Glutamate excitotoxicity is implicated in the pathogenesis of numerous diseases, such as stroke, traumatic brain injury, and Alzheimer’s disease, for which insulin resistance is a concomitant condition, and intranasal insulin treatment is believed to be a promising therapy. Excitotoxicity is initiated primarily by the sustained stimulation of ionotropic glutamate receptors and leads to a rise in intracellular Ca2+ ([Ca2+]i), followed by a cascade of intracellular events, such as delayed calcium deregulation (DCD), mitochondrial depolarization, adenosine triphosphate (ATP) depletion that collectively end in cell death. Therefore, cross-talk between insulin and glutamate signaling in excitotoxicity is of particular interest for research. In the present study, we investigated the effects of short-term insulin exposure on the dynamics of [Ca2+]i and mitochondrial potential in cultured rat cortical neurons during glutamate excitotoxicity. We found that insulin ameliorated the glutamate-evoked rise of [Ca2+]i and prevented the onset of DCD, the postulated point-of-no-return in excitotoxicity. Additionally, insulin significantly improved the glutamate-induced drop in mitochondrial potential, ATP depletion, and depletion of brain-derived neurotrophic factor (BDNF), which is a critical neuroprotector in excitotoxicity. Also, insulin improved oxygen consumption rates, maximal respiration, and spare respiratory capacity in neurons exposed to glutamate, as well as the viability of cells in the MTT assay. In conclusion, the short-term insulin exposure in our experiments was evidently a protective treatment against excitotoxicity, in a sharp contrast to chronic insulin exposure causal to neuronal insulin resistance, the adverse factor in excitotoxicity.
Федеральное государственное бюджетное учреждение «Национальный исследовательский центр эпидемиологии и микробиологии имени почетного академика Н.Ф. Гамалеи» Министерства здравоохранения Российской Федерации, 123098, г. Москва, Российская Федерация 2 Федеральное автономное образовательное учреждение высшего образования Первый Московский государственный медицинский университет имени И.М. Сеченова Министерства здравоохранения Российской Федерации (Сеченовский Университет), 119991, г. Москва, Российская Федерация 3 Федеральное государственное бюджетное научное учреждение «Федеральный научный центр исследований и разработки иммунобиологических препаратов им. М.П. Чумакова РАН» Министерства науки и высшего образования Российской Федерации, 108819, г. Москва, поселение Московский, поселок Института полиомиелита, Российская Федерация 4 Федеральное государственное бюджетное учреждение «48-й центральный научно-исследовательский институт» Министерства обороны Российской Федерации, 141306, г. Сергиев Посад-6, Российская Федерация Резюме Введение. Ближневосточный респираторный синдром (БВРС)-это острое воспалительное заболевание дыхательной системы с высокой летальностью, возбудителем которого является коронавирус БВРС-КоВ. В настоящее время в мире не существует специфических профилактических и терапевтических средств против БВРС. Вакцинопрофилактика позволит ограничить распространение данного заболевания и снизить летальность. Одной из ключевых характеристик вакцин является длительность индуцируемого иммунного ответа, от которой зависит продолжительность протективного эффекта вакцины. К сожалению, данных по длительности поствакцинального иммунного ответа для вакцин против БВРС сейчас недостаточно. Цель исследования-определение длительности гуморального иммунного ответа у грызунов и приматов и протективного иммунного ответа после иммунизации комбинированной векторной вакциной против БВРС (БВРС-ГамВак-Комби), разработанной нами ранее. Материал и методы. Длительность гуморального иммунитета исследовали на мышах линии C57BL/6 и обыкновенных игрунках. Животных иммунизировали вакциной БВРС-ГамВак-Комби на основе рекомбинантных векторов rAd26 и rAd5. Титр антигенспецифических антител определяли методом иммуноферментного анализа (ИФА). Титр вирус-нейтрализующих антител определяли с помощью реакции вирус-нейтрализации против вируса БВРС-КоВ (MERS-CoV EMC/2012). Длительность протективного иммунитета исследовали на модели летальной инфекции у трансгенных мышей, несущих ген человека DPP4, кодирующий рецептор к БВРС-КоВ. Результаты. Исследование длительности поствакцинального гуморального иммунного ответа у грызунов и приматов показало, что вакцинация животных БВРС-ГамВак-Комби индуцирует формирование напряженного гуморального иммунного ответа к гликопротеину S БВРС-КоВ, который сохраняется на протяжении не менее 18 мес. Также было показано, что вакцинация позволяет защитить 100 % животных от летальной инфекции, вызванной БВРС-КоВ (MERS-CoV EMC/2012, 100 ЛД 50 /мышь), через 7 мес после иммунизации. Заключение. Напряженность поствакциналь...
Peri-implant fibrosis (PIF) increases the postsurgical risks after implantation and limits the efficacy of the implantable drug delivery systems (IDDS). Pirfenidone (PF) is an oral anti-fibrotic drug with a short (<3 h) circulation half-life and strong adverse side effects. In the current study, disk-shaped IDDS prototype combining polylactic acid (PLA) and PF, PLA@PF, with prolonged (~3 days) PF release (in vitro) was prepared. The effects of the PLA@PF implants on PIF were examined in the rabbit ear skin pocket model on postoperative days (POD) 30 and 60. Matching blank PLA implants (PLA0) and PLA0 with an equivalent single-dose PF injection performed on POD0 (PLA0+injPF) served as control. On POD30, the intergroup differences were observed in α-SMA, iNOS and arginase-1 expressions in PLA@PF and PLA0+injPF groups vs. PLA0. On POD60, PIF was significantly reduced in PLA@PF group. The peri-implant tissue thickness decreased (532 ± 98 µm vs. >1100 µm in control groups) approaching the intact derma thickness value (302 ± 15 µm). In PLA@PF group, the implant biodegradation developed faster, while arginase-1 expression was suppressed in comparison with other groups. This study proves the feasibility of the local control of fibrotic response on implants via modulation of foreign body reaction with slowly biodegradable PF-loaded IDDS.
This article reports the electrospinning technique for the manufacturing of multilayered scaffolds for bile duct tissue engineering based on an inner layer of polycaprolactone (PCL) and an outer layer either of a copolymer of D,L-lactide and glycolide (PLGA) or a copolymer of L-lactide and ε-caprolactone (PLCL). A study of the degradation properties of separate polymers showed that flat PCL samples exhibited the highest resistance to hydrolysis in comparison with PLGA and PLCL. Irrespective of the liquid-phase nature, no significant mass loss of PCL samples was found in 140 days of incubation. The PLCL- and PLGA-based flat samples were more prone to hydrolysis within the same period of time, which was confirmed by the increased loss of mass and a significant reduction of weight-average molecular mass. The study of the mechanical properties of developed multi-layered tubular scaffolds revealed that their strength in the longitudinal and transverse directions was comparable with the values measured for a decellularized bile duct. The strength of three-layered scaffolds declined significantly because of the active degradation of the outer layer made of PLGA. The strength of scaffolds with the PLCL outer layer deteriorated much less with time, both in the axial (p-value = 0.0016) and radial (p-value = 0.0022) directions. A novel method for assessment of the physiological relevance of synthetic scaffolds was developed and named the phase space approach for assessment of physiological relevance. Two-dimensional phase space (elongation modulus and tensile strength) was used for the assessment and visualization of the physiological relevance of scaffolds for bile duct bioengineering. In conclusion, the design of scaffolds for the creation of physiologically relevant tissue-engineered bile ducts should be based not only on biodegradation properties but also on the biomechanical time-related behavior of various compositions of polymers and copolymers.
Insufficient vascular growth in the area of artificial-material implantation contributes to ischemia, fibrosis, the development of bacterial infections, and tissue necrosis around the graft. The purpose of this study was to evaluate angiogenesis after implantation of polycaprolactone microfiber scaffolds modified by a pCMV-VEGF165-plasmid in rats. Influence of vascularization on scaffold degradation was also examined. We investigated flat microfibrous scaffolds obtained by electrospinning polycaprolactone with incorporation of the pCMV-VEGF-165 plasmid into the microfibers at concentrations of 0.005 ng of plasmid per 1 mg of polycaprolactone (0.005 ng/mg) (LCGroup) and 0.05 ng/mg (HCGroup). The samples were subcutaneously implanted in the interscapular area of rats. On days 7, 16, 33, 46, and 64, the scaffolds were removed, and a histological study with a morphometric evaluation of the density and diameter of the vessels and microfiber diameter was performed. The number of vessels was increased in all groups, as well as the resorption of the scaffold. On day 33, the vascular density in the HCGroup was 42% higher compared to the control group (p = 0.0344). The dose-dependent effect of the pCMV-VEGF165-plasmid was confirmed by enhanced angiogenesis in the HCGroup compared to the LCGroup on day 33 (p-value = 0.0259). We did not find a statistically significant correlation between scaffold degradation rate and vessel growth (the Pearson correlation coefficient was ρ = 0.20, p-value = 0.6134). Functionalization of polycaprolactone by incorporation of the pCMV-VEGF165 plasmid provided improved vascularization within 33 days after implantation, however, vessel growth did not seem to correlate with scaffold degradation rate.
Mature hypertrophic scars (HSs) remain a challenging clinical problem, particularly due to the absence of biologically relevant experimental models as a standard rabbit ear HS model only reflects an early stage of scarring. The current study aims to adapt this animal model for simulation of mature HS by validating the time of the scar stabilization using qualitative and quantitative criteria. The full-thickness skin and perichondrium excision wounds were created on the ventral side of the rabbit ears. The tissue samples were studied on post-operation days (PODs) 30, 60, 90 and 120. The histopathological examination and morphometry were applied in parallel with biochemical analysis of protein and glycosaminoglycans (GAGs) content and amino acid composition. The supramolecular organization of collagen was explored by differential scanning calorimetry. Four stages of the rabbit ear HS maturation were delineated and attributed with the histolomorphometrical and physicochemical parameters of the tissue. The experimental scars formed in 30 days but stabilized structurally and biochemically only on POD 90–120. This evidence-based model can be used for the studies and testing of new treatments of the mature HSs.
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