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Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with increasing incidence. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin has been used for the treatment of T2DM worldwide. Although sitagliptin has excellent therapeutic outcome, adverse effects are observed. In addition, previous studies have suggested that sitagliptin may have pleiotropic effects other than treating T2DM. These pieces of evidence point to the importance of further investigation of the molecular mechanisms of sitagliptin, starting from the identification of sitagliptin-binding proteins. In this study, by combining affinity purification mass spectrometry (AP-MS) and stable isotope labeling by amino acids in cell culture (SILAC), we discover seven high-confidence targets that can interact with sitagliptin. Surface plasmon resonance (SPR) assay confirms the binding of sitagliptin to three proteins, i . e ., LYPLAL1, TCP1, and CCAR2, with binding affinities (K D ) ranging from 50.1 μM to 1490 μM. Molecular docking followed by molecular dynamic (MD) simulation reveals hydrogen binding between sitagliptin and the catalytic triad of LYPLAL1, and also between sitagliptin and the P-loop of ATP-binding pocket of TCP1. Molecular mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis indicates that sitagliptin can stably bind to LYPLAL1 and TCP1 in active sites, which may have an impact on the functions of these proteins. SPR analysis validates the binding affinity of sitagliptin to TCP1 mutant D88A is ~10 times lower than that to the wild-type TCP1. Our findings provide insights into the sitagliptin-targets interplay and demonstrate the potential of sitagliptin in regulating gluconeogenesis and in anti-tumor drug development.

Sustained expression of B-cell receptor (BCR) critically contributes to the development of diffuse large B-cell lymphoma (DLBCL). However, little is known on the mechanism regulating BCR expression. In the present study, we explored the biological significance of functional intergenic repeating RNA element (FIRRE) in DLBCL and its regulation on BCR. Functional impacts of FIRRE on cell viability, transformation, and apoptosis were examined by MTT, colony formation, and flow cytometry, respectively. The interaction between FIRRE and polypyrimidine tract binding protein 1 (PTBP1) was identified by RNA pull-down and verified using RNA immunoprecipitation (RIP) assays. The effects of FIRRE and PTBP1 on Smurf2 mRNA were examined by RIP, RNA pull-down, and mRNA stability assays. Smurf2-mediated BCR ubiquitination was investigated using co-immunoprecipitation, ubiquitination, and protein stability assays. In vivo, xenograft models were used to assess the impacts of targeting FIRRE on DLBCL growth. FIRRE was specifically up-regulated in and essentially maintained multiple malignant behaviors of BCR-dependent DLBCL cells. Through the interaction with PTBP1, FIRRE promoted the mRNA decay of Smurf2, a ubiquitin ligase for the degradation BCR protein. Targeting FIRRE was sufficient to regulat Smurf2 and BCR expressions and inhibit DLBCL malignancy both in vivo and in vitro. FIRRE-PTBP1 interaction, by simulating Smurf2 mRNA decay and stabilizing BCR, promotes the development of DLBCL. Consequently, targeting this signaling mechanism may provide therapeutic benefits for DLBCL., (© 2022 John Wiley & Sons Ltd.)

As a critically endangered (CR) fish species, Chinese Bahaba is a unique "Giant Panda" fish species in China and has been listed among the national first-class wildlife protection animals and China's top 10 genetic resources of aquatic products since 2021. This fish species is of high commercial value because its swim bladder is commonly used in traditional Chinese medicine. Its otoliths are the sensory organs immersed in the endolymph for maintaining its balance and hearing. However, rare information has been reported on the sound absorption structure and chambers of otoliths of such "Giant Panda" fish. The big "C" groove was found in the fish's front sagittal otolith with the crystal cluster in the back sagittal otolith, the former of which is a 3D layered structure, that is constructed by elongated prismatic crystals. Besides, there are numerous small holes and adhesion material in this 3D layered structure, where many chambers were also found, indicating that some specific sounds may be captured by this structure and these chambers may then amplify such sounds at a certain wavelength. This finding could be of great importance for protecting and conserving this critically endangered species., 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 Ltd. All rights reserved.)

Two new physalins, 7α-hydroxy-5-deoxy-4-dehydrophysalin IX ( 1 ) and 5-deoxy-4-dehydrophysalin IX ( 2 ), together with six known compounds, luteolin ( 3 ), luteolin-7- O -glucoside ( 4 ), neoechinulin A ( 5 ), 3-(4-hydroxy-3-methoxyphenyl)- N -(4-methylphenyl)-2-propenamide ( 6 ), physalin D ( 7 ) and blumenol A ( 8 ) were isolated from Physalis alkekengi L. var. franchetii (Mast.) Makino. Their structures were elucidated by NMR spectroscopic analysis, HR-ESI-MS, X-ray crystallographic data analysis and comparison with the known compounds. Among them, compounds 5 and 6 were isolated from the genus Physalis for the first time. Compound 1 exhibited weak NAD(P)H: quinone reductase (QR) inducing activity.

Sponge-derived bacteria are considered to be a promising source of novel drugs, owing to their abundant secondary metabolites that have diverse biological activities. In this study, we explored the antimicrobial biosynthetic potential and phylogenetics of culturable bacteria associated with the sponge Ophlitaspongia sp. from the Yellow Sea, China. Using culture-dependent methods, we obtained 151 bacterial strains, which were then analysed for their antimicrobial activities against seven indicator strains. The results indicate that 94 (62.3%) of the 151 isolated strains exhibited antimicrobial activities and inhibited at least one of the indicator strains. Fifty-two strains were selected for further phylogenetic analysis using 16S rRNA gene sequencing, as well as for the presence of polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) genes. These 52 strains belonged to 20 genera from 18 families in 4 phyla, including Actinobacteria , Bacteroidetes , Firmicutes , and Proteobacteria . Five strains with PKS genes and ten strains with NRPS genes were detected. Among them, two strains contained both PKS and NRPS genes. Notoacmeibacter sp. strain HMA008 (class Alphaproteobacteria ) exhibited potent antimicrobial activity; thus, whole genome sequencing methods were used to analyse its secondary metabolite biosynthetic gene clusters. The genome of HMA008 contained 12 biosynthetic gene clusters that potentially encode secondary metabolites belonging to compound classes such as non-ribosomal peptides, prodigiosin, terpene, β-lactones, and siderophore, among others. This study indicates that the sponge Ophlitaspongia sp. harbours diverse bacterial strains with antimicrobial properties and may serve as a potential source of bioactive compounds.

Aim: To perform a quantitative analysis of the peripapillary vessel density (VD) and retinal nerve fiber layer (RNFL) thickness changes in patients with early stage of diabetic retinopathy (DR)., Methods: In this case-control study, swept-source optical coherence tomography angiography (SS-OCTA) imaging was used to examine diabetic and age-matched healthy subjects. The optic disc HD 6×6 mm 2 blood flow imaging scan mode was selected. Automatic software was used to measure the peripapillary VD, capillary vessel density (CVD), and RNLF in an optic nerve head (ONH) filed based on the Garway-Heath map. In addition, the correlation between peripapillary VD, CVD, and RNFL was further investigated., Results: The cohort consisted of 32 healthy individuals and 72 patients with diabetes (34 eyes with no DR and 38 eyes with mild-moderate NPDR). Peripapillary VD decreased in the mild-moderate NPDR group compared to the control group in most regions ( P <0.05). Peripapillary CVD and RNFL thickness were significantly lower in the mild-moderate NPDR group in the superior temporal (ST) quadrants ( P =0.018, P =0.030). In the correlation analysis of each region, the RNFL thickness in the NS region was positively correlated with the peripapillary VD and CVD ( r =0.233, P =0.05; r =0.288, P =0.015). In the TI region, the RNFL thickness was positively correlated with the peripapillary CVD ( r =0.237, P =0.047)., Conclusion: The measurement based on the ONH topographic map may be helpful in detecting functional and structural impairments in DR. The peripapillary VD, CVD and RNFL decrease in early DR, and the RNFL thickness altered in association with the CVD or/and VD in some regions., (International Journal of Ophthalmology Press.)

Objective: BMI may play a protective role in reducing the mortality rate of patients with chronic obstructive pulmonary disease (COPD), but its effect on acute exacerbation of COPD remain unclear. Methods: Subjects were selected from the COPD patients registration system established in 2014 in Pudong new district, Shanghai. COPD patients from 8 communities were selected by cluster sampling and follow up was conducted prospectively for 18 months. Basic information and BMI were obtained from baseline survey, and acute exacerbations were collected during follow-up. The association between BMI and risk of acute exacerbation was evaluated by using multiple negative binomial regression. Results: Among 328 community COPD patients, 295 who completed the follow up were included in the analysis, in whom 96.3% (284/295) were mild COPD patients. During the follow-up, 11.1% (33/295) of the patients reported acute exacerbation. The results of multiple negative binomial regression suggested that, the risk for acute exacerbation decreased with the increase of BMI ( IRR =0.85, 95% CI :0.73-0.98), overweight patients with BMI ≥25.0 kg/m 2 ( IRR= 0.36, 95% CI :0.13-0.91) or moderate BMI ( T 2 vs. T 1 , IRR =0.31, 95% CI :0.11-0.77) had lower risk for acute exacerbation compared with the patients with normal or low BMI. BMI had a linear correlation with the risk of acute exacerbation. Conclusion: The risk for acute exacerbation in patients with mild or moderate COPD in communities decreased with the increase of BMI, and being overweight might be a protective factor for the acute exacerbation of COPD.

Dialysis adequacy is a known risk factor for mortality in maintenance hemodialysis (MHD) patients. However, the optimal dialysis dose remains controversial. Therefore, we aimed to explore the relationship between dialysis dose and all-cause and cardiovascular disease (CVD) mortality among MHD. We examined the associations of dialysis dose with mortality in a cohort (n = 558) of MHD patients from 31 December 2015 to 31 December 2020. Dialysis adequacy was assessed using baseline Single-pool Kt/V urea (spKt/V), which was categorized into three groups, and the lowest dose group was used as the reference category. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. A total of 214 patients died (64.5% for CVD). Compared with the low-dose group, high-dose group could reduce the risk of all-cause mortality by 33% (HR = 0.67, 95% CI: 0.47-0.98). Of note, when stratification by age, high-dose group was associated with both lower all-cause (HR = 0.46, 95% CI: 0.26-0.81) and CVD mortality (HR = 0.42, 95% CI: 0.20-0.88) among patients with age below 65 years. When stratification by dialysis age, high-dose group was associated with decreased risk of CVD mortality (HR = 0.43, 95% CI: 0.20-0.91) among patients with dialysis age over 60 months. spKt/V is a simple index of hemodialysis dose used in clinical practice and a useful modifiable factor in predicting the risk of death, especially in MHD patients under 65 years old or dialysis age more than 60 months., (© 2022. The Author(s).)

Removal of CO 2 or C 2 H 4 from C 2 H 2 is still a challenging task due to their similar physical-chemical properties. Here, a bifunctional ligand decorated with amino and sulfoxide groups, 5',5''''-sulfonylbis (2'-amino-[1,1':3',1''-terphenyl]-4,4''-dicarboxylic acid) (H 4 L), was employed to construct a new microporous iron-organic framework (Fe-MOF) with the formula [(Fe 3 O)(L) 1.5 (H 2 O) 3 ] n . This MOF can serve as a parent structure to obtain the isostructural Cr-MOF by solvent-assisted metal metathesis. Furthermore, the gas adsorption and separation performance of these two MOFs were systematically investigated. Compared to Fe-MOF, Cr-MOF shows a moderately higher CO 2 , C 2 H 2 and C 2 H 4 uptake capacity. Additionally, Cr-MOF can selectively adsorb C 2 H 2 over CO 2 and C 2 H 4 . The separation potential towards C 2 H 2 /C 2 H 4 and C 2 H 2 /CO 2 was further established via IAST calculations of mixture adsorption equilibrium. IAST selectivity values of Cr-MOF are 3.4 for C 2 H 2 /C 2 H 4 and 6.9 for C 2 H 2 /CO 2 at 298 K and initial pressure, indicating its potential C 2 H 2 separation ability.

Cancer vaccines-based cancer immunotherapy has drawn widespread concern. However, insufficient cancer antigens and inefficient antigen presentation lead to low immune response rate, which greatly restrict the practical application of cancer vaccines. Here, inspired by intracellular proteasome-mediated protein degradation pathway, we report an antigen presentation simplification strategy by extracellular degradation of antigen proteins into peptides with proteolytic enzyme for improving the utilization of cancer antigens and arousing restricted cancer immunity. The pre-degraded antigen peptides are first validated to exhibit an increased capacity on antigen-presenting cell (APC) stimulation compared with proteins and still reserve antigen specificity and major histocompatibility complex (MHC) affinity. Furthermore, by coordinating the pre-degraded peptides with calcium phosphate nanoparticles (CaP), a CaP-peptide vaccine (CaP-Pep) is constructed, which is verified to induce an efficient personalized immune response in vivo for multi-model anti-cancer therapy. Notably, this bioinspired strategy based on extracellular enzymatic hydrolysis for vaccine construction is not only applicable for multiple types of cancers, but also shows great potential in expanding immunology fields and translational medicine., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase that participates in various cellular processes. However, its regulatory role in the progression of diffuse large B-cell lymphoma (DLBCL), which is the most prevalent subtype of non-Hodgkin lymphoma (NHL), is still elusive and controversial.The expression of CDK12 was detected by immunohistochemistry (IHC), RT-qPCR was performed to detect miR-28-5p expression of OCI-LY3 and SU-DHL-4 cells. MTT and soft agarose colony formation assays were used to detect cell proliferation. The cell apoptosis was determined by flow cytometry. The protein expressions changes of MYC, EZH2 and the biomarkers of BCR signaling were also detected. A subcutaneous transplantation tumor model of OCI-LY3 cells in nude mice was established to evaluate anticarcinogenic activities of CDK12 knockdown. Elevated expression of CDK12 was observed while miR-28-5p was downregulated in DLBCL tissues. CDK12 knockdown or miR-28-5p overexpression could inhibit proliferation and promote apoptosis of DLBCL cells. miR-28-5p inhibition could reverse the effect of CDK12 knockdown on proliferation and apoptosis of DLBCL cells. In addition, CDK12 knockdown could inhibit DLBCL tumor growth in the mice model. CDK12 activated MYC to repress miR-28-5p/EZH2 and amplified tonic BCR signaling to promote the development of DLBCL, which might provide potential therapeutic targets for future therapeutic intervention in DLBCL., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

An efficient Tf 2 NH-catalyzed [2 + 2] cycloaddition of ynamides under mild conditions has been developed. Within short reaction times, various ynamides are transformed into the corresponding 3-aminocyclobutenones in good to excellent yields. This is the first example for the metal-free intermolecular [2 + 2] self-cycloaddition of ynamides. Meanwhile, the desired cycloaddition products can be easily transformed into aminonaphthol derivatives.

The soil environmental pollution situation has been severe in recent years, but studies on evaluating with bioavailability testing and prediction models are lacking, which makes it difficult to accurately assess the ecological risks of contaminated soil. As an important indicator of bioavailability, the bioaccessibility of cadmium (Cd), arsenic (As), copper (Cu), zinc (Zn), and lead (Pb) in the soil was analyzed in this study. The bioaccessibility content and their corresponding soil property data were screened and systematically analyzed to explore the relationship between bioaccessibility content and soil properties. Furthermore, some testing methods for bioaccessibility were summarized to analyze the relationship between bioaccessibility content, test methods, and bioavailability content. Additionally, the bioaccessibility content prediction models were established. The results showed that there was a strong correlation between the bioaccessibility content and the total content of heavy metals ( P <0.01) and a significant ( P <0.05) correlation with the soil pH. Different test methods had obvious effects on bioavailability. The proportion of bioaccessibility content determined via various test methods was as follows:in vitro gastrointestinal tract simulation>chemical reagent extraction. The proportions of bioaccessibility content of Cd and Pb in natural soil were relatively high, with mean values of 42.12% and 37.33%, respectively, indicating that Cd and Pb had higher risks of being absorbed by soil organisms. Moreover, 30 bioaccessibility prediction models for five heavy metals were constructed, which involved the soil properties and test methods. The results of this study can provide scientific information and bioaccessibility prediction models that can help in accurately assessing the ecological risks of contaminated soil.

Background: The association between serum total indoxyl sulfate (tIS), and cardiovascular disease (CVD) and all-cause mortality is a matter of debate. In the current study we sought to determine the association, if any, between serum tIS, and all-cause and CVD-associated mortality in patients on maintenance hemodialysis (MHD)., Methods: A prospective cohort study was conducted involving 500 MHD patients at Dalian Municipal Central Hospital from 31 December 2014 to 31 December 2020. Serum tIS levels were measured at baseline and classified as high (≥44.16 ng/ml) or low (< 44.16 ng/ml) according to the "X-tile" program. Besides, the associations between continuous serum tIS and outcomes were also explored. Predictors were tested for colinearity using variance inflation factor analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Restricted cubic spline model was performed to assess dose-response relationships between tIS concentration and all-cause and CVD mortality., Results: During a 58-month median follow-up period, 224 deaths (132 CVD deaths) were documented. After adjustment for potential confounders, the serum tIS level was positively associated with all-cause mortality (HR = 1.02, 95% = 1.01-1.03); however, we did not detect a significant association when tIS was a dichotomous variable. Compared with the MHD population with a serum tIS level < 44.16 ng/ml, the adjusted HR for CVD mortality among those with a serum tIS level ≥ 44.16 ng/ml was 1.76 (95% = 1.10-2.82). Furthermore, we also noted the same association when the serum tIS level was a continuous variable., Conclusion: The serum tIS level was associated with higher risk of all-cause and CVD mortality among MHD patients. Further prospective large-scale studies are required to confirm this finding., (© 2022. The Author(s).)

Background: Most complex renal stones are managed primarily with percutaneous nephrolithotomy (PCNL). However, PCNL is still a great challenge for surgeons because of poor comprehension on complex adjacent structures. Novel techniques are required to assist in planning and navigation., Aim: To apply and evaluate the Hisense computer-assisted surgery (CAS) system in PCNL., Methods: A total of 60 patients with complex renal stones were included. Thirty patients in the CAS group had three-dimensional (3D) virtual models constructed with the CAS system. The model assisted in planning and navigating in the CAS system. Thirty patients in the control group planned and navigated as standard PCNL, without the application of the CAS system. Success rate of one attempt, operation time, initial stone-free rate, decrease in hemoglobin, and complications were collected and analyzed., Results: There were no statistically significant differences in the baseline characteristics or planning characteristics. The success rate of one puncturing attempt (90% vs 67%, P = 0.028) and the initial stone-free rate (87% vs 63%, P = 0.037) were significantly higher in the CAS group. However, there were no statistically significant differences in the operation time (89.20 ± 29.60 min vs 92.33 ± 33.08 min, P = 0.859) or in the decrease in hemoglobin (11.07 ± 8.32 g/L vs 9.03 ± 11.72 g/L, P = 0.300) between the CAS group and the control group. No statistically significant differences in the incidence of complications (Clavien-Dindo grade ≥ 2) were found., Conclusion: Compared with standard PCNL, CAS-assisted PCNL had advantages in terms of the puncturing success rate and stone-free rate. The Hisense CAS System was recommended to assist in preoperative planning and intraoperative navigation for an intuitive, precise and convenient PCNL., Competing Interests: Conflict-of-interest statement: The authors had no conflict-of-interest to declare that are relevant to the content of this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To observe the effect of lipid regulating therapy on carotid atherosclerotic plaque in diabetic patients. Methods: The REACH study, conducted between March 2009 and February 2012, enrolled asymptomatic patients with magnetic resonance imaging (MRI) confirmed carotid atherosclerotic plaque, who had never taken lipid-lowering drugs. Patients were treated with a moderate dose of rosuvastatin for 24 months. Blood lipid levels were measured and carotid MRI was performed at baseline, 3 and 24 months after treatment. The volume of carotid wall and lipid-rich necrotic core (LRNC) were measured by image analysis software. This study retrospectively analyzed patients in the REACH study. Patients were divided into diabetes group and non-diabetic group. The changes of blood lipid level and MRI parameters of carotid atherosclerotic plaque were compared between the two groups and their correlation was analyzed. Results: A total of 38 patients with carotid atherosclerotic plaque were included in this study, including 13 patients (34.2%) in the diabetic group and 25 patients (65.8%) in the non-diabetic group. Baseline parameters were comparable between the two groups, except higher HbA1c level in diabetes group ( P <0.05). Compared with baseline, the total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels were significantly decreased at 3 and 24 months in both two groups ( P <0.05). The change of high-density lipoprotein cholesterol (HDL-C) in diabetes group was not obvious, while it was significantly increased in non-diabetic group at 24 months ((1.38±0.33) mmol/l vs. (1.26±0.26) mmol/l, P <0.05). MRI results showed that the volume and percentage of LRNC remained unchanged at 3 months, slightly decreased at 24 months (64.86 (45.37, 134.56) mm 3 vs. 75.76 (48.20, 115.64) mm 3 , P >0.05) and (15.84% (11.47%, 24.85%) vs. 16.95% (11.64%, 22.91%), P >0.05) in diabetic group. In non-diabetic group, the volume and percentage of LRNC were significantly decreased at 3 months (63.01 (44.25, 188.64) mm 3 vs. 72.49 (51.91, 199.59) mm 3 , P <0.05) and (13.76% (8.81%, 27.64%) vs. 16.04% (11.18%, 27.05%), P <0.05) respectively. Both parameters further decreased to (55.63 (27.18, 179.40) mm 3 ) and (12.71% (8.39%, 24.41%)) at 24 months (both P <0.05). Wall volume, lumen volume and percent wall volume (PWV) were not affected post therapy in both two groups( P >0.05). There were no correlations between the changes of plaque parameters including volume and percentage of LRNC, wall volume, lumen volume, PWV and the changes of blood lipid parameters (TC, LDL-C, HDL-C and TG) in 3 and 24 months ( P >0.05). Conclusion: Lipid-lowering therapy possesses different effects on carotid atherosclerotic plaque in diabetic and non-diabetic patients, and the LRNC improvement is more significant in non-diabetic patients as compared to diabetic patients.

Steroidal alkaloids possess the basic steroidal skeleton with a nitrogen atom in rings or side chains incorporated as an integral part of the molecule. They have demonstrated a wide range of biological activities, and some of them have even been developed as therapeutic drugs, such as abiraterone acetate (Zytiga ® ), a blockbuster drug, which has been used for the treatment of prostate cancer. Structurally diverse natural steroidal alkaloids present a wide spectrum of biological activities, which are attractive for natural product chemistry and medicinal chemistry communities. This review comprehensively covers the structural classification, isolation and various biological activities of 697 natural steroidal alkaloids discovered from 1926 to October 2021, with 363 references being cited., (© 2022. The Author(s).)

Heterogeneity of bone marrow mesenchymal stromal cells (MSCs, frequently referred to as "mesenchymal stem cells") clouds biological understanding and hampers their clinical development. In MSC cultures most commonly used in research and therapy, we have identified an MSC subtype characterized by CD317 expression (CD317 pos (29.77 ± 3.00% of the total MSC population), comprising CD317 dim (28.10 ± 4.60%) and CD317 bright (1.67 ± 0.58%) MSCs) and a constitutive interferon signature linked to human disease. We demonstrate that CD317 pos MSCs induced cutaneous tissue damage when applied a skin explant model of inflammation, whereas CD317 neg MSCs had no effect. Only CD317 neg MSCs were able to suppress proliferative cycles of activated human T cells in vitro , whilst CD317 pos MSCs increased polarization towards pro-inflammatory Th1 cells and CD317 neg cell lines did not. Using an in vivo peritonitis model, we found that CD317 neg and CD317 pos MSCs suppressed leukocyte recruitment but only CD317 neg MSCs suppressed macrophage numbers. Using MSC-loaded scaffolds implanted subcutaneously in immunocompromised mice we were able to observe tissue generation and blood vessel formation with CD317 neg MSC lines, but not CD317 pos MSC lines. Our evidence is consistent with the identification of an immune stromal cell, which is likely to contribute to specific physiological and pathological functions and influence clinical outcome of therapeutic MSCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kay, Fox, Hewitson, Stone, Robertson, James, Wang, Kapasa, Yang and Genever.)

Hydrogel-based bioinks are the main formulations used for Articular Cartilage (AC) regeneration due to their similarity to chondral tissue in terms of morphological and mechanical properties. However, the main challenge is to design and formulate bioinks able to allow reproducible additive manufacturing and fulfil the biological needs for the required tissue. In our work, we investigated an innovative Manuka honey (MH)-loaded photocurable gellan gum methacrylated (GGMA) bioink, encapsulating mesenchymal stem cells differentiated in chondrocytes (MSCs-C), to generate 3D bioprinted construct for AC studies. We demonstrated the beneficial effect of MH incorporation on the bioink printability, leading to the obtainment of a more homogenous filament extrusion and therefore a better printing resolution. Also, GGMA-MH formulation showed higher viscoelastic properties, presenting complex modulus G∗ values of ∼1042 ​Pa, compared to ∼730 ​Pa of GGMA. Finally, MH-enriched bioink induced a higher expression of chondrogenic markers col2a1 (14-fold), sox9 (3-fold) and acan (4-fold) and AC ECM main element production (proteoglycans and collagen)., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Annachiara Scalzone reports financial support was provided by 10.13039/501100000266Engineering and Physical Sciences Research Council. Kenny Dalgarno, Xiao Nong Wang reports financial support was provided by 10.13039/501100012041Versus Arthritis., (© 2022 The Authors.)

Efforts for developing a convenient and expeditious method for synthesizing alkoxy-substituted enamides via nucleophilic addition of alcohols to ynesulfonamides are described. This sequence is completely regioselective and highly stereoselective, and leads to the hydroalkoxylation products in high yields under mild reaction conditions.

Aortic dissection (AD) is a fatal cardiovascular disease. It is caused by a rupture of the aortic intima or bleeding of the aortic wall that leads to the separation of different aortic wall layers. Patients with untreated AD have a mortality rate of 1-2% per hour after symptom onset. Therefore, effective biomarkers and therapeutic targets are needed to reduce AD-associated mortality. With the development of molecular technology, researchers have begun to explore the pathogenesis of AD at gene and protein levels, and have made some progress, but the pathogenesis of AD remains unclear. Non-coding RNAs, such as microRNAs, lncRNAs, and circRNAs, have been identified as basic regulators of gene expression and are found to play a key role in the pathogenesis of AD. Thus, providing a theoretical basis for developing these non-coding RNAs as clinical biomarkers and new therapeutic targets for AD in the future. Previous studies on the pathogenesis of AD focused on miRNAs, but recently, there have been an increasing number of studies that explore the role of lncRNAs, and circRNAs in AD. This review summarizes the existing knowledge on the roles of various non-coding RNAs in the pathogenesis of AD, discusses their potential role as clinical biomarkers and therapeutic targets, states the limitations of existing evidence, and recommends future avenues of research on the pathogenesis of AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hu, Cheng, Wu, Tao and Wang.)

Oxidative stress (OS) refers to the enhancement of oxidation and the decreased of related antioxidant enzymes activity under pathological conditions, resulting in relatively excess reactive oxygen species (ROS), causing cytotoxicity, which leads to tissue damage and is linked to neurodegenerative diseases, cardiovascular diseases, diabetes, cancers, and many other pathologies. As an important intracellular signaling molecule, ROS can regulate numerous physiological actions, such as vascular reactivity and neuronal function. According to several studies, the uncontrolled production of ROS is related to vascular injury. The growing evidence revealing how traditional risk factors translate into ROS and lead to vasculitis and other vascular diseases. In this review, we sought to mainly discuss the role of ROS and antioxidant mechanisms in vascular-related diseases, especially cardiovascular and common macrovascular diseases., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Xin-Meng Cheng et al.)

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is one of the leading causes of early mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We investigated the efficacy, safety, prognostic factors, and optimal therapeutic protocol for SR-aGVHD patients treated with basiliximab in a real-world setting. Nine hundred and forty SR-aGVHD patients were recruited from 36 hospitals in China, and 3683 doses of basiliximab were administered. Basiliximab was used as monotherapy (n = 642) or in combination with other second-line treatments (n = 298). The cumulative incidence of overall response rate (ORR) at day 28 after basiliximab treatment was 79.4% (95% confidence interval [CI] 76.5%-82.3%). The probabilities of nonrelapse mortality and overall survival at 3 years after basiliximab treatment were 26.8% (95% CI 24.0%-29.6%) and 64.3% (95% CI 61.2%-67.4%), respectively. A 1:1 propensity score matching was performed to compare the efficacy and safety between the monotherapy and combined therapy groups. Combined therapy did not increase the ORR; conversely, it increased the infection rates compared with monotherapy. The multivariate analysis showed that combined therapy, grade III-IV aGVHD, and high-risk refined Minnesota aGVHD risk score before basiliximab treatment were independently associated with the therapeutic response. Hence, we created a prognostic scoring system that could predict the risk of having a decreased likelihood of response after basiliximab treatment. Machine learning was used to develop a protocol that maximized the efficacy of basiliximab while maintaining acceptable levels of infection risk. Thus, real-world data suggest that basiliximab is safe and effective for treating SR-aGVHD., (© 2022 Wiley Periodicals LLC.)

Five new α-pyrones, cryptowratones A-E (1-5), and five known congeners (6-10), together with four other known compounds 11-14 were isolated from the twigs of Cryptocarya wrayi. The structures of the new compounds were elucidated on the basis of extensive spectroscopic data analysis and ECD calculations. All α-pyrones except 6 were evaluated for their stimulatory effects on glucose uptake in vitro with CHO-K1/GLUT4 cells. The positive control insulin displayed an approximate 42 ± 0.14% promotion on glucose uptake at 25 μM, compared with the CHO-K1/GLUT4 group. Compounds 1a/2a, 2, 3, and 10 showed a more significant stimulation of glucose uptake than insulin (25 μM) by 36 ± 0.08%, 27 ± 0.12%, 28 ± 0.12%, and 25 ± 0.12% at 1.5 μM, respectively. Immunofluorescence assays indicated the glucose uptake-stimulatory activity of α-pyrones might be correlated with increased GLUT4 translocation., (Copyright © 2021. Published by Elsevier B.V.)

Rhamnazin (RN) is a flavonol isolated from the calyxes and fruits of Physalis alkekengi L. var. franchetii (Mast.) Makino, which has been used for treating pulmonary diseases in traditional Chinese medicine. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a therapeutic target for pulmonary diseases. In the present study, the underlying mechanism and pharmacological effect of RN against pulmonary disorders are investigated. Human lung epithelial Beas-2B cell and RAW 264.7 murine macrophage-based cell models, and a cigarette smoke (CS)-induced pulmonary impairment mice model are adopted for investigation in vitro and in vivo. RN is identified to be an Nrf2 activator, which promotes Nrf2 dissociation from Keap1 via reacting with the Cys151 cysteine residue of Keap1, and suppresses Nrf2 ubiquitination. In addition, RN is able to attenuate toxicant-stimulated oxidative stress and inflammatory response in vitro. Importantly, RN significantly relieves CS-induced oxidative insult and inflammation, and RN-induced inhibition of inflammation is related to inhibition of nuclear transcription factor-κB (NF-κB) and induction of cell autophagy. In conclusion, our data indicate that RN is an activator of the Nrf2 pathway and evidently alleviates pulmonary disorders via restricting NF-κB activation and promoting autophagy. RN is a promising candidate for the therapy of pulmonary disorders., (© 2022 John Wiley & Sons Ltd.)

1. This study investigated the effect of dietary calcium (Ca) levels on growth performance, bone development and Ca transporter gene expression levels in the small intestine of broiler chickens.2. On the day of hatch, 350, Ross 308 male broilers were randomly allotted to one of five treatments with five replicate pens each and 14 birds per pen. Dietary Ca levels in feed were 5.0, 7.0, 9.0, 11.0 and 13.0 g/kg, in which 9.0 g/kg was in the control diet. All diets contained 4.5 g/kg non-phytate phosphorus (NPP).3. The increase in dietary Ca levels from 5.0 to 13.0 g/kg did not affect the growth performance of 1- to 18-day-old broilers (P > 0.05).4. Increasing the Ca levels linearly increased the ash weight and the contents of ash, Ca and phosphorus (P) in the tibia of broilers at 18 days of age (P < 0.05). The contents of ash, Ca and P in broilers fed with 9.0 g/kg Ca were higher than those in birds fed with 5.0 g/kg Ca (P < 0.05).5. Increasing the Ca levels linearly decreased mRNA expression levels of the Ca-binding protein 28-kDa (CaBP-D28k), plasma membrane Ca-transporting ATPase 1b (PMCAlb), sodium (Na)/Ca exchanger 1 (NCX1), nuclear vitamin D receptor (nVDR) and membrane vitamin D receptor (mVDR) in the duodenum of broilers at 18 d of age (P < 0.05). Similar results were seen in the jejunum and ileum. Broilers fed 9.0-13.0 g/kg Ca in feed had lower mRNA expression levels of CaBP-D28k and PMCAlb in the small intestine than birds fed 5.0 g/kg Ca in feed (P < 0.05).6. The data indicated that low levels of dietary Ca stimulated its transporter gene transcription and promoted absorption, but high levels of Ca inhibited transporter gene expression and prevented excessive absorption in the small intestine of broiler chickens.

Large eyelid defect after excision of malignancies or trauma is difficult to reconstruct due to special structure and function of the eyelid. In this study, we aimed to present the outcomes of subcutaneous pedicled propeller flap for reconstructing the large eyelid defect after excision of malignancies or trauma. A retrospective review of patients diagnosed with eyelid defect due to excision of malignancies or trauma, and undergoing subcutaneous pedicled propeller flap for reconstructing the large eyelid defect, was conducted at our hospital. The clinical data were collected and analyzed. A total of 15 patients were included in the cases series. Nine patients were diagnosed with basal cell carcinoma, 3 patients with epidermoid carcinoma, and 3 patients with trauma. All the defects were successfully covered with this designed flap. There was no flap necrosis in all the cases. No functional problems were observed in all of the cases. At long-term postoperative follow-up, the average score of patients' satisfaction was good. This subcutaneous pedicled propeller flap is a feasible alternative technique for reconstructing the large eyelid defect after excision of malignancies or trauma. This flap option could avoid the use of free flaps for large defect., (© 2022. The Author(s).)

Background: To assess and characterize neovascularization of the optic disc (NVD) using optical coherence tomography angiography (OCTA) and different OCTA-based methods., Methods: This retrospective, observational study included patients who were suspected of having early PDR with no presence of clinically apparent neovascularization (NV) bur were clinically diagnosed with proliferative diabetic retinopathy (PDR), or severe NPDR. Patients underwent standard clinical examinations and OCTA imaging using a 6 × 6 montage scan. Two trained graders identified NVD using different imaging systems (ultra-widefield-colour fundus photography (UWF-CFP), OCT, OCTA and fluorescein angiography (FA)). Moreover, morphological classification of NVD was performed. The detection and morphological classification of NVD by different OCTA-based methods (B-scan OCTA, En-face OCTA, VRI Angio and VRI Structure) were compared., Results: A total of 169 eyes (126 eyes with PDR and 43 eyes with severe NPDR) of 123 participants were included in this study. The detection rate of NVD was 34.91% by UWF-CFP compared with 59.76% by OCT, 59.76% by OCTA, and 62.72% by FA. After excluding 2 cases with epiretinal membranes, the NVD diagnosis detected by OCT was used as the standard. Among 99 eyes diagnosed with NVD by OCT, B-scan OCTA detected NVD with a sensitivity of 97.98%, which was higher than that by en face OCTA (80.81%), VRI Angio (65.66%), and VRI Structure (61.62%) (all P < 0.05). According to its characteristics on OCTA, NVD was divided into four types (12 cases of type I, 6 cases of type II, 39 cases of type III, and 42 cases of type IV). For type I, B-scan OCTA exhibited a higher diagnostic sensitivity than other methods (P < 0.05). For types II and IV, there were no statistically significant differences in the sensitivity of various methods between the two groups (P > 0.05)., Conclusion: OCTA and different OCTA-based methods are significant to the diagnosis of NVD, and the diagnostic accuracy of different detection methods may be related to different types of NVD., (© 2022. The Author(s).)

Since more than 85% of lung cancer cases are non-small cell lung cancer (NSCLC), finding novel agents with anti-tumor activities is meaningful for NSCLC patients. Mitochondria is essential for cellular energy metabolism in cancer, and regulating mitochondrial bioenergetics is emerging as a practical approach for cancer treatment and prevention. The carbazole scaffold is an active structure showing anti-cancer biological activity, and the structural diversity has been expanded through the improvement and optimization of synthesizing methods. To find novel carbazole derivatives with great anti-tumor potential and explore structures variety, we designed and synthesized a series of 9-(pyrimidin-2-yl)-9H-carbazole derivatives based on the previously reported Cp∗Rh(III)/H + tandem catalytic system. With thoroughly bioactivity exploration, we found benzo[d] [1,3]dioxol-5-yl(9-(pyrimidin-2-yl)-9H-carbazol-1-yl)methanone (compound 5n) showed notable activity in disrupting the mitochondrial homeostasis, induced cell cycle arrest and apoptosis in human adenocarcinoma cells, and finally showed anti-tumor activity in an NSCLC-xenograft mice model., 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 Masson SAS. All rights reserved.)

In this work, we correlate the microstructure and passivation of the Al 95- x Ni x Y 5 lightweight glassy ribbons ( x = 7 and 10) using various techniques. The overdosed Ni ( x = 10) can increase the melt viscosity and then deteriorate its glass-forming ability (GFA), ribbon formability, and Y-depleted extra layer formation. Consequently, the overdosed Ni weakens the passivation stability and corrosion resistance of the as-spun ribbon. The key role of the overdosed Ni can form a strong network and crystalline grain boundary in the amorphous matrix, which can transport Y and O to participate in the oxidation. These results can help us explore a valuable method for designing new Al-based metallic glasses., Competing Interests: The authors declare that there is no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Objective: To investigate the correlation between thyroid nodules and microalbuminuria in type 2 diabetic mellitus., Methods: A total of 270 patients with type 2 diabetes at Tongzhou Branch of Dongzhimen Hospital were enrolled in this retrospective study. Data were collected from the inpatient electronic files between January 2018 and January 2020. The laboratory indexes of the two groups (thyroid nodule group with 172 cases and control group including 98 cases without thyroid nodules) were statistically analyzed by binomial logistic regression analysis and Spearman correlation analysis., Results: The proportion of microalbuminuria (MAU) in the thyroid nodule group was larger than that in the control group. Age, serum TT4, and FT4 in the thyroid nodule group were significantly higher compared with the control group. The binary logistic regression analysis indicated that age, sex, FT4, and MAU were the risk factors for thyroid nodule in T2DM patients. Spearman correlation analysis showed that the thyroid nodule was significantly positively correlated with MAU, age, FT4, and TT4., Conclusions: MAU might be an independent risk factor for thyroid nodule in type 2 diabetic mellitus., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Can Cao et al.)

Objective: To evaluate the efficacy and safety of intra-articular injection of adalimumab (ADA) in the treatment of refractory oligoarticular juvenile idiopathic arthritis (JIA). Methods: This was a retrospective study. Clinical data on age, gender, and symptoms of joint swelling and pain were collected from 11 children with refractory oligoarticular JIA involving only knee joints admitted to Department of Rheumatism and Immunology of Children's Hospital, Capital Institute of Pediatrics from November 2019 to October 2020. The physician and parent-child evaluation of disease activity, the number of active joints, and the level of erythrocyte sedimentation rate (ESR) at different treatment time points were analyzed at every 4-week observation point after drug administration, and the non-parametric Kruskal-Wallis test was used to compare the differences in clinical evaluation indicators and changes in laboratory tests at different treatment times. The follow-up period was 6 months. Results: Among the 11 children, 5 were boys and 6 were girls. The age was 3.0 (2.8) years. All 11 children had symptoms of joint swelling and pain as well as limitation of movement. After 3 intra-articular injections of ADA, the joint symptoms of 11 children were better than before treatment; the joint symptoms of 7 children disappeared completely, and no recurrence occurred during the 6-month follow-up period. At different treatment times, physician and parent-child evaluation of disease activity, a gradual decrease in the number of active joints in the children, ESR, and juvenile arthritis disease activity score with 27 joints were all statistically significant (χ 2 =53.99, 59.37, 32.87, 40.07, 54.00, all P <0.001).No significant adverse drug reactions were observed in any of the 11 children during treatment and follow-up. Conclusion: Intra-articular injection of ADA in the treatment of refractory oligoarticular JIA has a significant effect in controlling joint symptoms and is relatively safe.

Background: Prediction of drug-drug interactions (DDIs) can reveal potential adverse pharmacological reactions between drugs in co-medication. Various methods have been proposed to address this issue. Most of them focus on the traditional link prediction between drugs, however, they ignore the cold-start scenario, which requires the prediction between known drugs having approved DDIs and new drugs having no DDI. Moreover, they're restricted to infer whether DDIs occur, but are not able to deduce diverse DDI types, which are important in clinics., Results: In this paper, we propose a cold start prediction model for both single-type and multiple-type drug-drug interactions, referred to as CSMDDI. CSMDDI predict not only whether two drugs trigger pharmacological reactions but also what reaction types they induce in the cold start scenario. We implement several embedding methods in CSMDDI, including SVD, GAE, TransE, RESCAL and compare it with the state-of-the-art multi-type DDI prediction method DeepDDI and DDIMDL to verify the performance. The comparison shows that CSMDDI achieves a good performance of DDI prediction in the case of both the occurrence prediction and the multi-type reaction prediction in cold start scenario., Conclusions: Our approach is able to predict not only conventional binary DDIs but also what reaction types they induce in the cold start scenario. More importantly, it learns a mapping function who can bridge the drugs attributes to their network embeddings to predict DDIs. The main contribution of CSMDDI contains the development of a generalized framework to predict the single-type and multi-type of DDIs in the cold start scenario, as well as the implementations of several embedding models for both single-type and multi-type of DDIs. The dataset and source code can be accessed at https://github.com/itsosy/csmddi ., (© 2022. The Author(s).)

Objective: To examine the efficacy and safety of endothelin receptor antagonists (ERA) combined with phosphodiesterase 5 inhibitors (PDE5i) in the treatment of pulmonary artery hypertension (PAH). Methods: Computer-based retrieval was performed on PubMed, Cochrane Library, CNKI, Wanfang, and VIP database (up to February 12th, 2021). Randomized controlled trials about endothelin receptor antagonists (ERAs) or PDE5i in patients with PAH were collected. The change of 6-minute walking distance (6MWD) in 12-16 weeks was used as primary outcome index. Case fatality rate, worsening clinical events, WHO functional class (FC) improvement, adverse events (AEs), serious adverse events (SAE) were the key secondary outcomes indicators. STATA 16.0 software was used for network meta-analysis, and the pooled estimates of odds ratios ( OR s) or weighted mean differences (WMDs) and 95% confidence intervals ( CI s) of the results were shown. To help explain OR s and WMDs, we used the surface under the cumulative ranking curve (SUCRA) to calculate the probability of each intervention. Results: We included 29 trials with 5 949 participants. In network meta-analysis, Bosentan combined with Sildenafil ( WMD =53.93, 95% CI =6.19-101.66) had shown the greatest improvement in 6MWD compared with placebo, followed by Bosentan combined with Tadalafil ( WMD =50.84, 95% CI =7.05-94.62), Ambrisentan combined with Tadalafil ( WMD =46.67, 95% CI =15.88-77.45), Bosentan ( WMD =29.44, 95% CI =5.86-53.02), Ambrisentan ( WMD =23.90, 95% CI =0.31-47.48) and Macitentan ( WMD =21.57, 95% CI =2.45-40.69). According to SUCRA, the effects of different intervention measures on improving 6MWD in patients with arterial pulmonary hypertension were as follows: Bosentan+Sildenafil (82.9%)>Bosentan+Tadalafil (78.4%)>Ambrisentan+Tadalafil (77.1%)>Bosentan (49.2%)>Sildenafil (48.5%)>Ambrisentan (40.3%)>Macitentan (37.3%)>Tadalafil (33.0%)>Placebo (3.3%). For the WHO functional class, Sildenafil ( OR =2.90, 95% CI =1.04-8.08) was optimal compared with placebo, followed by Bosentan ( OR =2.15, 95% CI =1.15-4.04), and there was no significant difference in the rest. For clinical worsening, Bosentan combined with Tadalafil ( OR =0.08, 95% CI =0.01-0.49) performed best compared with placebo, followed by Bosentan ( OR =0.20, 95% CI =0.11-0.38), Bosentan combined with Sildenafil ( OR =0.21, 95% CI =0.09-0.46), Ambrisentan combined with Tadalafil ( OR =0.27, 95% CI =0.15-0.50), Sildenafil ( OR =0.33, 95% CI =0.17-0.66) and Tadalafil ( OR =0.44, 95% CI =0.21-0.90). There was no statistical difference between all interventions and placebo in terms of the incidence of adverse events and serious adverse events. For case fatality rate, Ambrisentan ( OR =0.28, 95% CI =0.11-0.74) was statistically superior to placebo and there was no statistics difference in the rest. Conclusions: The combination therapy of ERAs and PDE5i performed well in the short-term improvement of motor function. Furthermore, there was no significant difference with monotherapy in terms of safety. However, it is worth emphasizing that the choice of treatment should be based on the patient's individualized situation and the patient's requirements.

The complete mitochondrial genome (mitogenome) of Dacus haikouensis Wang and Cheng 2002 (Diptera: Tephritidae: Dacinae) was sequenced and annotated. The mitochondrial genome is 15,291 bp (GenBank No. MZ087939), containing 73.0% AT, which is the classical structure for insect mitogenome. Additionally, the phylogenetic tree confirmed that Dacus haikouedsis clustered with Dacus longicornis and Dacus conopsoides . The current study would enrich the mitogenomes of the fruit flies., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Two new triterpenoids, 3 β -hydroxytirucall-7,25-dien-24-one ( 1 ) and 3 β -acetoxytirucall-7,23,25-triene ( 2 ), along with one new sesquiterpenoid, alloaromadendrane-12 α ,14 β -dioic acid ( 3 ), were isolated from the vines and leaves of Chonemorpha megacalyx Pierre. Their structures were established on the basis of extensive spectroscopic data.

Ethnopharmacological Relevance: The flower buds of Tussilago farfara L. (Abbreviated as FTF) were widely used in traditional Chinese medicine (TCM) to treat respiratory diseases, including asthma, dry throat, great thirst, turbid saliva, stinky pus, and coughs caused by various causes., Aim of Study: The aim of study is to explore the efficiency of FTF in vitro and in vivo for the treatment of lung inflammation, and to illustrate the possible mechanisms of FTF in treating inflammation-related respiratory diseases targeting NOD-like receptor 3 (NLRP3) inflammasome, nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear transcription factor-κB (NF-κB)., Methods: Lung inflammation model in vivo was induced by exposure of mice to cigarette smoke (CS) for two weeks. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), inflammatory factors, and histology in lung tissues were investigated in presence or absence of ethanol extract of the flower buds of T. farfara L. (FTF-EtOH). In the cell-based models, nitric oxide (NO) assay, flow cytometry assay, enzyme-linked immunosorbent assay (Elisa), and glutathione (GSH) assay were used to explore the anti-inflammatory and anti-oxidant effects of FTF-EtOH. Possible anti-inflammatory mechanisms of FTF targeting NLRP3 inflammasome, Nrf2, and NF-κB have been determined using western blot, quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), immunofluorescence assay, nuclear and cytoplasmic extraction, and ubiqutination assay., Results: FTF-EtOH suppressed CS-induced overproduction of inflammatory factors [e.g., tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)], and upregulation of the content of intracellular MDA in the lung homogenate of mice. In cell-based models, FTF-EtOH reduced the lipopolysaccharide (LPS)-induced overproduction of inflammatory factors, and attenuated the CS extract-induced overgeneration of reactive oxygen species (ROS). Furthermore, FTF-EtOH up-regulated Nrf2 and its downstream genes through enhancing the stability of Nrf2 protein, and inhibited the activation of NF-κB and NLRP3 inflammasome, which have been confirmed by detecting the protein levels in the mouse model., Conclusions: FTF-EtOH effectively attenuated lung inflammation in vitro and in vivo. The protection of FTF-EtOH against inflammation was produced by activation of Nrf2 and inhibitions of NF-κB and NLRP3 inflammasome. These datas definitely support the ethnopharmacological use of FTF as an anti-inflammatory drug for treating respiratory diseases in TCM., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To investigate the morphological, histological and ultrastructural changes of acute closed rupture of Achilles tendon, in order to clarify the pathological basis of the injury and to explore the significance., Methods: From January 2015 to January 2019, 35 patients with acute Achilles tendon rupture who underwent the minimally invasive Achilles tendon suture technique were retrospectively analyzed. Among these patients, 12 cases in acute open Achilles tendon rupture group included 10 males and 2 females, with an average age of (35.1±9.7) years old ranging from 19 to 50, and the time from injury to operation was 2 to 8 hours with an average of(5.6±1.8);23 cases in acute closed Achilles tendon rupture group included 21 males and 2 females, with an average age of (35.5±6.6) years old ranging from 18 to 50, and the time from injury to operation was 3 to 15 hours with an average of (7.5±3.1). The gross appearance and imaging findings of the broken end of Achilles tendon tissue in the two groups were compared by naked eye observation and foot and ankle MRI at 4 to 6 hours before operation. HE staining, scanning and fluoroscopic electron microscopy, immunohistochemistry(Sirius red staining) were performed on the intraoperative Achilles tendon tissue specimens at 1 to 2 days after operation, the collagen fiber degeneration and local fat infiltration, collagen fiber shape, cell morphology and function, and the distribution of typeⅠand type Ⅲ collagen fibers in Achilles tendon were compared between the two groups., Results: Compared with the acute open Achilles tendon rupture group, the acute closed Achilles tendon rupture group had poor elasticity, hard texture, moderate edema, irregular shape of Achilles tendon broken end, horsetail shape, and more calcification around the broken end. HE staining results:the collagen fibers in the Achilles tendon of the acute open Achilles tendon rupture group were arranged irregularly, with hyaline degeneration and fat infiltration;The results of electron microscopy showed that collagen arranged disorderly and fibroblasts atrophied in the acute closed Achilles tendon rupture group. Immunohistochemical(Sirius staining) results:the proportion of collagenⅠin the acute open Achilles tendon rupture group and the acute closed Achilles tendon rupture group was(91.12±4.34)% and(54.71±17.78)% respectively, and the proportion of collagen Ⅲ was (8.88±4.34)% and (45.29±17.78)% respectively. The content of collagenⅠin the acute closed Achilles tendon rupture group was lower than that in the acute open Achilles tendon rupture group, and the content of collagen Ⅲ in the acute closed Achilles tendon rupture group was higher than that in the acute open Achilles tendon rupture group( P <0.05)., Conclusion: The morphology, histology and ultrastructure of the acute closed ruptured Achilles tendon are significantly altered compared with the normal Achilles tendon. The original fine and orderly spatial structure cannot be maintained, part of collagen Ⅰ is replaced by collagen Ⅲ, and the toughness and strength of the tendon tissue decreased, which may be the feature of degeneration of the Achilles tendon and an important pathological basis for closed Achilles tendon rupture.

Liver toxicity induced by Triptolide (TP) has limited its clinical application on rheumatoid arthritis (RA). Saponins have been proved as an efficacious remedy to mitigate hepatotoxicity. However, the mechanism of reducing hepatotoxicity by saponins intervention remains incompletely characterized. Tryptophan (Trp) metabolites activate transcriptional regulators to mediate host detoxification responses. Our study aimed to investigate whether Clematichinenoside AR (C-AR) could attenuate TP-induced liver damage by regulating Trp metabolism. We used targeted metabolomics to quantify Trp metabolites in the serum and liver samples of collagen-induced arthritis rats treated by TP. Multiple comparison analyses helped the evaluation of promising biomarkers. The pronounced changed levels of Trp, indole acetic acid, and indole-3-carboxaldehyde in the serum and indole acetic acid, indole, and tryptamine in the liver are relevant to TP-induced liver injury. Intervention with C-AR could relieve TP-induced hepatotoxicity evidenced by ameliorative serum parameters and hepatic histology. In addition, C-AR regulated the levels of these indoles biomarker candidates to normal. Therapeutic modulation with natural compounds might be a useful clinical strategy to ameliorate toxicity induced by TP. Deciphering Trp metabolism will facilitate a better understanding of the pathogenesis of diseases and drug responding., 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 © 2021 Elsevier B.V. All rights reserved.)

Surface-assisted laser desorption/ionization mass spectrometry (SALDI MS) has been successfully applied in the analysis of various small molecules. In this work, gold nanoparticles/thiol-β-cyclodextrin-functionalized TiO 2 nanowires (AuNPs/SH-β-CD-TiO 2 NWs) were prepared to enhance the performance of SALDI MS and mass spectrometry imaging (MSI). A monolithic TiO 2 film was first grown on an indium tin oxide (ITO) glass slide via a modified sol-gel method and treated in an alkaline environment to form nanowires. TiO 2 NWs were chemically modified by SH-β-CD for immobilizing AuNPs densely and strongly. Compared with the conventional organic matrix 2,5-dihydroxybenzoic acid (DHB), the prepared AuNPs/SH-β-CD-TiO 2 NWs showed superior performances on detection sensitivity, repeatability, and analyte coverage. Analytes typically detectable with negative-ion matrix-assisted laser desorption/ionization (MALDI) MS could also be observed using AuNPs/SH-β-CD-TiO 2 NWs in the positive ion mode. Its successful usage efficiently enhanced the SALDI MS detection of various small molecules such as carbohydrates, fatty acids, and bile acids in the positive ion mode. The developed SALDI substrate was further used to characterize and discriminate the natural and in vitro cultured Calculus Bovis, as well as natural and artificial Moschus. Furthermore, the spatial distribution of several natural products in spearmint leaves and potato tubers was explored by tissue imprinting and deposition on the AuNPs/SH-β-CD-TiO 2 NW surface for SALDI MSI in dual-polarity mode, respectively. The wide application and satisfied detection sensitivity make AuNPs/SH-β-CD-TiO 2 NWs ideal for SALDI MS and MSI of various natural products.

Hydrodynamics and jet quenching are responsible for the elliptic flow v&#95;{2} and suppression of large transverse momentum (p&#95;{T}) hadrons, respectively, two of the most important phenomena leading to the discovery of a strongly coupled quark-gluon plasma in high-energy heavy-ion collisions. A consistent description of the hadron suppression factor R&#95;{AA} and v&#95;{2}, especially at intermediate p&#95;{T}, however, remains a challenge. We solve this long-standing R&#95;{AA}⊗v&#95;{2} puzzle by including quark coalescence for hadronization and final state hadron cascade in the coupled linear Boltzmann transport-hydro model that combines concurrent jet transport and hydrodynamic evolution of the bulk medium. We illustrate that quark coalescence and hadron cascade, two keys to solving the puzzle, also lead to a splitting of v&#95;{2} for pions, kaons, and protons in the intermediate p&#95;{T} region. We demonstrate for the first time that experimental data on R&#95;{AA}, v&#95;{2}, and their hadron flavor dependence from low to intermediate and high p&#95;{T} in high-energy heavy-ion collisions can be understood within this coupled framework.

In vitro engineering of human articular cartilage (AC) is a regenerative medicine challenge. The main objective of this study was the development of a repeatable scaffold-free in vitro model of chondrocyte spheroid-based treatments of cartilage defects, to allow for systematic study and further optimization of this type of treatment. Human articular chondrocytes (HC) and immortalized mesenchymal cells differentiated in chondrocytes (Y201-Cs) were cultured in round-bottom 96-well plates to produce multicellular spheroids and their growth kinetics, and viability was evaluated over 7 days of culture. Then, the spheroids were assembled and cultured for 21 days on a gelatin-coated poly(lactic-co-glycolic acid) electrospun membrane (10 spheroids/cm 2 ), following a protocol in line with the clinically approved Chondrosphere ® (CO.DON AG) technique. Both HC and Y201-C cells formed compact and viable spheroids after 7 days of culture with a reduction of diameter over the 7 days from 1300 ± 150 μm to 600 ± 90 μm and from 1250 ± 60 μm to 800 ± 20 μm for HC and Y201-C, respectively. When the spheroids were transferred onto the support membrane, these adhered on the membrane itself and fused themselves, producing collagen type II (COL2A1) and aggrecan (ACAN), according to gene expression and glycosaminoglycans quantification analyses. We detected higher expression of COL2A1 in HC cells, while the Y201-C constructs were characterized by an increased ACAN expression. The approach we presented allows a standardizable production of spheroids with predictable geometry and the creation of a reproducible scaffold-free in vitro AC-like construct showing high expression of chondrogenic markers, using both HC and Y201-C. In addition, the bankable Y201-C cells provide an effective base model for experimentation with the spheroid approach to further enhance the process. Impact statement This is first work on the development of a repeatable scaffold-free in vitro model based on an optimized protocol in line with a recent clinically approved Chondrosphere ® (CO.DON AG) technique. In addition, we demonstrated that a bankable cell type (Y201-C) could produce an engineered cartilage-like construct, giving a repeatable model as a key tool for experimentation of therapeutic treatment ahead of studies with heterogeneous cell populations.

The presence of rare earth elements (REEs) in different trophic levels of wild fish species remains unknown. In this study, fish characteristics and distribution patterns of REEs at different trophic levels of wild fish species are studied for the first time. The northern coastal region of the South China Sea was selected as it has the highest fishing intensity in China. The concentrations of 15 REEs were measured in 14 marine wild fish species from this area. The total concentrations of REEs (ΣREEs) ranged from 1.02 to 178.55 μg/kg (wet weight). The average ratio of light REE (LREE) to heavy REE (HREE) was 13.04, indicating that the ∑REEs content was dominated by LREE. The distribution patterns demonstrated significant bioaccumulation of LREEs. The REE patterns of most of the fish species showed Ce, Gd, Tb, and Dy anomalies. Based on the estimated daily intake (EDI) levels, the consumption of these fish species poses a negligible risk to consumer health., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Five new lignans, euphorhirtins A-D ( 1 - 4 ), 5-methoxyvirgatusin ( 5 ), three artefacts, 7 S -ethoxyisolintetralin ( 6 ), 7 R -ethoxyisolintetralin ( 7 ), and 7 R -ethoxy-3-methoxyisolintetralin ( 8 ), together with 13 known ones ( 9 - 21 ) were isolated from the medicinal plant Euphorbia hirta L. The structures of the compounds were elucidated by means of extensive spectroscopic analysis, including 1D and 2D NMR and HR-ESI-MS experiments. The absolute configurations of compound 1 was determined by ECD calculation. The isolates were evaluated for their inhibitory effects against the proliferation of the cancer cell lines (Hep G2, A549, and DU145) and compounds 14 and 18 showed inhibitory activity against the Hep G2 cells with IC 50 values 7.2 ± 0.17 and 8.5 ± 0.36  μ M.

Two new isoquinoline alkaloids, cryptowrayines A (1) and B (2), along with one known pavine alkaloid (-)-12-hydroxyeschscholtzidine (3), were isolated from the twigs of Cryptocarya wrayi. The structures of new compounds were elucidated by extensive spectroscopic data analysis and electronic circular dichroism (ECD) calculations. Both compounds 1 and 2 exhibited moderate quinone reductase inducing activity in Hepa 1c1c7 cells., (Copyright © 2021. Published by Elsevier B.V.)

A study was conducted to investigate the inclusion effects of sugar beet pulp and rice straw mixture silage with inoculation (BRMS), in place of whole-plant corn silage (CS), on the dry matter intake, total-tract nutrient digestibility, plasma metabolites, rumen fermentation, and lactation performance in high-production dairy cows. Sixteen multiparous Holstein cows (body weight, 622 ± 35 kg; days in milk, 90 ± 11 d; mean ± standard deviation) were used in our experiments; the experiments were based on a repeated 4 × 4 Latin square design for 21 d, and each experimental period consisted of 14 d of adaptation, followed by 7 d of data collection. The 4 dietary treatments used were (dry matter basis): (1) 0% BRMS and 28.6% CS (0BRMS); (2) 4.3% BRMS and 24.3% CS (15BRMS); (3) 8.60% BRMS and 20.0% CS (30BRMS); and (4) 12.9% BRMS and 15.7% CS (45BRMS). The increasing inclusion of dietary BRMS was observed to linearly increase the total volatile fatty acids and the propionate concentration. The dry matter intake and digestibility values of neutral detergent fiber and acid detergent fiber increased linearly as the percentage of BRMS increased up to 45%. Milk yield linearly increased with the increase in the content of BRMS (39.0, 39.8, 40.9, and 40.3 kg/d for 0BRMS, 15BRMS, 30BRMS, and 45BRMS, respectively). The increasing inclusion of dietary BRMS induced a decrease in the ammonia nitrogen and milk urea nitrogen concentration, leading to a linear increase in milk protein production (1.15, 1.26, 1.35, and 1.27 kg/d for 0BRMS, 15BRMS, 30BRMS, and 45BRMS, respectively). In conclusion, the diets with the replacement of CS with BRMS up to 45% were beneficial to the production performance of high-production dairy cows, indicating that this method may be an appropriate use of sugar beet pulp and rice straw., (© 2022, The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The cigarette beetle Lasioderma serricorne (Fabricius) is a major pest of stored products worldwide, especially tobacco and foods, causing huge economic losses. This study aimed to experimentally investigate the population dynamics of this pest at different temperatures and provide theoretical input for its control. Populations of L. serricorne were established under laboratory conditions at five temperatures (21 °C, 24 °C, 27 °C, 30 °C, and 33 °C). Results showed that an increasing temperature significantly affected the developmental time, longevity, oviposition period, and fecundity of L. serricorne . Both the longevity and fecundity of adult beetles were significantly reduced as the temperature increased. High temperatures significantly reduced the total duration of the preoviposition period but prolonged the oviposition period of L. serricorne . Increasing the temperatures from 21 °C to 33 °C significantly influenced the life table parameters of L. serricorne . The intrinsic increase rate ( r ), finite increase rate ( λ ), and gross reproductive rate ( GRR ) all increased with a greater rearing temperature, but mean generation time ( T ) was significantly shortened. To our best knowledge, this is the first report to detail the entire life history of the cigarette beetle in response to different temperatures when reared on tobacco dry leaves. This finding may provide basic information on the occurrence of L. serricorne in a warehouse setting and its mass rearing.

Introduction: The COVID-19 global pandemic is far from ending. There is an urgent need to identify applicable biomarkers for early predicting the outcome of COVID-19. Growing evidences have revealed that SARS-CoV-2 specific antibodies evolved with disease progression and severity in COIVD-19 patients., Objectives: We assumed that antibodies may serve as biomarkers for predicting the clinical outcome of hospitalized COVID-19 patients on admission., Methods: By taking advantage of a newly developed SARS-CoV-2 proteome microarray, we surveyed IgG responses against 20 proteins of SARS-CoV-2 in 1034 hospitalized COVID-19 patients on admission and followed till 66 days. The microarray results were further correlated with clinical information, laboratory test results and patient outcomes. Cox proportional hazards model was used to explore the association between SARS-CoV-2 specific antibodies and COVID-19 mortality., Results: Nonsurvivors (n = 955) induced higher levels of IgG responses against most of non-structural proteins than survivors (n = 79) on admission. In particular, the magnitude of IgG antibodies against 8 non-structural proteins (NSP1, NSP4, NSP7, NSP8, NSP9, NSP10, RdRp, and NSP14) and 2 accessory proteins (ORF3b and ORF9b) possessed significant predictive power for patient death, even after further adjustments for demographics, comorbidities, and common laboratory biomarkers for disease severity (all with p trend < 0.05). Additionally, IgG responses to all of these 10 non-structural/accessory proteins were also associated with the severity of disease, and differential kinetics and serum positive rate of these IgG responses were confirmed in COVID-19 patients of varying severities within 20 days after symptoms onset. The area under curves (AUCs) for these IgG responses, determined by computational cross-validations, were between 0.62 and 0.71., Conclusions: Our findings might have important implications for improving clinical management of COVID-19 patients., 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., (© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

The rhizome of Ligusticum chuanxiong Hort. has been widely used for the therapy of diabetic nephropathy (DN) in traditional Chinese medicine (TCM). The nuclear transcription factor erythroid 2-related factor (Nrf2) is a potential target for treating DN. The purpose of this research was to study the chemical constituents from the rhizome of L. chuanxiong, evaluate their Nrf2 inducing activity, and find the molecules with potential therapeutic effect against DN. In this study, two new phthalides (1-2) along with twenty-seven known constituents were obtained from the rhizome of L. chuanxiong. Their structures were elucidated through various spectroscopic methods. Twelve constituents, including eight phthalides (2, 5, 6,10-13, 14) and four other compounds (17, 18, 20,28), stimulated NAD(P)H: quinone reductase (QR) activity, suggesting that these bioactive constituents were potential Nrf2 activators. Among the isolated compounds, phthalide levistolide A (LA, 14) upregulated the protein levels of Nrf2, NQO1, and γ-GCS in a dose-dependent manner. Our results implied that the clinical application of the rhizome of L. chuanxiong as an anti-DN drug in TCM might be attributed to the Nrf2 inducing effect of phthalides. Thus, phthalides is a group of promising leading molecules for discovering anti-DN agents., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Osteoarthritis (OA) is a heterogeneous disease in which the cross-talk between the cells from different tissues within the joint is affected as the disease progresses. Extracellular vesicles (EVs) are known to have a crucial role in cell-cell communication by means of cargo transfer. Subchondral bone (SB) resident cells and its microenvironment are increasingly recognised to have a major role in OA pathogenesis. The aim of this study was to investigate the EV production from OA SB mesenchymal stromal cells (MSCs) and their possible influence on OA chondrocytes. Small EVs were isolated from OA-MSCs, characterized and cocultured with chondrocytes for viability and gene expression analysis, and compared to small EVs from MSCs of healthy donors (H-EVs). OA-EVs enhanced viability of chondrocytes and the expression of chondrogenesis-related genes, although the effect was marginally lower compared to that of the H-EVs. miRNA profiling followed by unsupervised hierarchical clustering analysis revealed distinct microRNA sets in OA-EVs as compared to their parental MSCs or H-EVs. Pathway analysis of OA-EV miRNAs showed the enrichment of miRNAs implicated in chondrogenesis, stem cells, or other pathways related to cartilage and OA. In conclusion, OA SB MSCs were capable of producing EVs that could support chondrocyte viability and chondrogenic gene expression and contained microRNAs implicated in chondrogenesis support. These EVs could therefore mediate the cross-talk between the SB and cartilage in OA potentially modulating chondrocyte viability and endogenous cartilage regeneration., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Clara Sanjurjo-Rodríguez et al.)