RESUMO
PURPOSE: In combined anterior-posterior adult spinal deformity surgery, the optimal combination of anterior and posterior procedures remains unclear. We aimed to demonstrate the radiological outcomes and relevant factors in oblique lateral interbody fusion (OLIF) for lumbosacral fractional curve (FC) correction combined with open posterior surgery in degenerative lumbar scoliosis (DLS). METHODS: This study involved 42 consecutive patients with DLS who had a major curve (MC) ≥ 20° and an FC (L4 to S1) ≥ 10°, and underwent a combined anterior-posterior surgery Changes in the MC, FC, coronal balance distance, type of coronal imbalance, coronal/sagittal disc angle at L4-5 and L5-S1, L4 and L5 tilt, and sagittal parameters were examined. The associations between FC correction and demographic, surgical, and radiological factors were analysed. RESULTS: The FC decreased from 16.9 ± 7.3° preoperatively to 6.6 ± 4.4° at the last follow-up (P < 0.001). The coronal disc angle at L4-5 and L5-S1 were, respectively, 6.8 ± 2.2° and 6.0 ± 4.1° preoperatively and decreased to 2.2 ± 2.1 and 1.2 ± 1.3° at the last follow-up (both P < 0.001). The changes in FC were greater in uppermost instrumented level > T10 (P < 0.001), and associated with the preoperative FC (r = 0.820, P < 0.001), L4 tilt (r = 0.434, P = 0.007), and L5 tilt (r = 0.462, P = 0.003). CONCLUSION: OLIF at the FC combined with open posterior surgery is an effective combined anterior-posterior correction strategy in DLS.
Assuntos
Escoliose , Adulto , Humanos , Escoliose/diagnóstico por imagem , Escoliose/cirurgia , Procedimentos Neurocirúrgicos , Região LombossacralRESUMO
BACKGROUND: This study aimed to investigate the clinical outcomes of fixed-bearing medial unicompartmental knee arthroplasty (UKA) for tibia vara knees and the associated changes in joint space malalignment (JSM) and joint line obliquity (JLO). METHODS: We retrospectively analyzed a consecutive group of 100 patients who underwent fixed-bearing medial UKA with a preoperative medial proximal tibia angle (MPTA) ≥86° (n = 50) and MPTA <86° (n = 50) and who had a minimum 5-year follow-up. Radiological parameters, including the hip-knee-ankle angle, MPTA, and the postoperative JSM and JLO, were measured. Functional evaluation was performed using the range of motion, visual analog scale, Knee Society Knee Score, Knee Society Function Score, and Western Ontario and McMaster Universities Osteoarthritis Index score. RESULTS: The MPTA <86° group showed significantly higher postoperative JLO (91.8 versus 90.4°, respectively; P = .002) and JSM (6.1 versus 4.2°, respectively; P = .026) compared to the MPTA ≥86° group. Functional outcomes, including range of motion, visual analog scale, Knee Society Knee Score, Knee Society Function Score, and Western Ontario and McMaster Universities Osteoarthritis Index scores, were not significantly different between the 2 groups. CONCLUSIONS: Fixed-bearing medial UKA is a safe and effective surgical option for patients who have tibia vara knees, as an increase in JLO and JSM postoperatively does not have a clinically relevant impact, even after a minimum 5-year follow-up.
Assuntos
Artroplastia do Joelho , Doenças do Desenvolvimento Ósseo , Osteoartrite do Joelho , Osteocondrose/congênito , Humanos , Artroplastia do Joelho/métodos , Osteoartrite do Joelho/cirurgia , Seguimentos , Estudos Retrospectivos , Articulação do Joelho/cirurgia , Tíbia/cirurgiaRESUMO
Previous studies have demonstrated that G protein-coupled receptor kinase interacting-1 protein (GIT1) associates with endothelial nitric oxide synthase (eNOS) to regulate nitric oxide production in sinusoidal endothelial cells (SECs). Here, we hypothesized that GIT1's tightly associated binding partner, ß-PIX (p21-activated kinase-interacting exchange factor ß, ARHGEF7) is specifically important in the regulation of eNOS activity. We examined ß-PIX expression in normal rat liver by immunohistochemistry and explored ß-PIX protein-protein interactions using immunoprecipitation and immunoblotting. The role of ß-PIX in regulating eNOS enzymatic activity was studied in GIT1-deficient SECs. Finally, structural analysis of interaction sites in GIT1 and ß-PIX required to regulate eNOS activity were mapped. ß-PIX was expressed primarily in SECs in normal liver and was either absent or expressed at extremely low levels in other liver cells (stellate cells, Kupffer cells, and hepatocytes). ß-PIX interacted with GIT1 and eNOS to form a trimolecular signaling module in normal SECs and was important in stimulating eNOS activity. Of note, GIT1-ß-PIX interaction led to synergistic enhancement of eNOS activity, and ß-PIX-driven increase in eNOS activity was GIT1 dependent. Disruption of ß-PIX or GIT1 in normal SECs using ß-PIX siRNA or GIT1-deficient SECs led to reduced eNOS activity. Finally, specific GIT1 domains [Spa2 homology domain (SHD) and synaptic localization domain (SLD), aa 331-596] and the ß-PIX COOH terminal (aa 496-555) appeared to be critical in the regulation eNOS activity. The data indicate that ß-PIX regulates eNOS phosphorylation and function in normal SECs and highlight the importance of the GIT1/ß-PIX/eNOS trimolecular complex in normal liver SEC function.NEW & NOTEWORTHY ß-PIX is a multidomain protein known to be a GIT1 binding partner. We report here that in the normal liver, the distribution and cellular localization of ß-PIX are restricted largely to sinusoidal endothelial cells. Furthermore, ß-PIX interacts with eNOS and GIT1 promotes eNOS activity and NO production and therefore exerts a novel posttranslational regulatory function on eNOS activity in sinusoidal endothelial cells. We also have identified specific molecular domains important in GIT1 and ß-PIX's interaction with eNOS, which may represent novel therapeutic targets in the control of sinusoidal blood flow and intrahepatic resistance.
Assuntos
Proteínas de Ciclo Celular , Células Endoteliais , Óxido Nítrico Sintase Tipo III , Fatores de Troca de Nucleotídeo Guanina Rho , Animais , Ratos , Proteínas de Ciclo Celular/genética , Células Endoteliais/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Compared with posterior interbody fusion techniques, oblique lateral interbody fusion (OLIF) offers a larger fusion bed with greater intervertebral space access, use of larger cages, more sufficient discectomy, and better end-plate preparation. However, the fusion rate of OLIF is similar to that of other interbody fusions. This study aimed to examine the factors associated with nonunion in OLIF. METHODS: This study examined 201 disc levels from 124 consecutive patients who underwent OLIF for lumbar degenerative diseases with 1-year regular follow-up. Demographic and surgical factors were reviewed from the medical records. Radiological factors measured were sagittal parameters, intervertebral disc angle (DA) before surgery and at the final follow-up, presence of vertebral end-plate lesions, and cage subsidence. Multivariable logistic regression analysis was performed to identify the factors associated with nonunion. RESULTS: Among the 201 discs, 185 (92.0%) achieved union at 1-year followed up. Smoking, surgery at the L5-S1 level, not performing laminectomy, and a large intervertebral DA were factors associated with nonunion in OLIF (all P < 0.05). Multivariable logistic regression analysis showed two independent variables (surgery at L5-S1 level and not performing laminectomy) as risk factors for nonunion in OLIF. CONCLUSIONS: Not performing laminectomy and surgery at the L5-S1 level were risk factors for nonunion in OLIF. To reduce the nonunion rate, surgeons should consider additional stabilization strategies for the L5-S1 OLIF and perform laminectomy.
RESUMO
We have created a novel glutathione S-transferase π1 (gstp1) knockout (KO) zebrafish model and used it for comparative analyses of redox homeostasis and response to drugs that cause endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR). Under basal conditions, gstp1 KO larvae had higher expression of antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) accompanied by a more reduced larval environment and a status consistent with reductive stress. Compared with wild type, various UPR markers were decreased in KO larvae, but treatment with drugs that induce ER stress caused greater toxicities and increased expression of Nrf2 and UPR markers in KO. Tunicamycin and 02-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl}1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/nitric oxide) activated inositol-requiring protein-1/X-box binding protein 1 pathways, whereas thapsigargin caused greater activation of protein kinase-like ER kinase/activating transcription factor 4/CHOP pathways. These results suggest that this teleost model is useful for predicting how GSTP regulates organismal management of oxidative/reductive stress and is a determinant of response to drug-induced ER stress and the UPR. SIGNIFICANCE STATEMENT: A new zebrafish model has been created to study the importance of glutathione S-transferase π1 in development, redox homeostasis, and response to drugs that enact cytotoxicity through endoplasmic reticulum stress and induction of the unfolded protein response.
Assuntos
Glutationa S-Transferase pi/metabolismo , Resposta a Proteínas não Dobradas , Ácido 4-Aminobenzoico/toxicidade , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glutationa S-Transferase pi/genética , Homeostase , Larva/efeitos dos fármacos , Larva/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/toxicidade , Oxidantes/toxicidade , Oxirredução , Transcriptoma , Tunicamicina/toxicidade , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Integrase (IN) is an essential protein for HIV replication that catalyzes insertion of the reverse-transcribed viral genome into the host chromosome during the early steps of viral infection. Highly active anti-retroviral therapy is a HIV/AIDS treatment method that combines three or more antiviral drugs often formulated from compounds that inhibit the activities of viral reverse transcriptase and protease enzymes. Early IN inhibitors (INIs) mainly serve as integrase strand transfer inhibitors (INSTI) that disrupt strand transfer by binding the catalytic core domain of IN. However, mutations of IN can confer resistance to INSTI. Therefore, non-catalytic integrase inhibitors (NCINI) have been developed as next-generation INIs. METHODS: In this study, we evaluated and compared the activity of INSTI and NCINI according to the analysis method. Antiviral activity was compared using p24 ELISA with MT2 cell and TZM-bl luciferase system with TZM-bl cell. Each drug was serially diluted and treated to MT2 and TZM-b1 cells, infected with HIV-1 AD8 strain and incubated for 5 and 2 days, respectively. Additionally, to analyze properties of INSTI and NCINI, transfer inhibition assay and 3'-processing inhibition assay were performed. RESULTS: During screening of INIs using the p24 ELISA and TZM-bl luciferase systems, we found an inconsistent result with INSTI and NCINI drugs. Following infection of MT2 and TZM-bl cells with T-tropic HIV-1 strain, both INSTI and NCINI treatments induced significant p24 reduction in MT2 cells. However, NCINI showed no antiviral activity in the TZM-bl luciferase system, indicating that this widely used and convenient antiretroviral assay is not suitable for screening of NCINI compounds that target the second round of HIV-1 replication. CONCLUSION: Accordingly, we recommend application of other assay procedures, such as p24 ELISA or reverse transcription activity, in lieu of the TZM-bl luciferase system for preliminary NCINI drug screening. Utilization of appropriate analytical methods based on underlying mechanisms is necessary for accurate assessment of drug efficacy.
Assuntos
Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/análise , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Linhagem Celular , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/classificação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Replicação Viral/efeitos dos fármacosRESUMO
Outbreaks of infectious disease in shrimp pose a serious threat to shrimp agriculture worldwide. Shrimp lack adaptive immunity and depend only on innate immunity as a defense system against infectious disease. Toll-like receptors (TLR) are reported to play a critical role in the innate immune system. In this study, we identified a Toll-like receptor gene of a species of freshwater shrimp, Macrobrachium nipponense, designated MnToll, for the first time. The sequence of MnToll encoded 935 residues arranged as 10 leucine-rich repeat (LRR) domains, a leucine-rich repeat C-terminal (LRR CT) domain and a Toll/interleukin-1 receptor (TIR) domain and displayed 90% amino acid similarity to previously identified TLRs (Toll 1 and 2) of Macrobrachium rosenbergii. We additionally evaluated mRNA expression of MnToll in various tissues, including heart, gills, stomach, digestive gland, ventral nerve cord, antennal gland and muscle. Following infection with a viral pathogen, white spot syndrome virus (WSSV), MnToll expression was significantly upregulated between 12 and 72 h. Our data collectively suggest that the newly identified MnToll gene belongs to the TLR family in shrimp and is potentially involved in innate host defense, especially against WSSV.
Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Penaeidae/genética , Penaeidae/imunologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Vírus da Síndrome da Mancha Branca 1/fisiologia , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Sequência de Bases , Perfilação da Expressão Gênica , Filogenia , Alinhamento de Sequência , Receptores Toll-Like/químicaRESUMO
BACKGROUND: The depth of bolt in Femoral neck system (FNS, DePuy Synthes, Oberdorf, Switzerland) is difficult to finely control as the length of the bolt is in units of 5 mm. Thus, this study introduces a method to control the depth of FNS bolt in analogue scale in patients with femoral neck fracture. METHODS: By the technique of control of reaming and retraction of bolt, the tip of implant could be positioned close to subchondral bone without harming it. The position of implant tip in four cases in which the introduced technique was applied was compared to that of eight cases where the standard technique was performed. RESULTS: The average tip-apex distance measured in the cases that underwent surgery using the suggested technique in this study was statistically significantly shorter than that measured in the cases that underwent surgery under manufacturer guidelines. CONCLUSION: Even though the bolt of FNS is manufactured in the unit of 5 mm, the technique proposed in this study helps surgeons to adjust the depth of bolt for the fixation of femoral neck fracture using FNS.
Assuntos
Fraturas do Fêmur , Fraturas do Colo Femoral , Parafusos Ósseos , Fraturas do Colo Femoral/diagnóstico por imagem , Fraturas do Colo Femoral/cirurgia , Colo do Fêmur , Fixação Interna de Fraturas , Humanos , SuíçaRESUMO
PERV is a major virus concerning xenotransplantation study. However, the interesting part is that PERV is present in all kinds of pigs without pathogenicity and immune response. Furthermore, since pig cells have receptors for PERV, the gene delivery system using PERV envelope is highly likely to develop into an excellent viral vector in pigs. We developed a recombinant baculovirus with a modified surface for expressing the porcine endogenous retrovirus (PERV) envelope. Porcine reproductive and respiratory syndrome virus (PRRSV) infection is a severe concern in the porcine industry due to reproduction failure and respiratory symptoms. GP5 and M proteins are major immunogenic proteins of PRRSV. Using PERV-modified baculovirus (Ac mPERV) as a delivery vector, we constructed a dual antigen (GP5 and M)-encoding DNA vaccine system, Ac mPERV-C5/C6. Intramuscular immunization in mice and pigs, Ac mPERV-C5/C6 induced comparative high humoral and cellular immune responses. Our results support further development of Ac mPERV-C5/C6 as a potential PRRSV vaccine in the porcine industry. In addition, the Ac mPERV system may be applied to the generation of other effective DNA vaccines against porcine viral diseases.
Assuntos
Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Proteínas do Envelope Viral/imunologia , Proteínas da Matriz Viral/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/imunologia , Baculoviridae/genética , Retrovirus Endógenos/genética , Imunidade Humoral , Camundongos , Camundongos Endogâmicos BALB C , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Proteínas Recombinantes , Organismos Livres de Patógenos Específicos , Spodoptera , Suínos , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Proteínas do Envelope Viral/genética , Proteínas da Matriz Viral/genética , Vacinas Virais/genéticaRESUMO
Complications due to influenza are often associated with inflammation with excessive release of cytokines. The bulbs of Fritillariae thunbergii (FT) have been traditionally used to control airway inflammatory diseases, such as bronchitis and pneumonia. To elucidate active compounds, the targets, and underlying mechanisms of FT for the treatment of influenza-induced inflammation, systems biology was employed. Active compounds of FT were identified through the TCMSP database according to oral bioavailability (OB) and drug-likeness (DL) criteria. Other pharmacokinetic parameters, Caco-2 permeability (Caco-2), and drug half-life (HL) were also identified. Biological targets of FT were retrieved from DrugBank and STITCH databases, and target genes associated with influenza, lung, and spleen inflammation were collected from DisGeNET and NCBI databases. Compound-disease-target (C-D-T) networks were constructed and merged using Cytoscape. Target genes retrieved from the C-D-T network were further analyzed with GO enrichment and KEGG pathway analysis. In our network, GO and KEGG results yielded two compounds (beta-sitosterol (BS) and pelargonidin (PG)), targets (PTGS1 (COX-1) and PTGS2 (COX-2)), and pathways (nitric oxide, TNF) were involved in the inhibitory effects of FT on influenza-associated inflammation. We retrieved the binding affinity of each ligand-target, and found that PG and COX-1 showed the strongest binding affinity among four binding results using a molecular docking method. We identified the potential compounds and targets of FT against influenza and suggest that FT is an immunomodulatory therapy for influenza-associated inflammation.
Assuntos
Anti-Inflamatórios , Medicamentos de Ervas Chinesas , Fritillaria/química , Vírus da Influenza A/metabolismo , Influenza Humana/tratamento farmacológico , Simulação de Acoplamento Molecular , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Células CACO-2 , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Influenza Humana/metabolismo , Influenza Humana/patologiaRESUMO
Despite large economic losses attributable to white spot syndrome virus (WSSV), an infectious pathogen of penaeid shrimp and other crustaceans worldwide, no efficient vaccines or antiviral agents to control the virus are available at present. Here, we designed and constructed baculovirus-based vaccines delivering genes encoding the WSSV envelope proteins, VP28 and VP19. To enhance the immunogenicity of the baculovirus-based vaccine, we fused a Salmonella typhimurium flagellin 2 (FL2) gene with VP28 or VP19 gene. Both vaccine constructs elicited similar high titlers of anti-WSSV IgG after oral immunization in mice. The protective effect of oral vaccines upon WSSV challenge was observed in Macrobrachium nipponense. Bivalent vaccine displaying WSSV envelope proteins, VP19 and VP28, led to enhanced more than 10% survival protection against WSSV infection, compared to monovalent vaccine containing WSSV envelope protein, VP19 or VP28. Furthermore, a baculovirus-based WSSV vaccine fused with FL2 gene, Ac-VP28-ie1VP19FL2, efficiently protected mice against WSSV challenge (89.5% survival rate). In support of the efficacy of FL2 in our vaccine, we verified FL2 enhanced survival rate and induced the NF-κB gene in Palaemon paucidens. The collective results strongly suggest that our recombinant baculoviral system displaying WSSV envelope protein and delivering FL2-fused WSSV envelope gene effectively induced protective responses, supporting the utility of a potential new oral DNA vaccine against WSSV.
Assuntos
Penaeidae/virologia , Vacinas Virais , Animais , Flagelina/imunologia , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/farmacologia , Vírus da Síndrome da Mancha Branca 1RESUMO
Glycation of apolipoproteins is a major feature of the production of dysfunctional high-density lipoprotein (HDL), which is associated with the incidence of several metabolic diseases such as coronary artery disease and diabetes. In this report, fructated apoA-I (fA-I) induced by fructose treatment showed a covalently multimerized band without cross-linking, and lysine residues were irreversibly modified to prevent crosslinking. Using pancreatic ß-cells, insulin secretion was impaired by fA-I in the lipid-free and reconstituted HDL (rHDL) states, by up to 35%, and 40%, respectively, under hyperglycemic conditions (25 mmol/L glucose). Treatment of human umbilical vein endothelial cells (HUVECs) with fA-I and HDL from elderly patients caused a 1.8-fold and 1.5-fold increased cellular senescence, respectively, along with increased lysosomal enlargement. In the lipid-free and rHDL states, fA-I increased embryo death by 1.5-fold and 2.5-fold, respectively, along with the production of oxidized species. Furthermore, rHDL containing fA-I (fA-I-rHDL) showed a higher isoelectric point (pI, approximately 8.5), whereas rHDL containing nA-I (nA-I-rHDL) showed a narrow band range with lower pI (around 8.0) as well as a much smaller particle size than that of nA-I-rHDL. In conclusion, fructose-mediated apoA-I fructation resulted in the severe loss of several beneficial functions of apoA-I and HDL, including anti-senescence and insulin secretion activities, accompanied with increased susceptibility to protein degradation and structural modification.
Assuntos
Apolipoproteína A-I/farmacologia , Senescência Celular/fisiologia , Embrião não Mamífero/patologia , Frutose/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Insulina/metabolismo , Lipoproteínas HDL/metabolismo , Adulto , Idoso , Animais , Apolipoproteína A-I/química , Aterosclerose/induzido quimicamente , Aterosclerose/fisiopatologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Frutose/química , Glicosilação , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Adulto Jovem , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismoRESUMO
High density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediates selective cholesteryl ester uptake from lipoproteins into the liver as well as cholesterol efflux from macrophages to HDL. Recently, strong evidence has demonstrated the anti-inflammatory effect of HDL, although the mechanism of action is not fully understood. In this study, we showed that the anti-inflammatory effects of HDL are dependent on SR-BI expression in THP-1 macrophages. Consistent with earlier findings, pretreatment of macrophages with HDL abolished LPS-induced TNFα production. HDL also inhibited LPS-induced NF-κB activation. In addition, knockdown of SR-BI or inhibition of SR-BI ligand binding abolished the anti-inflammatory effect of HDL. SR-BI is a multi-ligand receptor that binds to modified lipoproteins as well as native HDL. Since modified lipoproteins have pro-inflammatory properties, it is unclear whether SR-BI activated by modified HDL has an anti- or pro-inflammatory effect. Glycated HDL induced NF-κB activation and cytokine production in macrophages in vitro, suggesting a pro-inflammatory effect for modified HDL. Moreover, inhibition of SR-BI function or expression potentiated glycated HDL-induced TNF-α production, suggesting an anti-inflammatory effect for SR-BI. In conclusion, SR-BI plays an important function in regulating HDL-mediated anti-inflammatory response in macrophages.
Assuntos
Anti-Inflamatórios/metabolismo , Antígenos CD36/metabolismo , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Glicosilação , Humanos , Inflamação/patologia , Modelos Biológicos , Regulação para CimaRESUMO
Liver cirrhosis is a severe chronic disease that results from various etiological factors and leads to substantial morbidity and mortality. Alcoholic cirrhosis (AC) and non-AC (NAC) arise from prolonged and excessive consumption of alcohol and metabolic syndromes, respectively. Precise molecular mechanisms of AC and NAC are yet to be comprehensively understood for diagnostics and therapeutic advances to materialize. This study reports novel findings to this end by utilizing high-throughput RNA sequencing and microarray data from the Gene Expression Omnibus (GEO). We performed a meta-analysis of transcriptomics data to identify the differentially expressed genes specific to AC and NAC. Functional enrichment and protein-protein interaction network analyses uncovered novel hub genes and transcription factors (TFs) critical to AC and NAC. We found that AC is primarily driven by metabolic dysregulation and oxidative stress, with key TFs such as RELA, NFKB1, and STAT3. NAC was characterized by fibrosis and tissue remodeling associated with metabolic dysfunction, with TFs including USF1, MYCN, and HIF1A. Key hub genes such as ESR1, JUN, FOS, and PKM in AC, and CD8A, MAPK3, CCND1, and CXCR4 in NAC were identified, along with their associated TFs, pointing to potential therapeutic targets. Our results underscore the unique and shared molecular mechanisms that underlie AC and NAC and inform the efforts toward precision medicine and improved patient outcomes in liver cirrhosis.
RESUMO
BACKGROUND: Alcohol-associated liver disease (ALD) encompasses a range of hepatic abnormalities, including isolated alcoholic steatosis, steatohepatitis, and cirrhosis. The flavanone-7-O-glycoside narirutin (NRT), the primary flavonoid in citrus peel, has antioxidant, anti-inflammatory, and lipid-lowering activity. We investigated the effects of NRT on liver injury induced by alcohol and explored the underlying mechanisms. METHODS: Zebrafish larvae were used to investigate the effects of NRT on acute exposure to ethanol (EtOH). Liver phenotypic, morphological, and biochemical assessments were performed to evaluate the hepatoprotective effects of NRT. Network pharmacology and molecular docking analyses were conducted to identify candidate targets of NRT in EtOH-induced liver injury. A drug affinity responsive target stability (DARTS) assay was conducted to evaluate the binding of NRT to mitogen-activated protein kinase 14 (MAPK14). The mechanism of action of NRT was validated by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and Western blot analysis. RESULTS: The liver phenotypic, morphological, and biochemical assessments revealed that NRT has potential therapeutic effects against acute EtOH-induced liver injury. RT-qPCR confirmed that NRT reversed the change in the expression of genes related to oxidative stress, lipogenesis, and the endoplasmic reticulum (ER)/unfolded protein response pathway. Network pharmacology and molecular docking analyses identified potential targets of NRT's protective effects and confirmed that NRT regulates the p38 MAPK signaling pathway by targeting mitogen-activated protein kinase 14 (MAPK14). CONCLUSIONS: NRT mitigates alcohol-induced liver injury by preventing lipid formation, protecting the antioxidant system, and suppressing ER stress-induced apoptosis through MAPK14 modulation.
Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Fígado Gorduroso , Flavanonas , Hepatopatias Alcoólicas , Proteína Quinase 14 Ativada por Mitógeno , Animais , Peixe-Zebra , Antioxidantes/farmacologia , Simulação de Acoplamento Molecular , Etanol/toxicidade , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/prevenção & controle , LipídeosRESUMO
Background: Traumatic spinal injuries in children are uncommon and result in different patterns of injuries due to the anatomical characteristics of children's spines. However, there are only a few epidemiological studies of traumatic spinal injury in children. The purpose of this study was to investigate the characteristics of traumatic spinal injury in children. Methods: We retrospectively reviewed the cases of pediatric patients (age < 18 years) with traumatic spinal injury who were treated at a level 1 trauma center between January 2017 and December 2021. We divided them into three groups according to age and analyzed demographics, injury mechanism, level of injury, and injury pattern. Results: A total of 62 patients (255 fractures) were included, and the mean age was 13.8 ± 3.2 years. There were 5 patients (22 fractures) in group I (0-9 years), 24 patients (82 fractures) in group II (10-14 years), and 33 patients (151 fractures) in group III (15-17 years). Both the Injury Severity Score and the Revised Trauma Score were highest in group I, but there was no statistical difference between the age groups. Fall from height was the most common injury mechanism, of which 63% were suicide attempts. The level of spinal injury was different in each age group, T10-L2 injury being the most common. In all age groups, the number of multilevel continuous injury was larger than that of single-level injury or multilevel noncontinuous injury. Surgical intervention was required in 33.9%, and mortality was 3.2%. Conclusions: In our study, fall from height was the most common mechanism of injury, and there were many suicide attempts associated with mental health issues. Thoracolumbar junction injuries were predominant, and the rate of multilevel contiguous injuries was high. The support and interest of the society and families for adolescent children seem crucial in preventing spinal trauma, and image testing of the entire spine is essential when evaluating pediatric spinal injuries.
Assuntos
Fraturas Ósseas , Fraturas da Coluna Vertebral , Traumatismos da Coluna Vertebral , Adolescente , Criança , Humanos , Estudos Retrospectivos , Fraturas da Coluna Vertebral/epidemiologia , Traumatismos da Coluna Vertebral/epidemiologia , Traumatismos da Coluna Vertebral/terapia , Coluna Vertebral , Centros de Traumatologia , Recém-Nascido , Lactente , Pré-EscolarRESUMO
BACKGROUND: Patients experience considerable postoperative pain after spinal surgery. As the spine is located at the centre of the body and supports body weight, severe postoperative pain hinders upper body elevation and gait which can lead to various complications, including pulmonary deterioration and pressure sores. It is important to effectively control postoperative pain to prevent such complications. Gabapentinoids are widely used as preemptive multimodal analgesia, but their effects and side effects are dose-dependent. This study was designed to examine the efficacy and side effects of varying doses of postoperative pregabalin for the treatment of postoperative pain after spinal surgery. METHODS: This is a prospective, randomized controlled, double-blind study. A total of 132 participants will be randomly assigned to the placebo (n = 33) group or to the pregabalin 25 mg (n = 33), 50 mg (n = 33), or 75 mg (n = 33) groups. Each participant will be administered placebo or pregabalin once prior to surgery and every 12 h after surgery for 72 h. The primary outcome will be the visual analogue scale pain score, total dose of administered intravenous patient-controlled analgesia, and frequency of rescue analgesic administered for 72 h from arrival to the general ward after surgery, subdivided into four periods: 1-6 h, 6-24 h, 24-48 h, and 48-72 h. The secondary outcomes will be the incidence and frequency of nausea and vomiting due to intravenous patient-controlled analgesia. Safety will be assessed by monitoring the occurrence of side effects such as sedation, dizziness, headache, visual disturbance, and swelling. DISCUSSION: Pregabalin is already widely used as preemptive analgesia and, unlike nonsteroidal anti-inflammatory drugs, is not associated with a risk of nonunion after spinal surgery. A recent meta-analysis demonstrated the analgesic efficacy and opioid-sparing effect of gabapentinoids with significantly decreased risks of nausea, vomiting, and pruritus. This study will provide evidence for the optimal dosage of pregabalin for the treatment of postoperative pain after spinal surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05478382. Registered on 26 July 2022.
Assuntos
Analgésicos , Humanos , Analgésicos/efeitos adversos , Método Duplo-Cego , Náusea/induzido quimicamente , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Pregabalina/efeitos adversos , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Vômito/induzido quimicamenteRESUMO
PURPOSE: Revision anterior cruciate ligament (ACL) reconstruction is technically challenging due to mispositioned tunnels, bone loss, and tunnel enlargement, which may compromise graft fixation and result in failure. To obtain firm graft fixation and strength in one stage, we utilized an over-the-top augmentation technique using an Achilles tendon allograft in revision ACL reconstruction (OA-ACLR). This study compared OA-ACLR with single-bundle ACL reconstruction (SB-ACLR). We hypothesized that OA-ACLR would enhance the postoperative knee joint rotational stability. METHODS: We retrospectively analyzed 47 patients who underwent revisional OA-ACLR and 48 who underwent primary SB-ACLR with minimum follow-up of 6 months. Knee instability was evaluated with the anterior drawer, Lachman, and pivot shift tests preoperatively and at the final follow-up. Side-to-side differences were compared with the non-affected side at the final follow-up. Function was evaluated using the IKDC subjective and Lysholm knee scores preoperatively and at the final follow-up. RESULTS: The groups did not differ in terms of sex, age, BMI, and etiology. There were no significant differences in concomitant surgical procedures, such as meniscectomy and meniscus repair, between the two groups (p = 0.335, > 0.99). Both groups significantly improved in the anterior drawer, Lachman, pivot shift tests, and IKDC and Lysholm knee scores after surgery (all p < 0.001). The OA-ACLR group showed significantly higher rotational stability in the pivot shift test than the SB-ACLR group (p = 0.017). The postoperative side-to-side difference, the IKDC and Lysholm scores showed no significant differences between the groups (p = 0.34, 0.301, 0.438). CONCLUSIONS: OA-ACLR showed enhanced rotational stability with pivot shift test compared to SB-ACLR. It may be considered a useful alternative for revision ACL reconstruction.
RESUMO
OBJECTIVE: This study aimed to examine the influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on pregnancy in cytokeratin-18 (K18)-hACE2 transgenic mice. METHODS: To determine the expression of hACE2 mRNA in the female reproductive tract of K18-hACE2 mice, real-time polymerase chain reaction (RT-PCR) was performed using the ovary, oviduct, uterus, umbilical cord, and placenta. SARS-CoV-2 was inoculated intranasally (30 µL/mouse, 1×104 TCID50/mL) to plug-checked K18-hACE2 homozygous female mice at the pre-and post-implantation stages at 2.5 days post-coitum (dpc) and 15.5 dpc, respectively. The number of implantation sites was checked at 7.5 dpc, and the number of normally born pups was investigated at 20.5 dpc. Pregnancy outcomes, including implantation and childbirth, were confirmed by comparison with the non-infected group. Tissues of infected mice were collected at 7.5 dpc and 19.5 dpc to confirm the SARS-CoV-2 infection. The infection was identified by performing RT-PCR on the infected tissues and comparing them to the non-infected tissues. RESULTS: hACE2 mRNA expression was confirmed in the female reproductive tract of the K18-hACE2 mice. Compared to the non-infected group, no significant difference in the number of implantation sites or normally born pups was found in the infected group. SARS-CoV-2 infection was detected in the lungs but not in the female reproductive system of infected K18-hACE2 mice. CONCLUSION: In K18-hACE2 mice, intranasal infection with SARS-CoV-2 did not induce implantation failure, preterm labor, or miscarriage. Although the viral infection was not detected in the uterus, placenta, or fetus, the infection of the lungs could induce problems in the reproductive system. However, lung infections were not related to pregnancy outcomes.