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1.
Front Bioeng Biotechnol ; 12: 1394314, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39086498

RESUMEN

Knee sleeves are commonly used to address knee-related concerns, particularly in older individuals. Although previous studies have demonstrated their efficacy in improving gait and functional outcomes in knees with pathological conditions, the effectiveness of knee sleeves for improving gait characteristics in healthy older adults remains unclear. The harmonic ratio (HR), an index for assessing gait symmetry commonly used to discriminate between individuals with different functional levels, can be used to detect alterations in gait characteristics. This study investigated the effects of knee sleeves on gait symmetry in healthy older adults. Sixteen healthy community-dwelling older adults walked barefoot with and without knee sleeves at normal and fast speeds. Gait symmetry indices (HR and improved HR [iHR]) and spatiotemporal gait parameters were compared under different conditions. A significant interaction between knee condition and walking speed was observed for mean iHR in the anteroposterior direction (p = 0.006). A significant simple main effect of knee condition was found during fast walking, with a larger iHR with knee sleeves than without (p = 0.002). In the condition without knee sleeves, the iHR was significantly lower during fast walking than during normal walking (p = 0.035). Furthermore, a significant main effect of knee condition was observed for the variability of iHR in the anteroposterior direction, with a smaller variability when walking with knee sleeves than when walking without (p = 0.006). These results suggest that knee sleeves may enhance gait symmetry along the anteroposterior direction, particularly during fast walking, where symmetry disruption is more likely than walking at a comfortable pace. A significant reduction in gait symmetry variability also suggests a stabilizing effect on gait dynamics. These findings provide the first evidence supporting the efficacy of knee sleeves for improving gait symmetry. The use of knee sleeves could be a valuable option for restoring disrupted gait symmetry during fast walking, with potential implications for reducing the risk of falls.

2.
J Sports Sci Med ; 22(4): 626-636, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38045743

RESUMEN

Static stretching (SS), dynamic stretching (DS), and combined stretching (CS; i.e., DS+SS) are commonly performed as warm-up exercises. However, the stretching method with the greatest effect on flexibility and performance remains unclear. This randomized crossover trial examined acute and prolonged effects of SS, DS, and CS on range of motion (ROM), peak passive torque (PPT), passive stiffness, and isometric and concentric muscle forces. Twenty healthy young men performed 300 sec of active SS, DS, or CS (150-sec SS followed by 150-sec DS and 150-sec DS followed by 150-sec SS) of the right knee flexors on four separate days, in random order. Subsequently, we measured ROM, PPT, and passive stiffness during passive knee extension. We also measured maximum voluntary isometric and concentric knee flexion forces and surface electromyographic activities during force measurements immediately before, immediately after, and 20 and 60 min after stretching. All stretching methods significantly increased ROM and PPT, while significantly decreasing isometric knee flexion force (all p < 0.05). These changes lasted 60 min after all stretching methods; the increases in ROM and PPT and the decreases in isometric muscle force were similar. All stretching methods also significantly decreased passive stiffness immediately after stretching (all p < 0.05). Decreases in passive stiffness tended to be longer after CS than after SS or DS. Concentric muscle force was decreased after SS and CS (all p < 0.05). On the other hand, concentric muscle force was unchanged after DS, while the decreases in surface electromyographic activities during concentric force measurements after all stretching methods were similar. Our results suggest that 300 sec of SS, DS, and CS have different acute and prolonged effects on flexibility and muscle force.


Asunto(s)
Ejercicios de Estiramiento Muscular , Músculo Esquelético , Masculino , Humanos , Músculo Esquelético/fisiología , Rodilla/fisiología , Pierna , Articulación de la Rodilla
3.
Sci Rep ; 12(1): 1676, 2022 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-35102162

RESUMEN

Frailty is associated with gait variability in several quantitative parameters, including high stride time variability. However, the associations between joint kinematics during walking and increased gait variability with frailty remain unclear. In the current study, principal component analysis was used to identify the key joint kinematics characteristics of gait related to frailty. We analyzed whole kinematic waveforms during the entire gait cycle obtained from the pelvis and lower limb joint angle in 30 older women (frail/prefrail: 15 participants; non-frail: 15 participants). Principal component analysis was conducted using a 60 × 1224 input matrix constructed from participants' time-normalized pelvic and lower-limb-joint angles along three axes (each leg of 30 participants, 51 time points, four angles, three axes, and two variables). Statistical analyses revealed that only principal component vectors 6 and 9 were related to frailty. Recombining the joint kinematics corresponding to these principal component vectors revealed that frail older women tended to exhibit greater variability of knee- and ankle-joint angles in the sagittal plane while walking compared with non-frail older women. We concluded that greater variability of knee- and ankle-joint angles in the sagittal plane are joint kinematic characteristics of gait related to frailty.


Asunto(s)
Anciano Frágil , Fragilidad/fisiopatología , Análisis de la Marcha , Grabación en Video , Caminata , Factores de Edad , Anciano , Articulación del Tobillo/fisiopatología , Fenómenos Biomecánicos , Estudios de Casos y Controles , Femenino , Fragilidad/diagnóstico , Humanos , Interpretación de Imagen Asistida por Computador , Articulación de la Rodilla/fisiopatología , Persona de Mediana Edad , Análisis de Componente Principal , Rango del Movimiento Articular , Factores Sexuales , Factores de Tiempo
4.
Food Nutr Bull ; 42(1): 91-103, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33878907

RESUMEN

BACKGROUND: Globally, ready-to-use therapeutic food (RUTF) with peanut and milk as the primary source of protein is used to treat children having severe acute malnutrition (SAM). Valid Nutrition in collaboration with Ajinomoto Co., Inc has developed a nonmilk RUTF from soybean, maize, and sorghum (SMS-RUTF) and demonstrated its efficacy. OBJECTIVE: To pilot SMS-RUTF in treatment of SAM within Community-Based Management of Acute Malnutrition (CMAM) program in Malawi, Africa. METHODS AND FINDINGS: This was implemented from January to July 2018 and its performance was based on the SPHERE criteria and Ministry of Health CMAM guidelines. A total of 742 children were treated with SMS-RUTF. Of these, 94.5% (95% CI: 92.6-96.0) were successfully discharged to supplementary feeding program (SFP) with middle upper arm circumference (MUAC) ≥115 mm or directly to their homes with MUAC ≥125 mm; 3.6% (95% CI: 2.4-5.3) defaulted, 1.9 % (95% CI: 1.0-2.1) died, and 0.0% nonresponders. Analysis of 222 children who were discharged home with MUAC ≥125 mm gave a recovery rate of 88.3% (95% CI: 88.3-92.2), a defaulter rate of 6.8 % (95% CI: 3.8-10.9), a mortality rate of 1.3% (95% CI: 0.3-3.9), and a nonresponders rate of 1.8% (95% CI: 0.5-4.5). These outcomes exceed SPHERE minimum performance standards. The mean (standard deviation) length of stay of children discharged to SFP and discharged directly home were 42.0 (20.9) and 46.1 (21.1) days, respectively. These outcomes are within the recommended average duration of <60 days. CONCLUSION: The pilot CMAM program using SMS-RUTF recipe that contains no milk or peanuts achieved SPHERE minimum standards. Based on this evidence, SMS-RUTF should be encouraged for treatment of SAM in children between 6 and 59 months in routine CMAM programs in Malawi and globally.


Asunto(s)
Desnutrición , Desnutrición Aguda Severa , Sorghum , Animales , Niño , Comida Rápida , Humanos , Lactante , Malaui , Desnutrición/terapia , Leche , Proyectos Piloto , Desnutrición Aguda Severa/terapia , Glycine max , Resultado del Tratamiento , Zea mays
5.
Am J Physiol Heart Circ Physiol ; 320(2): H679-H689, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33306444

RESUMEN

This study aimed to elucidate the effects of change in estrogen during the menstrual cycle and menopause on shear-mediated dilation of the internal carotid artery (ICA), a potential index of cerebrovascular endothelial function. Shear-mediated dilation of the ICA and serum estradiol were measured in 11 premenopausal (Pre-M, 21 ± 1 yr), 13 perimenopausal (Peri-M, 49 ± 2 yr), and 10 postmenopausal (Post-M, 65 ± 7 yr) women. Measurements were made twice within the Pre-M group at their early follicular (EF, lower estradiol) and late follicular (LF, higher estradiol) phases. Shear-mediated dilation was induced by 3 min of hypercapnia (target PETCO2 + 10 mmHg from individual baseline) and was calculated as the percent rise in peak diameter relative to baseline diameter. ICA diameter and blood velocity were simultaneously measured by Doppler ultrasound. In Pre-M, shear-mediated dilation was higher during the LF phase than during the EF phase (P < 0.01). Comparing all groups, shear-mediated dilation was reduced across the menopausal transition (P < 0.01), and Pre-M during the LF phase showed the highest value (8.9 ± 1.4%) compared with other groups (Pre-M in EF, 6.4 ± 1.1%; Peri-M, 5.5 ± 1.3%; Post-M, 5.2 ± 1.9%, P < 0.05 for all). Shear-mediated dilation was positively correlated with serum estradiol even after adjustment of age (P < 0.01, r = 0.55, age-adjusted; P = 0.02, r = 0.35). Collectively, these data indicate that controlling the menstrual cycle phase is necessary for the cross-sectional assessments of shear-mediated dilation of the ICA in premenopausal women. Moreover, current findings suggest that a decline in cerebrovascular endothelial function may be partly related to the reduced circulating estrogen levels in peri- and postmenopausal women.NEW & NOTEWORTHY The present study evaluated the effects of the menstrual cycle and menopause stages on the shear-mediated dilation of the ICA, a potential index of cerebrovascular endothelial function, in pre-, peri-, and postmenopausal women. Shear-mediated dilation of the ICA was increased from the low- to high-estradiol phases in naturally cycling premenopausal women and was reduced with advancing menopause stages. Furthermore, lower estradiol was associated with reduced shear-mediated dilation of the ICA, independent of age.


Asunto(s)
Arteria Carótida Interna/fisiología , Circulación Cerebrovascular , Estradiol/sangre , Menopausia/sangre , Ciclo Menstrual/sangre , Vasodilatación , Factores de Edad , Anciano , Velocidad del Flujo Sanguíneo , Arteria Carótida Interna/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad , Perimenopausia/sangre , Posmenopausia/sangre , Premenopausia/sangre , Flujo Sanguíneo Regional , Estrés Mecánico , Ultrasonografía Doppler , Adulto Joven
6.
Eur J Appl Physiol ; 121(2): 513-523, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33151438

RESUMEN

PURPOSE: The acute effects of static stretching have been frequently studied, but the chronic effects have not been studied concurrently. Thus, this study aimed to investigate both the acute and chronic effects of static stretching at different intensities on flexibility. METHODS: Twenty-three healthy men were randomly assigned to perform 1 min of static stretching 3 days/week for 4 weeks at 100% intensity (n = 12) or 120% intensity (n = 11). The acute effects of stretching were assessed by measuring the range of motion (ROM), peak passive torque, and passive stiffness before and after every stretching session; the chronic effects of stretching were assessed by measuring these outcomes at baseline and after 2 and 4 weeks of stretching. RESULTS: Compared with the 100% intensity group, the 120% intensity group had significantly greater acute increases in ROM after all 12 sessions, a significantly greater decrease in passive stiffness after 11 of 12 sessions, and a significantly greater increase in peak passive torque after six of 12 sessions. Regarding the chronic effects, ROM was significantly increased in both groups after 2 and 4 weeks of stretching. Peak passive torque significantly increased in the 100% intensity group after 2 and 4 weeks of stretching, and after 4 weeks in the 120% intensity group. CONCLUSION: Stretching at 120% intensity resulted in significantly greater acute improvements in ROM, peak passive torque, and stiffness than stretching at 100% intensity. Four weeks of stretching increased ROM and peak passive torque but did not decrease passive stiffness, regardless of the stretching intensity.


Asunto(s)
Ejercicios de Estiramiento Muscular/fisiología , Adulto , Humanos , Masculino , Músculo Esquelético/fisiología , Rango del Movimiento Articular/fisiología , Torque , Adulto Joven
7.
Sci Rep ; 10(1): 22248, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33335237

RESUMEN

In recent years, non-invasive measurement of tissue stiffness (hardness) using ultrasound elastography has attracted considerable attention. It has been used to evaluate muscle stiffness in the fields of rehabilitation, sports, and orthopedics. However, ultrasonic diagnostic devices with elastography systems are expensive and clinical use of such devices has been limited. In this study, we proposed a novel estimation method for vibration-based shear wave elastography measurement of human skeletal muscle, then determined its reproducibility and reliability. The coefficient of variation and correlation coefficient were used to determine reproducibility and reliability of the method by measuring the shear wave velocities in konjac phantom gels and agar phantom gels, as well as skeletal muscle. The intra-day, day-to-day, and inter-operator reliabilities were good when measuring the shear wave velocities in phantom gels. The intra-day and day-to-day reliabilities were good when measuring the shear wave velocities in skeletal muscle. The findings confirmed adequate reproducibility and reliability of the novel estimation method for vibration-based shear wave elastography. Therefore, the proposed measurement method may be a useful tool for evaluation of muscle stiffness.


Asunto(s)
Diagnóstico por Imagen de Elasticidad , Músculo Esquelético/fisiología , Voluntarios Sanos , Humanos , Masculino , Fantasmas de Imagen , Examen Físico , Reproducibilidad de los Resultados , Ultrasonografía Doppler , Vibración
8.
Biochem Biophys Rep ; 23: 100790, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32760814

RESUMEN

Nitric oxide (NO) is an important part of the host defense mechanism; however, it displays both pro- and anti-inflammatory properties depending on its location and concentration. Importantly, excessive or inappropriate NO production can cause tissue damage. Systemic and local administration of NO synthase (NOS) inhibitors ameliorates and may exacerbate the inflammatory response, respectively. Here, we used a carrageenan-induced pleurisy model of acute inflammation in rats to confirm the location-dependent effects of NO and investigate the underlying mechanisms. As expected, localized suppression of NO production exacerbated inflammation, as evidenced by increased pleural exudate volumes and leukocyte counts and enhanced activity of enzymes related to oxidative stress. In contrast, local NO supplementation reduced leukocyte infiltration, vascular permeability, and the activity of oxidative stress-related enzymes. Interestingly, inhibition of heme oxygenase-1 (HO-1) reversed the anti-inflammatory effects of localized NO production, while the addition of hemin (HO-1 substrate) or carbon monoxide (CO; HO-1 metabolite) decreased leukocyte migration and exudation. Together, these findings confirm a protective role for NO at the inflammatory site, which appears to be mediated via NOS induction of the HO-1/CO pathway. Thus, NO supplementation may be a potential new treatment for oxidative stress-associated inflammatory diseases.

9.
Sports Med Int Open ; 3(3): E89-E95, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31650019

RESUMEN

In this study, we examined the effects of static and dynamic stretching on range of motion (ROM), passive torque (PT) at pain onset, passive stiffness, and isometric muscle force. We conducted a randomized crossover trial in which 16 healthy young men performed a total of 300 s of active static or dynamic stretching of the right knee flexors on two separate days in random order. To assess the effects of stretching, we measured the ROM, PT at pain onset, passive stiffness during passive knee extension, and maximum voluntary isometric knee flexion force using an isokinetic dynamometer immediately before and after stretching. Both static and dynamic stretching significantly increased the ROM and PT at pain onset (p<0.01) and significantly decreased the passive stiffness and isometric knee flexion force immediately after stretching (p<0.01). However, the magnitude of change did not differ between the two stretching methods for any measurements. Our results suggest that 300 s of either static or dynamic stretching can increase flexibility and decrease isometric muscle force; however, the effects of stretching do not appear to differ between the two stretching methods.

10.
J Cell Physiol ; 232(3): 650-664, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27649272

RESUMEN

It is generally recognized that synthetic glucocorticoids induce skeletal muscle weakness, and endogenous glucocorticoid levels increase in patients with muscle atrophy. It is reported that heat stress attenuates glucocorticoid-induced muscle atrophy; however, the mechanisms involved are unknown. Therefore, we examined the mechanisms underlying the effects of heat stress against glucocorticoid-induced muscle atrophy using C2C12 myotubes in vitro, focusing on expression of key molecules and signaling pathways involved in regulating protein synthesis and degradation. The synthetic glucocorticoid dexamethasone decreased myotube diameter and protein content, and heat stress prevented the morphological and biochemical glucocorticoid effects. Heat stress also attenuated increases in mRNAs of regulated in development and DNA damage responses 1 (REDD1) and Kruppel-like factor 15 (KLF15). Heat stress recovered the dexamethasone-induced inhibition of PI3K/Akt signaling. These data suggest that changes in anabolic and catabolic signals are involved in heat stress-induced protection against glucocorticoid-induced muscle atrophy. These results have a potentially broad clinical impact because elevated glucocorticoid levels are implicated in a wide range of diseases associated with muscle wasting. J. Cell. Physiol. 232: 650-664, 2017. © 2016 The Authors. Journal of Cellular Physiology published by Wiley Periodicals, Inc.


Asunto(s)
Dexametasona/efectos adversos , Respuesta al Choque Térmico/efectos de los fármacos , Atrofia Muscular/inducido químicamente , Atrofia Muscular/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta , Proteínas del Choque Térmico HSP72/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/patología , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Factores de Tiempo
11.
J Strength Cond Res ; 31(12): 3403-3410, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27984497

RESUMEN

Kataura, S, Suzuki, S, Matsuo, S, Hatano, G, Iwata, M, Yokoi, K, Tsuchida, W, Banno, Y, and Asai, Y. Acute effects of the different intensity of static stretching on flexibility and isometric muscle force. J Strength Cond Res 31(12): 3403-3410, 2017-In various fields, static stretching is commonly performed to improve flexibility, whereas the acute effects of different stretch intensities are unclear. Therefore, we investigated the acute effects of different stretch intensities on flexibility and muscle force. Eighteen healthy participants (9 men and 9 women) performed 180-second static stretches of the right hamstrings at 80, 100, and 120% of maximum tolerable intensity without stretching pain, in random order. The following outcomes were assessed as markers of lower limb function and flexibility: static passive torque (SPT), range of motion (ROM), passive joint (muscle-tendon) stiffness, passive torque (PT) at onset of pain, and isometric muscle force. Static passive torque was significantly decreased after all stretching intensities (p ≤ 0.05). Compared with before stretching at 100 and 120% intensities, ROM and PT were significantly increased after stretching (p ≤ 0.05), and passive stiffness (p = 0.05) and isometric muscle force (p ≤ 0.05) were significantly decreased. In addition, ROM was significantly greater after stretching at 100 and 120% than at 80%, and passive stiffness was significantly lower after 120% than after 80% (p ≤ 0.05). However, all measurements except SPT were unchanged after 80% intensity. There was a weak positive correlation between the intensities of stretching and the relative change for SPT (p ≤ 0.05), a moderate positive correlation with ROM (p ≤ 0.05), and a moderate positive correlation with passive stiffness (p ≤ 0.05). These results indicate that static stretching at greater intensity is more effective for increasing ROM and decreasing passive muscle-tendon stiffness.


Asunto(s)
Músculos Isquiosurales/fisiología , Contracción Isométrica/fisiología , Fuerza Muscular/fisiología , Ejercicios de Estiramiento Muscular/métodos , Femenino , Humanos , Masculino , Rango del Movimiento Articular/fisiología , Tendones/fisiología , Torque , Adulto Joven
12.
J Strength Cond Res ; 27(12): 3367-76, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23524367

RESUMEN

Static stretching is widely applied in various disciplines. However, the acute effects of different durations of stretching are unclear. Therefore, this study was designed to investigate the acute effects of different stretching durations on muscle function and flexibility, and provide an insight into the optimal duration of static stretching. This randomized crossover trial included 24 healthy students (17 men and 7 women) who stretched their right hamstrings for durations of 20, 60, 180, and 300 seconds in a random order. The following outcomes were assessed using an isokinetic dynamometer as markers of lower-limb function and flexibility: static passive torque (SPT), dynamic passive torque (DPT), stiffness, straight leg raise (SLR), and isometric muscle force. Static passive torque was significantly decreased after all stretching durations (p < 0.05). Static passive torque was significantly lower after 60, 180, and 300 seconds of stretching compared with that after 20-second stretching, and stiffness decreased significantly after 180- and 300-second stretching (p < 0.05). In addition, DPT and stiffness were significantly lower after 300 seconds than after 20-second stretching (p < 0.05), and SLR increased significantly after all stretching durations (p < 0.05). Straight leg raise was higher after 180- and 300-second stretching than after 20-second stretching and higher after 300-second stretching than after 60-second stretching (p < 0.05). Isometric muscle force significantly decreased after all stretching durations (p < 0.05). Therefore, increased duration of stretching is associated with a decrease in SPT but an increase in SLR. Over 180 seconds of stretching was required to decrease DPT and stiffness, but isometric muscle force decreased regardless of the stretching duration. In conclusion, these results indicate that longer durations of stretching are needed to provide better flexibility.


Asunto(s)
Contracción Isométrica/fisiología , Pierna/fisiología , Ejercicios de Estiramiento Muscular/métodos , Músculo Esquelético/fisiología , Torque , Estudios Cruzados , Femenino , Voluntarios Sanos , Humanos , Articulación de la Rodilla/fisiología , Masculino , Dinamómetro de Fuerza Muscular , Rango del Movimiento Articular , Factores de Tiempo , Adulto Joven
13.
Int J Rehabil Res ; 36(2): 127-33, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23138636

RESUMEN

The simultaneous performance of multiple tasks is often required in daily life. The dual-task paradigm has been used extensively to evaluate the ability to perform simultaneous behavioral tasks. However, relatively few studies have been carried out to determine the muscle and brain activity underlying dual-task performance. This study determined the influence of single-task and dual-task conditions on muscle and brain activity by measuring ankle dorsiflexion, surface electromyography, and magnetoencephalography. Increased muscle activation and variability in the dorsiflexion interval was observed during dual-task performance compared with single-task performance, whereas brain activity in the contralateral motor and frontal areas was reduced. Incidental movement of the non-task-related ankle (contralateral ankle) showed a different pattern of brain activity during the dual-task performance in another experiment. These findings suggest that the activity decreased in several information-processing areas under dual-task conditions as a result of decentralization of attention. Activity in the right and left motor fields may play a role in the dual-task performance, as indicated by changes in brain activity during dual-task performance in two groups classified according to the activity level of the contralateral ankle.


Asunto(s)
Tobillo/fisiología , Corteza Motora/fisiología , Músculo Esquelético/fisiología , Análisis y Desempeño de Tareas , Adulto , Electromiografía , Femenino , Humanos , Magnetoencefalografía , Masculino , Movimiento/fisiología , Adulto Joven
14.
Mol Immunol ; 45(10): 2752-63, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18353438

RESUMEN

Antibody-dependent cellular cytotoxicity (ADCC) is a major mechanism by which antibodies exert anti-tumor effects. Here, we show that Fc multimerization augments the binding avidities for all of the low-affinity Fcgamma receptors, increasing ADCC activity very much. A chimeric antibody, designated M-Ab, was constructed with the V regions from mouse anti-CD20 mAb 1F5 and the C regions from human IgG1 and kappa chain. Two or three Fc domains were tandemly repeated downstream of the C-terminus of the M-Ab to give D0-Ab (Fc dimer Ab without a linker), T0-Ab (Fc trimer Ab without a linker), and T3-Ab (Fc trimer Ab with a (GGGGS)(3) linker in front of the second and third hinge regions). HPLC and SDS-PAGE analyses of the purified antibodies indicated that the H and L chains were appropriately linked with interchain disulfide bonds and that the Ab preparations did not contain aggregated molecules. Although flow cytometry indicated that Fc multimerization decreased the binding activity for CD20-bearing cells to 1/3 approximately 1/4, the binding avidities for the extracellular domains of low-affinity Fcgamma receptors were greatly augmented. The avidities were in the order of T3-Ab, T0-Ab, D0-Ab and M-Ab, with T3-Ab showing about 100 times greater avidity than M-Ab not only for FcgammaRIIIA, but also for FcgammaRIIA and FcgammaRIIB. The rank order of ADCC activity with human PBMC was the same, and T3-Ab induced ADCC at a 50-100 times less concentration, compared to M-Ab. These Fc tandem repeat antibodies are promising candidates for anti-tumor therapeutics, and should also be useful as tools to elucidate the biological roles of FcgammaRIIA, FcgammaRIIB, and FcgammaRIIIA.


Asunto(s)
Afinidad de Anticuerpos/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Receptores de IgG/química , Receptores de IgG/inmunología , Secuencias Repetitivas de Aminoácido , Animales , Anticuerpos Monoclonales/inmunología , Antígenos CD20/inmunología , Línea Celular , Cromatografía Líquida de Alta Presión , ADN Complementario , Electroforesis en Gel de Poliacrilamida , Humanos , Ratones , Estructura Terciaria de Proteína
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