Magnetically actuated pandanus fruit-like nanorobots for enhanced pH-stimulated drug release and targeted biofilm elimination in wound healing.

Conventional antibiotic treatment struggles to eliminate biofilms in wounds due to the formation compact barrier. Herein, we fabricate magnetic pandanus fruit-like nanorobots (NRs) that function as drug carriers while exhibit excellent maneuverability for enhanced antibacterial tasks. Specifically, zeolitic imidazolate framework-8 (ZIF-8) is self-assembled on the surface of Fe3O4 nanoparticles, loaded with a small quantity of ciprofloxacin, and covered with a layer of polydopamine (PDA). Energized by external magnetic fields, the NRs (F@Z/C/P) are steered in defined direction to penetrate the infection tissues, and effectively arrive targeted areas for pH stimulated drug release and near-infrared triggered phototherapy, contributing to an antibacterial rate of >99.9 %. The Zn2+ in ZIF-8 and the catechol group in PDA form catechol-ZIF-8-drug structures, which effectively reduce drug release by 11 % in high pH environments and promote rapid drug release by 14 % in low pH environments compared to NRs without PDA. Additionally, F@Z/C/P can remove the biofilms and bacteria in Staphylococcus aureus infected wounds, and eventually be discharged from the infected site after treatment, leading to faster healing with an intact epidermis and minimal harm to surrounding tissues and organs. The study provides a promising strategy for tackling biofilm-associated infections in vivo through the use of multi-functional NRs.

Neoteric Semiembedded ß-Tricalcium Phosphate Promotes Osteogenic Differentiation of Mesenchymal Stem Cells under Cyclic Stretch.

ß-Tricalcium phosphate (ß-TCP) is a bioactive material for bone regeneration, but its brittleness limits its use as a standalone scaffold. Therefore, continuous efforts are necessary to effectively integrate ß-TCP into polymers, facilitating a sturdy ion exchange for cell regulation. Herein, a novel semiembedded technique was utilized to anchor ß-TCP nanoparticles onto the surface of the elastic polymer, followed by hydrophilic modification with the polymerization of dopamine. Cell adhesion and osteogenic differentiation of mesenchymal stem cells (MSCs) under static and dynamic uniaxial cyclic stretching conditions were investigated. The results showed that the new strategy was effective in promoting cell adhesion, proliferation, and osteogenic induction by the sustained release of Ca2+ in the vicinity and creating a reasonable roughness. Specifically, released Ca2+ from ß-TCP could activate the calcium signaling pathway, which further upregulated calmodulin and calcium/calmodulin-dependent protein kinase II genes in MSCs. Meanwhile, the roughness of the membrane and the uniaxial cyclic stretching activated the PIEZO1 signaling pathway. Chemical and mechanical stimulation promotes osteogenic differentiation and increases the expression of related genes 2-8-fold. These findings demonstrated that the neoteric semiembedded structure was a promising strategy in controlling both chemical and mechanical factors of biomaterials for cell regulation.

Template Synthesis to Solve the Unreachable Ortho C-H Functionalization Reaction of Aryl Iodide.

This report describes the use of a simple Pd/NBE catalytic system to achieve ortho C-H oxylation and phosphonylation and other functionalizations of aryl iodide through templated conversion reactions. Dimethylamine is introduced in the ortho-site of aryl iodide through C-H amination, and aryl dimethylamine is quickly converted to methyl quaternary ammonium salt precipitation. Methyl quaternary ammonium salt avoids Hofmann elimination in subsequent functionalization. This method solves various ortho functionalization reactions of aryl iodide that have not been achieved for a long time in the field of Pd/NBE chemistry indirectly.

Stereoselective Synthesis of Multisubstituted Alkenes via Ruthenium-Catalyzed Remote Migration Arylation of Nonactivated Olefins.

Polysubstituted alkenes are an important class of organic intermediates that widely exist in various natural products and drug molecules. Herein, we reported a stereoselective synthesis of multisubstituted alkenes via ruthenium-catalyzed remote migration arylation of nonactivated olefins. This strategy exhibited wide substrate suitability and excellent functional group tolerance. In addition, we demonstrated the indispensable role of two types of ruthenium through mechanism experiments.

Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Cross-Coupling Reaction for the Stereoselective Synthesis of Multisubstituted Olefins.

The aryl-to-vinyl nickel 1,4-migration (1,4-Ni migration) reaction has been reported for the first time. The generated alkenyl Ni species undergo a reductive coupling reaction with unactivated brominated alkanes affording a series of trisubstituted olefins. This tandem reaction exhibits mild conditions, a broad substrate scope, high regioselectivity, and excellent Z/E stereoselectivity. A series of controlled experiments have shown that the critical 1,4-Ni migration process is reversible. In addition, the alkenyl nickel intermediates obtained after migration are highly Z/E stereoselective and do not undergo Z/E isomerization. The obtained trace isomerization products are caused by the instability of the product.

Natural polymer derived hydrogel bioink with enhanced thixotropy improves printability and cellular preservation in 3D bioprinting.

Three-dimensional (3D) bioprinting is evolving into a promising technology by spatially controlling the distribution of living cells for the biomedical field. However, maintaining high printability while protecting cells from damage due to shear stress remains the key challenge for extrusion-based 3D bioprinting. Herein, we developed a novel "protein-polyphenol-polysaccharide" extrusion-based bioink named Gel-TA-Alg@Ca2+ using gelatin (Gel), tannic acid (TA) and sodium alginate (Alg) with quantitative thixotropy by pre-crosslinking with a series of low concentrations of CaCl2 at 0.03, 0.04, 0.05 and 0.06 M, respectively. Our experimental design quantitatively presented the positive proportional functional relationship between the thixotropy of Gel-TA-Alg@Ca2+ and printability (including injectability and formability) for the first time. Importantly, the thixotropy proportionately and significantly elevated cellular viability after 3D bioprinting due to the reduced extrusion force involved in printing. 3D bioprinted constructs composed of Gel-TA-Alg@Ca2+ and MG-63 cells exhibited a good cell viability rate for more than 14 days. These findings provide valuable insights into the rational design of thixotropic bioink and offer more opportunities to probe the relationship between the thixotropy and the success of 3D bioprinting.

Synthesis of C-Aryl Glycosides by C-H Functionalization.

In recent years, the synthesis of C-aryl glycosides hrough C-H functionalization has attracted extensive attention of organic synthesis chemists due to its steps and atomic economy. In this concept, we systematically summarizes the synthesis of C-aryl glycosides with diverse regioselectivity and diastereoselectivity from the perspective of C-H arylation of glycosides and C-H glycosylation of arenes. It can be found that a series of recently developed C-H glycosylation reactions have higher site-selectivity and diastereomeric selectivity than Friedel-Crafts glycosylation reaction. The reaction conditions are milder, which can be compatible with acid-sensitive protective groups, such as acetals or ketals, and the deprotection is more convenient. It can be seen that there are few reports on remote C-H glycosylation of aromatic hydrocarbons, which is a new field and needs further research. In addition, C-H glycosylation has a lot of shortcomings, which need to be further explored: a) the precise regulation of stereoselectivity in the reaction process also needs further optimization; b) the research on the reaction mechanism is almost limited to DFT calculation, and there is no exact experimental evidence. For key parts, such as the specific reaction mechanism between cyclo-metal intermediates and glycosyl donors in ortho-CAr -H glycosylation is still unclear; c) due to the fact that aryl glycoside compounds contain bare hydroxyl groups in practical applications, it is an urgent problem to realize the compatibility of glycoside substrates containing naked hydroxyl groups or to remove the protective groups on hydroxyl groups by a mild and efficient method after the reaction; d) In this rapidly developing field, we need to study a greener, more economical and more practical C-H glycosylation of arenes in the future, which will be conducive to the synthesis of C-aryl glycosides with more biological application significance.

Synthesis of C4-Aminated Carbazoles and Their Derivatives via Pd/NBE Chemistry.

Carbazole, as one of the most important organic frameworks, has been used in optoelectronic materials and biochemistry. However, the synthesis of C4-substituted carbazole has always been an unsolved problem. This report describes the one-step synthesis of C4-aminated carbazoles and their derivatives through the series reaction of C-H amination and arylation. The substrate scope is wide. C4-Amino carbazoles substituted by C2, C6, C7, and C8 methyl groups, especially carbazole derivatives of fused rings, pyridine, and dibenzofuran, can be synthesized.

Dynamically evolving piezoelectric nanocomposites for antibacterial and repair-promoting applications in infected wound healing.

Wound healing from bacterial infections is one of the major challenges in the biomedical field. The traditional single administration methods are usually accompanied with side effects or unsatisfactory efficacy. Herein, we design dynamically evolving antibacterial and repair-promoting nanocomposites (NCs) by in situ self-assembling of zeolitic imidazolate framework-8 (ZIF-8) on the surface of barium titanate (BTO), and further loading with a small amount of ciprofloxacin (CIP). The new strategy of combining pH-stimulated drug delivery and ultrasound-controlled sonodyamics has the potential to dynamically evolve in infected wound sites, offering a multifunctional therapy. In vitro study demonstrates that the enhancement generation of reactive oxygen species through the sonodynamic process due to the heterostructures and a small amount of CIP released in an acidic environment are synergistically antibacterial, and the inhibition rate was >99.9%. In addition, reduced sonodynamic effect and Zn2+ generated along with the gradual degradation of ZIF-8 simultanously promote cell migration and tissue regeneration. The in vivo study of full-thickness skin wounds in mouse models demonstrate a healing rate of 99.3% could be achieved under the treatment of BTO@ZIF-8/CIP NCs. This work provides a useful improvement in rational design of multi-stimulus-responsive nanomaterials for wound healing. STATEMENT OF SIGNIFICANCE: A novel piezoelectric nanocomposite was proposed to realize sonodynamic therapy and pH-stimulated drug releasing simultaneously in wound healing treatment. The dynamically evolving structure of the piezoelectric nanocomposite in acidic microenvironment has been theoretically and experimentally verified to contribute to a continuous variation of sonodymanic strength, which accompanied with the gradual releasing of drug and biocompatible Zn2+effectively balanced antibacterial and repair-promoting effects. Both of the in vitro and in vivo study demonstrated that the strategy could significantly accelerate wound healing, inspiring researchers to optimize the design of multi-stimulus-responsive nanomaterials for various applications in biomedical and biomaterial fields.

Roosting-site Selection by Overwintering Black-necked Cranes in the Caohai Wetland, Guizhou Province, China: Implications for Conservation Management.

Stable and high-quality roosting-sites are crucial for the survival of migratory wading birds in winter. The black-necked crane (Grus nigricollis) is the only crane species that lives on the Tibetan plateau for its entire life. Every year, black-necked cranes routinely migrate to the wetlands on the southern lower plateau and roost at wetland sites. Currently, many roosting-sites are under threat from wetland degradation resulting from human disturbance, and changes in water depths and the landscape environment. To understand how the black-necked crane selects roosting-sites given these influencing factors, we conducted a study in the Caohai wetland in China by comparing and modeling the selection of roosting habitat. The vegetation factors mainly included the vegetation height of the swamp patch where the roosting-site was located (VHP) and the vegetation height in the roosting-site (VHR), and the geographic factors mainly included the height of the nearest hill (HNH) and the visible range (VR). These four factors were first considered by the black-necked cranes when choosing roosting-sites on the lakeshore. The roosting-site selection model of black-necked cranes was fitted as (P = e Logit(p) /(1 + e Logit(p)) Logit(p) = 1.243 + 8.397(VHP) -7.999(VHR) -4.105(HNH) + 1.584(VR)). In the Caohai wetland, black-necked cranes preferred roosting-sites away from human disturbances, such as villages/settlements and roads, and where the distance to main roads was > 1,300 m, the distance to villages/residential areas was > 650 m, the distance to rural/service roads was > 500 m, the relatively open area with surrounding hills had a relative height < 15 m, the visible range area was > 550,000 m2, and the shallow swamp area had a water depth of < 5 cm with a vegetation height of < 15 cm. Outside the area of the roosting-site, the surrounding vegetation height was 35 cm-60 cm. We believe that human disturbance, not energy savings or heat loss, was the main factor influencing crane roost site selection. We first gathered data about black-necked crane selection of roosting-sites in a highly complex wetland system. Based on our findings, we strongly recommend appropriately managing the habitat patches in the Caohai wetland, which will have implications for the conservation management of overwintering black-necked cranes in wetlands.

Enalapril increases the urinary excretion of metformin in rats by inducing multidrug and toxin excretion protein 1 in the kidney.

Two-thirds of patients with type 2 diabetes mellitus have hypertension, and thus the combination of two or more drugs to treat these diseases is common. It has been shown that the combination of metformin and enalapril has beneficial effects, but few studies have evaluated the interactions between these two drugs. This study investigated the effects of enalapril on the pharmacokinetics and urinary excretion of metformin in rats, with a focus on transporter-mediated drug interactions. Rats were dosed orally with metformin alone (100 mg/kg) or in combination with enalapril (4 mg/kg). The concentration of metformin was measured by high performance liquid chromatography and the level of organic cation transporters (rOCTs) and multidrug and toxin excretion protein 1 (rMATE1), which mediate the uptake and efflux of metformin, respectively, were evaluated by immunoblotting. After single and 7-day dosing, the plasma concentration of metformin in the co-administration group was significantly lower than that in the metformin-only group, and the CL/F and urinary excretion were increased in the co-administration group. Enalapril did not affect the Kp of metformin but reduced renal slice-uptake of metformin. The expression of rMATE1 was increased, whereas rOCT2 expression was decreased in rat kidney. Importantly, long-term co-administration of metformin and enalapril markedly decreased the level of lactic acid and uric acid in the blood. Enalapril increases the urinary excretion of metformin through the up-regulation of rMATE1. This reveals a new mechanism of drug interactions and provides a basis for drug dosage adjustment when these drugs are co-administered.

A Computational Model of Blood D-Dimer, Cystatin C, and CRP Levels Predicts the Risk of Intracranial Aneurysms and their Rupture.

Objective: The aim of this study is to construct a computational model of blood D-dimer, cystatin C, and CRP levels and to predict the risk of intracranial aneurysms and their rupture. Methods: A total of 69 intracranial aneurysms patients were selected as the case group, including 28 cases in the ruptured group and 41 cases in the unruptured group. Another 64 non-intracranial aneurysm patients were selected as the control group. The detection results of serum D-dimer, cystatin C, and CRP were collected. The logistic regression computational model was used to analyze the occurrence and risk factors of intracranial aneurysms. The receiver operating curves (ROC) of serum D-dimer, cystatin C, and C reactive protein (CRP) levels for predicting intracranial aneurysms and their rupture were drawn, and the area under the curve (AUC), sensitivity, and specificity were calculated. Results: The serum levels of D-dimer, cystatin C, and CRP in patients with intracranial aneurysms were significantly higher than those in the control group and the differences were statistically significant (P < 0.05). The serum levels of D-dimer, cystatin C, and CRP in patients with ruptured intracranial aneurysms were higher than those in patients with unruptured intracranial aneurysms, and the differences were also statistically significant (P < 0.05). The combined detection of serum D-dimer, cystatin C, and CRP levels has a higher AUC (0.9014) for predicting intracranial aneurysms and higher AUC (0.9412) for predicting ruptured intracranial aneurysms than D-dimer (0.7118 and 0.8750, respectively), cystatin C (0.6489 and 0.6180, respectively), and CRP (0.7764 and 0.6551, respectively) independent detection; the combined detection had a sensitivity of 93.75% and 87.80 for predicting the occurrence and rupture of intracranial aneurysms, and the specificity was 68.12% and 92.86%, respectively. Conclusion: The combined detection of serum D-dimer, cystatin C, and CRP levels is a very valuable indicator for predicting the occurrence and rupture of intracranial aneurysms, and combined detection can provide scientific evidence-based guidance for clinical prediction of the occurrence and rupture of intracranial aneurysms.

Therapeutic effects of JLX001 on neuronal necroptosis after cerebral ischemia-reperfusion in rats.

In recent years, more attention has been given to novel patterns of cell death observed during ischemia/reperfusion (I/R). Necroptosis is a regulable secondary cell death pathway; necroptosis is different from traditional forms of cell death, and it is regulated by the RIPK1-RIPK3-MLKL signaling pathway. JLX001 is the double hydrochloride of the natural compound cyclovirobuxine D (CVB-D). Previous studies have confirmed that CVB-D exerts a significant effect on cardiovascular and cerebrovascular diseases and that JLX001 can reduce ischemic brain injury by inhibiting cell apoptosis. For the first time, this project explored the in vivo and in vitro inhibitory effects of the therapeutic administration of JLX001 on the neuronal necroptosis caused by cerebral ischemia-reperfusion injury (CIRI). The middle cerebral artery occlusion reperfusion (MCAO/R) model was used to simulate I/R injury in rats in vivo, and oxygen-glucose deprivation and reperfusion (OGD/R) was used to simulate I/R injury in vitro. After the administration of JLX001, the relative expression of necroptosis-related molecules was measured by ELISA, RT-PCR, HE staining, immunofluorescence and Western blotting. The results showed that JLX001 significantly reduced pathological damage and the cerebral infarction rate in rat brain tissues, and the expression of neuronal necroptosis-related molecules was reduced, suggesting that JLX001 may regulate CIRI through the classic RIPK1-RIPK3-MLKL necroptosis pathway.

Polydimethylsiloxane/BaTiO3 Nanogenerators with a Surface-Assembled Mosaic Structure for Enhanced Piezoelectric Sensing.

Incorporation of inorganic piezoelectric ceramic nanoparticles into a highly elastic polymer matrix is an effective method to develop self-powered sensors and energy harvesters. Herein, a piezoelectrically enhanced nanogenerator (NG) obtained by dispersing lead-free BaTiO3 piezoelectric nanoparticles into elastic polydimethylsiloxane and further surface-modifying with a neoteric mosaic structure for self-powered sensing is proposed. The composites fabricated through this facile and low-cost approach exhibit enhanced voltage by a factor of 1.5 relative to those without modification and display improved mechanical properties with increased elongation at break (failure strain of 150%). The improved performance is mainly attributed to the embossed mosaic structure on the surface, which is theoretically verified by multiphysics simulation. The NGs exhibit highly sensitive and stable piezoelectric output under contact and noncontact working modes and can be applied to detect human vital signs, including bending of fingers and wrists, and various breathing activities, demonstrating wide applications in flexible and smart wearable electronics. The design of the neoteric mosaic structure could be extended to other composite-based NGs, offering significant advantages for the rational design of flexible electronics.

Complete mitochondrial genome of oriental pratincole Glareola maldivarum (Charadriiformes: Glareolidae) and its phylogenetic relationship.

Oriental Pratincole Glareola maldivarum is a widely distributed water bird species of the Charadriiformes group across Eurasia. In this study, we reveal the mitochondrial genome sequence of the Oriental Pratincole for the first time. The length of the mitochondrial genome is 18,422 bp and contains 2 ribosomal RNA genes, 13 protein coding genes, 22 transfer RNA genes, and 2 D-loop sequences. We further provide a phylogenetic tree showing relationships among Oriental Pratincole and other Charadriiformes species.

Site-selective coupling of remote C(sp3)-H/meta-C(sp2)-H bonds enabled by Ru/photoredox dual catalysis and mechanistic studies.

Construction of C(sp2)-C(sp3) bonds via regioselective coupling of C(sp2)-H/C(sp3)-H bonds is challenging due to the low reactivity and regioselectivity of C-H bonds. Here, a novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C-H bonds, including inert γ-C(sp3)-H bonds in amides and meta-C(sp2)-H bonds in arenes, to construct meta-alkylated arenes has been accomplished. This metallaphotoredox-enabled site-selective coupling between remote inert C(sp3)-H bonds and meta-C(sp2)-H bonds is characterized by its unique site-selectivity, redox-neutral conditions, broad substrate scope and wide use of late-stage functionalization of bioactive molecules. Moreover, this reaction represents a novel case of regioselective cross-dehydrogenative coupling of unactivated alkanes and arenes via a new catalytic process and provides a new strategy for meta-functionalized arenes under mild reaction conditions. Density functional theory (DFT) calculations and control experiments explained the site-selectivity and the detailed mechanism of this reaction.

Ruthenium-Catalyzed Stereo- and Site-Selective ortho- and meta-C-H Glycosylation and Mechanistic Studies.

C-aryl glycosides are popular basic skeletons in biochemistry and pharmaceutical chemistry. Herein, ruthenium-catalyzed highly stereo- and site-selective ortho- and meta-CAr -H glycosylation is described. A series of C-aryl pyranosides and furanosides were synthesized by this method. The strategy showed good substrate scope, and various N-heterocyclic directing groups were compatible with the reaction system. A mechanistic study suggested that the key pathway of ortho-CAr -H glycosylation might involve oxidative addition/reduction elimination, whereas aryl meta-C-H glycosylation was mediated by σ-activation. Density functional theory calculations also showed that the high stereoselectivity of meta-CAr -H glycosylation was due to steric hindrance.

Oxidative Stress and Antioxidative Therapy in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is clinically characterized by a progressive increase in pulmonary artery pressure, followed by right ventricular hypertrophy and subsequently right heart failure. The underlying mechanism of PAH includes endothelial dysfunction and intimal smooth muscle proliferation. Numerous studies have shown that oxidative stress is critical in the pathophysiology of PAH and involves changes in reactive oxygen species (ROS), reactive nitrogen (RNS), and nitric oxide (NO) signaling pathways. Disrupted ROS and NO signaling pathways cause the proliferation of pulmonary arterial endothelial cells (PAECs) and pulmonary vascular smooth muscle cells (PASMCs), resulting in DNA damage, metabolic abnormalities, and vascular remodeling. Antioxidant treatment has become a main area of research for the treatment of PAH. This review mainly introduces oxidative stress in the pathogenesis of PAH and antioxidative therapies and explains why targeting oxidative stress is a valid strategy for PAH treatment.

Synthesis of C8-Aminated Pyrrolo-Phenanthridines or -Indoles via Series C(sp2 or sp3)-H Activation and Fluorescence Study.

This report developed a method for the synthesis of C8-aminated pyrrolo-phenanthridines or -indoles by series ortho C(sp2)-H amination/ipso C(sp2)-H or C(sp3)-H arylation. N-benzoyloxyamines, as electrophilic amination reagents, did not undergo an electrophilic substitution reaction with the pyrrole side, but they did undergo a site-selective C-H amination reaction with the benzene side via Pd/NBE catalysis. The C8-aminated pyrrolo-phenanthridines have strong fluorescence in solution and solid state. X-ray single crystal diffraction shows that the steric hindrance of amino and ortho benzene ring may inhibit aggregation-caused quenching (ACQ).

Integrated osteochondral differentiation of mesenchymal stem cells on biomimetic nanofibrous mats with cell adhesion-generated piezopotential gradients.

Biomimetic piezoelectric scaffolds provide a noninvasive method for in vivo cell regulation and tissue regeneration. Herein, considering the gradually varied piezoelectric properties of native cartilage and bone tissues, we fabricated biomimetic electrospun poly(L-lactic acid) (PLLA) nanofibrous mats with gradient piezoelectric properties to induce the integrated osteochondral differentiation of rat mesenchymal stem cells (MSCs). Nanofibrous mats are polarized under electric fields with linear variation of strength to generate gradient piezoelectricity, and cell adhesion-derived contraction forces could produce gradient piezoelectric potential on the scaffolds. Our results demonstrated that the piezoelectric potential could positively modulate cell adhesion, intracellular calcium transients, Ca2+ binding proteins, and differentiation-related genes. In addition, the differentiation of MSCs into osteogenic and chondrogenic lineages was integrated on a single scaffold at different areas with relatively high and low piezoelectricity values, respectively. The continuous gradient scaffold exhibited the potential to provide a smooth transition between the cartilage and bone, offering new insights to probe the regeneration mechanisms of the osteochondral tissue in a single scaffold and inspiring a future efficient and rational design of piezoelectric smart biomaterials for tissue engineering.