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Epidemics caused by cyprinid herpesvirus 2 (Cy HV-2) in domestic cyprinid species have been reported in both European and Asian countries. Although the mechanisms remain unknown, acute Cy HV-2 infections generally result in high mortality, and the surviving carps become chronic carriers displaying no external clinical signs. In this study, in situ hybridization analysis showed that Cy HV-2 tended to infect peripheral blood cells during either acute or chronic infections in silver crucian carp, Carassius auratus gibelio (Bloch). Laboratory challenge experiments coupled with real-time PCR quantification assays further indicated that steady-state levels of the viral genomic copy number in fish serum exhibited a typical 'one-step' growth curve post-viral challenge. Transcriptional expression of open reading frames ( ORF) 121, which was selected due to its highest transcriptional levels in almost all tested tissues, was monitored to represent the replication kinetics of Cy HV-2 in peripheral blood cells. Similar kinetic curve of active viral gene transcription in blood cells was obtained as that of serum viral load, indicating that Cy HV-2 replicated in peripheral blood cells as well as in other well-characterized tissues. This study should pave the way for designing non-invasive and cost-effective serum diagnostic methods for quick detection of Cy HV-2 infection. [ABSTRACT FROM AUTHOR]

A Pd-catalyzed asymmetric higher-order dipolar cycloaddition between allenyl carbonates and azadienes is achieved by exploiting novel alkylidene-π-allyl-Pd dipoles. This research provides a modular platform for the synthesis of challenging chiral endocyclic allenes bearing a medium-sized heterocyclic motif and a centrally chiral stereocenter in good yields with high enantio- and diastereoselectivities (29 examples, up to 97% yield, 97:3 er and >19:1 dr). Experimental and computational studies elucidate the possible reaction mechanism and the observed stereochemical results. Based on the mechanistic understanding, a new π-propargyl-Pd dipole was designed to further extend the success of the higher order dipolar cycloaddition strategy to the synthesis of 10-membered endocyclic alkynes from propargyl carbonates and azadienes (13 examples, up to 98% yield and 94.5:5.5 er).

Pyroptosis has been found to contribute to myocardial ischemia/reperfusion (I/R) injury, but the exact mechanisms that initiate myocardial pyroptosis are not fully elucidated. Sonic hedgehog (SHH) signaling is activated in heart suffered I/R, and intervention of SHH signaling has been demonstrated to protect heart from I/R injury. Caspase recruitment domain-containing protein 10 (CARD10)-B cell lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex could transduce signals from the membrane and induce inflammatory pathways in non-hematopoietic cells, which could be a downstream effector of SHH signaling pathway. This study aims to explore the role of SHH signaling in I/R-induced myocardial pyroptosis and its relationship with the CBM complex. C57BL/6J mice were subjected to 45 min-ischemia followed by 24 h-reperfusion to establish a myocardial I/R model, and H9c2 cells underwent hypoxia/reoxygenation (H/R) to mimic myocardial I/R model in vitro. Firstly, SHH signaling was significantly activated in heart suffered I/R in an autocrine- or paracrine-dependent manner via its receptor PTCH1, and inhibition of SHH signaling decreased myocardial injury via reducing caspase-11-dependent pyroptosis, concomitant with attenuating CBM complex formation. Secondly, suppression of SHH signaling decreased protein kinase C α (PKCα) level, but inhibition of PKCα attenuated CBM complex formation without impacting the protein levels of SHH and PTCH1. Finally, disruption of the CBM complex prevented MALT1 from recruiting of TRAF6, which was believed to trigger the caspase-11-dependent pyroptosis. Based on these results, we conclude that inhibition of SHH signaling suppresses pyroptosis via attenuating PKCα-mediated CARD10-BCL10-MALT1 complex formation in mouse heart suffered I/R., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oxidative stress contributes greatly to doxorubicin (DOX)-induced cardiotoxicity. Down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) is a key factor in DOX-induced myocardial oxidative injury. Recently, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)-dependent k48-linked ubiquitination was responsible for down-regulation of myocardial Nrf2 in DOX-treated mice. Micafungin, an antifungal drug, was identified as a potential MALT1 inhibitor. This study aims to explore whether micafungin can reduce DOX-induced myocardial oxidative injury and if its anti-oxidative effect involves a suppression of MALT1-dependent k48-linked ubiquitination of Nrf2. To establish the cardiotoxicity models in vivo and in vitro, mice were treated with a single dose of DOX (15 mg/kg, i.p.) and cardiomyocytes were incubated with DOX (1 μM) for 24 h, respectively. Using mouse model of DOX-induced cardiotoxicity, micafungin (10 or 20 mg/kg) was shown to improve cardiac function, concomitant with suppression of oxidative stress, mitochondrial dysfunction, and cell death in a dose-dependent manner. Similar protective roles of micafungin (1 or 5 μM) were observed in DOX-treated cardiomyocytes. Mechanistically, micafungin weakened the interaction between MALT1 and Nrf2, decreased the k48-linked ubiquitination of Nrf2 while elevated the protein levels of Nrf2 in both DOX-treated mice and cardiomyocytes. Furthermore, MALT1 overexpression counteracted the cardioprotective effects of micafungin. In conclusion, micafungin reduces DOX-induced myocardial oxidative injury via suppression of MALT1, which decreases the k48-linked ubiquitination of Nrf2 and elevates Nrf2 protein levels. Thus, micafungin may be repurposed for treating DOX-induced cardiotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Isodesmic reactions, in which chemical bonds are redistributed between substrates and products, provide a general and powerful strategy for both biological and chemical synthesis. However, most isodesmic reactions involve either metathesis or functional-group transfer. Here, we serendipitously discovered a novel isodesmic reaction of indoles and anilines that proceeds intramolecularly under weakly acidic conditions. In this process, the five-membered ring of the indole motif is broken and a new indole motif is constructed on the aniline side, accompanied by the formation of a new aniline motif. Mechanistic studies revealed the pivotal role of σ→π* hyperconjugation on the nitrogen atom of the indole motif in driving this unusual isodesmic reaction. Furthermore, we successfully synthesized a diverse series of polycyclic indole derivatives; among quinolines, potential antitumor agents were identified using cellular and in vivo experiments, thereby demonstrating the synthetic utility of the developed methodology., (© 2024 Wiley-VCH GmbH.)

The interactions between corn amylose (CA) and Moringa oleifera seed salt-soluble protein (MOSP) were explored to improve the gel properties of MOSP. With increasing CA content, the MOSP-CA gel network structure was improved but the size of the gel porosity decreased firstly and then increased; the water holding retention (WHR) of MOSP-CA was decreased from approximately 94 % to 85.43 ± 2.54 %. The MOSP-CA-2.5 gel exhibited the best water holding stability (WHS), with a value of 37.1 ± 0.33 %. The MOSP-CA gel hardness increased with CA concentration, and MOSP-CA-2.5 showed relatively optimal cohesiveness, elasticity, adhesiveness, and chewiness. Meanwhile, MOSP-CA-2.5 exhibited gel strength. Incorporation of CA significantly increased the exposure of hydrophobic residues and the concentration-dependent increase in disulfide bonds in MOSP-CA gel. Thus, hydrophobic interactions, hydrogen bonds, and disulfide bonds collectively stabilized the structure of MOSP-CA gel. The findings would broaden the application of MOSP and improve the utilization value of MOSP in various industries., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Morpholines are widespread in many biologically and catalytically active agents, thus being an important aim of pharmaceutical and synthetic chemists. However, efficient strategies for the catalytic asymmetric synthesis of chiral morpholines bearing crowded stereogenic centers still remain elusive. Herein, we disclose a Cu-catalyzed asymmetric propargylic amination/desymmetrization strategy to help resolve this challenge. As a result, two kinds of structurally various chiral morpholines bearing rich functional groups and N-α-quaternary stereocenters were produced with high efficiency and selectivity (42 examples, up to 91 % yield, 97:3 er and > 19:1 dr). In addition, a series of transformations were performed to demonstrate the synthetic utility of this methodology. In particular, a hit compound for new antitumor drugs was identified through cellular evaluation. Furthermore, mechanistic investigations reveal that, hydrogen bonding in the key copper-allenylidene intermediate together with π-π stacking aids remote enantioinduction., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Purpose: Melatonin has promising protective effects for retinopathy. However, its roles in retinopathy of prematurity (ROP) and the underlying mechanisms remain unknown. We aimed to explore its roles and mechanisms in a ROP model., Methods: Hematoxylin and eosin staining were used to observe the morphology of the retina. Immunofluorescence was used to detect positive (Nrf2+ and VEGF+) cells. Immunohistochemistry was used to detect the level of nuclear expression of PCNA in retinal tissue. Transmission electron microscope (TEM) was used to observe the morphology and structure of pigment cells. qRT-PCR was used to assay the expression of miR-23a-3p, Nrf2, and HO-1. Western blotting was used to detect the expression of Nrf2, HO-1, β-actin, and Lamin B1., Results: Melatonin or miR-23a-3p antagomir treatment could ameliorate the Oxygen-induced pathological changes, increased the expression of Nrf2 and HO-1, SOD, and GSH-Px, and decreased the expression of VEGF, miR-23a-3p, MDA and the apoptosis in the ROP model. Further target prediction and luciferase reporter assays confirmed the targeted binding relationship between miR-23a-3p and Nrf2., Conclusion: Our study showed that melatonin could ameliorate H 2 O 2 -induced apoptosis and oxidative stress injury in RGC cells by mediating miR-23a-3p/Nrf2 signaling pathway, thereby improving retinal degeneration.

Background: Respiratory viruses are increasingly detected in children with community-acquired pneumonia. Further strategies to limit antibiotic use in children with viral pneumonia are warranted., Aim: To explore clinical efficacy of budesonide/formoterol inhalation powder for viral pneumonia in children and its impact on cellular immunity and inflammatory factor production., Methods: A total of 60 children with viral pneumonia were recruited: 30 receiving budesonide/formoterol inhalation powder and 30 conventional symptomatic treatment. Outcome measures included peripheral blood levels of inflammatory cytokines, CD4 + , CD8 + , Th1, Th2, Th17 and Treg, clinical efficacy, and incidence of adverse reactions., Results: Compared with the control group, the observation group showed a significant reduction in interleukin-6 and high-sensitivity C-reactive protein levels after treatment. Compared with the control group, the observation group showed a significant increase in CD4 + /CD8 + and Th1/Th2 levels, and a decrease in Th17/Treg levels after treatment. The total effective rates in the observation group and the control group were 93.75% and 85.00%, respectively, which was a significant difference ( P = 0.003)., Conclusion: Budesonide/formoterol inhalation powder significantly improved therapeutic efficacy for viral pneumonia in children. The mechanism of action may be related to downregulation of the inflammatory response and improved cellular immune function., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Herein, we designed a reaction for the desymmetrization-addition of cyclopropenes to imines by leveraging the synergy between photoredox and asymmetric cobalt catalysis. This protocol facilitated the synthesis of a series of chiral functionalized cyclopropanes with high yield, enantioselectivity, and diastereoselectivity (44 examples, up to 93% yield and >99% ee). A possible reaction mechanism involving cyclopropene desymmetrization by Co-H species and imine addition by Co-alkyl species was proposed. This study provides a novel route to important chiral cyclopropanes and extends the frontier of asymmetric metallaphotoredox catalysis.

Aims: Downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) contributes to doxorubicin (DOX)-induced myocardial oxidative stress, and inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) increased Nrf2 protein level in rat heart suffering ischemia/reperfusion, indicating a connection between MALT1 and Nrf2. This study aims to explore the role of MALT1 in DOX-induced myocardial oxidative stress and the underlying mechanisms. Results: The mice received a single injection of DOX (15 mg/kg, i.p.) to induce myocardial oxidative stress, evidenced by increases in the levels of reactive oxidative species as well as decreases in the activities of antioxidative enzymes, concomitant with a downregulation of Nrf2; these phenomena were reversed by MALT1 inhibitor. Similar phenomena were observed in DOX-induced oxidative stress in cardiomyocytes. Mechanistically, knockdown or inhibition of MALT1 notably attenuated the interaction between Nrf2 and MALT1 and decreased the k48-linked ubiquitination of Nrf2. Furthermore, inhibition or knockdown of calcium/calmodulin-dependent protein kinase II (CaMKII-δ) reduced the phosphorylation of caspase recruitment domain-containing protein 11 (CARD11), subsequently disrupted the assembly of CARD11, B cell lymphoma 10 (BCL10), and MALT1 (CBM) complex, and reduced the MALT1-dependent k48-linked ubiquitination of Nrf2 in DOX-treated mice or cardiomyocytes. Innovation and Conclusion: The E3 ubiquitin ligase function of MALT1 accounts for the downregulation of Nrf2 and aggravation of myocardial oxidative stress in DOX-treated mice, and CaMKII-δ-dependent phosphorylation of CARD11 triggered the assembly of CBM complex and the subsequent activation of MALT1.

Organic molecules bearing chiral sulfur stereocenters exert a great impact on asymmetric catalysis and synthesis, chiral drugs, and chiral materials. Compared with acyclic ones, the catalytic asymmetric synthesis of thio-heterocycles has largely lagged behind due to the lack of efficient synthetic strategies. Here we establish the first modular platform to access chiral thio-oxazolidinones via Pd-catalyzed asymmetric [3+2] annulations of vinylethylene carbonates with sulfinylanilines. This protocol is featured by readily available starting materials, and high enantio- and diastereoselectivity. In particular, an unusual effect of a non-chiral supporting ligand on the diastereoselectivity was observed. Possible reaction mechanisms and stereocontrol models were proposed., (© 2024 Wiley-VCH GmbH.)

Objective: This study aims to explore the risk factors of vascular complications following free flap reconstruction and to develop a clinical auxiliary assessment tool for predicting vascular complications in patients undergoing free flap reconstruction leveraging machine learning methods., Methods: We reviewed the medical data of patients who underwent free flap reconstruction at the Affiliated Hospital of Zunyi Medical University retrospectively from January 1, 2019, to December 31, 2021. Statistical analysis was used to screen risk factors. A training data set was generated and augmented using the synthetic minority oversampling technique. Logistic regression, random forest and neural network, models were trained, using this dataset. The performance of these three predictive models was then evaluated and compared using a test set, with four metrics, area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity., Results: A total of 570 patients who underwent free flap reconstruction were included in this study, 46 of whom developed postoperative vascular complications. Among the models tested, the neural network model exhibited superior performance on the test set, achieving an AUC of 0.828. Multivariate logistic regression analysis identified that preoperative hemoglobin levels, preoperative fibrinogen levels, operation duration, smoking history, the number of anastomoses, and peripheral vascular injury as statistically significant independent risk factors for vascular complications post-free flap reconstruction. The top five predictive factors in the neural network were fibrinogen content, operation duration, donor site, body mass index (BMI), and platelet count., Conclusion: Hemoglobin levels, fibrinogen levels, operation duration, smoking history, and anastomotic veins are independent risk factors for vascular complications following free flap reconstruction. These risk factors enhance the ability of machine learning models to predict the occurrence of vascular complications and identify high-risk patients. The neural network model outperformed the logistic regression and random forest models, suggesting its potential to aid clinicians in early identification of high-risk patients thereby mitigating patient suffering and improving prognosis., Competing Interests: None., (AJTR Copyright © 2024.)

The construction of an all-in-one catalyst, in which the photosensitizer and the transition metal site are close to each other, is important for improving the efficiency of metallaphotoredox catalysis. However, the development of convenient synthetic strategies for the precise construction of an all-in-one catalyst remains a challenging task due to the requirement of precise installation of the catalytic sites. Herein, we have successfully established a facile bottom-up strategy for the direct synthesis of Ni(II)-incorporated covalent organic framework (COF), named LZU-713@Ni, as a versatile all-in-one metallaphotoredox catalyst. LZU-713@Ni showed excellent activity and recyclability in the photoredox/nickel-catalyzed C-O, C-S, and C-P cross-coupling reactions. Notably, this catalyst displayed a better catalytic activity than its homogeneous analogues, physically mixed dual catalyst system, and, especially, LZU-713/Ni which was prepared through post-synthetic modification. The improved catalytic efficiency of LZU-713@Ni should be attributed to the implementation of bottom-up strategy, which incorporated the fixed, ordered, and abundant catalytic sites into its framework. This work sheds new light on the exploration of concise and effective strategies for the construction of multifunctional COF-based photocatalysts., (© 2023 Wiley-VCH GmbH.)

The exploration of value-added conversions of naturally abundant amino acids has received considerable attention from the synthetic community. Compared with the well-established asymmetric decarboxylative transformation, the asymmetric deaminative transformation of amino acids still remains a formidable challenge, mainly due to the lack of effective strategies for the C-N bond activation and the potential incompatibility with chiral catalysts. Here, we disclose a photoinduced Cu-catalyzed asymmetric deaminative coupling reaction of amino acids with arylboronic acids. This new protocol provides a series of significant chiral phenylacetamides in generally good yields and excellent stereoselectivity under mild and green conditions (42-85 % yields, up to 97 % ee). Experimental investigations and theoretical calculations were performed to reveal the crucial role of additional phenols in improving catalytic efficiency and enantiocontrol., (© 2023 Wiley-VCH GmbH.)

Impaired endothelium-dependent vasodilation in atherosclerosis is a high-risk factor for myocardial infarction and ischemic stroke, and inflammation, necroptosis and apoptosis contribute to endothelial dysfunction in atherosclerosis. Although DL-3-n-butylphthalide (NBP) has been widely used in treating ischemic stroke, its effect on endothelium-dependent vasodilation remains unknown. This study aims to explore whether NBP is able to improve endothelium-dependent vasodilation in atherosclerosis and the underlying mechanisms. Male ApoE -/- mice were fed with a high-fat diet (HFD) for 9-16 weeks to establish a model of atherosclerosis. NBP were given to the mice after eating HFD for 6 weeks and atorvastatin served as a positive control. The endothelium-dependent vasodilation, the blood flow velocity, the atherosclerotic lesion area, the serum levels of lipids, inflammatory cytokines and necroptosis-relevant proteins (RIPK1, RIPK3 and MLKL), and the endothelial necroptosis and apoptosis within the aorta were measured. Human umbilical vein endothelial cells (HUVECs) were incubated with oxidized low-density lipoprotein (ox-LDL) for 48 h to mimic endothelial injury in atherosclerosis, lactate dehydrogenase release, the ratio of necroptosis and apoptosis and the expression of necroptosis-relevant proteins were examined. Similar to atorvastatin, NBP improves endothelium-dependent vasodilation, decreases aortic flow velocity and reduces atherosclerotic lesion area in HFD-fed ApoE -/- mice, concomitant with a reduction in serum lipids, inflammatory cytokines and necroptosis-relevant proteins, and endothelial necroptosis and apoptosis. Consistently, NBP inhibited necroptosis and apoptosis in ox-LDL-treated HUVECs. Based on these observations, we conclude that NBP exerts beneficial effects on improving the endothelium-dependent vasodilation in atherosclerosis via suppressing inflammation, endothelial necroptosis and apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this study, the transmittance of tanshinone Ⅱ_A(Tan Ⅱ_A) and cryptotanshinone(CTS) through the blood-prostate barrier and their distributions in the prostate tissue were compared between tanshinone extract(Tan E) treatment group and the corresponding monomer composition group under the equivalent dose conversion in vitro and in vivo. First, the human prostate epithelial cell line RWPE-1 was cultured in vitro for 21 days for the establishment of a blood-prostate barrier model, and the transmission of Tan Ⅱ_A and CTS through the barrier model was investigated after administration of Tan E and corresponding single active components. Second, SD rats were administrated with 700 mg·kg~(-1) Tan E, 29 mg·kg~(-1) CTS, and 50 mg·kg~(-1) Tan Ⅱ_A by gavage, and plasma and prostate tissue samples were collected at the time points of 2, 4, 8, 12, and 24 h. The Tan Ⅱ_A and CTS concentrations in the samples were determined. The results showed that in the cell model, the cumulative transmission amounts of CTS and Tan Ⅱ_A in the extract at each time point were higher than those of the corresponding single active components(P<0.01). In rats, after the administration of Tan E, the concentrations of Tan Ⅱ_A and CTS in rat plasma and prostate were higher than those of the corresponding single active components. This study demonstrated that the coexisting components in Tan E promoted the penetration of its main pharmacological components Tan Ⅱ_A and CTS through the blood-prostate barrier. The findings provide a theoretical and experimental basis for the application of Tan E in the clinical treatment of prostate-related diseases.

The results of association between Obstructive Sleep Apnea (OSA) and gout are not consistent. Participants aged 20 years or older in the National Health and Nutrition Examination Survey (NHANES) 2007-2008 and 2015-2018 were included. Weighted univariable and multivariable logistic regressions were used to evaluate the association between OSA symptoms and gout. The subgroup and sensitivity analyses were also performed. Among the 15,947 participants in this study, the mean age was 47.8 years old, 48.87% of whom were male, 4891 had OSA symptoms, and 842 had gout. In multivariable logistic regression analyses, OSA symptoms were positively associated with gout in all models. The odds ratio (OR) was 1.315 and 95% confidence interval (CI) was 1.070-1.616 in fully adjusted model 4. In the subgroup analyses, we found a considerable interaction between OSA symptoms and gender with gout (P for interaction = 0.003). In the sensitivity analyses, the association between OSA symptoms and gout remained stable after adjustment for congestive heart failure and diuretics using. OSA symptoms were associated with an increased likelihood of gout. This association could especially be found in female participants., (© 2023. The Author(s).)

Metal-polarized aza-ortho-quinone methides (aza-o-QMs) are a unique and efficient handle for azaheterocycle synthesis. Despite great achievements, the potential of these reactive intermediates has not yet been fully exploited, especially the new reaction modes. Herein, we disclosed an unprecedented dearomatization process of metal-polarized aza-o-QMs, affording transient dearomatized spiroaziridine intermediates. Based on this serendipity, we accomplished three sequential dearomatization-rearomatization reactions of benzimidazolines with aza-sulfur ylides, enabling the divergent synthesis of bis-nitrogen heterocycles with high efficiency and flexibility. Moreover, experimental and theoretical studies were performed to explain the proposed mechanisms and observed selectivity. Further cellular evaluation of the dibenzodiazepine products identified a hit compound for new antitumor drugs., (© 2023 Wiley-VCH GmbH.)

Conjugate addition is among the most important synthetic protocols for constructing carbon skeletons and is widely used to synthesize natural products and drugs. However, asymmetric catalysis studies have mainly focused on constructing stereogenic centers arising from conjugate alkenes. Here, we report the first photoinduced cobalt-catalyzed dynamic kinetic reductive conjugate addition reaction that enables the formation of heterobiaryls with axial chirality (45 examples, up to 91% yield and 97% ee). This method features mild reaction conditions, good functional-group tolerance, and excellent enantiomeric control. Significantly, large amounts of metal waste and precious metal catalysts can be avoided under these conditions. Migration of the chiral arylcobalt species into the alkene might be the rate-determining step based on kinetic studies.

Nonalcoholic fatty liver disease (NAFLD) has become an important risk of type 2 diabetes mellitus (T2DM). Peripheral neuropathy (PN) is regarded as one of the main microvascular complications of diabetes. But the association of NAFLD with PN is still unclear. We aimed to investigate the association between NAFLD and PN in US population by conducting a cross-sectional study. We enrolled 3029 participants aged 40-85 years from National Health and Nutrition Examination Survey (NHANES) 1999-2004. NAFLD was defined as a US Fatty Liver Index (FLI) score ≥ 30, and PN was defined as having one or more insensate areas on either foot. Participants were divided into two groups (with or without PN). We performed multivariate logistic regression models to evaluate the association between NAFLD and PN. Subgroup analyses were used to find out whether the association was stable in different stratified groups. Sensitivity analyses were conducted to assess the robustness of the results. All the analyses were weighted. Among the individuals, 524 (17.3%) had PN and 1250 (41.27%) had NAFLD. In the multivariate logistic regression models, NAFLD was associated with an increased risk of PN (OR 1.44 [1.03 ~ 2.02]) after fully adjusting for covariates. In the subgroup analyses, NAFLD was significantly associated with PN in the age group (40-64 years), compared with those in the age group (65-85 years), (P for interaction: 0.004). The results of association of NAFLD with PN were stable in sensitivity analyses. In this cross-sectional study among US adults aged 40-85 years old, NAFLD was associated with an increased likelihood of prevalent PN., (© 2023. The Author(s).)

Enantioselective metallaphotoredox catalysis, which combines photoredox catalysis and asymmetric transition-metal catalysis, has become an effective approach to achieve stereoconvergence under mild conditions. Although many impressive synthetic approaches have been developed to access central chirality, the construction of axial chirality by metallaphotoredox catalysis still remains underexplored. Herein, we report two visible light-induced cobalt-catalyzed asymmetric reductive couplings of biaryl dialdehydes to synthesize axially chiral aldehydes (60 examples, up to 98% yield, >19:1 dr, and >99% ee). This protocol shows good functional group tolerance, broad substrate scope, and excellent diastereo- and enantioselectivity.

A new whitefly species, Aleurolobusrutae sp. nov. , collected on Murrayaexotica (Sapindales, Rutaceae) leaves in the Maolan National Nature Reserve, Guizhou, China, is described and illustrated. Some of the individuals were infected with Aschersoniaplacenta , an entomopathogenic fungus. The insect is circular in shape and characterized by a very wide submarginal region, and the submarginal furrow is almost continuous, with only a small break at the caudal furrow. Anterior and posterior marginal setae are absent, but setae are present on the 8 th abdominal segment. Thoracic and caudal tracheal folds are discernible., (Qing-Song Lin, Lin-Qian Lu, Ji-Rui Wang.)

Ring-opening transformations of donor-acceptor (D-A) cyclopropanes enable the rapid assembly of complex molecules. However, the enantioselective formation of chiral quaternary stereocenters using substrates bearing two different acceptors remains a challenge. Herein, we describe the first palladium-catalyzed highly diastereo- and enantioselective (3+2) cycloaddition of vinyl cyclopropanes bearing two different electron-withdrawing groups, a subset of D-A cyclopropanes. The key to the success of this reaction is the remote stereoinduction through hydrogen bond from chiral ligands, which thereby addressed the aforementioned challenge. A variety of chiral five-membered heterocycles were produced in good yields and with high stereoselectivity (up to 99 % yields, 99 : 1 er and >19 : 1 dr). In-depth mechanistic investigations, including control experiments and theoretical calculations, revealed the origin of the stereoselectivity and the importance of H-bonding in stereocontrol., (© 2022 Wiley-VCH GmbH.)

Ferroptosis is an iron-dependent cell death and contributes to doxorubicin-induced cardiotoxicity, but the mechanisms behind intracellular iron overload in cardiomyocyte after administration of doxorubicin remain largely unknown. Ferritinophagy is a selective type of autophagy and could be a novel source for intracellular free iron. Spermatogenesis-associated protein 2 (SPATA2), a member of the TNF signaling pathway, can recruit cylindromatosis (CYLD, a deubiquitinating enzyme) to regulate cell death. This study aims to explore whether ferritinophagy is the source for intracellular iron overload in cardiomyocyte upon doxorubicin treatment and whether the SPATA2/CYLD pathway is involved in regulation of nuclear receptor coactivator 4 (NCOA4) level, the selective cargo receptor for ferritinophagy. The C57BL/6J mice were subjected to a single injection of doxorubicin, which showed the compromised cardiac functions, accompanied by the upregulation of SPATA2 and CYLD and the enhanced interaction between them, the increases in ferritinophagy (reflecting by increases in NCOA4 and ratio of LC3Ⅱ/LC3Ⅰ while decreases in NCOA4 ubiquitination and ferritin) and ferroptosis (reflecting by intracellular iron overload and increase of acyl-CoA synthetase long chain family member 4). Consistently, similar results were achieved in the cultured cardiomyocytes after incubation with doxorubicin. Knocked down of SPATA2 notably reduced doxorubicin-induced cardiomyocyte injury concomitant with the attenuated ferritinophagy and the decreased ferroptosis. Based on these observations, we conclude that a novel pathway of SPATA2/CYLD has been identified, which contributes to doxorubicin-induced cardiomyocyte ferroptosis via enhancing ferritinophagy through a mechanism involving the deubiquitination of NCOA4., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Searching for efficient strategies to access structurally novel aminoindolines is of great significance for drug discovery. However, catalytic asymmetric de novo construction of aminoindoline scaffolds with functionality primed for diversification still remains elusive. Here, we report a Cu-catalyzed asymmetric cyclization of ethynyl benzoxazinones with amines, producing chiral 3-aminoindolines in good yield and with high enantioselectivity (up to 97% yield and 98:2 er). Moreover, a radical-mediated sulfonyl migration of these products was unexpectedly found, further affording new chiral 3-aminoindolines bearing alkenyl sulfonyl groups with retained enantiopurity (up to 84% yield and 98:2 er). Bioactivity evaluations indicate that these 3-aminoindolines show notable antitumor activities and chirality is proven to have a significant impact on their antitumor activity.

This study aimed to compare the regulatory effects of Arenga pinnata retrograded starch (APRS), Arenga pinnata starch (APS), and whole Arenga pinnata flour (APF) on gut microbiota and improvement of intestinal inflammation in aged mice. APF, APS, and APRS altered gut microbiota composition and exhibited different prebiotic effects. Bifidobacterium showed the greatest increase in feces of aged mice fed APF. The abundance of genus Lachnospiraceae_NK4A136 was highest in the APS group. APRS supplementation led to a greatest increasement in abundance of Lactobacillus, Roseburia, and Faecalibacterium prausnitzii. APRS induced significantly more short-chain fatty acid (SCFAs) production than APF and APS. APF, APS, and APRS treatments improved intestinal inflammation in aged mice and the order of ameliorative effect was APRS > APS > APF. APRS significantly decreased relative mRNA expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and increased anti-inflammatory cytokines (IL-10). In addition, APF, APS, and APRS significantly downregulated the relative mRNA expression of senescence-associated gene p53 and upregulated the expression of anti-aging gene Sirt1. These results provide potentially useful information about the beneficial effects of Arenga pinnata products on human health.

Catalytic asymmetric synthesis of chiral endocyclic allenes remains a challenge in allene chemistry owing to unfavored tension and complex chirality. Here, we present a new relay strategy merging Pd-catalyzed asymmetric [3+2] annulation with enyne-Cope rearrangement, providing a facile route to chiral 9-membered endocyclic allenes with high efficiency and enantioselectivity. Moreover, theoretical calculations and experimental studies were performed to illustrate the critical, but unusual Cope rearrangement that allows for the complete central-to-axial chirality transfer., (© 2022 Wiley-VCH GmbH.)

Medium-sized heterocycles are widespread among a spectrum of structurally intriguing and biologically significant natural products and synthetic pharmaceuticals. Metal-catalyzed high-order dipolar annulations resembling reactions of metal-containing reactive dipoles with dipolarophiles constitute a highly efficient and flexible strategy for constructing medium-sized heterocycles. Mechanistically, these annulation reactions usually proceeding through stepwise pathways are different from the classic high-order pericyclic reactions that follow the Woodward-Hoffman rules. More significantly, asymmetric high-order dipolar annulations using chiral organometallic catalysts have been proven successful for constructing chiral medium-sized heterocycles with high enantio- and diastereoselectivity. This review highlights the impressive advances in this area and is focused on the reactivity, scope, mechanisms and applications of high-order dipolar annulation reactions.

Grignard addition is one of the most important methods used for syntheses of alcohol compounds and has been known for over a hundred years. However, research on asymmetric catalysis relies on the use of organometallic nucleophiles. Here, we report the first visible-light-induced cobalt-catalyzed asymmetric reductive Grignard-type addition for synthesizing chiral benzyl alcohols (>50 examples, up to 99% yield, and 99% ee). This methodology has the advantages of mild reaction conditions, good functionality tolerance, excellent enantiocontrol, the avoidance of mass metal wastes, and the use of precious metal catalysts. Kinetic realization studies suggested that migratory insertion of an aryl cobalt species into the aldehyde was the rate-determining step of the reductive addition reaction.

Background: Blunt snout bream (Megalobrama amblycephala) is sensitive to hypoxia. A new blunt snout bream strain, "Pujiang No.2", was developed to overcome this shortcoming. As a proteasome inhibitor, bortezomib (PS-341) has been shown to affect the adaptation of cells to a hypoxic environment. In the present study, bortezomib was used to explore the hypoxia adaptation mechanism of "Pujiang No.2". We examined how acute hypoxia alone (hypoxia-treated, HN: 1.0 mg·L - 1 ), and in combination with bortezomib (hypoxia-bortezomib-treated, HB: Use 1 mg bortezomib for 1 kg fish), impacted the hepatic ultrastructure and transcriptome expression compared to control fish (normoxia-treated, NN)., Results: Hypoxia tolerance was significantly decreased in the bortezomib-treated group (LOE crit , loss of equilibrium, 1.11 mg·L - 1 and 1.32 mg·L - 1 ) compared to the control group (LOE crit , 0.73 mg·L - 1 and 0.85 mg·L - 1 ). The HB group had more severe liver injury than the HN group. Specifically, the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the HB group (52.16 U/gprot, 32 U/gprot) were significantly (p < 0.01) higher than those in the HN group (32.85 U/gprot, 21. 68 U/gprot). In addition, more severe liver damage such as vacuoles, nuclear atrophy, and nuclear lysis were observed in the HB group. RNA-seq was performed on livers from the HN, HB and NN groups. KEGG pathway analysis disclosed that many DEGs (differently expressed genes) were enriched in the HIF-1, FOXO, MAPK, PI3K-Akt and AMPK signaling pathway and their downstream., Conclusion: We explored the adaptation mechanism of "Pujiang No.2" to hypoxia stress by using bortezomib, and combined with transcriptome analysis, accurately captured the genes related to hypoxia tolerance advantage., (© 2022. The Author(s).)

Background: Lung cancer is one of the deadliest cancers in the world with the highest incidence and mortality rate among all cancers. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of primary lung cancer. However, efficacy and safety of the current regimens for NSCLC is unsatisfactory. Therefore, there has been an increasing urgency for development of potential therapeutic therapies for NSCLC., Aim: To investigate the therapeutic outcomes and safety of continuous intravenous infusion of recombinant human endostatin (Rh-endostain) using an infusion pump in retreated advanced NSCLC., Methods: Patients with retreated advanced NSCLC who were admitted to Zhejiang Provincial People's Hospital from October 2017 to April 2019 were recruited. These patients received continuous intravenous infusion of Rh-endostain using an infusion pump. Objective response rate (ORR), clinical benefit rate (CBR), median progression-free survival (mPFS), and incidences of adverse events (AEs) were analyzed after treatment., Results: A total of 45 patients with retreated advanced NSCLC were included, and all of them were evaluated. In these patients, ORR was 22.2%, CBR was 84.4%, and mPFS was 5.3 mo. The following AEs were observed, decreased hemoglobin (34 cases, 75.6%), nausea/vomiting (32 cases, 71.1%), elevated transaminase (24 cases, 53.3%), leukopenia (16 cases, 35.6%), thrombocytopenia (14 cases, 31.1%), and constipation (1 case, 3.4%). None of the patients had leukopenia, nausea /vomiting, and constipation of grade III and above., Conclusion: The patients showed improved adherence to 5-d continuous intravenous infusion of Rh-endostain using an infusion pump. Favorable efficacy and safety of this treatment regimen were achieved in retreated advanced NSCLC., Competing Interests: Conflict-of-interest statement: The authors declared no conflicts of interest for this manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

DHA has been shown to be neuroprotective and important to neurogenesis, but its role in HG-induced brain injury and the underlying mechanisms remain unknown. To elucidate the therapeutic effect of DHA, we established a mouse model with insulin-induced hypoglycemic brain injury and an in vitro model of HT-22 cells using a sugar-free medium. DHA treatment significantly reduced neuronal death and improved HG-induced learning and memory deficits. Moreover, DHA inhibited neuronal necroptosis and decreased the concentrations of TNF-α, IL-1β and TNFR1. DHA also activated PPAR-γ and suppressed the NF-κB pathway in mouse brain tissues. In vitro, DHA treatment restored the viability and decreased necroptosis of HT-22 cells treated with glucose deprivation. However, the inhibition of PPAR-γ with T0070907 reversed neuroprotective and anti-necroptosis effects of DHA in HG-induced brain injury, which is associated with the activation of the downstream NF-κB pathway. We conclude that DHA displays a protective effect against HG-induced brain injury through the PPAR-γ/NF-κB pathway and represents a promising method to prevent HG-induced brain injury., (Copyright © 2021. Published by Elsevier B.V.)

Transition metal-catalyzed cycloaddition has been established as a powerful tool for heterocycle synthesis. Despite impressive advances, the exploitation of new catalysis strategies and systems is still highly significant to enrich the heterocycle family. Herein, we disclosed a cooperative catalysis system merging an achiral Pd catalyst and a chiral Co catalyst for the asymmetric [4+2] cycloaddition between vinyl benzoxazinones and N -acylpyrazoles. Chiral tetrahydroquinolines bearing two contiguous, unusual cis -configured stereocenters were produced in high yields and enantio- and diastereoselectivities. The pyrazole directing group can be easily converted into many other functional groups, thus demonstrating the flexibility of the present methodology.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

Transition metal-catalysed asymmetric coupling has been established as a robust tool for constructing complex organic molecules. Although this area has been extensively studied, the development of efficient protocols to construct stereogenic centres with excellent regio- and enantioselectivities is highly desirable and remains challenging. Asymmetric transition metal catalysis with light intervention provides a practical alternative strategy to current methods and considerably expands the synthetic utility as a result of abundant feedstocks and mild conditions. This tutorial review comprehensively summarizes the recent advances in transition-metal-catalysed asymmetric coupling reactions with light intervention; in particular, a concise analysis of substrate scope and the mechanistic scenarios governing stereocontrol is discussed.

Allopurinol, a xanthine oxidase (XO) inhibitor, is reported to alleviate myocardial ischemia/reperfusion (I/R) injury by reducing the production of reactive oxygen species (ROS). As an XO-derived product, H 2 O 2 can act as a substrate of vascular peroxidase 1 (VPO1) to induce the generation of hypochlorous acid (HOCl), a potent oxidant. This study aims to explore whether the XO/VPO1 pathway is involved in the anti-oxidative effects of allopurinol on the myocardial I/R injury. In a rat heart model of I/R, allopurinol alleviated I/R oxidative injury accompanied by decreased XO activity, XO-derived products (H 2 O 2 and uric acid), and VPO1 expression (mRNA and protein). In a cardiac cell model of hypoxia/reoxygenation (H/R), allopurinol or XO siRNA reduced H/R injury concomitant with decreased XO activity, VPO1 expression as well as the XO and VPO1-derived products (H 2 O 2 , uric acid, and HOCl). Although knockdown of VPO1 could also exert a beneficial effect on H/R injury, it did not affect XO activity, XO expression, and XO-derived products. Based on these observations, we conclude that the novel pathway of XO/VPO1 is responsible for, at least partly, myocardial I/R-induced oxidative injury, and allopurinol exerted the cardioprotective effects on myocardial I/R injury via inhibiting the XO/VPO1 pathway., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

A DBU-catalyzed desymmetric [3+2] cycloaddition between para-quinamines and photogenerated ketenes was developed for the first time. Under the irradiation of low-energy blue LEDs, a variety of hydroindoles bearing all-carbon quaternary centers were produced with good reaction efficiency and complete diastereoselectivity (34 examples, 45-99% yields and >95 : 5 dr). This protocol represents a new approach to synthetically significant hydroindoles, and features broad substrate scope, high functional group compatibility and mild reaction conditions.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide. In addition to respiratory symptoms, COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases. Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates the expression of antioxidant proteins, participating in COVID-19-mediated inflammation and liver injury. Here, we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury. Additionally, we describe some mechanisms and treatment strategies., Competing Interests: Conflict-of-interest statement: None of the authors have any conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

1,3-Dienes are readily available feedstocks that are widely used in the laboratory and industry. However, the potential of converting 1,3-dienes into value-added products, especially chiral products, has not yet been fully exploited. By synergetic photoredox/copper catalysis, we achieve the first visible-light-induced, enantioselective carbocyanation of 1,3-dienes by using carboxylic acid derivatives and trimethylsilyl cyanide. Under mild and neutral conditions, a diverse range of chiral allyl cyanides are produced in generally good efficiency and with high enantioselectivity from bench-stable and user-safe chemicals. Moreover, preliminary results also confirm that this success can be expanded to 1,3-enynes and the four-component carbonylative carbocyanation of 1,3-dienes and 1,3-enynes.