Corrigendum: Study of quality of life and its correlated factors in patients after lumbar fusion for lumbar degenerative disc disease.

[This corrects the article DOI: 10.3389/fsurg.2022.939591.].

Synthesis, Crystal Structure, Spectral Characterization and Antifungal Activity of Novel Phenolic Acid Triazole Derivatives.

At present, phenolic acid derivatives and triazole derivatives have a good antifungal effect, which has attracted widespread attention. A series of novel phenolic acid triazole derivatives were synthesized, and their structures were characterized by IR, MS, NMR, and X-ray crystal diffraction. Compound methyl 4-(2-bromoethoxy)benzoate, methyl 4-(2-(1H-1,2,4-triazol-1-yl) ethoxy)benzoate, 4-(2-(1H-1,2,4-triazol-1-yl)ethoxy)benzoic acid and 4-(2-(1H-1,2,4-triazol-1-yl) ethoxy)-3-methoxybenzoic acid crystallize in the monoclinic system with space group P21/n, the monoclinic system with space group P21, the monoclinic system with space group P21 and the orthorhombic system with space group Pca21, respectively. At a concentration of 100 µg/mL and 200 µg/mL, the antifungal activity against seven plant pathogen fungi was determined. Compound methyl 4-(2-bromoethoxy)benzoate has the best inhibitory effect on Rhizoctonia solani AG1, and the inhibitory rate reached 88.6% at 200 µg/mL. The inhibitory rates of compound methyl 4-(2-(1H-1,2,4-triazol-1-yl) ethoxy)benzoate against Fusarium moniliforme and Sphaeropsis sapinea at a concentration of 200 µg/mL were 76.1% and 75.4%, respectively, which were better than that of carbendazim.

Synthesis, Antioxidant, and Antifungal Activities of ß-Ionone Thiazolylhydrazone Derivatives and Their Application in Anti-Browning of Freshly Cut Potato.

In order to develop a new type of antioxidants with high efficiency, a series of ß-ionone thiazolylhydrazone derivatives were designed and synthesized from ß-ionone, and their structures were characterized by 1H-NMR, 13C-NMR, FT-IR, and HR-MS. The antioxidant test in vitro indicated that most of the target compounds had high biological activity. Among them, compound 1k exhibited very strong DPPH (1,1-diphenyl-2-picrylhydrazyl radical)-scavenging activity with a half-maximal effective concentration (IC50) of 86.525 µM. Furthermore, in the ABTS (2,2-azinobis (3-ethylbenzothiazoline-6-sulfonate) diammonium salt)-scavenging experiment, compound 1m exhibited excellent activity with an IC50 of 65.408 µM. Their biological activities were significantly better than those of the positive control Trolox. These two compounds, which have good free-radical-scavenging activity in vitro, were used as representative compounds in the anti-browning experiment of fresh-cut potatoes. The results showed that 1k and 1m had the same anti-browning ability as kojic acid, and they were effective browning inhibitors. In addition, it is well known that microbial infection is one of the reasons for food oxidation. Therefore, we investigated the antifungal activity of 25 target compounds against eight plant fungi at a concentration of 125 mg/L. The results indicated that these compounds all have some antifungal activity and may become new potential fungicides. Notably, compound 1u showed the best inhibitory effect against Poria vaporaria, with an inhibition rate as high as 77.71%; it is expected to become the dominant structure for the development of new antifungal agents.

The Antibacterial Effect, Biocompatibility, and Osteogenesis of Vancomycin-Nanodiamond Composite Scaffold for Infected Bone Defects.

Purpose: The repair and treatment of infected bone defects (IBD) is a common challenge faced by orthopedic clinics, medical materials science, and tissue engineering. Methods: Based on the treatment requirements of IBD, we utilized multidisciplinary knowledge from clinical medicine, medical materials science, and tissue engineering to construct a high-efficiency vancomycin sustained-release system with nanodiamond (ND) and prepare a composite scaffold. Its effect on IBD treatment was assessed from materials, cytology, bacteriology, and zoology perspectives. Results: The results demonstrated that the Van-ND-45S5 scaffold exhibited an excellent antibacterial effect, biocompatibility, and osteogenesis in vitro. Moreover, an efficient animal model of IBD was established, and a Van-ND-45S5 scaffold was implanted into the IBD. Radiographic and histological analyses and bone repair-related protein expression, confirmed that the Van-ND-45S5 scaffold had good biocompatibility and osteogenic and anti-infective activities in vivo. Conclusion: Collectively, our findings support that the Van-ND-45S5 scaffold is a promising new material and approach for treating IBD with good antibacterial effects, biocompatibility, and osteogenesis.

Investigating the induction of polyphenol biosynthesis in the cultured Cycolocarya paliurus cells and the stimulatory mechanism of co-induction with 5-aminolevulinic acid and salicylic acid.

Background: Plant cell culture technology is a potential way to produce polyphenols, however, this way is still trapped in the dilemma of low content and yield. Elicitation is regarded as one of the most effective ways to improve the output of the secondary metabolites, and therefore has attracted extensive attention. Methods: Five elicitors including 5-aminolevulinic acid (5-ALA), salicylic acid (SA), methyl jasmonate (MeJA), sodium nitroprusside (SNP) and Rhizopus Oryzae Elicitor (ROE) were used to improve the content and yield of polyphenols in the cultured Cyclocarya paliurus (C. paliurus) cells, and a co-induction technology of 5-ALA and SA was developed as a result. Meanwhile, the integrated analysis of transcriptome and metabolome was adopted to interpret the stimulation mechanism of co-induction with 5-ALA and SA. Results: Under the co-induction of 50 µM 5-ALA and SA, the content and yield of total polyphenols of the cultured cells reached 8.0 mg/g and 147.12 mg/L, respectively. The yields of cyanidin-3-O-galactoside, procyanidin B1 and catechin reached 28.83, 4.33 and 2.88 times that of the control group, respectively. It was found that expressions of TFs such as CpERF105, CpMYB10 and CpWRKY28 increased significantly, while CpMYB44 and CpTGA2 decreased. These great changes might further make the expression of CpF3'H (flavonoid 3'-monooxygenase), CpFLS (flavonol synthase), CpLAR (leucoanthocyanidin reductase), CpANS (anthocyanidin synthase) and Cp4CL (4-coumarate coenzyme A ligase) increase while CpANR (anthocyanidin reductase) and CpF3'5'H (flavonoid 3', 5'-hydroxylase) reduce, ultimately enhancing the polyphenols accumulation Conclusion: The co-induction of 5-ALA and SA can significantly promote polyphenol biosynthesis in the cultured C. paliurus cells by regulating the expression of key transcription factors and structural genes associated with polyphenol synthesis, and thus has a promising application.

Chalcone-1-Deoxynojirimycin Heterozygote Reduced the Blood Glucose Concentration and Alleviated the Adverse Symptoms and Intestinal Flora Disorder of Diabetes Mellitus Rats.

Chalcone-1-deoxynojirimycin heterozygote (DC-5), a novel compound which was designed and synthesized in our laboratory for diabetes treatment, showed an extremely strong in vitro inhibitory activity on α-glucosidase in our previous studies. In the current research, its potential in vivo anti-diabetic effects were further investigated by integration detection and the analysis of blood glucose concentration, blood biochemical parameters, tissue section and gut microbiota of the diabetic rats. The results indicated that oral administration of DC-5 significantly reduced the fasting blood glucose and postprandial blood glucose, both in diabetic and normal rats; meanwhile, it alleviated the adverse symptoms of elevated blood lipid level and lipid metabolism disorder in diabetic rats. Furthermore, DC-5 effectively decreased the organ coefficient and alleviated the pathological changes of the liver, kidney and small intestine of the diabetic rats at the same time. Moreover, the results of 16S rDNA gene sequencing analysis suggested that DC-5 significantly increased the ratio of Firmicutes to Bacteroidetes and improved the disorder of gut microbiota in diabetic rats. In conclusion, DC-5 displayed a good therapeutic effect on the diabetic rats, and therefore had a good application prospect in hypoglycemic drugs and foods.

Design, Synthesis and Bioactivity Evaluation of Coumarin-BMT Hybrids as New Acetylcholinesterase Inhibitors.

Coumarin possesses the aromatic group and showed plentiful activities, such as antioxidant, preventing asthma and antisepsis. In addition, coumarin derivatives usually possess good solubility, low cytotoxicity and excellent cell permeability. In our study, we synthesized the compound bridge methylene tacrine (BMT), which has the classical pharmacophore structure of Tacrine (THA). Based on the principle of active substructure splicing, BMT was used as a lead compound and synthesized coumarin-BMT hybrids by introducing coumarin to BMT. In this work, 21 novel hybrids of BMT and coumarin were synthesized and evaluated for their inhibitory activity on AChE. All obtained compounds present preferable inhibition. Compound 8b was the most active compound, with the value of Ki as 49.2 nM, which was higher than Galantamine (GAL) and lower than THA. The result of molecular docking showed that the highest binding free energy was -40.43 kcal/mol for compound 8b, which was an identical trend with the calculated Ki.

Study of quality of life and its correlated factors in patients after lumbar fusion for lumbar degenerative disc disease.

Background: In the present work, we aimed to explore the correlated factors of quality of life in patients receiving lumbar fusion for lumbar degenerative disc disease (DDD) in China. Methods: A total of 180 patients treated with lumbar fusion were included in the present study. Their general demographic characteristics, Visual Analog Scale (VAS) scores, Japanese Orthopedic Association (JOA) scores, Simplified Coping Style Questionnaire (SCSQ), Social Support Questionnaire (SSQ), and Medical Outcomes Study Short Form 36 (MOS SF-36) were collected and evaluated preoperatively and at 1 year postoperatively. Results: There were significant improvements in scores of VAS, JOA, and quality of life of patients from preoperation to 1-year postoperation after lumbar fusion. Marital status, with or without children, education level, economic pressure, and social support had significant predictive effects on the physical health of patients undergoing lumbar fusion. Marital status, education level, and economic pressure had significant predictive effects on the mental health of patients undergoing lumbar fusion. Conclusions: Factors correlated with the physical health of patients after lumbar fusion included positive coping style, negative coping style, social support, age, education level (high school college), disease duration (5-10), suffering from other diseases (combined with two or more other disease) and the number of surgical segments (double and three or more). Factors correlated with the mental health included negative coping style, social support, age, education level (middle school and high school college) and the number of surgical segments (double and three or more). The results verify that these factors were correlated to the patient's quality of life after lumbar fusion. Emphasizing and selectively intervening these correlated factors can further improve the quality of life in patients receiving lumbar fusion for lumbar degenerative disc disease.

Synthesis, in vitro inhibitory activity, kinetic study and molecular docking of novel N-alkyl-deoxynojirimycin derivatives as potential α-glucosidase inhibitors.

A series of novel N-alkyl-1-deoxynojirimycin derivatives 25 ∼ 44 were synthesised and evaluated for their in vitro α-glucosidase inhibitory activity to develop α-glucosidase inhibitors with high activity. All twenty compounds exhibited α-glucosidase inhibitory activity with IC50 values ranging from 30.0 ± 0.6 µM to 2000 µM as compared to standard acarbose (IC50 = 822.0 ± 1.5 µM). The most active compound 43 was ∼27-fold more active than acarbose. Kinetic study revealed that compounds 43, 40, and 34 were all competitive inhibitors on α-glucosidase with Ki of 10 µM, 52 µM, and 150 µM, respectively. Molecular docking demonstrated that the high active inhibitors interacted with α-glucosidase by four types of interactions, including hydrogen bonds, π-π stacking interactions, hydrophobic interactions, and electrostatic interaction. Among all the interactions, the π-π stacking interaction and hydrogen bond played a significant role in a various range of activities of the compounds.

Design, Synthesis, and Activity Evaluation of Novel N-benzyl Deoxynojirimycin Derivatives for Use as α-Glucosidase Inhibitors.

To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyl-deoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NB-DNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound 18a (1-(4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC50 value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC50: 0.276 ± 0.13 mM). Both IC50 values of 18a and 18b were significantly lower than that of acarbose (IC50: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound 18a and amino acids in the active site of α-glucosidase. Additionally, an arene‒arene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the arene‒arene interaction resulted in a low binding energy (-5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type Ⅱ diabetes.

Two new oleanane derivatives from the fruits of Leonurus japonicus and their cytotoxic activities.

Two new oleanane derivatives, leonuronins A and B (1 and 2), along with three known oleanane triterpenes (3-5) were isolated from the fruits of Leonurus japonicus. Their structures were elucidated on the basis of NMR, MS, IR and UV spectroscopic data. The new compounds were tested for cytotoxic activities against A549 and Hela cancer cell lines. Compounds 1 and 2 exhibited weak cytotoxicity with IC50 values ranging from 6.97 to 18.13 µM.

Astaxanthin improves cognitive performance in mice following mild traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) produces lasting neurological deficits that plague patients and physicians. To date, there is no effective method to combat the source of this problem. Here, we utilized a mild, closed head TBI model to determine the modulatory effects of a natural dietary compound, astaxanthin (AST). AST is centrally active following oral administration and is neuroprotective in experimental brain ischemia/stroke and subarachnoid hemorrhage (SAH) models. We examined the effects of oral AST on the long-term neurological functional recovery and histological outcomes following moderate TBI in a mice model. METHODS: Male adult ICR mice were divided into 3 groups: (1) Sham+olive oil vehicle treated, (2) TBI+olive oil vehicle treated, and (3) TBI+AST. The olive oil vehicle or AST were administered via oral gavage at scheduled time points. Closed head brain injury was applied using M.A. Flierl weight-drop method. NSS, Rotarod, ORT, and Y-maze were performed to test the behavioral or neurological outcome. The brain sections from the mice were stained with H&E and cresyl-violet to test the injured lesion volume and neuronal loss. Western blot analysis was performed to investigate the mechanisms of neuronal cell survival and neurological function improvement. RESULTS: AST administration improved the sensorimotor performance on the Neurological Severity Score (NSS) and rotarod test and enhanced cognitive function recovery in the object recognition test (ORT) and Y-maze test. Moreover, AST treatment reduced the lesion size and neuronal loss in the cortex compared with the vehicle-treated TBI group. AST also restored the levels of brain-derived neurotropic factor (BDNF), growth-associated protein-43 (GAP-43), synapsin, and synaptophysin (SYP) in the cerebral cortex, which indicates the promotion of neuronal survival and plasticity. CONCLUSION: To the best of our knowledge, this is the first study to demonstrate the protective role and the underlining mechanism of AST in TBI. Based on these neuroprotective actions and considering its longstanding clinical use, AST should be considered for the clinical treatment of TBI.

De Novo Transcriptome Assembly and Annotation of the Leaves and Callus of Cyclocarya Paliurus (Bata1) Iljinskaja.

Cyclocarya Paliurus (Bata1) Iljinskaja contains various bioactive secondary metabolites especially in leaves, such as triterpenes, flavonoids, polysaccharides and alkaloids, and its leaves are widely used as an hyperglycemic tea in China. In the present paper, we sequenced the transcriptome of the leaves and callus of Cyclocarya Paliurus using Illumina Hiseq 4000 platform. After sequencing and de novo assembly, a total of 65,654 unigenes were generated with an N50 length of 1,244bp. Among them, 35,041 (53.37%) unigenes were annotated in NCBI Non-Redundant database, 19,453 (29.63%) unigenes were classified into Gene Ontology (GO) database, and 7,259 (11.06%) unigenes were assigned to Clusters of Orthologous Group (COG) categories. Furthermore, 11,697 (17.81%) unigenes were mapped onto 335 pathways in Kyoto Encyclopedia of Genes and Genomes (KEGG), among which 1,312 unigenes were identified to be involved in biosynthesis of secondary metabolites. In addition, a total of 11,247 putative simple sequence repeats (SSRs) were detected. This transcriptome dataset provides a comprehensive sequence resource for gene expression profiling, genetic diversity, evolution and further molecular genetics research on Cyclocarya Paliurus.

Defective Function of CD24(+)CD38(+) Regulatory B Cells in Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease strongly associated with HLA-B*27, an major histocompatibility complex (MHC) molecule that presents peptide antigen to T cells. Previously, regulatory B cells were found to suppress T cell-mediated autoimmunity induction and chronic inflammation, partially through interleukin (IL)-10 production. Here, we examined the role of regulatory B cells in AS pathogenesis. Apheresis samples from HLA-B*27-positive AS patients and non-AS healthy controls were collected. We found that although AS patients and non-AS controls presented similar frequencies of CD24(+)CD38(+) B cells, compared to non-AS controls, those from AS patients produced less IL-10 under ex vivo condition and after CD40 and B-cell receptor (BCR) stimulation. Purified T cell-B cell cocultures showed that compared to non-AS controls, CD24(+)CD38(+) B cells from AS patients were defective at suppressing naive and memory CD8(+) T cell activation. The suppression of memory CD8(+) T cells in non-AS controls appeared to be mediated by IL-10, since the addition of IL-10 mAb suppressed CD24(+)CD38(+) B cell-mediated downregulation of proinflammatory cytokine production and proliferation. To rescue the defect in AS patients, CD24(+)CD38(+) B cells were pretreated by CD40 and BCR stimulation, which enhanced CD24(+)CD38(+) B cell-mediated memory CD8(+) T cell suppression. Together, our data discovered a regulatory B cell defect in AS patients.

Efficacy of etanercept for treating the active rheumatoid arthritis: an updated meta-analysis.

AIM: To evaluate the efficacy of etanercept (ETA) for treating active rheumatoid arthritis (RA) compared to placebo or methotrexate (MTX). METHODS: We searched Medline, Cochrane Library and Wiley databases. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare efficacy. RESULTS: In total, 12 studies with 3878 active RA patients (including 2046 patients treated with ETA and 1832 patients treated with placebo or MTX) were included. The overall RRs in ACR20, 50 and 70 (20%, 50%, 70% improvement based on the criteria of American Rheumatism Association) were 2.10 (95% CI: 1.45-3.02, P < 0.0001), 2.87 (95% CI: 1.66-4.97, P = 0.0002) and 2.16 (95% CI: 1.49-3.13, P < 0.0001) within 24 weeks, respectively and were 1.19 (95% CI: 1.11-1.28, P < 0.00001), 1.37 (95% CI: 1.22-1.53, P < 0.00001) and 1.57 (95% CI: 1.28-1.92, P < 0.00001) within 1-3 years, respectively. Further, the overall RRs of 25 mg versus 10 mg ETA twice weekly in ACR20, 50 and 70 were 1.10 (95% CI: 1.02-1.19, P < 0.02), 1.37 (95% CI: 0.98-1.92, P < 0.07) and 1.27 (95% CI: 1.02-1.58, P < 0.03), respectively. CONCLUSIONS: In active RA patients treated with ETA, there was significantly higher efficacy compared to the treatment of placebo or MTX. High doses of ETA were more effective for active RA patients.

TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells.

Osteoarthritis (OA) is the most common type of arthritis, in which T cell responses and cytokines may play critical roles in the development of the disease. TIM-3 may affect immune responses and is correlated with decreased expression of interferon gamma (INF-γ) in CD4+ T cells. In the current study, we investigated the association between polymorphisms in the TIM-3 gene and susceptibility to OA. Two polymorphisms in TIM-3, -574G/T and +4259T/G polymorphisms, were identified in OA cases and healthy donors by polymerase chain reaction-restriction fragment length polymorphism method. Data revealed that the prevalence of TIM-3 +4259T/G genotype was significantly elevated in OA patients than in the healthy donors after adjustment (Odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.32-5.11, P < 0.001). Similarly, the TIM-3 +4259G allele presented a positive association with the risk of OA after adjustment (OR = 2.58, 95% CI 1.29-4.82, P = 0.003). The TIM-3 -574G/T polymorphism did not show any correlation with the disease. We further examined whether the two TIM-3 polymorphisms could affect INF-γ expression in CD4+ T cells. Data revealed that subjects carrying polymorphic +4259TG genotype had significantly higher mRNA and protein levels of INF-γ in CD4+ T cells compared to wild-type GG genotype (P < 0.001 and P < 0.01). These results indicated that TIM-3 polymorphism is associated with increased susceptibility to OA possibly by upregulating INF-γ expression in CD4+ T cells.

Production of chlorogenic acid and its derivatives in hairy root cultures of Stevia rebaudiana.

Chlorogenic acid and its derivatives (CADs) are valuable bioactive plant secondary metabolites with many health benefits. In the present study, Stevia rebaudiana hairy root cultures were established, and the culture conditions for the production of CADs were optimized. The hairy roots were induced by coculture of S. rebaudiana leaves and Agrobacterium rhizogenes (C58C1) after infection, which were further verified by PCR detection of rolB and rolC genes. HPLC-MS and HPLC analysis showed that chlorogenic acid (3-caffeoylquinic acid, 3-CQA), 3,5-dicaffeoylquinic acid (3,5-CQA), and 4,5-dicaffeoylquinic acid (4,5-CQA) were the major CADs in the hairy roots. Eight single roots with rapid growth rate were selected. Among them, T3 had the highest yield of CADs. B5 medium supplemented with 40 g/L sucrose was more suitable for the production of CADs than others. Under optimal culture conditions, the total content of these three compounds reached 105.58 mg/g and total yield was 234.40 mg/100 mL.

Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aß aggregation, and ß-secretase.

Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aß aggregation and ß-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.