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BACKGROUND: N6-Methyladenosine (m6A) modification has been implicated in many bioprocesses. However, its functions in diabetic nephropathy (DN) have not been determined. Here, we investigated the role of METTL14, a key component of the m6A methyltransferase complex, in DN. METHODS: The expression of METTL14 was detected in DN patients and human renal glomerular endothelial cells (HRGECs). In vitro and in vivo experiments were performed to explore the functions of METTL14 on high glocse-induced HRGECs and renal injury of DN mice. We also investigated whether METTL14 works by regulating α-klotho expression through m6A modification. RESULTS: METTL14 were highly expressed in kidneys of DN patients and high glocse-induced HRGECs both at the mRNA and protein level. Overexpression of METTL14 increased ROS, TNF-α and IL-6 levels and apoptosis in HRGECs. Conversely, METTL14 silence decreased the levels of ROS, TNF-α and IL-6 and cell apoptosis. We confirmed that METTL14 down-regulated α-klotho expression in an m6A-dependent manner. In addition, we also found that METTL14 aggravated renal injury and inflammation of db/db mice, which could partially rescued by α-klotho. CONCLUSION: Our data revealed that METTL14 plays a vital role in high glucose-induced glomerular endothelial cells and diabetic nephropathy through m6A modification of α-klotho.
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Adenina/análogos & derivados , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Células Endoteliales/metabolismo , Glomérulos Renales/metabolismo , Proteínas Klotho/genética , Metiltransferasas/metabolismo , ARN Mensajero/genética , Adenina/metabolismo , Animales , Biomarcadores , Glucemia , Células Cultivadas , Nefropatías Diabéticas/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Células Endoteliales/patología , Regulación de la Expresión Génica , Humanos , Inmunohistoquímica , Glomérulos Renales/patología , Proteínas Klotho/metabolismo , Metiltransferasas/genética , Ratones , ARN Mensajero/metabolismoRESUMEN
Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability.
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Antineoplásicos/toxicidad , Cisplatino/toxicidad , Pérdida Auditiva/prevención & control , Indoles/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Cisplatino/administración & dosificación , Cisplatino/farmacología , Cóclea/efectos de los fármacos , Cóclea/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Relación Dosis-Respuesta a Droga , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Femenino , Células HT29 , Pérdida Auditiva/inducido químicamente , Humanos , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Endogámicas F344 , Ratas DesnudasRESUMEN
Rituximab (RTX) has been the first option in idiopathic membranous nephropathy (IMN). However, the clinical effect was not very satisfactory. This study aimed to explore the clinical efficacy and safety of the combination of RTX and glucocorticoids (GC) in anti-phospholipase A2 receptor (anti-PLA2R) antibody positive IMN. Sixty-six patients were randomly divided into RTX/GC group (RTX infusion plus short-term oral GC) and RTX group (RTX infusion alone) in this prospective cohort study. Complete remission (CR) and partial remission (PR) were the primary outcomes. Adverse events were the secondary outcomes. The laboratory index including serum albumin, 24 h urinary protein, serum creatinine, estimated glomerular filtration rate, and anti-PLA2R antibody titer were also monitored. All patients were followed for at least 12 months. During the 12-month follow-up, the composite remission rates in RTX/GC and RTX groups were 74.3% and 67.7%, and the CR rates were 34.3% and 19.4%, respectively. The median time of remission in RTX/GC group was shorter than the RTX group (P < 0.001). Compared with RTX monotherapy, the combination of RTX and GC significantly decreased the anti-PLA2R antibody titer (P = 0.028). No significant difference was observed in the incidence of adverse events. The results of the Kaplan-Meier survival analysis indicated that the cumulative CR rate and cumulative composite remission rate in RTX/GC group were all better than the RTX group (P = 0.043, P = 0.040, respectively). The combination of RTX and GC was better than RTX monotherapy without increasing the adverse events in the treatment of IMN.
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Glomerulonefritis Membranosa , Humanos , Rituximab/efectos adversos , Glomerulonefritis Membranosa/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Estudios Prospectivos , Resultado del Tratamiento , Autoanticuerpos , Estudios RetrospectivosRESUMEN
As aging increases, monoclonal gammopathy is becoming more common and monoclonal gammopathy of renal significance (MGRS) is gaining attention due to frequent renal involvement. Within MGRS, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a special category. The disease was first described in 2004 and the research history on it is relatively short. Compared with other MGRS, the detection rate of circulating clones is lower in patients with PGNMID, which is easy to miss and misdiagnose in clinical work. In this review, the etiology and clinical features of PGNMID are discussed. It is noted that PGNMID is associated not only with MGRS, but also with malignancy, infection and other factors. PGNMID is not a disease exclusive to the elderly-young people can also develop this disease. Due to the low detection rate of circulating clones in most patients, confirmation of the disease needs to be combined with renal pathology, which emphasizes the importance of completing light and heavy chain subtype staining. Treatment options for patients with PGNMID differ by etiology. For MGRS-associated PGNMID, the current treatment is primarily empirical and more research evidence is needed to fill the treatment gap.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with multiple complex mechanisms involved. Among them, mitochondrial dysfunction plays an important role in ALS. Multiple studies have shown that mitochondria are closely associated with reactive oxygen species production and oxidative stress and exhibit different functional states in different genetic backgrounds. In this review we explored the roles of Ca2+, autophagy, mitochondrial quality control in the regulation of mitochondrial homeostasis and their relationship with ALS. In addition, we also summarized and analyzed the roles of protein misfolding and abnormal aggregation in the pathogenesis of ALS. Moreover, we also discussed how epigenetic mechanisms such as DNA methylation and protein post-translational modification affect initiation and progression of ALS. Nevertheless, existing events still cannot fully explain the pathogenesis of ALS at present, more studies are required to explore pathological mechanisms of ALS.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Esclerosis Amiotrófica Lateral/metabolismo , Epigénesis Genética , Humanos , Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Introduction: Immunomodulatory drugs (IMiDs) plus dexamethasone are effective for plasma cell dyscrasias, but the treatment efficacy of IMiD in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) has been rarely reported. Methods: We retrospectively analyzed the clinicopathologic data of 64 patients with PGNMID (steroid, IMiD, and bortezomib and dexamethasone/Rituximab [BD/RTX] groups) from January 1, 2010 to December 31, 2020, at the National Clinical Research Center of Kidney Disease in Nanjing. The prognosis of patients receiving different treatment regimens were compared. Factors potentially affecting renal prognosis and renal response were evaluated. Results: Twenty-eight, 26 and 10 PGNMID patients were divided into IMiD group, steroid group and BD/RTX group respectively. The rate of serum M protein detection was significantly lower in the steroid group than in the other 2 groups. Renal remission (P = 0.001 and P = 0.03, respectively) rates and renal complete remission (CR) (P = 0.001 and P = 0.01, respectively) rates were significantly higher in the IMiD and BD/RTX groups than in the steroid group at the last follow-up. Multivariate logistic analysis identified that hypertension and high serum creatinine (SCr) levels (>1.24 mg/dl) decreased renal remission, whereas low C3 levels, IMiD and BD/RTX treatments were positively associated with renal remission. Multivariate Cox analysis identified IgG3 in renal tissue and high SCr levels as poor renal prognostic indicators. Severe adverse events were more common in the IMiD and BD/RTX groups than in the steroid group (P = 0.072 and P = 0.035, respectively). Conclusion: Our results suggest that IMiDs plus dexamethasone is effective for achieving renal remission in PGNMID patients.
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A GO (graphene oxide)/ZnO/Cu2O antibacterial coating was successfully sprayed on the ultrafine glass fibers using room temperature hydrothermal synthesis and air spraying techniques. The microstructures of the antibacterial coating were characterized, and the results showed that the Cu2ONPs (nano particles)/ZnONPs were uniformly dispersed on the surface of GO. Then, the antibacterial properties of the GO/ZnO/Cu2O (GZC) antibacterial coating were evaluated using the disc diffusion test. It was found that the coating exhibits excellent antibacterial properties and stability against E. coli and S. aureus, and the antibacterial rate of each group of antibacterial powder against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) was 100%. To explore the antibacterial mechanism of the GZC antibacterial powder on the ultrafine glass fibers based on the photocatalysis/oxidative stress method, the photoelectric coupling synergistic effect between GZC antibacterial coating was analyzed deeply. The results all showed that the photochemical activity of GZC antibacterial powder was significantly improved compared with pure component materials. The enhancement of its photochemical activity is beneficial to the generation of ROS (including hydroxyl radicals, superoxide anion radicals, etc.), which further confirms the speculation of the photocatalytic/oxidative stress mechanism.
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This retrospective study aimed to explore the relative efficacy and safety of different tacrolimus (TAC) concentrations in the treatment of patients with idiopathic membranous nephropathy (IMN). A total of 260 IMN patients with nephrotic syndrome (NS) were recruited. Among these, 125 patients had TAC concentrations no greater than 5 ng/ml (CTAC ≤ 5 ng/ml), and 135 patients had TAC concentrations greater than 5 ng/ml (CTAC > 5 ng/ml). The primary outcomes included complete remission (CR) rates and overall (OR) response rates. The secondary outcomes included 24-h urinary protein (24-h UP), serum albumin and serum creatinine, and adverse events (AEs). During the 12-month follow-up, the overall response rates were significantly different between the CTAC ≤ 5 ng/ml group and the CTAC > 5 ng/ml group (P < 0.0001). However, there was no significant difference in the CR at 12 months between the two groups (chi-square, 62% vs 63%, P = 0.852). Compared with the CTAC ≤ 5 ng/ml group, the CTAC > 5 ng/ml group had improved levels of 24 h UP (P = 0.017) and serum albumin (P = 0.010). Moreover, the incidences of acute reversible nephrotoxicity (P < 0.001), hepatotoxicity (P = 0.036), new-onset diabetes mellitus (P = 0.036), and glucose intolerance (P = 0.005) were lower in the CTAC ≤ 5 ng/ml group than in the CTAC > 5 ng/ml group. The CTAC > 5 ng/ml group was improved relative to the CTAC ≤ 5 ng/ml group in terms of a PR and CR at 6 months, but there was no difference in the CR between the two groups at 12 months.
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Glomerulonefritis Membranosa/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Tacrolimus/uso terapéutico , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Proteinuria/orina , Curva ROC , Inducción de Remisión , Estudios Retrospectivos , Albúmina Sérica/análisis , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Resultado del TratamientoRESUMEN
Obesity has a strong impact on the pathogenesis of cardiovascular disease, which raises enthusiasm to understand how excess adiposity causes vascular injury. Adipose tissue is an essential regulator of cardiovascular system through its endocrine and paracrine bioactive products. Obesity induces endothelial dysfunction, which often precedes and leads to the development of cardiovascular diseases. Connecting adipose tissue-endothelial cell interplay to endothelial dysfunction may help us to better understand obesity-induced cardiovascular disease. This Mini Review discussed (1) the general interactions and obesity-induced endothelial dysfunction, (2) potential targets, and (3) the outstanding questions for future research.
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The objective of the study was to evaluate the characteristics and prognosis of 56 patients with rheumatoid arthritis (RA)-associated renal involvement by retrospective review of their renal biopsy specimens. Included in this cross-sectional study were 56 RA patients with renal involvement, in whom renal biopsy was performed to analyze the histological pattern and renal prognosis. IgA nephropathy (IgAN) was detected in 48.2% of the 56 included patients as the most common renal histological pattern, followed by membranous nephropathy (MN) in 23.2% cases, focal segmental glomerular sclerosis (FSGS) in 19.6% cases, chronic interstitial nephritis (CIN) in 5.4% cases, membranoproliferative glomerulonephritis (MPGN) in 1.8% cases, and non-IgA mesangial proliferative glomerulonephritis in 1.8% cases. No significant relationship was observed between the histopathologic type and the RA duration, joint deformity or treatment. Renal dysfunction was mainly found in IgAN patients, and MN occurred more frequently in older patients. Renal function decline occurred in two IgAN patients, one with FSGS and the other with MPGN. Another CIN patient progressed to dialysis during the follow-up period. The patients with renal function decline had a significantly higher level of serum creatinine at presentation. The high percentage of glomeruli sclerosis and interstitial fibrosis/tubular atrophy was also related to renal function decline. IgAN was the major RA-associated renal histological lesion in our series. Renal biopsy can provide useful information about the histological pattern and renal prognosis and therefore should be considered in RA patients with renal involvement.
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Artritis Reumatoide/patología , Glomerulonefritis/patología , Riñón/patología , Adulto , Anciano , Artritis Reumatoide/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Glomerulonefritis por IGA/patología , Glomerulonefritis Membranosa/patología , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Masculino , Persona de Mediana Edad , Nefritis Intersticial/patología , Proteinuria/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to have high potency, a fine pharmacokinetic profile, and a long-acting inâ vivo efficacy.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Administración Oral , Biotransformación , Diabetes Mellitus Tipo 2/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/química , Relación Dosis-Respuesta a Droga , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Estructura Molecular , Pirimidinas/administración & dosificación , Pirimidinas/química , Pirroles/administración & dosificación , Pirroles/química , Relación Estructura-ActividadRESUMEN
Apoptotic cell death has been implicated in cochlear degeneration during aging. To better understand the impact and the biological process of outer hair cell (OHC) apoptosis, we investigated the contribution of apoptotic cell death to the formation of the OHC lesions, and observed the temporal patterns of the occurrence of apoptotic events associated with the mitochondrial pathway in Fischer 344/NHsd rats, with ages ranging from 20 to 27 months. The results showed that the ratio of apoptotic to necrotic OHCs was 8:1. During the process of cell degeneration, the onset of Bax expression, cytochrome c release, and nuclear DNA fragmentation preceded the onset of nuclear condensation. In contrast, the activation of caspases-3 and -9, as well as the degradation of F-actin, took place after the onset of nuclear condensation. The results of this study suggest that the initiation of nuclear degradation is a caspase-3-independent process. Moreover, the study revealed that OHCs with Bax expression or cytochrome c release could enter either the apoptotic or necrotic pathway, suggesting the presence of a regulatory mechanism that guides degenerating OHCs to die via either the apoptotic or necrotic pathway.
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Envejecimiento/patología , Apoptosis , Células Ciliadas Auditivas Externas/patología , Actinas/metabolismo , Envejecimiento/fisiología , Animales , Caspasa 3/metabolismo , Núcleo Celular/patología , Núcleo Celular/fisiología , Citocromos c/metabolismo , Fragmentación del ADN , Potenciales Evocados Auditivos del Tronco Encefálico , Células Ciliadas Auditivas Externas/fisiología , Mitocondrias/patología , Mitocondrias/fisiología , Necrosis , Ratas , Ratas Endogámicas F344 , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Studies of the F344 rat have shown a variety of age-related auditory anatomy and physiology changes. The current study was undertaken to clarify the ARHL in the F344 rat, by examining the auditory pathway of the F344/NHsd substrain that is distributed by Harlan Laboratories for research in the United States. The F344/NHsd rat begins to lose its hearing at about 12 months, and by 24 months, there are 50-60 dB auditory brainstem response threshold shifts at 20 and 40 kHz and 20 dB losses at 5-10 kHz. Distortion product otoacoustic emissions (DPOAE) amplitudes at 1.8-12 kHz stimuli were depressed in the older (18-24 months) rats. Amplitude input-output functions of the compound action potential (CAP) were also depressed across frequency. The endocochlear potential (EP) was 90-100 mV in the 3 month old rats. All but one of the 24 month old rats' EPs were in the +75-85 mV range. Tympanometry revealed no differences in middle ear function between the young and older rats. Collectively, these findings suggest damage to the outer hair cells, but anatomical examination of the outer hair cells revealed a relative lack of cell loss compared to the magnitude of the hearing and DPOAE loss.
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Envejecimiento , Vías Auditivas/fisiopatología , Pérdida Auditiva/fisiopatología , Pruebas de Impedancia Acústica , Estimulación Acústica , Factores de Edad , Animales , Vías Auditivas/patología , Umbral Auditivo , Cóclea/fisiopatología , Nervio Coclear/fisiopatología , Potenciales Evocados Auditivos del Tronco Encefálico , Células Ciliadas Auditivas Externas/patología , Pérdida Auditiva/patología , Masculino , Emisiones Otoacústicas Espontáneas , Ratas , Ratas Endogámicas F344 , Especificidad de la EspecieRESUMEN
Atherosclerosis is a chronic progressive inflammatory process that can eventually lead to cardiovascular disease (CVD). Despite available treatment, the prevalence of atherosclerotic CVD, which has become the leading cause of death worldwide, persists. Identification of new mechanisms of atherogenesis are highly needed in order to develop an effective therapeutic treatment. The blood vessels contain two primary major cell types: endothelial cells (EC) and vascular smooth muscle cells (VSMC). Each of these performs an essential function in sustaining vascular homeostasis. EC-VSMC communication is essential not only to development, but also to the homeostasis of mature blood vessels. Aberrant EC-VSMC interaction could promote atherogenesis. Identification of the mode of EC-VSMC crosstalk that regulates vascular functionality and sustains homeostasis may offer strategic insights for prevention and treatment of atherosclerotic CVD. Here we will review the molecular mechanisms underlying the interplay between EC and VSMC that could contribute to atherosclerosis. We also highlight open questions for future research directions.
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Obesity is a worldwide epidemic that predisposes individuals to metabolic complications, such as type 2 diabetes mellitus and non-alcoholic fatty liver disease, all of which are related to an imbalance between food intake and energy expenditure. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are urgently needed. A well-accepted paradigm is that crosstalk between organs/tissues contributes to diseases. Endothelial dysfunction characterizes metabolic disorders and the related vascular complications. Over the past two decades, overwhelming studies have focused on mechanisms that lead to endothelial dysfunction. New investigations, however, have begun to appreciate the opposite direction of the crosstalk: endothelial regulation of metabolism, although the underlying mechanisms remain to be elucidated. This review summarizes the evidence that supports the concept of endothelial regulation of obesity and the associated insulin resistance in fat, liver, and skeletal muscles, the classic targets of insulin. Outstanding questions and future research directions are highlighted. Identification of the mechanisms of vascular endothelial regulation of metabolism may offer strategies for prevention and treatment of obesity and the related metabolic complications.
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HYPOTHESIS: Triple semicircular canal occlusion will eliminate rotatory stimulation to the vestibular peripheral system (as it blocks endolymphatic fluid movement) and therefore release rotatory vertigo attack. This surgery is safe in ears with endolymphatic hydrops. BACKGROUND: Semicircular canal occlusion has been used as an alternative treatment of intractable benign paroxysmal positional vertigo with varied success. Triple semicircular canal occlusion in animal models blocks the responses of the semicircular canals to rotation and spares cochleae and the otolithic apparatus. This result suggests that triple semicircular canal occlusion is a prospective method in vertigo management for patients with Ménière's disease. However, the effectiveness and safety of triple semicircular canal occlusion has not been fully evaluated in ears with endolymphatic hydrops. METHODS: Endolymphatic hydrops was established in 20 guinea pigs by endolymphatic sac obliteration. Triple semicircular canal occlusion was performed in 12 of them 120 days after endolymphatic hydrops surgery, whereas 8 others were killed for morphologic observation to confirm endolymphatic hydrops. Auditory and vestibular functions were monitored from the time before endolymphatic hydrops until 1 month after triple semicircular canal occlusion. Endolymphatic hydrops and canal occlusion were confirmed by morphologic observation. RESULTS: Successful establishment of endolymphatic hydrops was indicated by mild elevation of the auditory brainstem response threshold and tentative asymmetry in nystagmus. Endolymphatic hydrops was confirmed by cochlear morphology in all eight animals that were killed 120 days after endolymphatic hydrops surgery. After triple semicircular canal occlusion, all 12 animals showed spontaneous nystagmus with a slow component toward the side that had been operated on, head tilt, rotated walking, and tentative asymmetry in rotatory nystagmus. The static symptoms disappeared within 1 month after triple semicircular canal occlusion. Caloric nystagmus was only slightly reduced after endolymphatic hydrops as compared with the contralateral ears but could not be elicited at all after triple semicircular canal occlusion. No significant elevation in auditory brainstem response threshold was found after triple semicircular canal occlusion. The canal occlusion and endolymphatic hydrops were confirmed in all surgical ears. CONCLUSION: Triple semicircular canal occlusion is effective for eliminating the response of semicircular canals to rotation and caloric stimulation and is safe in ears with endolymphatic hydrops. Also, the static compensation to the disequilibrium is quick and complete. These results suggest that triple semicircular canal occlusion should be an option for controlling rotatory vertigo in Ménière's disease.
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Hidropesía Endolinfática/cirugía , Canales Semicirculares/cirugía , Vértigo/cirugía , Animales , Modelos Animales de Enfermedad , Hidropesía Endolinfática/complicaciones , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Cobayas , Masculino , Nistagmo Fisiológico , Resultado del Tratamiento , Vértigo/etiología , Vestíbulo del Laberinto/fisiologíaRESUMEN
Our study was to elucidate the mechanisms whereby BMS-345541 (BMS, a specific IκB kinase ß inhibitor) inhibits the repair of DNA double-strand breaks (DSBs) and evaluate whether BMS can sensitize MCF-7 breast cancer cells (MCF-7 cells) to ionizing radiation (IR) in an apoptosis-independent manner. In this study, MCF-7 cells were exposed to IR in vitro and in vivo with or without pretreatment of BMS. The effects of BMS on the repair of IR-induced DSBs by homologous recombination (HR) and non-homologous end-joining (NHEJ) were analyzed by the DR-GFP and EJ5-GFP reporter assays and IR-induced γ-H2AX, 53BP1, Brca1 and Rad51 foci assays. The mechanisms by which BMS inhibits HR were examined by microarray analysis and quantitative reverse transcription PCR. The effects of BMS on the sensitivity of MCF-7 cells to IR were determined by MTT and clonogenic assays in vitro and tumor growth inhibition in vivo in a xenograft mouse model. The results showed that BMS selectively inhibited HR repair of DSBs in MCF-7 cells, most likely by down-regulation of several genes that participate in HR. This resulted in a significant increase in the DNA damage response that sensitizes MCF-7 cells to IR-induced cell death in an apoptosis-independent manner. Furthermore, BMS treatment sensitized MCF-7 xenograft tumors to radiation therapy in vivo in an association with a significant delay in the repair of IR-induced DSBs. These data suggest that BMS is a novel HR inhibitor that has the potential to be used as a radiosensitizer to increase the responsiveness of cancer to radiotherapy.
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Neoplasias de la Mama/patología , Roturas del ADN de Doble Cadena/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de la radiación , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Recombinación Homóloga/efectos de los fármacos , Imidazoles/farmacología , Quinoxalinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Transformación Celular Neoplásica , Reparación del ADN/efectos de la radiación , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/efectos de la radiación , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Recombinación Homóloga/efectos de la radiación , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Ratones , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
In the present study, glial cell responses to spiral ganglion neuron (SGN) degeneration were evaluated using a murine model of auditory neuropathy. Ouabain, a well-known Na,K-ATPase inhibitor, has been shown to induce SGN degeneration while sparing hair cell function. In addition to selectively removing type I SGNs, ouabain leads to hyperplasia and hypertrophy of glia-like cells in the injured auditory nerves. As the transcription factor Sox2 is predominantly expressed in proliferating and undifferentiated neural precursors during neurogenesis,we sought to examine Sox2 expression patterns following SGN injury by ouabain. Real-time RT-PCR and Western blot analyses of cochlea indicated a significant increase in Sox2 expression by 3 days posttreatment with ouabain. Cells incorporating bromodeoxyuridine(BrdU) and expressing Sox2 were counted in the auditory nerves of control and ouabain-treated ears. The glial phenotype of Sox2+cells was identified by two neural glial markers: S100 and Sox10. The number of Sox2+ glial cells significantly increased at 3 days post-treatment and reached its maximum level at 7 days post-treatment. Similarly,the number of BrdU+ cells increased at 3 and 7 days post-treatment in the injured nerves. Quantitative analysis with dual-immunostaining procedures indicated that about 70% of BrdU+ cells in the injured nerves were Sox2+ glial cells. These results demonstrate that up-regulation of Sox2 expression is associated with increased cell proliferation in the auditory nerve after injury.
Asunto(s)
Proliferación Celular , Oído Interno/inervación , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuroglía/metabolismo , Neuroglía/patología , Factores de Transcripción SOXB1/metabolismo , Animales , Nervio Coclear/efectos de los fármacos , Nervio Coclear/metabolismo , Nervio Coclear/patología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Femenino , Pérdida Auditiva Central/metabolismo , Pérdida Auditiva Central/patología , Masculino , Ratones , Ratones Endogámicos CBA , Degeneración Nerviosa/inducido químicamente , Ouabaína/efectos adversos , Ouabaína/farmacología , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ganglio Espiral de la Cóclea/metabolismo , Ganglio Espiral de la Cóclea/patología , Regulación hacia Arriba/fisiologíaRESUMEN
With the exception of humans, the somata of type I spiral ganglion neurons (SGNs) of most mammalian species are heavily myelinated. In an earlier study, we used Ly5.1 congenic mice as transplant recipients to investigate the role of hematopoietic stem cells in the adult mouse inner ear. An unanticipated finding was that a large percentage of the SGNs in this strain were unmyelinated. Further characterization of the auditory phenotype of young adult Ly5.1 mice in the present study revealed several unusual characteristics, including 1) large aggregates of unmyelinated SGNs in the apical and middle turns, 2) symmetrical junction-like contacts between the unmyelinated neurons, 3) abnormal expression patterns for CNPase and connexin 29 in the SGN clusters, 4) reduced SGN density in the basal cochlea without a corresponding loss of sensory hair cells, 5) significantly delayed auditory brainstem response (ABR) wave I latencies at low and middle frequencies compared with control mice with similar ABR threshold, and 6) elevated ABR thresholds and deceased wave I amplitudes at high frequencies. Taken together, these data suggest a defect in Schwann cells that leads to incomplete myelinization of SGNs during cochlear development. The Ly5.1 mouse strain appears to be the only rodent model so far identified with a high degree of the "human-like" feature of unmyelinated SGNs that aggregate into neural clusters. Thus, this strain may provide a suitable animal platform for modeling human auditory information processing such as synchronous neural activity and other auditory response properties.