Cobalt-Catalyzed Enantioselective Reductive Arylation, Heteroarylation, and Alkenylation of Michael Acceptors via an Elementary Mechanism of 1,4-Addition.

Cobalt complexes with chiral quinox ligands effectively promote the enantioselective conjugate addition of enones using aryl, heteroaryl, and alkenyl halides and sulfonates. Additionally, a cobalt complex with a strongly donating diphosphine, BenzP*, successfully catalyzes the asymmetric reductive arylation and alkenylation of α,ß-unsaturated amides. Both catalytic systems show broad scopes and tolerance of sensitive functional groups. Both reactions can be scaled up with low loadings of cobalt catalysts. Experimental results and density functional theory (DFT) calculations suggest a new mechanism of elementary 1,4-addition of aryl cobalt(I) complexes.

Biosynthesis of silver nanoparticles using Burkholderia contaminans ZCC and mechanistic analysis at the proteome level.

The biogenic synthesis of silver nanoparticles (AgNPs) by microorganisms has been a subject of increasing attention. Despite extensive studies on this biosynthetic pathway, the mechanisms underlying the involvement of proteins and enzymes in AgNPs production have not been fully explored. Herein, we reported that Burkholderia contaminans ZCC was able to reduce Ag+ to AgNPs with a diameter of (10±5) nm inside the cell. Exposure of B. contaminans ZCC to Ag+ ions led to significant changes in the functional groups of cellular proteins, with approximately 5.72% of the (C-OH) bonds being converted to (C-C/C-H) (3.61%) and CO (2.11%) bonds, and 4.52% of the CO (carbonyl) bonds being converted to (C-OH) bonds. Furthermore, the presence of Ag+ and AgNPs induced the ability of extracellular electron transfer for ZCC cells via specific membrane proteins, but this did not occur in the absence of Ag+ ions. Proteomic analysis of the proteins and enzymes involved in heavy metal efflux systems, protein secretion system, oxidative phosphorylation, intracellular electron transfer chain, and glutathione metabolism suggests that glutathione S-transferase and ubiquinol-cytochrome c reductase iron-sulfur subunit play importance roles in the biosynthesis of AgNPs. These findings contribute to a deeper understanding of the functions exerted by glutathione S-transferase and ferredoxin-thioredoxin reductase iron-sulfur subunits in the biogenesis of AgNPs, thereby hold immense potential for optimizing biotechnological techniques aimed at enhancing the yield and purity of biosynthetic AgNPs.

Nickel-Catalyzed Enantioselective Reductive Conjugate Arylation and Heteroarylation via an Elementary Mechanism of 1,4-Addition.

A nickel complex of isoquinox promoted enantioselective conjugate arylation and heteroarylation of enones using aryl and heteroaryl halides directly. The reaction was successfully applied to stereoselective syntheses of ar-turmerone, chiral fragments of (+)-tolterodine and AZD5672. Mechanistically, experiments and calculations supported that an arylnickel(I) complex inserted to enones via an elementary 1,4-addition.

Mitofusin 2 but not mitofusin 1 mediates Bcl-XL-induced mitochondrial aggregation.

Bcl-2 family proteins, as central players of the apoptotic program, participate in regulation of the mitochondrial network. Here, a quantitative live-cell fluorescence resonance energy transfer (FRET) two-hybrid assay was used to confirm the homo-/hetero-oligomerization of mitofusins 2 and 1 (MFN2 and MFN1), and also demonstrate the binding of MFN2 to MFN1 with 1:1 stoichiometry. A FRET two-hybrid assay for living cells co-expressing CFP-labeled Bcl-XL (an anti-apoptotic Bcl-2 family protein encoded by BCL2L1) and YFP-labeled MFN2 or MFN1 demonstrated the binding of MFN2 or MFN1 to Bcl-XL with 1:1 stoichiometry. Neither MFN2 nor MFN1 bound with monomeric Bax in healthy cells, but both MFN2 and MFN1 bind to punctate Bax (pro-apoptotic Bcl-2 family protein) during apoptosis. Oligomerized Bak (also known as BAK1; a pro-apoptotic Bcl-2 family protein) only associated with MFN1 but not MFN2. Moreover, co-expression of Bcl-XL with MFN2 or MFN1 had the same anti-apoptotic effect as the expression of Bcl-XL alone to staurosporine-induced apoptosis, indicating the Bcl-XL has its full anti-apoptotic ability when complexed with MFN2 or MFN1. However, knockdown of MFN2 but not MFN1 reduced mitochondrial aggregation induced by overexpression of Bcl-XL, indicating that MFN2 but not MFN1 mediates Bcl-XL-induced mitochondrial aggregation.

Magnetic hollow bimetallic zinc/cobalt zeolitic imidazolate framework as sorbent for efficiently enriching aflatoxins combined with UHPLC-IT-MSn determination.

A novel magnetic hollow bimetallic zinc/cobalt-based zeolitic imidazolate framework (MHB-Zn/Co-ZIF-8) was prepared via a microwave-assisted chemical etching in methanol. The structure, morphology, and specific surface area were characterized by X-ray diffraction and FTIR spectroscopy, scanning and transmission electron microscopy, and N2 adsorption. The hollow nanostructures with high internal specific surface area, abundant active sites, and reduced aggregation of nanoparticles endow the hollow zeolitic imidazolate framework (ZIF) nanoparticle with high chemical stability, desirable durability, and excellent adsorption abilities. The MHB-Zn/Co-ZIF-8 nanoparticle was used as an effective sorbent for magnetic solid-phase extraction (MSPE) of trace aflatoxins B1, B2, G1, and G2 from fruit juice and fruit samples. The main parameters affecting the efficiency of MSPE procedures were investigated and optimized. The results show that, under optimized conditions, enrichment factors ranging from 67- to 355-fold are obtained for the target analytes. The method is linear in the range 1.0 to 100.0 ng mL-1 with correlation coefficients (R2) from 0.9960 to 0.9992. The limits of detection of four aflatoxins are in the range 0.18 to 1.50 ng mL-1 and the average recoveries range from 75.1 to 102.4%, with relative standard deviations (RSDs) less than 13.6%. This work presents the excellent extraction performance of aflatoxins B1, B2, G1, and G2 on MHB-Zn/Co-ZIF-8. In addition, the applicability of the MSPE coupling with ultrahigh-performance liquid chromatography-ion trap tandem mass spectrometry (UHPLC-IT-MSn) for trace analysis in complex matrices is shown. Graphical abstract Schematic presentation of magnetic hollow bimetallic zinc/cobalt zeolitic imidazolate framework as sorbent for efficiently enriching aflatoxins B1, B2, G1, and G2 from fruit juice samples prior to ultrahigh-performance liquid chromatography-ion trap tandem mass spectrometry (UHPLC-IT-MSn) determination.

A water resistance magnetic graphene-anchored zeolitic imidazolate framework for efficient adsorption and removal of residual tetracyclines in wastewater.

Water-resistant magnetic graphene-anchored zeolite imidazolate (Fe3O4/ZIF-8-G) composite materials with the largest surface area are formed by directly growing a hydrophobic ZIF-8 skeleton onto a graphene support through self-assembly in methanol. Fe3O4/ZIF-8-G hybrid composite has water resistance and super strong adsorption capacity, and is used as an effective adsorbent for adsorption and removal of residual tetracycline in wastewater. The morphologies and structure, as well as water resistance of Fe3O4/ZIF-8-G, were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetry analysis (TGA), N2 adsorption and pHPZC. The adsorption for tetracycline (TC), oxytetracycline (OTC) and chlortetracycline (CTC) followed pseudo-second-order kinetics and fitted the Freundlich adsorption model with the simultaneous adsorption capacity for TC (382.58 mg g-1), OTC (565.94 mg g-1) and CTC (608.06 mg g-1) at pH 5-6 for 10 h. These were much higher than previously reported results for the removal of tetracycline from aqueous solutions. The used Fe3O4/ZIF-8-G could be effectively reused and recycled at least five times without significant loss of adsorption capacity. The hydrophobic and π-π interaction between the aromatic rings of TCs and the aromatic imidazole rings of the ZIF-8-G framework were the main adsorption mechanism on the surface of Fe3O4/ZIF-8-G. Constructing a hydrophobic surface of ZIF-8/G framework resulted in a reduction of the hydrophilic sites of the surface. This can improve stability and selective adsorption of ZIF-8-G framework. In addition, the results show no significant difference in the adsorption kinetics and adsorption capacity of Fe3O4/ZIF-8-G for TC, OTC and CTC in pure water and wastewater.

Aspirin induces oncosis in tumor cells.

In contrast to the well-known anti-tumor mechanisms of aspirin in inducing apoptosis or autophagy, we here for the first time report oncosis induced by aspirin in tumor cells. In vitro and in vivo analysis showed that aspirin induced compromised Bcl-XL level and subsequent ATP depletion. Overexpression of CFP-Bcl-XL in Hela and A549 cells observably inhibited aspirin-induced ATP depletion and almost completely inhibited the aspirin-induced cells bubbling, while pharmacological inhibition of endogenous Bcl-XL activity by ABT-737 remarkably promoted aspirin-induced ATP depletion and cells bubbling, suggesting the key inhibitory role of Bcl-XL in aspirin-induced oncosis. Overexpression of Bax/Bad significantly promoted aspirin-induced oncosis. In addition, cells cultured in a glucose-free medium with low ATP level exhibited higher percentage of bubbling cells than the cells cultured in a glucose medium with high ATP level under aspirin treatment, indicating the important role of ATP depletion in aspirin-induced oncosis. Furthermore, caspase-3 was demonstrated to be not involved in aspirin-induced oncosis. Animal studies showed that aspirin treatment significantly inhibited tumors growth, but did not induce toxicities to mice. Collectively, aspirin inhibits tumors growth in mice and induces oncosis in which the compromised Bcl-XL and intracellular ATP depletion play a dominant role, which provides insights into the therapeutic strategy of aspirin in oncology.

Full anti-apoptotic function of Bcl-XL complexed with Beclin-1 verified by live-cell FRET assays.

Binding of Bcl-XL to Beclin-1 reduces Beclin-1's capacity to induce autophagy. This report aims to explore whether this interaction affects Bcl-XL's anti-apoptotic function. Using fluorescence resonance energy transfer (FRET) two-hybrid assay to quantify the stoichiometry of Bcl-XL-Beclin-1 complex in living cells coexpressing Bcl-XL-CFP and Beclin-1-YFP, we showed that Bcl-XL bond to Beclin-1 to form hetero-oligomers whose stoichiometry increases from 1:1 to 2:1 or higher with the increasing relative expression level of Bcl-XL, indicating the multiple binding sites of Beclin-1 with Bcl-XL. Co-expression of Bcl-XL and Beclin-1 exhibited consistent anti-apoptotic ability against staurosporine (STS)-induced apoptosis with expression of Bcl-XL alone irrespective of the relative expression level between Beclin-1 and Bcl-XL. Collectively, Bcl-XL complexed with Beclin-1 maintains full anti-apoptotic ability independent of the stoichiometry of Bcl-XL-Beclin-1 complex.

Dissimilar responses of fungal and bacterial communities to soil transplantation simulating abrupt climate changes.

Both fungi and bacteria play essential roles in regulating soil carbon cycling. To predict future carbon stability, it is imperative to understand their responses to environmental changes, which is subject to large uncertainty. As current global warming is causing range shifts toward higher latitudes, we conducted three reciprocal soil transplantation experiments over large transects in 2005 to simulate abrupt climate changes. Six years after soil transplantation, fungal biomass of transplanted soils showed a general pattern of changes from donor sites to destination, which were more obvious in bare fallow soils than in maize cropped soils. Strikingly, fungal community compositions were clustered by sites, demonstrating that fungi of transplanted soils acclimatized to the destination environment. Several fungal taxa displayed sharp changes in relative abundance, including Podospora, Chaetomium, Mortierella and Phialemonium. In contrast, bacterial communities remained largely unchanged. Consistent with the important role of fungi in affecting soil carbon cycling, 8.1%-10.0% of fungal genes encoding carbon-decomposing enzymes were significantly (p < 0.01) increased as compared with those from bacteria (5.7%-8.4%). To explain these observations, we found that fungal occupancy across samples was mainly determined by annual average air temperature and rainfall, whereas bacterial occupancy was more closely related to soil conditions, which remained stable 6 years after soil transplantation. Together, these results demonstrate dissimilar response patterns and resource partitioning between fungi and bacteria, which may have considerable consequences for ecosystem-scale carbon cycling.

Solithromycin monotherapy for treatment of community-acquired bacterial pneumonia: A meta-analysis of randomised controlled trials.

OBJECTIVES: Solithromycin is a new monotherapy option for community-acquired bacterial pneumonia (CABP) patients. However, the efficacy and safety of solithromycin monotherapy for the treatment of CABP remains controversial. The aim of this meta-analysis was to evaluate the role that solithromycin played in the treatment of CABP. METHODS: We systematically retrieved randomised controlled trials (RCTs) compared solithromycin with other antibiotics in the treatment of CABP, which were published on PubMed, ScienceDirect, Cochrane libary and the Clinical Trials.gov before July 2018. Ultimately, a meta-analysis of all RCTs eligible for inclusion criteria was performed. RESULTS: Three RCTs, comprising 1855 patients, were included in the meta-analysis. There were no statistically significant differences between patients given solithromycin and those given other antibiotics with regard to early clinical response (ECR) [1855 patients, odds ratio (OR) = 1.00, 95% confidence interval (CI) 0.80 to 1.24, P = 0.99] and clinical success rates at short-term follow-up (SFU) (1855 patients, OR = 0.78, 95% CI 0.60 to 1.01, P = 0.06) in the intention-to-treat (ITT) population, as were the ECR (787 patients, OR = 0.90, 95% CI 0.64 to 1.27, P = 0.55) and clinical success rates at SFU (358 patients, OR = 0.73, 95% CI 0.41 to 1.31, P = 0.30) in microbiological intention-to-treat population (mITT). Similarly, with regard to the occurrence of treatment-emergent adverse events (TEAEs), drug-related adverse events (AEs), serious AEs, serious drug-related AEs and mortality, no statistically significant difference between patients given solithromycin and those given other antibiotics was observed. CONCLUSION: In the treatment of CABP, solithromycin monotherapy is an effective and safe antibiotic regimen. Other advantages (ie anti-inflammatory effect, potent activity against expected pathogens of CABP and convenient clinical use) of solithromycin may make it a more fascinating option compared with the currently used regimens.

A magnetic graphene-like MoS2 nanocomposite for simultaneous preconcentration of multi-residue herbicides prior to UHPLC with ion trap mass spectrometric detection.

A magnetic graphene-like molybdenum disulfide nanocomposite was prepared by liquid-phase exfoliation and hydrothermal synthesis. The morphology, structure, and magnetic behavior of the nanocomposite were characterized by X-ray diffraction, FTIR spectroscopy, thermogravimetric analysis, vibrating sample magnetometry, scanning electron microscopy and transmission electron microscopy. The nanocomposite was employed as a sorbent for magnetic solid-phase extraction (MSPE) of eight triazine and ten sulfonylurea herbicides from environmental water and corn samples. Specifically, this was studied with cyanazine, simetryn, atrazine, methoprotryne, ametryn, prometryn, terbutryn, dipropetryn, metsulfuron-methyl, sulfometuron-methyl, amidosulfuron, rimsulfuron, nicosulfuron, bensulfuron-methyl, halosulfuron-methyl, pyrazosulfuron-ethyl, chlorimuron-ethyl, and cyclosulfamuron. The parameters affecting extraction efficiency (sorbent amount, pH value of the sample, extraction and elution conditions) were studied and optimized. Following MSPE, the multi-residue herbicides were quantified by ultra-high performance liquid chromatography combined with ion trap mass spectrometry and electrospray ionization. The limits of detection range between 20 and 170 ng·L-1. The extraction recoveries of eighteen herbicides from corn samples were in the range between of 64.7% and 103.1%, with RSDs of <17.6%. Graphical abstract Schematic presentation of magnetic graphene-like MoS2 nanocomposite as an absorbent for simultaneous preconcentration of eight triazine and ten sulfonylurea herbicides in corn and water prior to ultra-high performance liquid chromatography (UHPLC) with ion trap mass spectrometry detection.

Microbial responses to inorganic nutrient amendment overridden by warming: Consequences on soil carbon stability.

Eutrophication and climate warming, induced by anthropogenic activities, are simultaneously occurring worldwide and jointly affecting soil carbon stability. Therefore, it is of great interest to examine whether and how they interactively affect soil microbial community, a major soil carbon driver. Here, we showed that climate warming, simulated by southward transferring Mollisol soil in agricultural ecosystems from the cold temperate climate zone (N) to warm temperate climate (C) and subtropical climate zone (S), decreased soil organic matter (SOM) by 6%-12%. In contrast, amendment with nitrogen, phosphorus and potassium enhanced plant biomass by 97% and SOM by 6% at the N site, thus stimulating copiotrophic taxa but reducing oligotrophic taxa in relative abundance. However, microbial responses to nutrient amendment were overridden by soil transfer in that nutrient amendment had little effect at the C site but increased recalcitrant carbon-degrading fungal Agaricomycetes and Microbotryomycetes taxa derived from Basidiomycota by 4-17 folds and recalcitrant carbon-degrading genes by 23%-40% at the S site, implying a possible priming effect. Consequently, SOM at the S site was not increased by nutrient amendment despite increased plant biomass by 108%. Collectively, we demonstrate that soil transfer to warmer regions overrides microbial responses to nutrient amendment and weakens soil carbon sequestration.

Visual colorimetric detection of tin(II) and nitrite using a molybdenum oxide nanomaterial-based three-input logic gate.

We report a molybdenum oxide (MoO3) nanomaterial-based three-input logic gate that uses Sn2+, NO2-, and H+ ions as inputs. Under acidic conditions, Sn2+ is able to reduce MoO3 nanosheets, generating oxygen-vacancy-rich MoO3-x nanomaterials along with strong localized surface plasmon resonance (LSPR) and an intense blue solution as the output signal. When NO2- is introduced, the redox reaction between the MoO3 nanosheets and Sn2+ is strongly inhibited because the NO2- consumes both H+ and Sn2+. The three-input logic gate was employed for the visual colorimetric detection of Sn2+ and NO2- under different input states. The colorimetric assay's limit of detection for Sn2+ and the lowest concentration of NO2- detectable by the assay were found to be 27.5 nM and 0.1 µM, respectively. The assay permits the visual detection of Sn2+ and NO2- down to concentrations as low as 2 µM and 25 µM, respectively. The applicability of the logic-gate-based colorimetric assay was demonstrated by using it to detect Sn2+ and NO2- in several water sources.

Reversible pH switchable oxidase-like activities of MnO2 nanosheets for a visual molecular majority logic gate.

Although the enzyme-like activities of MnO2 nanosheets have been investigated, effective strategies for modulating their activities are still lacking. Herein, inspired by the pH-dependent activity of natural enzymes, we demonstrate that the oxidase-like activities of the MnO2 nanosheets are pH switchable and reversible. The MnO2 nanosheets show oxidase-like activities in an acidic medium, which can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) to form blue oxidized TMB (oxTMB), while the corresponding activities are greatly weakened under alkaline conditions. The reaction mechanism is attributed to the fact that the MnO2 nanosheets can be transformed into hexagonal Na4MnO4 with a low reaction activity in an alkaline environment. Using the pH switchable oxidase-like activities of the MnO2 nanosheets and other reaction processes, we construct a visual three-input molecular majority logic gate with a single-vote veto function. In addition, an OR-INH cascade logic circuit is successfully realized as well.

Puccinia striiformis f. sp. tritici microRNA-like RNA 1 (Pst-milR1), an important pathogenicity factor of Pst, impairs wheat resistance to Pst by suppressing the wheat pathogenesis-related 2 gene.

Small RNAs (sRNAs), an important type of pathogenicity factor, contribute to impairing host immune responses. However, little is known about sRNAs in Puccinia striiformis f. sp. tritici (Pst), one of the most destructive pathogens of wheat (Triticum aestivum L.). Here, we report a novel microRNA-like RNA (milRNA) from Pst termed microRNA-like RNA 1 (Pst-milR1), which suppresses wheat defenses during wheat-Pst interactions. We identified Pst-milR1 as a novel milRNA in Pst. Biological prediction and co-transformation showed that Pst-milR1 takes part in cross-kingdom RNA interference (RNAi) events by binding the wheat pathogenesis-related 2 (PR2) gene. Silencing of the Pst-milR1 precursor resulted in increased wheat resistance to the virulent Pst isolate CYR31. PR2 knock-down plants increased the susceptibility of wheat to the avirulent Pst isolate CYR23. This suggests that Pst-milR1 represses the plant immune response by suppressing the expression of PR2. Taking our findings together, we postulate that Pst-milR1 is an important pathogenicity factor in Pst, which acts as an effector to suppress host immunity. Our results provide significant new insights into the pathogenicity of the stripe rust pathogen.

The shifts of sediment microbial community phylogenetic and functional structures during chromium (VI) reduction.

The Lanzhou reach of the Yellow River, located at the upstream of Lanzhou, has been contaminated by heavy metals and polycyclic aromatic hydrocarbons over a long-time. We hypothesized that indigenous microbial communities would remediate those contaminants and some unique populations could play an important role in this process. In this study, we investigated the sediment microbial community structure and function from the Lanzhou reach. Sediment samples were collected from two nearby sites (site A and site B) in the Lanzhou reach along the Yellow River. Sediment geochemical property data showed that site A sediment samples contained significantly (p < 0.05) higher heavy metals than site B, such as chromium (Cr), manganese (Mn), and copper (Cu). Both site A and B samples were incubated with or without hexavalent chromium (Cr (VI)) for 30 days in the laboratory, and Cr (VI) reduction was only observed in site A sediment samples. After incubation, MiSeq sequencing of 16S rRNA gene amplicons revealed that the phylogenetic composition and structure of microbial communities changed in both samples, and especially Proteobacteria, as the most abundant phylum increased from 45.1 % to 68.2 % in site A, and 50.1 % to 71.3 % in site B, respectively. Some unique OTUs and populations affiliated with Geobacter, Clostridium, Desulfosporosinus and Desulfosporosinus might be involved in Cr (VI) reduction in site A. Furthermore, GeoChip 4.0 (a comprehensive functional gene array) data showed that genes involved in carbon and nitrogen cycling and metal resistance significantly (p < 0.05) increased in site A sediment samples. All the results indicated that indigenous sediment microbial communities might be able to remediate contaminants like Cr (VI), and this information provides possible strategies for future bioremediation of the Lanzhou reach.

Gold nanorod-chitosan based nanocomposites for photothermal and chemoembolization therapy of breast cancer.

Gold nanorods (AuNR) have received significant attention in tumor thermo-chemotherapy. However, insufficient thermal availability limits the in vivo highly efficient applications of AuNR in photothermal therapy. In this study, we have fabricated N-isopropylacrylamide grafted O-carboxymethyl chitosan nanoparticles (NCMC NPs) with thermo-responsive properties for co-encapsulating AuNR and doxorubicin (DOX), forming AuNR@NCMC/DOX nanocomposites (NCs). As a result of the thermo- and photothermal-responsiveness, AuNR@NCMC/DOX NCs exhibited irreversible aggregation at high temperature and under near-infrared (NIR) irradiation with an increase of size to 3 µm. When AuNR@NCMC/DOX NCs reached tumor sites following intravenous administration, they were located in the tumor vessels under NIR irradiation due to an embolization effect. This response enhanced tumor targeting, on-demand release, and the thermal performance of AuNR@NCMC/DOX NCs. We have observed higher tumor accumulation of DOX and AuNR with subsequent stronger inhibition of tumor growth than that achieved without NIR irradiation. The development of AuNR-based NCs with multiple smart responsivenesses at tumors can provide a promising paradigm for solid tumor treatment via the cooperative effects of photothermal therapy and chemoembolization.

The complete chloroplast genome sequence of an invasive plant, Tragopogon dubius Scopoli (asteraceae).

Tragopogon dubius Scopoli is native to Europe and western Asia and is considered an invasive plant in China. In this study, the complete chloroplast genome of T. dubius was obtained using high-throughput next-generation sequencing technology. The whole chloroplast genome was 153,017 bp long with a GC content of 38% and comprised 130 genes (86 protein-coding genes, 36 tRNA genes, and 8 rRNA genes). Phylogenetic analysis based on the concatenated chloroplast protein-coding sequences showed that T. dubius is most closely related to Tragopogon pratensis. This study provides valuable genetic data for further phylogenetic analysis and molecular identification of species in the genus Tragopogon.

Gold Nanorod-Loaded Nano-Contrast Agent with Composite Shell-Core Structure for Ultrasonic/Photothermal Imaging-Guided Therapy in Ischemic Muscle Disorders.

Purpose: This study aims to broaden the application of nano-contrast agents (NCAs) within the realm of the musculoskeletal system. It aims to introduce novel methods, strategies, and insights for the clinical management of ischemic muscle disorders, encompassing diagnosis, monitoring, evaluation, and therapeutic intervention. Methods: We developed a composite encapsulation technique employing O-carboxymethyl chitosan (OCMC) and liposome to encapsulate NCA-containing gold nanorods (GNRs) and perfluoropentane (PFP). This nanoscale contrast agent was thoroughly characterized for its basic physicochemical properties and performance. Its capabilities for in vivo and in vitro ultrasound imaging and photothermal imaging were authenticated, alongside a comprehensive biocompatibility assessment to ascertain its effects on microcirculatory perfusion in skeletal muscle using a murine model of hindlimb ischemia, and its potential to augment blood flow and facilitate recovery. Results: The engineered GNR@OCMC-liposome/PFP nanostructure exhibited an average size of 203.18±1.49 nm, characterized by size uniformity, regular morphology, and a good biocompatibility profile. In vitro assessments revealed NCA's potent photothermal response and its transformation into microbubbles (MBs) under near-infrared (NIR) irradiation, thereby enhancing ultrasonographic visibility. Animal studies demonstrated the nanostructure's efficacy in photothermal imaging at ischemic loci in mouse hindlimbs, where NIR irradiation induced rapid temperature increases and significantly increased blood circulation. Conclusion: The dual-modal ultrasound/photothermal NCA, encapsulating GNR and PFP within a composite shell-core architecture, was synthesized successfully. It demonstrated exceptional stability, biocompatibility, and phase transition efficiency. Importantly, it facilitates the encapsulation of PFP, enabling both enhanced ultrasound imaging and photothermal imaging following NIR light exposure. This advancement provides a critical step towards the integrated diagnosis and treatment of ischemic muscle diseases, signifying a pivotal development in nanomedicine for musculoskeletal therapeutics.