Snake venom disintegrins update: insights about new findings

ABSTRACT Snake venom disintegrins are low molecular weight, non-enzymatic proteins rich in cysteine, present in the venom of snakes from the families Viperidae, Crotalidae, Atractaspididae, Elapidae, and Colubridae. This family of proteins originated in venom through the proteolytic processing of metalloproteinases (SVMPs), which, in turn, evolved from a gene encoding an A Disintegrin And Metalloprotease (ADAM) molecule. Disintegrins have a recognition motif for integrins in their structure, allowing interaction with these transmembrane adhesion receptors and preventing their binding to proteins in the extracellular matrix and other cells. This interaction gives disintegrins their wide range of biological functions, including inhibition of platelet aggregation and antitumor activity. As a result, many studies have been conducted in an attempt to use these natural compounds as a basis for developing therapies for the treatment of various diseases. Furthermore, the FDA has approved Tirofiban and Eptifibatide as antiplatelet compounds, and they are synthesized from the structure of echistatin and barbourin, respectively. In this review, we discuss some of the main functional and structural characteristics of this class of proteins and their potential for therapeutic use.

Effects of venoms on neutrophil respiratory burst: a major inflammatory function

Neutrophils play a pivotal role in innate immunity and in the inflammatory response. Neutrophils are very motile cells that are rapidly recruited to the inflammatory site as the body first line of defense. Their bactericidal activity is due to the release into the phagocytic vacuole, called phagosome, of several toxic molecules directed against microbes. Neutrophil stimulation induces release of this arsenal into the phagosome and induces the assembly at the membrane of subunits of the NAPDH oxidase, the enzyme responsible for the production of superoxide anion that gives rise to other reactive oxygen species (ROS), a process called respiratory burst. Altogether, they are responsible for the bactericidal activity of the neutrophils. Excessive activation of neutrophils can lead to extensive release of these toxic agents, inducing tissue injury and the inflammatory reaction. Envenomation, caused by different animal species (bees, wasps, scorpions, snakes etc.), is well known to induce a local and acute inflammatory reaction, characterized by recruitment and activation of leukocytes and the release of several inflammatory mediators, including prostaglandins and cytokines. Venoms contain several molecules such as enzymes (phospholipase A2, L-amino acid oxidase and proteases, among others) and peptides (disintegrins, mastoporan, parabutoporin etc.). These molecules are able to stimulate or inhibit ROS production by neutrophils. The present review article gives a general overview of the main neutrophil functions focusing on ROS production and summarizes how venoms and venom molecules can affect this function.(AU)

Effects of blocking αvβ3 integrin by a recombinant RGD disintegrin on remodeling of wound healing after induction of incisional hernia in rats

PURPOSE: To investigate the changes induced by DisBa-01 on repair of wound healing after induced incisional hernia (IH) in rats. METHODS: Thirty two male albino rats were submitted to IH and divided into four experimental groups: G1, placebo control; G2, DisBa-01-treated; G3, anti-αvβ3 antibodies-treated and G4, anti-α2 antibodies-treated. Histological, biochemical and extracellular matrix remodeling analysis of abdominal wall were evaluated. RESULTS: After 14 days, 100% of the G2 did not present hernia, and the hernia ring was closed by a thin membrane. In contrast, all groups maintained incisional hernia. DisBa-01 also increased the number macrophages and fibroblasts and induced the formation of new vessels. Additionally, MMP-2 was strongly activated only in G2 (p<0.05). Anti- αvβ3-integrin antibodies produced similar results than DisBa-01 but not anti-α2 integrin blocking antibodies. CONCLUSION: DisBa-01 has an important role in the control of wound healing and the blocking of this integrin may be an interesting therapeutically strategy in incisional hernia. .

Uso potencial de componentes del veneno de serpiente en el tratamiento del cáncer / Potential use of snake venom components in cancer treatment

El desarrollo del cáncer es posible en la medida que las células tumorales proliferen, se dispersen e invadan otros tejidos del cuerpo. Las integrinas son una familia de receptores heterodiméricos de superficie celular que cumplen un papel crucial en el desarrollo de la angiogénesis, crecimiento y metástasis de un tumor señalándolas como un atractivo blanco terapéutico. Los venenos de serpientes contienen péptidos de bajo peso molecular conocidos como desintegrinas, las que se unen con una alta afinidad a las integrinas e inhiben su accionar en un proceso cancerígeno. En el siguiente articulo revisamos los resultados de investigaciones, tanto in vitro como in vivo, que han mostrado resultados promisorios, por lo cual el uso de las desintegrinas podrían constituir una alternativa promisoria para el tratamiento de diversas neoplasias.

Cancer can develop to the extent tumor cells grow, divide and grow into other body tissues. Integrins are a family of cell-surface heterodimeric receptors that play an important role in the development of tumor angiogenesis, growth and metastasis, thus being recognized as an attractive therapeutic target. Snake venom contains low-molecular weight peptides known as “disintegrins” that bind to integrins with high affinity, and prevent their action in cancer. In the next article, we go over the results of investigations, both in vitro and in vivo, which have shown promising results, thus revealing that the use of disintegrins could be a promising alternative for the treatment of different neoplasias.

Metalloproteinases and disintergrins of snake venom: Structures and functions / 第二军医大学学报

Snake venom metalloproteinase is one of the main function proteins in snake venom. It directly affects the interactions between capillary endothelium cells and basement membrane in local tissues. Snake venom disintegrin and metalloproteinase are derived from the same pre-pro-metalloproteinase, which contains 4 common structural domains: Pre-domain, Pro-domain, Proteinase domains, and Spacer region. Disintegrin, a low molecular weight protein containing several Cys residues, can block the binding of integrins and their ligands and inhibit adhering reaction(cell to cell and cell to extracellular matrix) mediated by integrin. It also plays a significant role in platelet aggregation, infection, inflammation reaction, tumor metastasis, etc..

Effect of hypoxia and reoxygenation on the expression of a disintegrin and metalloprotease10,?-amyloid precursor protein cleaving enzyme mRNA in SH-SY5Y cells / 中华神经科杂志

Objective To study the effects of hypoxia and reoxygenation on expression of a disintegrin and metalloprotease10(ADAM10),?-amyloid precursor protein cleaving enzyme(BACE1) mRNA in SH-SY5Y cells.Methods SH-SY5Y cells were grouped into hypoxic and control groups.The hypoxic cells were incubated in hypoxic condition(95%N_2,5%CO_2) for 12 hours and 24 hours,and then cells were reoxygenated for 0 hours,12 hours and 24 hours.The expression of ADAM10,BACE1 mRNA were tested respectively at different time points after reoxygenation by RT-PCR.Control groups were incubated in normal conditions,seeded and treated at the same time with the hypoxic cells.Results The expression of ADAM10 mRNA was down-regulated by 19.8%,41.4% and 64.6%(P=0.005,0.038,0.001) at different time after reoxygenation with 12 hours hypoxia and down-regulated by 30.1%,75.9% and 86.5%(P=0.009,0.005,0.043)after reoxygenation with 24 hours hypoxia.The expression of BACE1 mRNA was up-regulated by 31.5% and 35.1%(P=0.028,0.005)only at 12 hours and 24 hours points after reoxygenation with 24 hours hypoxia.Conclusion Hypoxia and reoxygenation might alter the expression of ADAM10 and BACE1,which demonstrates that the vascular factors should make the amyloid precursor protein easy to be processed by ?-secrease pathway,thus to involve the pathology of Alzheimer's disease.

Metalloproteinases and disintergrins of snake venom:structures and functions / 第二军医大学学报

Snake venom metalloproteinase is one of the main function proteins in snake venom.It directly affects the interactions between capillary endothelium cells and basement membrane in local tissues.Snake venom disintegrin and metalloproteinase are derived from the same pre-pro-metalloproteinase,which contains 4 common structural domains: Pre-domain,Pro-domain,Proteinase domains,and Spacer region.Disintegrin,a low molecular weight protein containing several Cys residues,can block the binding of integrins and their ligands and inhibit adhering reaction(cell to cell and cell to extracellular matrix) mediated by integrin.It also plays a significant role in platelet aggregation,infection,inflammation reaction,tumor metastasis,etc..