Photoinduced Transition-MetalExternal Photosensitizer Free Benzylic Fluorination of Unactivated Alkylarenes.

A green and efficient protocol for the direct monofluorination of unactivated alkylarenes under visible-light irradiation has been developed, without any extraneous transition-metal catalysts or photosensitizers. This method is compatible with a broad spectrum of functional groups, including carboxylic and alcoholic scaffolds, under mild reaction conditions. Gram-scale synthesis of a fluorine-containing pharmaceutical analogue was successfully executed, underscoring the strategy's reliability and practicality. Furthermore, mechanistic studies suggest that a single-electron transfer mechanism might be responsible for the generation of the benzylic radicals in initiation step.

Visible-Light-Induced Hydrodifluoromethylation of Unactivated Alkenes with Difluoroacetic Anhydride.

We herein described a practical and efficient protocol for hydrodifluoromethylation of unactivated alkenes using readily available difluoroacetic anhydride as a difluoromethyl source by merging photocatalysis and N-hydroxyphthalimide activation. This method features a wide substrate scope and excellent compatibility with various functional groups, as demonstrated by more than 50 examples, including bioactive molecules and pharmaceutical derivatives. Mechanism investigation indicated that N-hydroxyphthalimide may also serve as the hydrogen atom donor.

Dehydrogenative synthesis of N-functionalized 2-aminophenols from cyclohexanones and amines: Molecular complexities via one-shot assembly.

Polyfunctionalized arenes are privileged structural motifs in both academic and industrial chemistry. Conventional methods for accessing this class of chemicals usually involve stepwise modification of phenyl rings, often necessitating expensive noble metal catalysts and suffering from low reactivity and selectivity when introducing multiple functionalities. We herein report dehydrogenative synthesis of N-functionalized 2-aminophenols from cyclohexanones and amines. The developed reaction system enables incorporating amino and hydroxyl groups into aromatic rings in a one-shot fashion, which simplifies polyfunctionalized 2-aminophenol synthesis by circumventing issues associated with traditional arene modifications. The wide substrate scope and excellent functional group tolerance are exemplified by late-stage modification of complex natural products and pharmaceuticals that are unattainable by existing methods. This dehydrogenative protocol benefits from using 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) as oxidant that offers interesting chemo- and regio-selective oxidation processes. More notably, the essential role of in situ generated water is disclosed, which protects aliphatic amine moieties from overoxidation via hydrogen bond-enabled interaction.

Effect of respiratory muscle training in patients with stable chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Objectives: Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory disorder characterized by progressive airflow limitation. This meta-analysis aims to evaluate the effectiveness of respiratory muscle training (RMT) on key pulmonary function parameters, inspiratory muscle strength and quality of life in patients with stable COPD. Methods: A comprehensive search was conducted in the databases including PubMed, Cochrane, Web of Science, Embase, and ClinicalTrials.gov, from their inception to June 12, 2023. Randomized controlled trials (RCTs) evaluating the impact of RMT on stable COPD were included for meta-analysis. Results: In total, 12 RCTs involving 453 participants were included in the meta-analysis. RMT demonstrated a significant increase in maximal inspiratory pressure (PImax, MD, 95% CI: 14.34, 8.17 to 20.51, P < 0.001) but not on maximal expiratory pressure (PEmax). No significant improvement was observed in 6-Min walk test (6MWT), dyspnea, forced expiratory volume in 1 s (FEV1), forced vital capacity ratio (FVC) and quality of life between RMT and control groups. However, subgroup analysis revealed a significant negative effect of RMT alone on FEV1/FVC (MD, 95% CI: 2.59, -5.11 to -0.06, P = 0.04). When RMT was combined with other interventions, improvements in FEV1/FVC and FEV1 were found, although not statistically significant. Conclusion: RMT can effectively improve maximal inspiratory pressure in stable COPD patients, but the effect is slight in improving lung function, dyspnea and quality of life. It is recommended to combine with other treatment strategies to comprehensively improve the prognosis of COPD patients.

Remote-carbonyl-directed sequential Heck/isomerization/C(sp2)-H arylation of alkenes for modular synthesis of stereodefined tetrasubstituted olefins.

Modular and regio-/stereoselective syntheses of all-carbon tetrasubstituted olefins from simple alkene materials remain a challenging project. Here, we demonstrate that a remote-carbonyl-directed palladium-catalyzed Heck/isomerization/C(sp2)-H arylation sequence enables unactivated 1,1-disubstituted alkenes to undergo stereoselective terminal diarylation with aryl iodides, thus offering a concise approach to construct stereodefined tetrasubstituted olefins in generally good yields under mild conditions; diverse carbonyl groups are allowed to act as directing groups, and various aryl groups can be introduced at the desired position simply by changing aryl iodides. The stereocontrol of the protocol stems from the compatibility between the E/Z isomerization and the alkenyl C(sp2)-H arylation, where the vicinal group-directed C(sp2)-H arylation of the Z-type intermediate product thermodynamically drives the reversible E to Z isomerization. Besides, the carbonyl group not only promotes the Pd-catalyzed sequential transformations of unactivated alkenes by weak coordination, but also avoids byproducts caused by other possible ß-H elimination.

Cytoprotective E-WE thrombin reduces disease severity in a murine model of relapsing-remitting multiple sclerosis.

The blood-brain barrier is composed of microvascular endothelial cells, immune cells, and astrocytes that work in concert with the coagulation cascade to control inflammation and immune cell infiltration into the central nervous system. Endothelial cell dysfunction leading to increased permeability and compromised barrier function are hallmarks of neuroinflammatory and autoimmune disorders, including multiple sclerosis (MS). Therapeutic strategies that improve or protect endothelial barrier function may be beneficial in the treatment or prevention of neuroinflammatory diseases. We therefore tested the hypothesis that biasing thrombin toward anticoagulant and cytoprotective activities would provide equivalent or even additive benefit compared with standard-of-care therapeutic strategies, including corticosteroids. In a mouse model of relapsing-remitting MS, treatment with the thrombin mutant, E-WE thrombin, an engineered thrombin mutant with cytoprotective activities that is biased toward anticoagulant and cytoprotective activity, reduced neuroinflammation and extracellular fibrin formation in SJL mice inoculated with proteolipid protein (PLP) peptide. When administered at the onset of detectable disease, E-WE thrombin significantly improved the disease severity of the initial attack as well as the relapse and delayed the onset of relapse to a similar extent as observed with methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment. These results provide rationale for considering engineered forms of thrombin biased toward anticoagulant and cytoprotective activity as a therapeutic strategy and perhaps an effective alternative to high-dose methylprednisolone for the management of acute relapsing MS attacks.NEW & NOTEWORTHY There are limited treatment options for mitigating acute relapsing attacks for patients with multiple sclerosis. We tested the hypothesis that harnessing the cytoprotective activity of the blood coagulation enzyme, thrombin, would provide benefit and protection against relapsing disease in a mouse model of MS. Our results provide rationale for considering engineered forms of thrombin biased toward cytoprotective activity as a therapeutic strategy and perhaps an alternative to steroids for the management of relapsing MS attacks.

Identification of Novel Alkaloids from Portulaca oleracea L. and Characterization of Their Pharmacokinetics and GLP-1 Secretion-Promoting Activity in STC-1 Cells.

Six new alkaloids (compounds 1-6) were isolated from Portulaca oleracea L. The compounds were triple pair (1 and 2, 3 and 4, and 5 and 6) enantiomers, with 1, 3, and 5 in the R-configuration and 2, 4, and 6 in the S-configuration, and all could bind to SUR1 according to molecular docking analysis. Treatment of STC-1 cells with each compound led to an influx of intracellular Ca2+, eventually leading to the secretion of glucagon-like peptide-1 (GLP-1), with compound 3 giving the highest secretion, resulting in 24.3 ± 7.03% more GLP-1 than nateglinide-treated cells, suggesting that these alkaloids may be able to reduce blood glucose based on their ability to stimulate the release of GLP-1. Furthermore, compound 3 also exhibited slightly faster absorption than nateglinide, as shown by pharmacokinetic analysis conducted in rats. Therefore, the results showed that some purslane alkaloids (such as compound 3) had good pharmacological activity in vivo and may have preventive and therapeutic effects on diabetes.

Substituent-Determined Intramolecular Hydrogen Transfer for Photopromoted Intermolecular Cycloaddition of Anthraquinones with Aryl Olefins.

The formation of intramolecular hydrogen bonds in anthraquinones makes them inert to photoinduced reactions; therefore, it is a great challenge to phototransform these compounds. Herein, we reported a formal visible-light-induced [4 + 2] cycloaddition of both 1-hydroxyanthraquinones and 1-aminoanthraquinones with olefins under external photocatalyst-free conditions with high regioselectivity. More than 60 substrates are disclosed, demonstrating the reliability of this protocol to construct diverse functionalized anthraquinone derivatives.

PLGA nanoparticles engineering extracellular vesicles from human umbilical cord mesenchymal stem cells ameliorates polyethylene particles induced periprosthetic osteolysis.

The wear particle-induced dissolution of bone around implants is a significant pathological factor in aseptic loosening, and controlling prosthetic aseptic loosening holds crucial social significance. While human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exos, Exos) have been found to effectively promote osteogenesis and angiogenesis, their role in periprosthetic osteolysis remains unexplored. To enhance their in vivo application, we engineered HucMSCs-Exos-encapsulated poly lactic-co-glycolic acid (PLGA) nanoparticles (PLGA-Exos). In our study, we demonstrate that PLGA-Exos stimulate osteogenic differentiation while inhibiting the generation of reactive oxygen species (ROS) and subsequent osteoclast differentiation in vitro. In vivo imaging revealed that PLGA-Exos released exosomes slowly and maintained a therapeutic concentration. Our in vivo experiments demonstrated that PLGA-Exos effectively suppressed osteolysis induced by polyethylene particles. These findings suggest that PLGA-Exos hold potential as a therapeutic approach for the prevention and treatment of periprosthetic osteolysis. Furthermore, they provide novel insights for the clinical management of osteolysis.

Direct synthesis of alkylated 4-hydroxycoumarin derivatives via a cascade Cu-catalyzed dehydrogenation/conjugate addition sequence.

An efficient approach for the direct synthesis of alkylated 4-hydroxycoumarin derivatives via a Cu-catalyzed cascade dehydrogenation/conjugate addition sequence starting from simple saturated ketones and 4-hydroxycoumarins has been developed. This protocol features excellent functional-group tolerance, easy scale-up, and a broad substrate scope including bioactive molecules. More importantly, a series of marketed drugs, such as warfarin, acenocoumarol, coumachlor, and coumafuryl, can be obtained by this method.

E-WE thrombin, a protein C activator, reduces disease severity and spinal cord inflammation in relapsing-remitting murine experimental autoimmune encephalomyelitis.

Objective: Relapses in patients with relapsing-remitting multiple sclerosis (RRMS) are typically treated with high-dose corticosteroids including methylprednisolone. However, high-dose corticosteroids are associated with significant adverse effects, can increase the risk for other morbidities, and often do not impact disease course. Multiple mechanisms are proposed to contribute to acute relapses in RRMS patients, including neuroinflammation, fibrin formation and compromised blood vessel barrier function. The protein C activator, E-WE thrombin is a recombinant therapeutic in clinical development for its antithrombotic and cytoprotective properties, including protection of endothelial cell barrier function. In mice, treatment with E-WE thrombin reduced neuroinflammation and extracellular fibrin formation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We therefore tested the hypothesis that E-WE thrombin could reduce disease severity in a relapsing-remitting model of EAE. Methods: Female SJL mice were inoculated with proteolipid protein (PLP) peptide and treated with E-WE thrombin (25 µg/kg; iv) or vehicle at onset of detectable disease. In other experiments, E-WE thrombin was compared to methylprednisolone (100 mg/kg; iv) or the combination of both. Results: Compared to vehicle, administration of E-WE thrombin significantly improved disease severity of the initial attack and relapse and delayed onset of relapse as effectively as methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment, and the combination of both treatments had an additive effect. Conclusion: The data presented herein demonstrate that E-WE thrombin is protective in mice with relapsing-remitting EAE, a widely used model of MS. Our data indicate that E-WE thrombin is as effective as high-dose methylprednisolone in improving disease score and may exert additional benefit when administered in combination. Taken together, these data suggest that E-WE thrombin may be an effective alternative to high-dose methylprednisolone for managing acute MS attacks.

Rh-Catalyzed Direct Decarbonylative Borylation of Carboxylic Acids.

Carboxylic acids are abundant, low cost and environmentally friendly, direct convert carboxylic acids into valued-added compounds are in high demand. Herein, we report a Rh(I) catalyzed direct decarbonylative borylation of aryl and alkyl carboxylic acid using TFFH as activator. This protocol features excellent functional-group tolerance and a broad substrate scope including natural product and drugs. A gram-scale decarbonylative borylation reaction of Probenecid is also presented. In addition, the utility of this strategy is highlighted by a one-pot decarbonylative borylation/ derivatization sequence.

Targeted therapy for peri-prosthetic osteolysis using macrophage membrane-encapsulated human urine-derived stem cell extracellular vesicles.

Aseptic loosening of the prosthesis is a severe complication after joint replacement. It is of great practical significance and social value to discover the prevention and treatment strategies for this condition. Exosomes from urine-derived stem cells (Exos) have great potential in promoting bone repair, reconstruction, and regulating bone metabolism. However, they are easily eliminated by macrophages and incapable of targeting the osteolysis zone. In this study, based on macrophage "homing" into periprosthetic osteolysis region and cell membrane encapsulating nanotechnology, exosomes from urine-derived stem cells were encapsulated with macrophage membrane (MM) to prevent periprosthetic osteolysis. We found that macrophage membrane encapsulated urine-derived stem cell-derived exosomes (MM-Exos) can be targeted delivery to the osteolysis zone and enhance the therapeutic effectiveness of Exos, which alleviated wear particles-induced calvarial osteolysis. Furthermore, MM-Exos could provide immunological camouflage and allow the Exos to avoid phagocytosis by macrophages and stimulate cellular uptake by bone marrow-derived stem cells (BMSCs). Therefore, we demonstrated the unique ability of the macrophage membrane as a targeted transport of exosomes from urine-derived stem cells for the prevention and treatment of periprosthetic osteolysis. These biomimetic nanoparticles provided a new therapeutic exosome delivery system for preventing wear particles-induced osteolysis. STATEMENT OF SIGNIFICANCE: Macrophage membrane encapsulated urine-derived stem cell-derived exosomes (MM-Exos) can be targeted delivery to the osteolysis zone and enhance the therapeutic effect of Exos on peri­prosthetic osteolysis prevention. MM-Exos could allow the Exos to avoid phagocytosis by macrophages and promote the uptake of Exos by BMSCs.

Clearance of senescent cells by navitoclax (ABT263) rejuvenates UHMWPE-induced osteolysis.

Periprosthetic osteolysis is the leading cause of prosthesis failure and subsequent total joint revision. Wear particles produced by prosthetic materials are the main biological factors that cause periprosthetic osteolysis. Reducing the inflammatory response induced by the phagocytosis of wear particles by macrophages, blocking the activation of osteoclastogenesis, and promoting bone regeneration are essential for preventing the aseptic loosening of prostheses. In this study, we demonstrated that cellular senescence played a vital role during the process of ultra-high molecular weight polyethylene (UHMWPE) particle-induced osteolysis. Administration of the senolytic drug navitoclax (ABT263) could eliminate senescent cells and inhibit the secretion and inflammatory state of the senescence-associated secretory phenotype (SASP). We also discovered that ABT263 inhibited the formation of osteoclasts and had a significant therapeutic effect on UHMWPE particle-induced osteolysis based on the results of UHMWPE-induced mouse cranial osteolysis. Therefore, our research provided innovative strategies and ideas for the prevention and treatment of periprosthetic osteolysis.

Photocatalytic Decarboxylative Coupling of Arylacetic Acids with Aromatic Aldehydes.

An efficient protocol was proposed for the preparation of secondary alcohols in good to excellent yields via photoredox-catalyzed decarboxylative couplings between readily available arylacetic acids and a variety of less reactive (hetero)aromatic aldehydes. The formation of carbanion is the key intermediate in this reaction. Various substituted arylacetic acids and aldehydes were all compatible with this transformation under mild reaction conditions. Furthermore, the current protocol was successfully applied to the direct alcoholization of several drug acids.

Multiple remote C(sp3)-H functionalizations of aliphatic ketones via bimetallic Cu-Pd catalyzed successive dehydrogenation.

The dehydrogenation-triggered multiple C(sp3)-H functionalizations at remote positions γ, δ or ε, ζ to carbonyl groups of aliphatic ketones with aryl/alkenyl carboxylic acids as coupling partners have been achieved using a bimetallic Cu-Pd catalyst system. This reaction allows access to alkenylated isocoumarins and their derivatives in generally good yields with high functional group tolerance. The identification of bimetallic Cu-Pd synergistic catalysis for efficient successive dehydrogenation of aliphatic ketones, which overcomes the long-standing challenge posed by the successive dehydrogenation desaturation of terminally unsubstituted alkyl chains in aliphatic ketones, is essential to achieving this bimetallic Cu-Pd catalyzed dehydrogenation coupling reaction.

Toxicokinetics of Two Oxathiapiprolin Enantiomers in Rats and Their Stereoselective Interaction with Oxysterol Binding Protein.

Oxathiapiprolin is a chiral fungicide, and it can affect the metabolism of the cholesterol compounds by inhibiting oxysterol binding protein (OSBP) to exert its fungicidal effect. The application of oxathiapiprolin in agriculture is widespread, and its residue in the environment is a threat to both human and animal health. The two oxathiapiprolin enantiomers differ in their fungicidal activity, biotoxicity, and degradation by environmental forces. However, their biotoxicity has not been reported in animals. The toxicokinetics of a pesticide should be a crucial component for the evaluation of its toxicity in vivo. In this study, we investigated the absorption, bioavailability, tissue distribution, and excretion of the two oxathiapiprolin enantiomers in rats to verify their toxicokinetic process in animals. An ultrahigh-performance liquid chromatography triple quadrupole tandem mass spectrometry (UHPLC-QQQ/MS) method was established to quantify the two oxathiapiprolin enantiomers in vivo. The two oxathiapiprolin enantiomers were found to have approximately the same absorption rate and bioavailability, and both were excreted mainly in the feces. The half-life of R-(-)-oxathiapiprolin was nearly twice that of S-(+)-oxathiapiprolin. R-(-)-oxathiapiprolin also had greater distribution than S-(+)-oxathiapiprolin in the liver, lungs, heart, spleen, kidneys, stomach, large intestine, small intestine, brain, and pancreas, supporting the notion that R-(-)-oxathiapiprolin could better bind with OSBP. The stereoselectivity of S-(+)-oxathiapiprolin in these tissues may be responsible for it being readily metabolized in vivo. The molecular docking technique was subsequently used to verify the more superior binding between R-(-)-oxathiapiprolin and OSBP compared with the binding between S-(+)-oxathiapiprolin and OSBP. The findings of this study could provide more reliable data for determining the toxicokinetics of a single enantiomer of oxathiapiprolin in animals, thereby providing some theoretical basis for its subsequent toxicological study.

Senescent preosteoclast secretome promotes metabolic syndrome associated osteoarthritis through cyclooxygenase 2.

Background: Metabolic syndrome-associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA. Methods: Analysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system. Results: Humans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal antiinflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA. Conclusions: Our findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential. Funding: This work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to MW, R01AR079620 to SD, and P01AG066603 to XC.

A Tandem Dehydrogenation-Driven Cross-Coupling between Cyclohexanones and Primary Amines for Construction of Benzoxazoles.

Herein, we report a transition metal-free, operationally simple, general method for straightforward syntheses of 2-substituted benzoxazoles from readily available cyclohexanones and aliphatic primary amines by an imine α-oxygenation-initiated cascade reaction sequence. The key to achieving high selectivity and excellent functional-group tolerance is the use of TEMPO as a mild oxidant that selectively oxidizes the reaction intermediates through its multiple reactivity modes, thus facilitating the individual steps to proceed in succession. More than 70 substrate combinations are disclosed, demonstrating the reliability of this protocol to synthesize structurally diverse products, including marketed drugs, drug candidate, and natural products that are unattainable by the existing methods.

Synthesis of 3-substituted 2-oxindoles from secondary α-bromo-propionanilides via palladium-catalyzed intramolecular cyclization.

In contrast to aromatic halides, coupling reactions involving oxidative addition of alkyl halides, especially secondary or tertiary halides, to transition metals tend to be more challenging. Herein a palladium-catalyzed intramolecular cyclization of α-bromo-propionanilides has been developed, delivering a series of 3-substituted 2-oxindoles in high yields. The method features easy to prepare starting materials, broad substrate scope and excellent functional group tolerance. A detailed mechanistic investigation has been performed.