First and second order optimality conditions for optimal control problems of state constrained integral equations

This paper deals with optimal control problems of integral equations, with initial-final and running state constraints. The order of a running state constraint is defined in the setting of integral dynamics, and we work here with constraints of arbitrary high orders. First and second-order necessary conditions of optimality are obtained, as well as second-order sufficient conditions

Aspectos clínico-patológicos do envenenamento botrópico experimental em equinos

Estudou-se as alterações clínico-patológicas e laboratoriais em equinos, inoculados experimentalmente com a peçonha de Bothropoides jararaca, Bothrops jararacussu, Bothrops moojeni e Bothropoides neuwiedi, com a finalidade de fornecer subsídios para o diagnóstico do envenenamento pela picada dessas. Os venenos liofilizados foram diluídos em 1ml de solução fisiológica e administrados a seis equinos, por via subcutânea, nas doses de 0,5 e 1mg/kg (B. jararaca), 0,8 e 1,6mg/kg (B. jararacussu), 0,205mg/kg (B. moojeni) e 1mg/kg (B. neuwiedi). Todos os equinos, menos os que receberam o veneno de B. jararacussu, morreram Os sinais clínicos iniciaram-se entre 8min e 2h10min após a inoculação. O período de evolução variou, nos quatro casos de êxito letal, de 24h41min a 70h41min, e nos dois equinos que se recuperaram foi de 16 dias. O quadro clínico, independente do tipo de veneno e das doses, caracterizou-se por aumento de volume no local da inoculação, arrastar da pinça do membro inoculado no solo, inquietação, apatia, diminuição da resposta aos estímulos externos, mucosas pálidas e hemorragias. Os exames laboratoriais revelaram anemia normocítica normocrômica com progressiva diminuição no número de hemácias, da hemoglobina e do hematócrito, e leucocitose por neutrofilia. Houve aumento de alamina aminotransferase, creatinaquinase, dehidrogenase láctica, ureia e glicose, bem como aumento do tempo de ativação da protrombina e do tempo de tromboplastina parcial ativada. Os achados de necropsia foram extensas hemorragias no tecido subcutâneo, com presença de sangue não coagulado e em boa parte associadas a edema (edema hemorrágico), que se estendia desde o local da inoculação até as regiões cervical, torácica, escapular e membro. Na periferia das áreas hemorrágicas havia predominantemente edema gelatinoso. Havia ainda presença de grande quantidade de líquido sanguinolento nas cavidades torácica, pericárdica e abdominal. Não foram encontradas alterações histológicas significativas

Rat Skin Wound Healing Induced By Alternagin-c, A Disintegrin-like, Cys-rich Protein From Bothrops Alternatus Venom

Alternagin-C (ALT-C) is a disintegrin-like, Cys-rich protein isolated from Bothrops alternatus snake venom, which has been shown to induce in vivo angiogenesis. Therefore, this protein could be interesting as a new approach for tissue regeneration studies. Here the effects of ALT-C on fibroblasts and inflammatory cells, collagen type III and type I and TGF-α expression in a rat wounded skin model were studied. Thirty-five male Wistar rats (weight 270 ± 20 g) were divided into seven groups with five animals in each of the following groups: a control group which wounded animals received treatment with natrozol® gel only; ALT-C10, ALT-C60 and ALT-C100 groups of wounded animals that were treated with the same amount of gel containing 10, 60 and 100 ng of ALT-C, respectively. Animals were treated once a day with 20 μl of gel associated or not with ALT-C for 1, 3, 5 or 7 days. ALT-C treatment increased the fibroblast density, collagen deposition and accelerated the inflammatory process, mostly in the ALT-C60 group. These results indicate that ALT-C improves wound repair process in rat skin. Thus, ALT-C could be a candidate to the development of a novel therapeutic strategy for wounded skin repair. © 2011 The Authors. © 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc.83245252Singer, A.J., Clark, R.A., Cutaneous wound healing. (1999) N Engl J Med, 341, pp. 738-746Werner, S., Grose, R., Regulation of wound healing by growth factors and cytokines. (2003) Physiol Rev, 83, pp. 835-870Martin, P., Wound healing-aiming for perfect skin regeneration. (1997) Science, 276, pp. 75-81Clark, R.A., Basics of cutaneous wound repair. (1993) J Dermatol Surg Oncol, 19, pp. 693-706Schultz, G.S., Wysocki, A., Interactions between extracellular matrix and growth factors in wound healing. (2009) Wound Repair Regen, 17, pp. 153-162Tsahar, E., Moyer, J.D., Waterman, H., Barbacci, E.G., Bao, J., Levkowitz, G., Shelly, M., Yarden, Y., Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. (1998) EMBO J, 15, pp. 5948-5963Yang, X., Letterio, J.J., Lechleider, R.J., Chen, L., Hayman, R., Gu, H., Roberts, A.B., Deng, C., Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. (1999) EMBO J, 18, pp. 1280-1291Strachan, L., Murison, J.G., Prestidge, R.L., Sleeman, M.A., Watson, J.D., Kumble, K.D., Cloning and biological activity of epigen, a novel member of the epidermal growth factor superfamily. (2001) J Biol Chem, 276, pp. 18265-18271Hashimoto, K., Regulation of keratinocyte function by growth factors. (2000) J Dermatol Sci, 24, pp. S46-S50Bennett, S.P., Griffiths, G.D., Schor, A.M., Leese, G.P., Schor, S.L., Growth factors in the treatment of diabetic foot ulcers. (2003) Br J Surg, 90, pp. 133-146Li, Y., Fan, J., Chen, M., Li, W., Woodley, D.T., Transforming growth factor-alpha: a major human serum factor that promotes human keratinocyte migration. (2006) J Invest Dermatol, 126, pp. 2096-2105Barrandon, Y., Green, H., Cell migration is essential for sustained growth of keratinocyte colonies: the roles of transforming growth factor-alpha and epidermal growth factor. (1987) Cell, 50, pp. 1131-1137Ellis, I.R., Schor, A.M., Schor, S.L., EGF AND TGF-α motogenic activities are mediated by the EGF receptor via distinct matrix-dependent mechanisms. (2007) Exp Cell Res, 313, pp. 732-741Kim, I., Mogford, J.E., Chao, J.D., Mustoe, T.A., Wound epithelialization deficits in the transforming growth factor-α knockout mouse. (2001) Wound Repair Regen, 9, pp. 386-390Mariano-Oliveira, A., Coelho, A.L., Terruggi, C.H., Selistre-de-Araújo, H.S., Barja-Fidalgo, C., De Freitas, M.S., Alternagin-C, a non-RGD-disintegrin, induces neutrophil migration via integrin signaling. (2003) Eur J Biochem, 270, pp. 4799-4808Selistre-de-Araujo, H.S., Cominetti, M.R., Terruggi, C.H., Mariano-Oliveira, A., De Freitas, M.S., Crepin, M., Figueiredo, C.C., Morandi, V., Alternagin-C, a disintegrin-like protein from the venom of Bothrops alternatus, modulates α2β1 integrin-mediated cell adhesion, migration and proliferation. (2005) Braz J Med Biol Res, 38, pp. 1505-1511Souza, D.H., Iemma, M.R., Ferreira, L.L., Faria, J.P., Oliva, M.L., Zingali, R.B., Niewiarowski, S., Selistre-de-Araujo, H.S., The disintegrin-like domain of the snake venom metalloprotease alternagin inhibits α2β1 integrin-mediated cell adhesion. (2000) Arch Biochem Biophys, 384, pp. 341-350Cominetti, M.R., Ribeiro, J.U., Fox, J.W., Selistre-de-Araujo, H.S., BaG, a new dimeric metalloproteinase/disintegrin from the Bothrops alternatus snake venom that interacts with α5β1 integrin. (2003) Arch Biochem Biophys, 416, pp. 171-179Ramos, O.H., Terruggi, C.H., Ribeiro, J.U., Cominetti, M.R., Figueiredo, C.C., Bérard, M., Crepin, M., Selistre-de-Araujo, H.S., Modulation of in vitro and in vivo angiogenesis by alternagin-C, a disintegrin-like protein from Bothrops alternatus snake venom and by a peptide derived from its sequence. (2007) Arch Biochem Biophys, 461, pp. 1-6Mesquita-Ferrari, R.A., Moraes, C.K., Micocci, K.C., Selistre-de-Araujo, H.S., ALT-C, a disintegrin-like Cys-rich protein from Bothrops alternatus, increases skeletal myoblast viability. (2009) J Venom Anim Toxins Incl Trop Disv, 15, pp. 325-339Durigan, J.L., Peviani, S.M., Russo, T.L., Delfino, G.B., Ribeiro, J.U., Cominetti, M.R., Selistre-de-Araujo, H.S., Salvini, T.F., Effects of alternagin-C from Bothrops alternatus on gene expression and activity of metalloproteinases in regenerating skeletal muscle. (2008) Toxicon, 52, pp. 687-694Sant'ana, E.M.C., Gouvêa, C.M.C.P., Nakaie, C.R., Selistre-de-Araújo, H.S., Angiogenesis and growth factor modulation induced by alternagin C, a snake venom disintegrin-like, cysteine-rich protein on a rat skin wound model. (2008) Arch Biochem Biophys, 479, pp. 20-27Junqueira, L.C.U., Cossermely, W., Brentani, R., Diferential staining of collagens type-I, Type-II and Type-III by picrosirius red and polarization microscopy. (1978) Arch Hist Jpn, 41, pp. 267-274Lapiere, C.M., Nusgens, B., Pierard, G.E., Interaction between collagen type I and type III in conditioning bundles organization. (1977) Connect Tissue Res, 5, pp. 21-29Robins, S.P., Milne, G., Duncan, A., Davies, C., Butt, R., Greiling, D., James, I.T., Increased skin collagen extractability and proportions of collagen type III are not normalized after 6 months healing of human excisional wounds. (2003) J Invest Dermatol, 121, pp. 267-272Witte, M., Barbul, A., General principles of wound healing. (1997) Surg Clin North Am, 77, pp. 509-528Terruggi, C.H.B., Cominetti, M.R., Bérard, M., Selistre-de-Araújo, H.S., The disintegrin alternagin-C modulates migration and viability of breast tumor cells. (2006) Rencontres en Toxinologie., pp. 201-8. , Toxines et cancer: LavoisierZigrino, P., Kamiguti, A.S., Eble, J., Drescher, C., Nischt, R., Fox, J.W., Mauch, C., The reprolysin jararhagin, a snake venom metalloproteinase, functions as a fibrillar collagen agonist involved in fibroblast cell adhesion and signaling. (2002) J Biol Chem, 277, pp. 40528-4053

Sarcopenia, frailty and their prevention by exercise

Sarcopenia is a major component of the frailty syndrome, both being considered as strong predictors of morbidity, disability, and death in older people. In this review, we explore the definitions of sarcopenia and frailty and summarize the current knowledge on their relationship with oxidative stress and the possible therapeutic interventions to prevent or treat them, including exercise-based interventions and multimodal strategies. We highlight the relevance of the impairment of the nervous system and of the anabolic response (protein synthesis) in muscle aging leading to frailty and sarcopenia. We also discuss the importance of malnutrition and physical inactivity in these geriatric syndromes. Finally, we propose multimodal interventions, including exercise programs and nutritional supplementation, as the strategies to prevent and treat both sarcopenia and frailty

MicroRNA 221 Targets ADAM10 mRNA and is Downregulated in Alzheimer's Disease

ADAM10 is the \uce\ub1-secretase that cleaves amyloid-\uce\ub2 protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation

Alternagin-C, a disintegrin-like protein from the venom of Bothrops alternatus, modulates a2ß1 integrin-mediated cell adhesion, migration and proliferation

The alpha2ß1 integrin is a major collagen receptor that plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Alternagin-C (ALT-C), a disintegrin-like protein purified from the venom of the Brazilian snake Bothrops alternatus, competitively interacts with the alpha2ß1 integrin, thereby inhibiting collagen binding. When immobilized in plate wells, ALT-C supports the adhesion of fibroblasts as well as of human vein endothelial cells (HUVEC) and does not detach cells previously bound to collagen I. ALT-C is a strong inducer of HUVEC proliferation in vitro. Gene expression analysis was done using an Affimetrix HU-95A probe array with probe sets of ~10,000 human genes. In human fibroblasts growing on collagen-coated plates, ALT-C up-regulates the expression of several growth factors including vascular endothelial growth factor, as well as some cell cycle control genes. Up-regulation of the vascular endothelial growth factor gene and other growth factors could explain the positive effect on HUVEC proliferation. ALT-C also strongly activates protein kinase B phosphorylation, a signaling event involved in endothelial cell survival and angiogenesis. In human neutrophils, ALT-C has a potent chemotactic effect modulated by the intracellular signaling cascade characteristic of integrin-activated pathways. Thus, ALT-C acts as a survival factor, promoting adhesion, migration and endothelial cell proliferation after binding to alpha2ß1 integrin on the cell surface. The biological activities of ALT-C may be helpful as a therapeutic strategy in tissue regeneration as well as in the design of new therapeutic agents targeting alpha2ß1 integrin

ADAM10 in Alzheimer's disease: Pharmacological modulation by natural compounds and its role as a peripheral marker

Alzheimer's disease (AD) represents a global burden in the economics of healthcare systems. Amyloid-β (Aβ) peptides are formed by amyloid-β precursor protein (AβPP) cleavage, which can be processed by two pathways. The cleavage by the α-secretase A Disintegrin And Metalloprotease 10 (ADAM10) releases the soluble portion (sAβPPα) and prevents senile plaques. This pathway remains largely unknown and ignored, mainly regarding pharmacological approaches that may act via different signaling cascades and thus stimulate non-amyloidogenic cleavage through ADAM10. This review emphasizes the effects of natural compounds on ADAM10 modulation, which eventuates in a neuroprotective mechanism. Moreover, ADAM10 as an AD biomarker is revised. New treatments and preventive interventions targeting ADAM10 regulation for AD are necessary, considering the wide variety of ADAM10 substrates. © 2019 Elsevier Masson SASUniversidad Autónoma de ChileInstituto de Ciencias Biomédica