RESUMEN
Central and peripheral nerve injuries can lead to permanent paralysis and organ dysfunction. In recent years, many cell and exosome implantation techniques have been developed in an attempt to restore function after nerve injury with promising but generally unsatisfactory clinical results. Clinical outcome may be enhanced by bio-scaffolds specifically fabricated to provide the appropriate three-dimensional (3D) conduit, growth-permissive substrate, and trophic factor support required for cell survival and regeneration. In rodents, these scaffolds have been shown to promote axonal regrowth and restore limb motor function following experimental spinal cord or sciatic nerve injury. Combining the appropriate cell/exosome and scaffold type may thus achieve tissue repair and regeneration with safety and efficacy sufficient for routine clinical application. In this review, we describe the efficacies of bio-scaffolds composed of various natural polysaccharides (alginate, chitin, chitosan, and hyaluronic acid), protein polymers (gelatin, collagen, silk fibroin, fibrin, and keratin), and self-assembling peptides for repair of nerve injury. In addition, we review the capacities of these constructs for supporting in vitro cell-adhesion, mechano-transduction, proliferation, and differentiation as well as the in vivo properties critical for a successful clinical outcome, including controlled degradation and re-absorption. Finally, we describe recent advances in 3D bio-printing for nerve regeneration.
Asunto(s)
Axones , Exosomas/trasplante , Traumatismos de los Nervios Periféricos , Impresión Tridimensional , Nervio Ciático , Andamios del Tejido/química , Animales , Axones/metabolismo , Axones/patología , Humanos , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/terapia , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Nervio Ciático/patologíaRESUMEN
Transcriptional co-activator with PDZ-binding motif (TAZ) is a key downstream effector of the Hippo tumor-suppressor pathway. The functions of TAZ in the kidney, especially in tubular epithelial cells, are not well-known. To elucidate the adaptive expression, protective effects on kidney injury, and signaling pathways of TAZ in response to acute kidney injury (AKI), we used in vitro (hypoxia-treated human renal proximal tubular epithelial cells [RPTECs]) and in vivo (mouse ischemia-reperfusion injury [IRI]) models of ischemic AKI. After ischemic AKI, TAZ was up-regulated in RPTECs and the renal cortex or tubules. Up-regulation of TAZ in RPTECs subjected to hypoxia was controlled by IκB kinase (IKK)/nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) signaling. TAZ overexpression attenuated hypoxic and oxidative injury, inhibited apoptosis and activation of p38 and c-Jun N-terminal kinase (JNK) proteins, and promoted wound healing in an RPTEC monolayer. However, TAZ knockdown aggravated hypoxic injury, apoptosis, and activation of p38 and JNK signaling, delayed wound closure of an RPTEC monolayer, and promoted G0/G1 phase cell-cycle arrest. Chloroquine and verteporfin treatment produced similar results to TAZ overexpression and knockdown in RPTECs, respectively. Compared with vehicle-treated mice, chloroquine treatment increased TAZ in the renal cortex and tubules, improved renal function, and attenuated tubular injury and tubular apoptosis after renal IRI, whereas TAZ siRNA and verteporfin decreased TAZ in the renal cortex and tubules, deteriorated renal failure and tubular injury, and aggravated tubular apoptosis. Our findings indicate the renoprotective role of tubular TAZ in ischemic AKI. Drugs augmenting (e.g., chloroquine) or suppressing (e.g., verteporfin) TAZ in the kidney might be beneficial or deleterious to patients with AKI.
Asunto(s)
Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Daño por Reperfusión/complicaciones , Transactivadores/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Proteínas Adaptadoras Transductoras de Señales , Animales , Apoptosis , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Humanos , Túbulos Renales/citología , Túbulos Renales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Daño por Reperfusión/metabolismo , Transducción de Señal , Transactivadores/genéticaRESUMEN
Psoriasis is a chronic autoimmune disease with keratinocyte activation and lymphocyte infiltration in the skin. Our previous study found that 5-hydroxytryptophan (5(OH)Trp), a tryptophan metabolite, alleviated collagen-induced arthritis and suppressed cytokine production. In this study, we evaluated the effects of 5(OH)Trp in a mouse model for psoriasiform dermatitis, induced by imiquimod (IMQ). We showed that 5(OH)Trp significantly reduced the cumulative scores, epidermal thickness and ki-67 expression in the skin. In addition, 5(OH)Trp decreased local and systemic inflammation. Moreover, 5(OH)Trp significantly inhibited keratinocyte activation with decrease in IL-6 production and p-Erk1/2 and p-STAT3 expression. 5(OH)Trp also inhibited the differentiation of IFN-γ- and IL-17A-expressing CD4+ T cells and related cytokine production (TNF-α, IL-6, IL-17A and IFN-γ) in splenocytes. In conclusion, 5(OH)Trp can inhibit imiquimod-induced psoriasiform dermatitis in mice and inhibit activation in keratinocytes and splenocytes.
Asunto(s)
5-Hidroxitriptófano/uso terapéutico , Interleucina-17/antagonistas & inhibidores , Queratinocitos/fisiología , Psoriasis/tratamiento farmacológico , 5-Hidroxitriptófano/farmacología , Animales , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Epidermis/patología , Humanos , Imiquimod , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Interleucina-6/biosíntesis , Interleucina-6/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Biosíntesis de Proteínas/efectos de los fármacos , Psoriasis/inducido químicamente , Psoriasis/patología , Bazo/citología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND/PURPOSE: Heavy metal pollution in farm soils is a problem in some parts of Taiwan. Copper can be a factor associated with increased disease activities of rheumatoid arthritis (RA). Thus, the aim of this study was to investigate whether copper pollution in farm soils is associated with worsened RA. METHODS: Clinical parameters from 122 RA patients were collected from a medical center in central Taiwan. Levels of heavy metals in the blood were measured using inductively coupled plasma mass spectrometry. Levels of copper in farm soils were retrieved from a national survey. These data were analyzed to find the factors related to RA disease activities. RESULTS: RA patients living where farm soils contained high levels of copper had increased white blood cell counts, erythrocyte sedimentation rate, and disease activity score 28, compared with patients living where copper levels were low. Among the nine types of heavy metal measured in the study, blood levels of copper and nickel correlated with erythrocyte sedimentation rate. CONCLUSION: Our cross-sectional data suggest a correlation between RA disease activity and the level of copper at township farm soils samples. Further longitudinal studies using more rigorous methodologies are warranted to examine whether this correlation is causal.
Asunto(s)
Artritis Reumatoide/sangre , Cobre/sangre , Inflamación/sangre , Contaminantes del Suelo/efectos adversos , Suelo/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Granjas , Femenino , Gota/sangre , Humanos , Modelos Lineales , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Espondilitis Anquilosante/sangre , Encuestas y Cuestionarios , Taiwán , Adulto JovenRESUMEN
BACKGROUND: Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. METHODS: SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. RESULTS: For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN+, Iba1+, GFAP+, and OLIG2+ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. CONCLUSION: Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment.
Asunto(s)
Modelos Animales de Enfermedad , Exosomas , Células Madre Mesenquimatosas , Neuralgia , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/terapia , Exosomas/metabolismo , Neuralgia/terapia , Neuralgia/metabolismo , Ratas , Femenino , Humanos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Locomoción , Esponja de Gelatina Absorbible , Cordón Umbilical/citologíaRESUMEN
BACKGROUND: Copper is an essential metal for maintenance of many biological functions; however, excessive amount can induce inflammation and oxidative stress. Tetrathiomolybdate (TM) is a copper chelator for treatment of Wilson's disease, and decreased the severity of autoimmune arthritis in mice. OBJECTIVE: In this report, we evaluated the effects of TM in a mouse model for psoriasis. METHODS: Imiquimod-induced psoriasis murine model was used. We applied immunohistochemistry staining and ELISA to determine levels of cytokines in the inflamed skin, splenocytes, and draining lymph nodes. In addition, we used keratinocytes and splenocytes to test the inhibitory effects of TM on cytokine production and activation of transcription factors. RESULTS: Our results showed that TM significantly reduced cumulative scores, epidermis thickness, and ki-67 expression in the inflamed skin. In addition, TM decreased skin cytokine levels and systemic inflammation. Moreover, TM suppressed activation in keratinocytes and splenocytes with reduction in phosphorylation of Erk1/2 and STAT3. CONCLUSION: These findings are strong evidence that TM can inhibit psoriasis in the model.
Asunto(s)
Antiinflamatorios/farmacología , Quelantes/farmacología , Cobre/metabolismo , Imiquimod , Molibdeno/farmacología , Psoriasis/prevención & control , Piel/efectos de los fármacos , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Mediadores de Inflamación/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/inmunología , Queratinocitos/metabolismo , Masculino , Ratones Endogámicos C57BL , Fosforilación , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Piel/inmunología , Piel/metabolismo , Piel/patología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Hydroxychloroquine is widely used in patients with rheumatoid arthritis. However, large-scale studies examining the long-term effects of hydroxychloroquine on the development of kidney disease in patients with rheumatoid arthritis are lacking. We aimed to assess the long-term association of hydroxychloroquine use with the risk of developing CKD in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an observational cohort study for patients with newly diagnosed rheumatoid arthritis who were enrolled prospectively in Taiwan's National Health Insurance Research Database between January 1, 2000 and December 31, 2013. We used multivariable Cox proportional hazard regression to analyze the association of hydroxychloroquine use with incident CKD. RESULTS: A total of 2619 patients, including 1212 hydroxychloroquine users and 1407 hydroxychloroquine nonusers, were analyzed. Incident CKD was reported in 48 of 1212 hydroxychloroquine users and 121 of 1407 hydroxychloroquine nonusers. The incidence rate of CKD was lower in hydroxychloroquine users than in hydroxychloroquine nonusers (10.3 versus 13.8 per 1000 person-years). After multivariable adjustment, hydroxychloroquine users still had a lower risk of incident CKD (adjusted hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.90; P=0.01) than hydroxychloroquine nonusers. The lower risk of subsequent CKD development was dose dependent and consistent across subgroup analyses. CONCLUSIONS: Hydroxychloroquine use in patients with newly diagnosed rheumatoid arthritis is associated with a significantly lower risk of incident CKD compared with in nonusers.
Asunto(s)
Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Hidroxicloroquina/efectos adversos , Insuficiencia Renal Crónica/inducido químicamente , Adulto , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/epidemiologíaRESUMEN
Peroxiredoxin 3 (PRX3) is a mitochondrial antioxidant that regulates apoptosis in various cancers. However, whether tubular PRX3 predicts recovery of renal function following acute kidney injury (AKI) remains unknown. This retrospective cohort study included 54 hospitalized patients who had AKI with biopsy-proven acute tubular necrosis (ATN). The study endpoint was renal function recovery within 6 months. Of the 54 enrolled patients, 25 (46.3%) had pre-existing chronic kidney disease (CKD) and 33 (61%) recovered renal function. Tubular PRX3 expression was higher in patients with ATN than in those without renal function recovery. The level of tubular but not glomerular PRX3 expression predicted renal function recovery from AKI (AUROC = 0.76). In multivariate Cox regression analysis, high PRX3 expression was independently associated with a higher probability of renal function recovery (adjusted hazard ratio = 8.99; 95% CI 1.13-71.52, P = 0.04). Furthermore, the discriminative ability of the clinical model for AKI recovery was improved by adding tubular PRX3. High tubular PRX3 expression was associated with a higher probability of renal function recovery from ATN. Therefore, tubular PRX3 in combination with conventional predictors can further improve recovery prediction and may help with risk stratification in AKI patients with pre-existing CKD.
Asunto(s)
Necrosis Tubular Aguda/etiología , Necrosis Tubular Aguda/metabolismo , Túbulos Renales/metabolismo , Peroxiredoxina III/metabolismo , Insuficiencia Renal Crónica/complicaciones , Adulto , Anciano , Biomarcadores , Biopsia , Comorbilidad , Femenino , Expresión Génica , Tasa de Filtración Glomerular , Humanos , Pruebas de Función Renal , Necrosis Tubular Aguda/diagnóstico , Necrosis Tubular Aguda/mortalidad , Túbulos Renales/patología , Masculino , Persona de Mediana Edad , Peroxiredoxina III/genética , Pronóstico , Modelos de Riesgos Proporcionales , Curva ROC , Recuperación de la FunciónRESUMEN
BACKGROUND: Traumatic brain injury (TBI) is an important cause of death and disability worldwide. The relationship between TBI and kidney diseases is largely unknown. METHODS: We aimed to determine whether TBI is associated with long-term adverse renal outcomes. We performed a nationwide, population-based, propensity score-matched cohort study of 32,152 TBI patients and 128,608 propensity score-matched controls. Data were collected by the National Health Insurance Research Database of Taiwan from 2000 to 2012. Our clinical outcomes were chronic kidney disease (CKD), end-stage renal disease (ESRD) and the composite endpoint of ESRD or all-cause mortality. RESULTS: The incidence rate of CKD was higher in the TBI than in the control cohort (8.99 vs. 7.4 per 1000 person-years). The TBI patients also showed higher risks of CKD (adjusted hazard ratio [aHR] 1.14, 95% confidence interval [CI] 1.08-1.20; P < 0.001) and composite endpoints (aHR 1.08, 95% CI 1.01-1.15; P = 0.022) than the control groups, but the ESRD was not significantly different between the groups. In subgroup analyses, the risks of incident CKD and composite endpoints were significantly raised in TBI patients aged < 65 years and/or without comorbidities. However, the risks of both CKD and composite outcome were little affected by the severity of TBI. CONCLUSIONS: TBI has a modest but significant effect on incident CKD and composite endpoint, but not on ESRD alone. TBI patients under 65 are at greater risk of CKD and composite outcome than their older counterparts.
Asunto(s)
Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/mortalidad , Fallo Renal Crónico/etiología , Fallo Renal Crónico/mortalidad , Adulto , Factores de Edad , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
BACKGROUND: There is little information about the association between stroke and kidney diseases. We aimed to investigate the impact of stroke on long-term renal outcomes. METHODS: In this large population-based retrospective cohort study, we identified 100,353 subjects registered in the National Health Insurance Research Database of Taiwan from January 1, 2000, through December 31, 2012, including 33,451 stroke patients and 66,902 age-, sex- and Charlson's comorbidity index score-matched controls. RESULTS: The incidence rate of chronic kidney disease (CKD) was higher in the stroke than in the control cohort (17.5 vs. 9.06 per 1000 person-years). After multivariate adjustment, the risk of developing CKD was significantly higher in patients with stroke (adjusted hazard ratio [aHR] 1.43, 95% confidence interval [CI] 1.36-1.50, P<0.001). Subgroup analysis showed that stroke patients <50 years (aHR 1.61, P<0.001) and those with concomitant diabetes mellitus (aHR 2.12, P<0.001), hyperlipidemia (aHR 1.53, P<0.001) or gout (aHR 1.84, P<0.001) were at higher risk of incident CKD. Additionally, the risks of progression to advanced CKD and end-stage renal disease (ESRD) were significantly higher for stroke patients (aHRs, 1.22 and 1.30; P = 0.04 and P = 0.008, respectively), independent of age, sex, comorbidities and long-term medications. CONCLUSIONS: Stroke is associated with higher risks for incident CKD, decline in renal function and ESRD. Younger stroke patients, as well as those with concomitant diabetes mellitus, hyperlipidemia or gout are at greater risk for kidney diseases.
Asunto(s)
Enfermedades Renales/epidemiología , Fallo Renal Crónico/epidemiología , Accidente Cerebrovascular/epidemiología , Adulto , Anciano , Comorbilidad , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/diagnóstico , Masculino , Persona de Mediana Edad , Prevalencia , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Taiwán , Resultado del TratamientoRESUMEN
BACKGROUND: Evidence is accumulating that a preclinical phase is present before the onset of clinical signs and symptoms of rheumatoid arthritis (RA). This phase represents an important therapeutic window within which interventions can dramatically modulate outcomes. An agent able to prevent RA for high risk individuals in this phase is therefore desired. In this study, we investigated whether tryptophan metabolite, 5-hydroxytryptophan (5-HTP) or 5-methoxytryptophan (5-MTP), can act as such an agent for primary prevention of collagen-induced arthritis (CIA). METHODS: Mouse splenocytes were pretreated with 5-HTP or 5-MTP and activated by anti-CD3 plus anti-CD28 antibodies in vitro. The percentages of interferon-γ (IFNγ)(+)CD4(+) T cells and interleukin-17 (IL-17)(+)CD4(+) T cells were measured by flow cytometry. The production of pro-inflammatory cytokines, serotonin and kynurenine was measured by enzyme-linked immunosorbent assay. A CIA model was used to investigate the in vivo effects of 5-HTP on the prevention of arthritis. RESULTS: 5-HTP decreased the percentages of IFNγ(+)CD4(+) T cells and IL-17(+)CD4(+) T cells and suppressed the production of IL-2, IL-4, IL-6, IL-17, tumor necrosis factor-α (TNFα) and IFNγ in activated splenocytes. 5-HTP administered before induction decreased the disease activities in CIA mice and suppressed the production of TNFα, IL-6 and cyclooxygenase-2 in arthritic joints. 5-HTP also increased serotonin, but decreased kynurenine in the CIA mice. CONCLUSIONS: 5-HTP suppresses inflammation and arthritis through decreasing the production of pro-inflammatory mediators. 5-HTP supplement before induction ameliorates arthritis in a CIA model.