techniques, have limitations in achieving complete removal of the refractory pollutants. Chemical methods, particularly advanced oxidation processes (AOPs), have gained special attention for their strong oxidation capacity and minimal secondary pollution. Among the various catalysts used in AOPs, natural minerals offer distinct advantages, such as low cost, abundant resources, and environmental friendliness. Currently, the utilization of natural minerals as catalysts in AOPs lacks thorough investigation and review. This work addresses the need for a comprehensive review of natural minerals as catalysts in AOPs. The structural characteristics and catalytic performance of different natural minerals are discussed, emphasizing their specific roles in AOPs. Furthermore, the review analyzes the influence of process factors, including catalyst dosage, oxidant addition, pH value, and temperature, on the catalytic performance of natural minerals. Strategies for enhancing the catalytic efficiency of AOPs mediated by natural minerals are explored, mainly including physical fields, reductant addition, and cocatalyst utilization. The review also examines the practical application prospects and main challenges associated with the use of natural minerals as heterogeneous catalysts in AOPs. This work contributes to the development of sustainable and efficient approaches for organic pollutant degradation in wastewater.

Hydrogen-bonded Complex-based Frameworks for Stable Lithium Storage.

Metal-complex-based materials for lithium storage have attracted great interest due to their highly designable structures with multiple active sites and well-defined lithium transport pathways. Their cycling and rate performances, however, are still constrained by structural stability and electrical conductivity. Herein, we present two hydrogen-bonded complex-based frameworks with excellent lithium storage capability. Multiple hydrogen bonds among the mononuclear molecules result in three-dimensional frameworks that are stable in electrolyte. The origin of the remarkable lithium storage performance of this family was revealed through kinetic analysis and DFT calculations.

Influence of different implant designs on replacement of four teeth of the posterior free-end edentulism: Three-dimensional finite element analysis and clinic case validation.

BACKGROUND: With periodontal disease having an increasing incidence, mandibular free-end edentulism caused by periodontitis is clinically more common. Finite element analysis and clinical case reports were used to evaluate the influence of different designs on the load distribution of implant prosthesis in mandibular posterior free-end edentulism. METHOD: A finite element model of a mandible with posterior free-end edentulism was established. Considering the implant position and selection of single crown repair or splint repair, four designs were conducted including model A: 3435 × 37(four-unit fixed bridge supported by three implants, implant positions were 34, 35, 37); model B: 34,35 × 37, (34: a single implant crown) (35 ×37: three-unit fixed bridge supported by two implants, implant positions were 35, 37); model C: 34 × 3637(four-unit fixed bridge supported by three implants, implant positions were 34, 36, 37); and model D: 34 × 36, 37(37: a single implant crown)(34 ×36: three-unit fixed bridge supported by two implants, implant positions were 34, 36). Stress distribution and the Von Mises stress value of the implants, the crown and the bone around the implants were analyzed at vertical and 45° inclined load. RESULTS: Stress in the cortical bone was mainly concentrated around the implant neck, and maximum Von Mises stress (MVMS) of the four models was 11.6-16.1 MPa at vertical load and 61.74-96.49 MPa at 45° inclined load. Stress in the cancellous bone was concentrated around the implant base, and MVMS of four models was 3.075-3.899 MPa at vertical load and 5.021-6.165 MPa at 45° inclined load. Stress of the restoration crowns was mainly concentrated in the connector of the bridge, and MVMS of four models was 23.38-26.28 MPa at vertical load and 53.14-56.35 MPa at 45° inclined load. Stress of the implant interface was mainly concentrated on the surface of the smaller implants near the bridge, and MVMS of four models was 21.12-33.25 MPa at vertical load and 83.73-138.7 MPa at 45° inclined load. CONCLUSION: There was favorable stress distribution of the four models at vertical load and 45° inclined load. Design of a three-unit fixed bridge combined with a partial crown may be an available option for devising patient treatment plans with mandibular free-end edentulism.

The driving mechanism of soil organic carbon biodegradability in the black soil region of Northeast China.

The biodegradability of soil organic carbon (BSOC), defined as soil mineralization C per unit of soil organic carbon (SOC), is considered to be an important indicator of SOC stability and is closely related to the global C cycle. However, the magnitude and driving mechanism of BSOC in farmland remain largely unexplored, especially at the regional scale. Here, we conducted regional scale sampling to investigate latitude distribution pattern of BSOC and the relative contributions of biotic (soil micro-food web) and abiotic (climate and soil) drivers to BSOC in the black soil region of Northeast China. Results showed that BSOC declined with increasing latitude, which indicates that as the latitude increases, SOC becomes more stable in the black soil region of Northeast China. Over a range of latitude from 43°N to 49°N, BSOC was negatively correlated with soil micro-food web metrics of diversity (indicated by species richness), biomass and connectance, and soil factors of soil pH and clay content (CC), while it was positively correlated with climate factors of mean annual temperature (MAT), mean annual precipitation (MAP) and soil factor of soil bulk density (SBD). Among those predictors, soil micro-food web metrics were the most direct factors contributing to the variations of BSOC, which exerted the largest total effect on BSOC (-0.809). Collectively, our results provide convincing evidence that soil micro-food web metrics play a direct vital role in determining the distribution pattern of BSOC over a range of latitudes in the black soil region of Northeast China. This highlights the necessity of considering the role of soil organisms in regulating C dynamics in prediction of SOC mineralization and retention in the terrestrial ecosystem.

A Quencher-Based Blood-Autofluorescence-Suppression Strategy Enables the Quantification of Trace Analytes in Whole Blood.

Precise quantification of trace components in whole blood via fluorescence is of great significance. However, the applicability of current fluorescent probes in whole blood is largely hindered by the strong blood autofluorescence. Here, we proposed a blood autofluorescence-suppressed sensing strategy to develop an activable fluorescent probe for quantification of trace analyte in whole blood. Based on inner filter effect, by screening fluorophores whose absorption overlapped with the emission of blood, a redshift BODIPY quencher with an absorption wavelength ranging from 600-700 nm was selected for its superior quenching efficiency and high brightness. Two 7-nitrobenzo[c] [1,2,5] oxadiazole ether groups were introduced onto the BODIPY skeleton for quenching its fluorescence and the response of H2 S, a gas signal molecule that can hardly be quantified because of its low concentration in whole blood. Such detection system shows a pretty low background signal and high signal-to-back ratio, the probe thus achieved the accurate quantification of endogenous H2 S in 20-fold dilution of whole blood samples, which is the first attempt of quantifying endogenous H2 S in whole blood. Moreover, this autofluorescence-suppressed sensing strategy could be expanded to other trace analytes detection in whole blood, which may accelerate the application of fluorescent probes in clinical blood test.

Copper Increases the Sensitivity of Cholangiocarcinoma Cells to Tripterine by Inhibiting TMX2-Mediated Unfolded Protein Reaction Activation.

Chemotherapy-induced adaptive resistance is a significant factor that contributes to low therapeutic efficacy in tumor cells. The unfolded protein response (UPR) is a key mechanism in the development of drug resistance and serves as a critical reactive system for endoplasmic reticulum stress. Cu(II) can reduce the abundance of 60S ribosomal subunits and inhibit rRNA processing, leading to a decrease in the translation efficiency of the GRP78/BiP mRNA, which serves as a primary sensor for UPR activation. In this study, CuET-Lipid@Cela, composed of CuET and tripterine (Cela), demonstrates a significant synergistic antitumor effect on cholangiocarcinoma (CCA) cells. RNA-Seq is used to investigate the underlying mechanism, which suggests that the transmembrane protein 2 (TMX2) gene may be crucial in Cu(II) regulation of UPR by inhibiting the activation of GRP78/BiP and PERK/eIF2α. The synergistic antitumor efficacy of CuET-Lipid@Cela via inhibition of TMX2 is also confirmed in a myrAKT/YapS127A plasmid-induced primary CCA mouse model, providing new insights into the reversal of acquired chemotherapy-induced resistance in CCA.

Hydrogen-bond-driven self-assembly of chemiluminophore affording long-lasting in vivo imaging.

Developing chemiluminescence probe with a slow kinetic profile, even a constant emission within analytical time, would improve the analytical sensitivity, but still remains challenging. This work reports a novel strategy to afford long-lasting in vivo imaging by developing a self-assembled chemiluminophore HPQCL-Cl via the introduction of the hydrogen-bond-driven self-assembled dye HPQ to Schaap's dioxetane. Compared with classical chemiluminophore HCL, self-assembled HPQCL-Cl was isolated from the physiological environment, thereby lowering its deprotonation and prolonging its half-life. Based on HPQCL-Cl, the long-lasting in vivo imaging of 9L-lacz tumor was achieved by developing a ß-gal-responsive probe. Its signals remained constant (<5% change) for about 20 min, which may provide a wide time window for the determination of ß-gal. This probe also showed high tumor-to-normal tissue ratio throughout tumor resection, highlighting its potential in image-guided clinical surgery.

In situ detection of alkaline phosphatase in a cisplatin-induced acute kidney injury model with a fluorescent/photoacoustic bimodal molecular probe.

Kidneys play an important part in drug metabolism and excretion. High local concentration of drugs or drug allergies often cause acute kidney injury (AKI). Identification of effective biomarkers of initial stage AKI and constructing activable molecular probes with excellent detection properties for early evaluation of AKI are necessary, yet remain significant challenges. Alkaline phosphatase (ALP), a key hydrolyzing protease, exists in the epithelial cells of the kidney and is discharged into the urine following kidney injury. However, no studies have revealed its level in drug-induced AKI. Existing ALP fluorescent molecular probes are not suitable for testing and imaging of ALP in the AKI model. Drug-induced AKI is accompanied by oxidative stress, and many studies have indicated that a large increase in reactive oxygen species (ROS) occur in the AKI model. Thus, the probe used for imaging of AKI must be chemically stable in the presence of ROS. However, most existing near-infrared fluorescent (NIRF) ALP probes are not stable in the presence of ROS in the AKI model. Hence, we built a chemically stable molecular sensor (CS-ALP) to map ALP level in cisplatin-induced AKI. This novel probe is not destroyed by ROS generated in the AKI model, thus allowing high-fidelity imaging. In the presence of ALP, the CS-ALP probe generates a new absorbance peak at 685 nm and a fluorescent emission peak at 716 nm that could be used to "turn on" photoacoustic (PA) and NIRF imaging of ALP in AKI. Levels of CS-ALP build up rapidly in the kidney, and CS-ALP has been successfully applied in NIRF/PA bimodal in vivo imaging. Through the NIRF/PA bimodal imaging results, we demonstrate that upregulated expression of ALP occurs in the early stages of AKI and continues with injury progression.

The Inhibitory Effects and Cytotoxic Activities of the Stem Extract of Sarracenia purpurea against Melanoma Cells and the SsbA Protein.

The Staphylococcus aureus SsbA protein (SaSsbA) is a single-stranded DNA-binding protein (SSB) that is categorically required for DNA replication and cell survival, and it is thus an attractive target for potential antipathogen chemotherapy. In this study, we prepared the stem extract of Sarracenia purpurea obtained from 100% acetone to investigate its inhibitory effect against SaSsbA. In addition, the cytotoxic effects of this extract on the survival, apoptosis, proliferation, and migration of B16F10 melanoma cells were also examined. Initially, myricetin, quercetin, kaempferol, dihydroquercetin, dihydrokaempferol, rutin, catechin, ß-amyrin, oridonin, thioflavin T, primuline, and thioflavin S were used as possible inhibitors against SaSsbA. Of these compounds, dihydrokaempferol and oridonin were capable of inhibiting the ssDNA-binding activity of SaSsbA with respective IC50 values of 750 ± 62 and 2607 ± 242 µM. Given the poor inhibition abilities of dihydrokaempferol and oridonin, we screened the extracts of S. purpurea, Nepenthes miranda, and Plinia cauliflora for SaSsbA inhibitors. The stem extract of S. purpurea exhibited high anti-SaSsbA activity, with an IC50 value of 4.0 ± 0.3 µg/mL. The most abundant compounds in the stem extract of S. purpurea were identified using gas chromatography−mass spectrometry. The top five most abundant contents in this extract were driman-8,11-diol, deoxysericealactone, stigmast-5-en-3-ol, apocynin, and α-amyrin. Using the MOE-Dock tool, the binding modes of these compounds, as well as dihydrokaempferol and oridonin, to SaSsbA were elucidated, and their binding energies were also calculated. Based on the S scores, the binding capacity of these compounds was in the following order: deoxysericealactone > dihydrokaempferol > apocynin > driman-8,11-diol > stigmast-5-en-3-ol > oridonin > α-amyrin. Incubation of B16F10 cells with the stem extract of S. purpurea at a concentration of 100 µg/mL caused deaths at the rate of 76%, reduced migration by 95%, suppressed proliferation and colony formation by 99%, and induced apoptosis, which was observed in 96% of the B16F10 cells. Overall, the collective data in this study indicate the pharmacological potential of the stem extract of S. purpurea for further medical applications.

Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth.

Regulation of fatty acid uptake, lipid production and storage, and metabolism of lipid droplets (LDs), is closely related to lipid homeostasis, adipocyte hypertrophy and obesity. We report here that stomatin, a major constituent of lipid raft, participates in adipogenesis and adipocyte maturation by modulating related signaling pathways. In adipocyte-like cells, increased stomatin promotes LD growth or enlargements by facilitating LD-LD fusion. It also promotes fatty acid uptake from extracellular environment by recruiting effector molecules, such as FAT/CD36 translocase, to lipid rafts to promote internalization of fatty acids. Stomatin transgenic mice fed with high-fat diet exhibit obesity, insulin resistance and hepatic impairments; however, such phenotypes are not seen in transgenic animals fed with regular diet. Inhibitions of stomatin by gene knockdown or OB-1 inhibit adipogenic differentiation and LD growth through downregulation of PPARγ pathway. Effects of stomatin on PPARγ involves ERK signaling; however, an alternate pathway may also exist.