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OBJECTIVE: To determine the prevalence of and risk factors for overweight and obese among Chinese children and adolescents. METHODS: This analytical cross-sectional study included 16,640 children and adolescents aged 6-18 years across four provinces of China in 2016. Physical characteristics and responses to questionnaires were analyzed. Body Mass Index (BMI) and the prevalence of overweight and obesity were calculated. RESULTS: Among children and adolescents, the overall prevalence of overweight and obesity in 2016 in four regions of China was 27.2% and 29.6%, respectively. Among different stages and sexes, the highest prevalence of obesity (15.8%) was observed in adolescent boys. From childhood to adolescence, the obesity rate among boys increased by 0.7% (from 15.1% to 15.8%), while the obesity rate among girls decreased by 0.9% (from 10.8% to 9.9%). Children and adolescents who were overweight or obese had significantly higher systolic blood pressures, larger waist circumferences and larger hip sizes than those with a normal BMI. Logistic regression analyses identified thirteen factors associated with overweight or obesity in children and adolescents. CONCLUSIONS: Our results indicate that the prevalence of overweight and obesity is high among children and adolescents, especially among male adolescents in four regions of China. A suitable intervention program should not only help parents understand the serious risk of childhood obesity but also, more importantly, help to encourage a healthy lifestyle among children and adolescents.
Subject(s)
Body Mass Index , Pediatric Obesity , Humans , Adolescent , China/epidemiology , Cross-Sectional Studies , Male , Female , Child , Pediatric Obesity/epidemiology , Prevalence , Risk Factors , Overweight/epidemiology , Sex DistributionABSTRACT
Nonribosomal peptide synthetases (NRPSs) produce diverse natural products including siderophores, chelating agents that many pathogenic bacteria produce to survive in low iron conditions. Engineering NRPSs to produce diverse siderophore analogs could lead to the generation of novel antibiotics and imaging agents that take advantage of this unique iron uptake system in bacteria. The highly pathogenic and antibiotic-resistant bacteria Acinetobacter baumannii produces fimsbactin, an unusual branched siderophore with iron-binding catechol groups bound to a serine or threonine side chain. To explore the substrate promiscuity of the assembly line enzymes, we report a structure-guided investigation of the stand-alone aryl adenylation enzyme FbsH. We report on structures bound to its native substrate 2,3-dihydroxybenzoic acid (DHB) as well as an inhibitor that mimics the adenylate intermediate. We produced enzyme variants with an expanded binding pocket that are more tolerant for analogs containing a DHB C4 modification. Wild-type and mutant enzymes were then used in an in vitro reconstitution analysis to assess the production of analogs of the final product as well as several early-stage intermediates. This analysis shows that some altered substrates progress down the fimsbactin assembly line to the downstream domains. However, analogs from alternate building blocks are produced at lower levels, indicating that selectivity exists in the downstream catalytic domains. These findings expand the substrate scope of producing condensation products between serine and aryl acids and identify the bottlenecks for chemoenzymatic production of fimsbactin analogs.
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BACKGROUND: Sleep problems are common among nurses and can lead to various health problems. Further, the relationship between multiple sleep problems and memory impairment in clinical nurses remains unknown. Therefore, in this study, we aimed to explore the relationship between sleep problems and memory impairment among nurses. METHODS: Multistage cluster-stratified random sampling was performed from tertiary hospitals in Shandong, China. Overall, a total of 1833 nurses were included in the final analysis. The Chinese version of the Pittsburgh Sleep Quality Index and prospective and retrospective memory questionnaire were administered to the participants. RESULTS: The sleep quality of the nurses decreased during the normal epidemic prevention and control period compared with that before the epidemic in terms of sleep duration, sleep efficiency, and sleep disturbances. Nurses who reported cumulative or specific sleep problems (e.g., high sleep latency, sleep disturbances, and daytime dysfunction) and those in the "daily disturbances" and "poor sleep quality" groups had a higher risk of memory impairment than the others. CONCLUSION: Sleep problems might be important for memory impairment among nurses. These findings may help identify nurses at considerable risk of memory impairment in clinical practice.
ABSTRACT
Metabolites derived from the intestinal microbiota play an important role in maintaining skeletal muscle growth, function, and metabolism. Here, we found that D-malate (DMA) is produced by mouse intestinal microorganisms and its levels increase during aging. Moreover, we observed that dietary supplementation of 2% DMA inhibits metabolism in mice, resulting in reduced muscle mass, strength, and the number of blood vessels, as well as the skeletal muscle fiber type I/IIb ratio. In vitro assays demonstrate that DMA decreases the proliferation of vascular endothelial cells and suppresses the formation of blood vessels. In vivo, we further demonstrated that boosting angiogenesis by muscular VEGFB injection rescues the inhibitory effects of D-malate on muscle mass and fiber area. By transcriptomics analysis, we identified that the mechanism underlying the effects of DMA depends on the elevated intracellular acetyl-CoA content and increased Cyclin A acetylation rather than redox balance. This study reveals a novel mechanism by which gut microbes impair muscle angiogenesis and may provide a therapeutic target for skeletal muscle dysfunction in cancer or aging.
Subject(s)
Endothelial Cells , Microbiota , Mice , Animals , Endothelial Cells/metabolism , Acetylation , Cyclin A/metabolism , Angiogenesis , Malates/metabolism , Muscle, Skeletal/metabolism , AgingABSTRACT
Leiomyomas, the most common benign neoplasms of the female reproductive tract, currently have limited medical treatment options. Drugs targeting estrogen/progesterone signaling are used, but side effects and limited efficacy in many cases are major limitation of their clinical use. Previous studies from our laboratory and others demonstrated that 2-methoxyestradiol (2-ME) is promising treatment for uterine fibroids. However, its poor bioavailability and rapid degradation hinder its development for clinical use. The objective of this study is to evaluate the in vivo effect of biodegradable and biocompatible 2-ME-loaded polymeric nanoparticles in a patient-derived leiomyoma xenograft mouse model. PEGylated poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles loaded with 2-ME were prepared by nanoprecipitation. Female 6-week age immunodeficient NOG (NOD/Shi-scid/IL-2Rγnull) mice were used. Estrogen-progesterone pellets were implanted subcutaneously. Five days later, patient-derived human fibroid tumors were xenografted bilaterally subcutaneously. Engrafted mice were treated with 2-ME-loaded or blank (control) PEGylated nanoparticles. Nanoparticles were injected intraperitoneally and after 28 days of treatment, tumor volume was measured by caliper following hair removal, and tumors were removed and weighed. Up to 99.1% encapsulation efficiency was achieved, and the in vitro release profile showed minimal burst release, thus confirming the high encapsulation efficiency. In vivo administration of the 2-ME-loaded nanoparticles led to 51% growth inhibition of xenografted tumors compared to controls (P < 0.01). Thus, 2-ME-loaded nanoparticles may represent a novel approach for the treatment of uterine fibroids.
Subject(s)
Leiomyoma , Nanoparticles , Humans , Mice , Female , Animals , 2-Methoxyestradiol/therapeutic use , Progesterone , Heterografts , Mercaptoethanol/therapeutic use , Mice, Inbred NOD , Leiomyoma/drug therapy , Leiomyoma/pathology , Polymers , Polyethylene Glycols , EstrogensABSTRACT
Desferrioxamine siderophores are assembled by the nonribosomal-peptide-synthetase-independent siderophore (NIS) synthetase enzyme DesD via ATP-dependent iterative condensation of three N1-hydroxy-N1-succinyl-cadaverine (HSC) units. Current knowledge of NIS enzymology and the desferrioxamine biosynthetic pathway does not account for the existence of most known members of this natural product family, which differ in substitution patterns of the N- and C-termini. The directionality of desferrioxamine biosynthetic assembly, N-to-C versus C-to-N, is a longstanding knowledge gap that is limiting further progress in understanding the origins of natural products in this structural family. Here, we establish the directionality of desferrioxamine biosynthesis using a chemoenzymatic approach with stable isotope incorporation and dimeric substrates. We propose a mechanism where DesD catalyzes the N-to-C condensation of HSC units to establish a unifying biosynthetic paradigm for desferrioxamine natural products in Streptomyces.
Subject(s)
Siderophores , Streptomyces , Siderophores/metabolism , Deferoxamine/metabolism , Peptide Synthases/metabolism , Streptomyces/metabolismABSTRACT
BACKGROUND/AIM: High resistance of triple-negative breast cancer has prompted scientists to look for new targets susceptible to treatment. CDK16 has been suggested as a promising target whose inhibition can lead to tumor growth suppression. Rebastinib, a potent inhibitor of CDK16, has been reported to exhibit anti-tumor activity both in vitro and in vivo. MATERIALS AND METHODS: The anticancer activity of rebastinib was studied in vitro using cell proliferation, cell cycle arrest and cell apoptosis assays and in vivo in xenograft tumor models using MDA-MB-231 and MDA-MB-468-derived tumors. The safety and drug-like properties of rebastinib were assessed using a panel of Absorption, Distribution, Metabolism, and Excretion (ADME) assays, Ames tests, human Ether-a-go-go Related Gene (hERG) experiments and pharmacokinetic studies in mice and rats. RESULTS: Rebastinib demonstrates antitumor activity against breast cancer both in vitro and in vivo. However, the response of the tumor strongly depends on the type of triple-negative breast cancer. Rebastinib-induced cell cycle arrest was observed in G0/G1 phase suggesting a more complex mechanism than just CDK16 inhibition. ADME and PK studies confirmed the drug-like properties and reasonable safety of rebastinib. CONCLUSION: Our studies confirmed rebastinib to be a promising drug candidate for breast cancer treatment with high oral bioavailability and reasonable safety. Our data suggest that the mechanism of action of rebastinib is not limited to CDK16 inhibition but also involves other pathways. This does not diminish the importance of rebastinib as a drug candidate, but reveals the presence of several mechanisms, suggesting a wider scope of possible applications.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Humans , Rats , Mice , Animals , Female , Triple Negative Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Pyrazoles/therapeutic use , Cell Proliferation , Pyridines/pharmacology , Cell Line, Tumor , Apoptosis , Xenograft Model Antitumor AssaysABSTRACT
Background: The aim of this study was to clarify the mechanism of tendon-regulating and bone-setting manipulation in the treatment of knee osteoarthritis (KOA). Methods: A total of 30 adult healthy specific pathogen-free (SPF) New Zealand white rabbits (male; weight 2.0-2.5 kg) were selected and divided into a normal control (NC) group, KOA group, and KOA + manual treatment (MT) group. Each group comprised 10 rabbits. A KOA model was established using the modified Hulth method in the KOA and KOA + MT groups. The 3 groups were fed under the same conditions for 8 weeks. The Lequesne index for KOA was used to evaluate the behavioral status of the model rabbits; hematoxylin and eosin (HE) staining was employed to observe the pathological morphology of the tibial plateau and medial femoral condyle cartilage; the Mankin scoring scale was used to evaluate the cartilage morphology of the model rabbits; Western blot was used to detect the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor κB (NF-κB) proteins in the synovial tissue of the model rabbits; the contents of interleukin (IL)-1ß, IL-6, and, tumor necrosis alpha (TNF-α) in the synovial fluid of the model rabbits were determined using the enzyme-linked immunosorbent assay (ELISA) method. Results: Compared with those in the NC group, Lequesne index score, Mankin score of cartilage tissue, protein expression, and content of inflammatory factors were significantly increased in the KOA and KOA + MT groups (P<0.05), and these values were significantly higher in the KOA group. Microscopy showed that the cartilage tissue of the experimental rabbits in the KOA and KOA + MT groups was significantly degenerated. Compared with those in the KOA group, the Lequesne index score, Mankin score, protein expression, and inflammatory factor content of the model rabbits in the KOA + MT group were significantly reduced (P<0.05), and microscopy showed that cartilage tissue degeneration of the experimental rabbits in the KOA + MT group was significantly improved. Conclusions: Tendon-regulating and bone-setting manipulation can significantly improve the activity state and motor function of KOA model rabbits and significantly inhibit the expression of the TLR4-MyD88-NF-κB signaling pathway in synovial tissue, thereby reducing knee joint synovial inflammation and delaying the occurrence and development of KOA.
ABSTRACT
The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.
Subject(s)
Pro-Opiomelanocortin , Toll-Like Receptor 4 , Female , Mice , Male , Animals , Pro-Opiomelanocortin/genetics , Pro-Opiomelanocortin/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Obesity/metabolism , Body Weight , Adipose Tissue, Brown/metabolism , Thermogenesis/genetics , Neurons/metabolism , Lipids , Energy MetabolismABSTRACT
BACKGROUND AND AIMS: Perforation is a common complication during endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) associated with secondary infections, sepsis, hospitalization time and cost. However, the risk factors of perforation remain controversial. This study aimed to investigate the risk factors for perforation during ER of gGISTs. METHODS: This retrospective case-control study included consecutive patients with gGISTs who underwent ER between June 2009 and November 2021 at the Nanjing Drum Tower Hospital. Univariate and multivariate analyses were performed to investigate the risk factors for perforation. Sensitivity analyses with propensity scoring (PS) were performed to evaluate the stability of the independent effects. RESULTS: In total, 422 patients with gGISTs were included. The following factors were associated with perforation during ER: in the non-intraluminal growth patterns (all confounders adjusted odds ratio [aOR]: 5.39, 95% CI 2.99-9.72, P < 0.001), in the gastric fundus (aOR 2.25, 95% CI 1.40-3.60, P = 0.007), sized ≥ 2 cm (aOR 1.70, 95% CI 1.04-2.77, P = 0.035), in the lesser curvature (aOR 0.12, 95% CI 0.05-0.27, P < 0.001), and in the gastric cardia (aOR 0.13, 95% CI 0.04-0.50, P = 0.003). The PS analysis confirmed the stable independent effects of these identified risk factors. CONCLUSIONS: ERs of gGISTs in non-intraluminal growth patterns, in the gastric fundus, and with larger tumor size were independent risk factors for perforation. While tumors in the lesser curvature or gastric cardia were independent protective factor for perforation.
Subject(s)
Endoscopic Mucosal Resection , Gastrointestinal Stromal Tumors , Stomach Neoplasms , Humans , Stomach Neoplasms/pathology , Retrospective Studies , Case-Control Studies , Cardia/pathology , Gastrointestinal Stromal Tumors/surgery , Gastrointestinal Stromal Tumors/pathology , Risk Factors , Treatment Outcome , GastroscopyABSTRACT
BACKGROUND AND AIMS: The objective of this study was to compare the safety and efficacy of endoscopic resection with surgical resection in the treatment of intermediate-risk gastric gastrointestinal stromal tumors (GISTs) and to further evaluate whether imatinib adjuvant treatment is necessary for resected intermediate-risk gastric GIST by ER. METHODS: We retrospectively studied 128 cases for intermediate-risk gastric GISTs that were distributed in endoscopic (n = 33) and surgical groups (n = 95) at our center between December 2009 to July 2020. We statistically compared the clinical features, pathological reports, perioperative data, and long-term follow-up outcomes. RESULTS: Compared with the surgery group, the endoscopy group was associated with smaller tumor size (2.4 ± 1.0 vs. 6.0 ± 1.7 cm, p < 0.001), shorter operating time (67.3 ± 36.5 vs. 145.9 ± 74.8 min, p < 0.001), fewer incidence of short-term postoperative complications (3% vs. 32.6%, p = 0.002). Shorter postoperative hospital days (4.5 ± 1.4 vs. 8.5 ± 2.4 days, p < 0.001), shorter gastric functional recovery time (p < 0.001), and a lower overall medical cost of hospitalization (p < 0.001) was detected in the endoscopy group. During the median 44.5 months follow-up period, there were no cases of recurrence, metastasis, and death in the endoscopy group. Among 128 patients, 68 accepted adjuvant therapy with imatinib after resection. It was observed that the OS of the adjuvant treatment group with imatinib was lower than that of the group without imatinib (p = 0.033). CONCLUSION: Endoscopic resection for intermediate-risk gastric GIST is a feasible and safe method, and there is no significant benefit for patients with intermediate-risk gastric GIST to accept imatinib adjuvant treatment after ER.
Subject(s)
Gastrointestinal Stromal Tumors , Stomach Neoplasms , Humans , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/surgery , Gastrointestinal Stromal Tumors/pathology , Imatinib Mesylate/adverse effects , Treatment Outcome , Retrospective Studies , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Endoscopy, GastrointestinalABSTRACT
Siderophores produced via nonribosomal peptide synthetase (NRPS) pathways serve as critical virulence factors for many pathogenic bacteria. Improved knowledge of siderophore biosynthesis guides the development of inhibitors, vaccines, and other therapeutic strategies. Fimsbactin A is a mixed ligand siderophore derived from human pathogenic Acinetobacter baumannii that contains phenolate-oxazoline, catechol, and hydroxamate metal chelating groups branching from a central l-Ser tetrahedral unit via amide and ester linkages. Fimsbactin A is derived from two molecules of l-Ser, two molecules of 2,3-dihydroxybenzoic acid (DHB), and one molecule of l-Orn and is a product of the fbs biosynthetic operon. Here, we report the complete in vitro reconstitution of fimsbactin A biosynthesis in a cell-free system using purified enzymes. We demonstrate the conversion of l-Orn to N1-acetyl-N1-hydroxy-putrescine (ahPutr) via ordered action of FbsJ (decarboxylase), FbsI (flavin N-monooxygenase), and FbsK (N-acetyltransferase). We achieve conversion of l-Ser, DHB, and l-Orn to fimsbactin A using FbsIJK in combination with the NRPS modules FbsEFGH. We also demonstrate chemoenzymatic conversion of synthetic ahPutr to fimsbactin A using FbsEFGH and establish the substrate selectivity for the NRPS adenylation domains in FbsH (DHB) and FbsF (l-Ser). We assign a role for the type II thioesterase FbsM in producing the shunt metabolite 2-(2,3-dihydroxyphenyl)-4,5-dihydrooxazole-4-carboxylic acid (DHB-oxa) via cleavage of the corresponding thioester intermediate that is tethered to NRPS peptidyl carrier domains during biosynthetic assembly. We propose a mechanism for branching NRPS-derived peptides via amide and ester linkages via the dynamic equilibration of N-DHB-Ser and O-DHB-Ser thioester intermediates via hydrolysis of DHB-oxa thioester intermediates. We also propose a genetic signature for NRPS "branching" in the presence of a terminating C-T-C motif (FbsG).
Subject(s)
Acinetobacter baumannii , Carboxy-Lyases , Humans , Siderophores/metabolism , Acinetobacter baumannii/metabolism , Putrescine/metabolism , Ligands , Peptide Synthases/metabolism , Catechols/metabolism , Virulence Factors/metabolism , Hydroxybenzoates/chemistry , Amides/metabolism , Esters/metabolism , Flavins/metabolism , Mixed Function Oxygenases/metabolism , Acetyltransferases/metabolism , Carboxy-Lyases/metabolism , Peptides/metabolismABSTRACT
Siderophores are conditionally essential metabolites used by microbes for environmental iron sequestration. Most Streptomyces strains produce hydroxamate-based desferrioxamine (DFO) siderophores composed of repeating units of N1-hydroxy-cadaverine (or N1-hydroxy-putrescine) and succinate. The DFO biosynthetic operon, desABCD, is highly conserved in Streptomyces; however, expression of desABCD alone does not account for the vast structural diversity within this natural product class. Here, we report the in vitro reconstitution and biochemical characterization of four DesD orthologs from Streptomyces strains that produce unique DFO siderophores. Under in vitro conditions, all four DesD orthologs displayed similar saturation steady-state kinetics (Vmax = 0.9-2.5 µMâ min-1) and produced the macrocyclic trimer DFOE as the favored product, suggesting a conserved role for DesD in the biosynthesis of DFO siderophores. We further synthesized a structural mimic of N1-hydroxy-N1-succinyl-cadaverine (HSC)-acyl-adenylate, the HSC-acyl sulfamoyl adenosine analog (HSC-AMS), and obtained crystal structures of DesD in the ATP-bound, AMP/PPi-bound, and HSC-AMS/Pi-bound forms. We found HSC-AMS inhibited DesD orthologs (IC50 values = 48-53 µM) leading to accumulation of linear trimeric DFOG and di-HSC at the expense of macrocyclic DFOE. Addition of exogenous PPi enhanced DesD inhibition by HSC-AMS, presumably via stabilization of the DesD-HSC-AMS complex, similar to the proposed mode of adenylate stabilization where PPi remains buried in the active site. In conclusion, our data suggest that acyl-AMS derivatives may have utility as chemical probes and bisubstrate inhibitors to reveal valuable mechanistic and structural insight for this unique family of adenylating enzymes.
Subject(s)
Siderophores , Streptomyces , Adenosine Monophosphate/metabolism , Cadaverine/metabolism , Deferoxamine , Ligases/metabolism , Streptomyces/metabolismABSTRACT
Background: This study was designed to evaluate the influence of vitamin D receptor (VDR) gene polymorphisms on systemic lupus erythematosus (SLE) susceptibility. Methods: All eligible investigations were identified, the number of the various genotypes in the case and control groups were reviewed. A pooled analysis was performed using the Stata software. The study was carried out according to the Ethics Review Committee of The Third Xiangya Hospital, Central South University. Results: This meta-analysis included 19 studies. In our analysis, the VDR Apal polymorphism was correlated with SLE susceptibility in the overall population (AA vs. aa: odds ratio [OR] = 1.374, 95% confidence interval [CI]: 1.115-1.692, p = 0.003; AA + Aa vs. aa: OR = 1.342, 95% CI: 1.139-1.583, p < 0.01). The VDR Bsml and Apal polymorphisms were correlated with SLE susceptibility in Caucasian subjects (BB vs. Bb + bb: OR = 0.734, 95% CI: 0.593-0.909, p = 0.005; B vs. b: OR = 0.865, 95% CI: 0.760-0.983, p = 0.026; AA vs. aa: OR = 1.329, 95% CI: 1.016-1.740, p = 0.038). The VDR BsmI and FokI polymorphisms were correlated with SLE in African subjects (B vs. b: OR = 1.898, 95% CI: 1.458-2.470, pï¼0.01; BB + Bb vs. bb: OR = 2.935, 95% CI: 1.944-4.430, p < 0.01; FF vs. Ff + ff: OR = 2.424, 95% CI: 1.673-3.512, p < 0.01; F vs. f: OR = 1.720, 95% CI: 1.417-2.087, p < 0.01; FF vs. ff: OR = 3.154, 95% CI: 2.083-4.774, p < 0.01; FF + Ff vs. ff: OR = 1.803, 95% CI: 1.363-2.384, p < 0.01). In addition, the VDR Apal polymorphism was correlated with SLE in female subjects (AA vs. aa: OR = 1.392, 95% CI: 1.049-1.849, p = 0.022) when stratified by gender. But there was no association between the VDR TaqI polymorphism and SLE susceptibility in our analysis. Conclusions: The VDR Apal polymorphism was associated with SLE susceptibility in general populations; in addition, Apal polymorphism was associated with SLE in female subjects. The VDR Bsml gene polymorphism was correlated with SLE susceptibility in Caucasian and African populations, whereas the VDR FokI polymorphism was correlated with SLE in African populations. But there was no association between the VDR TaqI polymorphism and SLE susceptibility in our analysis.
Subject(s)
Lupus Erythematosus, Systemic , Receptors, Calcitriol/genetics , Alleles , Female , Genetic Predisposition to Disease/genetics , Humans , Lupus Erythematosus, Systemic/genetics , Polymorphism, Genetic/geneticsABSTRACT
Uterine leiomyomas are complex tumours with limited medical treatment options. Simvastatin is used to treat hypercholesterolaemia and has shown promising effects as a treatment option for leiomyomas. Previously, our group demonstrated a promising effect of simvastatin treatment in a patient-derived xenograft mouse model. Here, we tested the efficacy of simvastatin liposomal nanoparticles (NPs). After bilateral leiomyoma xenograft implantation, mice (N = 12) were divided into three treatment arms: control, simvastatin and simvastatin-loaded liposome NPs (simvastatin-NPs). Treatment with simvastatin significantly reduced tumour volume and inhibited the Ki67 expression when compared to the control group. There was a trend of reduced tumour volume and Ki67 expression after treatment with simvastatin-NP; however, the results were not significant. Due to low bioavailability and short half-life of simvastatin, liposomal NPs have the potential to enhance drug delivery, however, in this study NP did not provide improvement over simvastatin, but did demonstrate their potential for the delivery of simvastatin.Impact statementWhat is already known on this subject? Simvastatin treatment in a patient-derived xenograft mouse model reduced tumour growth and decreased proliferation.What do the results of this study add? Treatment with simvastatin significantly reduced tumour volume and inhibited the Ki67 expression when compared to the control group. There was a trend of reduced tumour volume and Ki67 expression after treatment with simvastatin-NP, however, it did not improve the efficacy of simvastatin at reducing tumour growth and proliferation.What are the implications of these findings for clinical practice and/or further research? More studies are needed to optimise the formulation of NPs to further enhance the sustainable delivery of simvastatin.
Subject(s)
Leiomyoma , Nanoparticles , Animals , Disease Models, Animal , Heterografts , Humans , Ki-67 Antigen , Leiomyoma/drug therapy , Leiomyoma/pathology , Liposomes , Mice , Pilot Projects , Simvastatin/pharmacologyABSTRACT
Polycyclic tetramate macrolactams (PTMs) are a class of structurally complex hybrid polyketide-nonribosomal peptide (PK-NRP) natural products produced by diverse bacteria. Several PTMs display pharmaceutically interesting bioactivities, and the early stages of PTM biosynthesis involving polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) enzymology are well studied. However, the timing and mechanisms of post PKS-NRPS oxidations by P450 monooxygenases encoded in PTM biosynthetic gene clusters (BGCs) remain poorly characterized. Here we demonstrate that CftA, encoded in clifednamide-type PTM BGCs, is a multifunctional P450 monooxygenase capable of converting the C29-C30 ethyl side chain of ikarugamycin to either a C29-C30 methyl ketone or a C29-C30 hydroxymethyl ketone through C-H bond activation, resulting in the formation of clifednamide A or clifednamide C, respectively. We also report the complete structure of clifednamide C solved via multidimensional NMR (COSY, HSQC, HMBC, NOESY, and TOCSY) using material purified from an engineered Streptomyces strain optimized for production. Finally, the in vitro reconstitution of recombinant CftA catalytic activity revealed the oxidation cascade for sequential conversion of ikarugamycin to clifednamide A and clifednamide C. Our findings confirm prior genetics-based predictions on the origins of clifednamide complexity via P450s encoded in PTM BGCs and place CftA into a growing group of multifunctional P450s that tailor PTM natural products through late-stage regioselective C-H bond activation.
Subject(s)
Mixed Function Oxygenases , Polyketides , Carbon/chemistry , Catalysis , Hydrogen/chemistry , Mixed Function Oxygenases/metabolism , Multigene Family , Nuclear Magnetic Resonance, Biomolecular , Oxidation-Reduction , Polyketide Synthases/genetics , Polyketides/chemistry , Polyketides/metabolismABSTRACT
Increased agricultural surface runoff in rural watersheds is a leading cause of nonpoint source pollution. In this study, a new biomass concentrator reactor (BCR) is conducted to degrade simulated agricultural surface runoff for both start-up process and treatment process. The results show that both in the start-up phase and in the stable phase, BCR had a good degradation effect on simulated agricultural surface runoff. Within 13 days-15 days of completed start-up of BCR, degradation of COD can be considered to the first-order kinetics: lnCt=lnC0-0.1377t (R2 = 0.78). During the stabilization phase, the average removal rate of COD, NH4+-N, NO3--N, TN and TP from the effluents through the BCR membrane was 94.58%, 85.79%, 53.58%, 37.87%, and 60.62%, respectively, which was increased by 7.4%, 2.5%, 5.1%, 0.18% and 11.4%, respectively, compared to control experiment which the effluents without membrane. The pollutants degradation by BCR in stable phase show a partly relative model of Lawrence-McCarty equation, which the nitrogen and phosphorus degradation is vN=(4.1+S)/(2.53×S) (R2 = 0.69) and vP=(8.78+S)/(3.0×S) (R2 = 0.67), respectively. In the stable phase, the operation cost of BCR is about $0.08/(Lâ¢d). Future research on improved BCR maybe focus on the membrane pollution and cleaning, optimized operation conditions, new materials of membrane.