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1.
Theranostics ; 10(9): 4217-4232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226549

RESUMO

In this study, we observe that the ischemic tissues of type-2 diabetic (T2D) patients and mice have significantly more CD8+ T-cells than that of their normoglycemic counterparts, respectively. However, the role of CD8+ T-cells in the pathogenesis of diabetic vascular complication has been less studied. Methods: We employed loss-of-function studies in mouse models using the non-lytic anti-CD8 antibody that blocks tissue infiltration of CD8+ T-cells into the injured tissue. We also performed genome-wide, single-cell RNA-sequencing of CD8+ T-cells to uncover their role in the pathogenesis of diabetic vascular diseases. Results: The vascular density is negatively correlated with the number of CD8+ T-cells in the ischemic tissues of patients and mice after injury. CD8+ T-cells or their supernatant can directly impair human and murine angiogenesis. Compared to normoglycemic mice that can regenerate their blood vessels after injury, T2D mice fail in this regeneration. Treatment with the CD8 checkpoint blocking antibody increases the proliferation and function of endothelial cells in both Leprdb/db mice and diet-induced diabetic Cdh5-Cre;Rosa-YFP lineage-tracing mice after ischemic injury. Furthermore, single-cell transcriptomic profiling reveals that CD8+ T-cells of T2D mice showed a de novo cell fate change from the angiogenic, tissue-resident memory cells towards the effector and effector memory cells after injury. Functional revascularization by CD8 checkpoint blockade is mediated through unleashing such a poised lineage commitment of CD8+ T-cells from T2D mice. Conclusion: Our results reveal that CD8+ T-cell plasticity regulates vascular regeneration; and give clinically relevant insights into the potential development of immunotherapy targeting vascular diseases associated with obesity and diabetes.

2.
Comp Med ; 70(2): 131-139, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32156324

RESUMO

To facilitate rational experimental design and fulfill the NIH requirement of including sex as a biologic variable, we examined the influences of genetic background and sex on responses to intervertebral disc (IVD) injury in the mouse tail. The goal of this study was to compare gene expression and histologic changes in response to a tail IVD injury (needle puncture) in male and female mice on the DBA and C57BL/6 (B6) backgrounds. We hypothesized that extracellular matrix gene expression in response to IVD injury differs between mice of different genetic backgrounds and sex. Consistent changes were detected in gene expression and histologic features after IVD injury in mice on both genetic backgrounds and sexes. In particular, expression of col1a1 and adam8 was higher in the injured IVD of DBA mice than B6 mice. Conversely, col2a1 expression was higher in B6 mice than DBA mice. Sex-associated differences were significant only in B6 mice, in which col2a1 expression was greater in male mice than in female. Histologic differences in response to injury were not apparent between DBA and B6 mice or between males and females. In conclusion, mouse tail IVD showed sex- and strain-related changes in gene expression and histology after needle puncture. The magnitude of change in gene expression differed with regard to genetic background and, to a lesser degree, sex.

3.
Biomed Pharmacother ; 126: 110094, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32200257

RESUMO

UVA radiation from the sun is the main external stimulus in the pathogenesis of skin photo-aging. This process is associated with cellular oxidative stress. Here we aim at showing the protective effect of d-Tetramannuronic Acid Tetrasodium Salt (M4), a natural product, against UVA (30J/cm2) irradiation-induced oxidative stress and photo-aging in HaCaT cells, and to reveal the molecular mechanism underlying the protective efficacy. M4 pretreatment significantly increased HaCaT cell viability and MMP, suppressing UVA-induced ROS generation. Moreover, M4 treatment prevented the UVA-induced photo-aging of HaCaT cells (the reduction of cell viability, mitochondria dysfunction, and SIRT1/pGC-1α deregulation). Notably, the anti-photo-aging potential of M4 was directly associated with the increased expression of MMP and SIRT1, which was followed by the up-regulation of pGC-1α, D-LOOP, and Mt-TFA, and the transcriptional activation of NRF1/NRF2. Therefore, M4 is useful for the protection of skin cells from UVA-induced photo-aging.

4.
Arthritis Rheumatol ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32162789

RESUMO

OBJECTIVE: This study aimed to elucidate the role of decorin, a small leucine-rich proteoglycan, in the degradation of cartilage matrix during the progression of post-traumatic osteoarthritis (PTOA). METHODS: The destabilization of the medial meniscus (DMM) surgery was applied to 3-month-old decorin-null and inducible decorin knockout mice to induce PTOA. The resulted OA phenotype was evaluated by assessing joint morphology and sulfated glycosaminoglycan (sGAG) staining via histology (n = 6/group), surface collagen fibril nanostructure via scanning electron microscopy (n = 4), tissue modulus via atomic force microscopy-nanoindentation (n ≥ 5) and subchondral bone structure via micro-computed tomography (n = 5). Femoral head cartilage explants from wild-type and decorin-null mice were subjected to the stimuli of inflammatory cytokine interleukin-1ß (IL-1ß) in vitro (n = 6). The resulting chondrocyte response to IL-1ß and release of sGAGs were quantified. RESULTS: In both decorin-null and inducible decorin knockout mice, the absence of decorin results in accelerated sGAG loss and formation of highly aligned collagen fibrils on cartilage surface relative to the control (p < 0.05). Also, decorin-null mice developed more salient osteophytes, illustrating more severe OA. In cartilage explants, with IL-1ß treatment, loss of decorin did not alter the expression of either anabolic or catabolic genes. However, a greater proportion of sGAGs was released to the media from decorin-null explants, in both live and devitalized conditions (p < 0.05). CONCLUSION: In PTOA, decorin delays the loss of fragmented aggrecan and fibrillation of cartilage surface, and thus, plays a protective role in ameliorating cartilage degeneration.

5.
Cardiovasc Ther ; 2020: 8647837, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190122

RESUMO

Background: Anemia following acute myocardial infarction (AMI) is associated with poor outcomes. While previous studies in patients with AMI have focused on anemia at admission, we hypothesized that hemoglobin (Hb) decline during hospitalization and lower discharge Hb would be associated with greater long-term mortality in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods: We analyzed records of 983 STEMI patients who were treated with primary PCI. The primary end point was all-cause mortality at 1 year and 2 years. The relationship between discharge Hb levels, decline in Hb levels, bleeding event classification, and all-cause mortality was determined. Results: Overall, 16.4% of patients had bleeding events, which were classified by the Thrombolysis in Myocardial Infarction (TIMI) score as 7% minimal, 8.6% minor, and 0.9% major. No significant gastrointestinal bleed and cerebral hemorrhage occurred in hospitals among these patients. The incidence rate of the 2-year all-cause mortality increased with severity of the bleeding event score (8.78% for no bleeding vs. 11.59% for minimal bleeding vs. 20.24% for minor bleeding vs. 55.56% for major bleeding, P < 0.001). Discharge Hb was significantly associated with 2-year mortality in an unadjusted model (hazard ratio (HR) per 1 g/L decrease in discharge Hb = 1.020, 95% confidence interval (CI): 1.006-1.034, P < 0.001). Discharge Hb was significantly associated with 2-year mortality in an unadjusted model (hazard ratio (HR) per 1 g/L decrease in discharge Hb = 1.020, 95% confidence interval (CI): 1.006-1.034, P < 0.001). Discharge Hb was significantly associated with 2-year mortality in an unadjusted model (hazard ratio (HR) per 1 g/L decrease in discharge Hb = 1.020, 95% confidence interval (CI): 1.006-1.034. Conclusions: In this population of patients hospitalized for STEMI, all-cause mortality increased with lower discharge Hb, and discharge Hb was a significant predictor of mortality risk.

6.
J Pharmacol Exp Ther ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029577

RESUMO

Cinnamaldehyde (Cin), a bioactive cinnamon essential oil from traditional Chinese medicine (TCM) herb Cinnamomum cassia, has been reported to have multi-pharmacological activities including anti-inflammation. However, its role and molecular mechanism of anti-inflammatory activity in musculoskeletal tissues remains unclear. Here, we first investigated the effects and molecular mechanisms of Cin in human synoviocyte cells. Then in vivo therapeutic effect of Cin on collagen-induced arthritis (CIA) also studied. Cell cytotoxicity was measured by CCK-8 Assay. Pro-inflammatory cytokine expression was evaluated using qPCR and ELISA. Protein expression was measured by western blotting. The in vivo effect of Cin (75 mg/kg/day) was evaluated in rats with CIA by gavage administration. Disease progression was assessed by clinical scoring, radiographic, and histological examinations. Cin significantly inhibited IL-1ß-induced interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) release from human synoviocyte cells. The molecular analysis revealed that Cin impaired IL-6-induced janus kinase 2 (JAK2), signal transducer and activator of transcription 1 (STAT1) and STAT3 signaling pathway by inhibiting the phosphorylation of JAK2, STAT1 and STAT3, without affecting NF-κB pathway. Cin reduced collagen-induced swollen paw volume of arthritic rats. The anti-inflammation effects of Cin were associated with decreased severity of arthritis, joint swelling, and reduced bone erosion and destruction. Furthermore, serum IL-6 level was decreased when Cin administered therapeutically to CIA rats. Cin suppresses IL-1ß-induced inflammation in synoviocytes through the JAK/STAT pathway and alleviated collagen-induced arthritis in rats. These data indicated that Cin might be a potential TCM-derived disease modifying anti-rheumatic herbal drug. SIGNIFICANCE STATEMENT: Cin suppresses pro-inflammatory cytokines secretion in RA synoviocyte cells by JAK/STAT pathway. Cin ameliorates collagen-induced arthritis in rats. Cin is a potential TCM-derived disease modifying anti-rheumatic herbal drug.

7.
J Reconstr Microsurg ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32040964

RESUMO

BACKGROUND: Immunosuppression risks are a major concern with vascularized composite allotransplantation (VCA). As an emerging strategy, the antirejection role played by mesenchymal stem cells (MSCs) is receiving attention. However, the current literature reports are inconclusive regarding the robustness of the MSC monotherapy. Using a rat forelimb VCA model, this study tested the robustness of the immunomodulation efficacy of gingival-derived MSCs (GMSCs) and bone marrow-derived MSCs (BMMSCs). METHODS: Forelimbs were transplanted on pairs of major histocompatibility complex-incompatible rats (Wistar-Kyoto donor, Lewis [LEW] recipient). Twenty-four LEW rats were randomly divided into four groups, including control (no treatment) and three treatment groups: rapamycin (2 mg/kg/day for 28 days, postoperatively), BMMSC and GMSC, both of which received donor-derived stem cells administered intravenously on postoperative days (PODs) 0, 3, 7, and 14. Rejection was considered as 80% skin necrosis of the allograft. Microcomputed tomography (µCT) was performed to evaluate healing at osteosynthesis site. On POD 14, limbs from each group underwent histological analysis and rejection grading using the Banff system. RESULTS: Both BMMSC (15.0 days) and GMSC (14.7 days) treatment failed to prolong VCA survival in comparison with the control group (13.8 days; p > 0.050), while the rapamycin significantly delayed acute VCA rejection (24.5 days; p = 0.003). Micro-CT imaging revealed no gross visual difference across all groups. Histology revealed that the control group was most severely affected (grades III and IV) followed by MSC (grade II) and rapamycin (grade I). CONCLUSION: MSC monotherapy, both BMMSC and GMSC, did not inhibit rejection in our VCA model. Skin immunogenicity is an important issue in promoting rejection, and a concomitant immunosuppression regimen should be considered to prolong allograft survival.

8.
Sci Transl Med ; 12(532)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32102932

RESUMO

Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces ß-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of ß-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/ß-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.

9.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054061

RESUMO

This study aimed to show the α-L-Hexaguluroic acid hexasodium salt (G6) protective effect against UVA-induced photoaging of human keratinocyte cells. We found that G6 localized to the mitochondria and improved mitochondrial functions. G6 increased respiratory chain complex activities, which led to increased cellular ATP content and NAD+/NADH ratio. Thus, G6 alleviated the oxidative stress state in UVA-irradiated cells. Moreover, G6 can regulate the SIRT1/pGC-1α pathway, which enhanced the cells' viability and mitochondria energy metabolism. Notably, the anti-photoaging potential of G6 was directly associated with the increased level of MMP and SIRT1, which was followed by the upregulation of pGC-1α, D-LOOP, and Mt-TFA, and with the transcriptional activation of NRF1/NRF2. Taking all of the results together, we conclude that G6 could protect HaCaT cells from UVA-induced photo-aging via the regulation of mitochondria energy metabolism and its downstream signaling pathways.

11.
J Plant Res ; 133(2): 257-270, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32036472

RESUMO

The Chinese chestnut (Castanea mollissima Blume) 'Huaihuang' was chosen as the experimental material to observe embryogenesis and the dynamic changes of cell wall components during this process. Various developmental stages of embryos, including globular embryos, heart embryos, torpedo embryos and cotyledon embryos, were observed. The results showed that during embryogenesis, cellulose increased, and callose rapidly degraded. In the cell walls of developing embryos, pectic homogalacturonan (HG), especially low-esterified HG, was abundant, suggesting rapid synthesis and de-methyl-esterification of HG. Extensin and galactan increased with the development of the embryos. In contrast, the arabinan epitopes decreased in developing embryos but were more abundant than galactan epitopes at all stages. Xylan epitopes showed explicit boundaries between the outer epidermal wall and the rest of the inner tissues, and the fluorescence intensity of the outer epidermal wall was significantly higher than that of the inner tissues. Furthermore, the results indicated that the outer epidermal wall contained high amounts of cellulose, HG pectin and hemicellulose, especially arabinan and xylan. These results suggested the presence of rapid pectin metabolism, cellulose synthesis, rapid degradation of callose, different distributive patterns and dynamic changes of hemicellulose (galactan, arabinan and xylan) and extensin during embryogenesis. Various cell wall components exist in different tissues of the embryo, and dynamic changes in cell wall components are involved in the embryonic development process.

12.
Biomaterials ; 238: 119828, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32045781

RESUMO

Magnesium (Mg)-based biometal attracts clinical applications due to its biodegradability and beneficial biological effects on tissue regeneration, especially in orthopaedics, yet the underlying anabolic mechanisms in relevant clinical disorders are lacking. The present study investigated the effect of magnesium (Mg) and vitamin C (VC) supplementation for preventing steroid-associated osteonecrosis (SAON) in a rat experimental model. In SAON rats, 50 mg/kg Mg, or 100 mg/kg VC, or combination, or water control was orally supplemented daily for 2 or 6 weeks respectively. Osteonecrosis was evaluated by histology. Serum Mg, VC, and bone turnover markers were measured. Microfil-perfused samples prepared for angiography and trabecular architecture were evaluated by micro-CT. Primary bone marrow cells were isolated from each group to evaluate their potentials in osteoblastogenesis and osteoclastogenesis. The mechanisms were tested in vitro. Histological evaluation showed SAON lesions in steroid treated groups. Mg and VC supplementation synergistically reduced the apoptosis of osteocytes and osteoclast number, and increased osteoblast surface. VC supplementation significantly increased the bone formation marker PINP, and the combination significantly decreased the bone resorption marker CTX. TNFα expression and oxidative injury were decreased in bone marrow in Mg/VC/combination group. Mg significantly increased the blood perfusion in proximal tibia and decreased the leakage particles in distal tibia 2 weeks after SAON induction. VC significantly elevated the osteoblast differentiation potential of marrow cells and improved the trabecular architecture. The combination supplementation significantly inhibited osteoclast differentiation potential of marrow cells. In vitro study showed promoting osteoblast differentiation effect of VC, and anti-inflammation and promoting angiogenesis effect of Mg with underlying mechanisms. Mg and VC supplementation could synergistically alleviate SAON in rats, indicating great translational potentials of metallic minerals for preventing SAON.

13.
J Neuroinflammation ; 17(1): 31, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31973738

RESUMO

OBJECTIVE: Autoantibodies against ribosomal P proteins (anti-P antibodies) are strongly associated with the neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE). The present study was designed to assess whether anti-P antibodies can induce abnormal brain electrical activities in mice and investigate the potential cytopathological mechanism. METHODS: Affinity-purified human anti-ribosomal P antibodies were injected intravenously into mice after blood-brain barrier (BBB) disruption. The auditory steady-state response (ASSR) was evaluated based on electroencephalography (EEG) signals in response to 40-Hz click-train stimuli, which were recorded from electrodes implanted in the skull of mice. Immunofluorescence staining was used to examine the morphology and density of neurons and glia in the hippocampus and cortex. The presence of apoptosis in the brain tissues was studied using the TUNEL assay. A PLX3397 diet was used to selectively eliminate microglia from the brains of mice. RESULTS: Circulating anti-P antibodies caused an enhancement of the ASSR and the activation of microglia through the disrupted BBB, while no obvious neural apoptosis was observed. In contrast, when microglia were depleted, anti-P antibodies induced a serious reduction in the ASSR and neural apoptosis. CONCLUSION: Our study indicates that anti-P antibodies can directly induce the dysfunction of auditory-evoked potentials in the brain and that microglia are involved in the protection of neural activity after the invasion of anti-P antibodies, which could have important implications for NPSLE.

14.
Biomaterials ; 233: 119721, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31954958

RESUMO

The orbital floor (OF) is an anatomical location in the craniomaxillofacial (CMF) region known to be highly variable in shape and size. When fractured, implants commonly consisting of titanium meshes are customized by plying and crude hand-shaping. Nevertheless, more precise customized synthetic grafts are needed to meticulously reconstruct the patients' OF anatomy with better fidelity. As alternative to titanium mesh implants dedicated to OF repair, we propose a flexible patient-specific implant (PSI) made by stereolithography (SLA), offering a high degree of control over its geometry and architecture. The PSI is made of biodegradable poly(trimethylene carbonate) (PTMC) loaded with 40 wt % of hydroxyapatite (called Osteo-PTMC). In this work, we developed a complete work-flow for the additive manufacturing of PSIs to be used to repair the fractured OF, which is clinically relevant for individualized medicine. This work-flow consists of (i) the surgical planning, (ii) the design of virtual PSIs and (iii) their fabrication by SLA, (iv) the monitoring and (v) the biological evaluation in a preclinical large-animal model. We have found that once implanted, titanium meshes resulted in fibrous tissue encapsulation, whereas Osteo-PMTC resulted in rapid neovascularization and bone morphogenesis, both ectopically and in the OF region, and without the need of additional biotherapeutics such as bone morphogenic proteins. Our study supports the hypothesis that the composite osteoinductive Osteo-PTMC brings advantages compared to standard titanium mesh, by stimulating bone neoformation in the OF defects. PSIs made of Osteo-PTMC represent a significant advancement for patients whereby the anatomical characteristics of the OF defect restrict the utilization of traditional hand-shaped titanium mesh.

15.
Environ Pollut ; 259: 113849, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31931410

RESUMO

The present study evaluated the feasibility of using a marine cage fish Larimichthys crocea as a model for monitoring short-time Cd discharge near the sewage outlet. Fish were exposed to 0, 20, 100, 500 and 2500 µg/L for 6 h. Cd concentrations in gills, and left and right lobes of hepatopancreas were examined as well as activity levels of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathion-S-transferase (GST), glutathione reductase (GR), lipid peroxidation, glutathione (GSH) and mRNA levels of 19 genes encoding these enzymes. Cd concentrations increased at 100, 500 and 2500 µg/L Cd in gill and at 2500 µg/L Cd in hepatopancreas. Lipid peroxidation increased and GSH levels declined in gills at 2500 µg/L Cd. On the contrary, oxidative damage was not observed in hepatopancreas but GSH levels increased at all tested concentrations of Cd in the left lobe and at 20 µg/L Cd in the right lobe. The enhanced antioxidant response was confirmed in gills due to the increased activity levels of antioxidant enzymes and the up-regulated mRNA levels of most genes. However, disordered antioxidant response was observed in hepatopancreas, showing a dose- and lobe-dependent effect. RNA-seq and q-PCR analyses were performed to investigate differently expressed genes between both lobes under different concentrations of Cd. The most significantly enriched pathway term was pancreatic secretion, where the right lobe showed higher mRNA levels of 18 genes encoding pancreatic digestive enzymes than the left one under Cd stress. Interestingly, both lobes had the same mRNA levels of digestive enzyme genes and antioxidant genes in fish without Cd exposure. Overall, Larimichthys crocea is very sensitive to environmental exposure to cadmium. The present study for the first time investigates Cd-induced antioxidant response in Larimichthys crocea, also is the first to find lobe-dependent effects in fish.

16.
J Cell Mol Med ; 24(5): 2761-2771, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31970850

RESUMO

Lung immune responses to respiratory pathogens and allergens are initiated in early life which will further influence the later onset of asthma. The airway epithelia form the first mechanical physical barrier to allergic stimuli and environmental pollutants, which is also the key regulator in the initiation and development of lung immune response. However, the epithelial regulation mechanisms of early-life lung immune responses are far from clear. Our previous study found that integrin ß4 (ITGB4) is decreased in the airway epithelium of asthma patients with specific variant site. ITGB4 deficiency in adult mice aggravated the lung Th2 immune responses and enhanced airway hyper-responsiveness (AHR) with a house dust mite (HDM)-induced asthma model. However, the contribution of ITGB4 to the postnatal lung immune response is still obscure. Here, we further demonstrated that ITGB4 deficiency following birth mediates spontaneous lung inflammation with ILC2 activation and increased infiltration of eosinophils and lymphocytes. Moreover, ITGB4 deficiency regulated thymic stromal lymphopoietin (TSLP) production in airway epithelial cells through EGFR pathways. Neutralization of TSLP inhibited the spontaneous inflammation significantly in ITGB4-deficient mice. Furthermore, we also found that ITGB4 deficiency led to exaggerated lung allergic inflammation response to HDM stress. In all, these findings indicate that ITGB4 deficiency in early life causes spontaneous lung inflammation and induces exaggerated lung inflammation response to HDM aeroallergen.

17.
Cartilage ; : 1947603519900800, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31997656

RESUMO

OBJECTIVE: The purposes of this study are to evaluate which growth plate parameters are associated with bone growth in mice and to compare the mouse results with those in humans. DESIGN: The sagittal sections of the proximal growth plate of the mouse tibia from neonate to young adult stages were subjected to histomorphometric and functional analyses. The radiographic images of tibias of human patients until puberty were analyzed to obtain the tibia length and the proximal growth plate height. It was found that a linear correlation best modeled the relationship between the growth plate variables with the tibia growth rate and length. RESULTS: In mice, total height, resting zone height, combined height of the proliferation and prehypertrophic zones, proliferation activity, and the total width of tibia growth plate showed high linear correlation with tibia bone length and bone growth rate, but the hypertrophic zone height and the growth plate area did not. In both mice and humans, the total growth plate width of tibia was found to have the strongest correlation with tibia length and growth rate. CONCLUSIONS: The results validated that growth plate total height, the height of the resting zone and cell proliferation activity are appropriate parameters to evaluate the balance between growth plate activity and bone growth in mice, consistent with previous reports. The study also provided a new growth plate parameter candidate, growth plate width for growth plate activity evaluation in both mouse and human tibia bone.

18.
J Agric Food Chem ; 68(5): 1347-1353, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31961681

RESUMO

A facile approach is introduced here for the synthesis of rare ketoses from glycerol and d-/l-glyceraldehyde (d-/l-GA). The reactions were carried out in a one-pot multienzyme fashion in which the only carbon source is glycerol. In the enzymatic cascade, glycerol is phosphorylated and then oxidized at C2 to afford dihydroxyacetone phosphate (DHAP), the key donor for enzymatic aldol reaction. Meanwhile, the primary alcohol of glycerol is also oxidized to give the acceptor molecule GA in situ (d- or l-isomer could be formed stereospecifically with either alditol oxidase or horse liver alcohol dehydrogenase). Different DHAP-dependent aldolases were used to generate the aldol adducts (rare ketohexose phosphates) with various stereoconfigurations and diastereomeric ratios. It is worth noting that the enzyme that catalyzes the phosphorylation reaction in the first step could also help recycle the phosphate in the last step to provide free rare sugar molecules. This study provides a useful method for rare ketose synthesis on a 100 mg to g scale, starting from relatively inexpensive materials which solved the problem of supplying both glycerol 3-phosphate and GA in our previous work. It also demonstrates an example of green synthesis due to highly efficient carbon usage and recycling of cofactors.


Assuntos
Álcool Desidrogenase/química , Aldeído Liases/química , Glicerol/química , Cetoses/química , Animais , Biocatálise , Fosfato de Di-Hidroxiacetona/química , Cavalos , Fosforilação
19.
Medicine (Baltimore) ; 99(4): e18951, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31977912

RESUMO

RATIONALE: An amniotic fluid embolism (AFE) is a rare, lethal syndrome that is commonly associated with disseminated intravascular coagulation (DIC). Anticoagulation therapy is the most important strategy to inhibit excessive activation of the coagulation cascade in patients with AFE and DIC. At present, treatment of AFE with rivaroxaban has not been reported. PATIENT CONCERNS: We report a 37-year-old woman (gravida 2, para 1) at 39 weeks' gestation with irregular contractions of the uterus was admitted to the obstetrical department. Ten minutes after the spontaneous rupture of the membranes, the patient complained of dyspnea and dysphoria and exhibited cyanosis of her lips. The patient's blood pressure decreased and heart rate increased rapidly, and 2100 mL of unclotted blood flowed from her vagina within 1 hour. Her platelet count dropped to 21 × 10/L, and the results from routine coagulation tests, and D-dimer and fibrin degradation product tests were obviously abnormal. DIAGNOSES: According to the current research consensus, AFE with DIC should be considered immediately when sudden cardiovascular collapse occurs around the time of labor and delivery, followed by the development of coagulopathy and hemorrhage. INTERVENTIONS: In addition, the variety of supportive treatments, rivaroxaban was used in anticoagulant therapy. OUTCOMES: At follow-up 30 and 60 days, there were no complaints of discomfort or abnormal laboratory assays. The patient recovered completely. LESSONS: This case highlights that rivaroxaban, as a direct inhibitor of activated factor Xa, demonstrates a good therapeutic efficacy for treating AFE with DIC.


Assuntos
Coagulação Intravascular Disseminada/tratamento farmacológico , Embolia Amniótica/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Rivaroxabana/administração & dosagem , Adulto , Transfusão de Eritrócitos , Feminino , Humanos , Gravidez , Resultado do Tratamento
20.
J Bone Miner Res ; 35(1): 196-210, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31610061

RESUMO

Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-ß as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-ß-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research.

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