Biomedical applications of synthetic peptides derived from venom of animal origin: A systematic review.

Development of therapeutic agents that have fewer adverse effects and have higher efficacy for diseases, such as cancer, metabolic disorders, neurological diseases, infections, cardiovascular diseases, and respiratory diseases, are required. Recent studies have focused on identifying novel sources for pharmaceutical molecules to develop therapies against these diseases. Among the sources for potentially new therapies, animal venom-derived molecules have generated much interest. Various animal venom-derived proteins and peptides have been isolated, identified, synthesized, and tested to develop drugs. Venom-derived peptides have several biomedical properties, such as proapoptotic, cell migration, and autophagy regulation activities in cancer cell models; induction of vasodilation by nitric oxide and regulation of angiotensin II; modification of insulin response by controlling calcium and potassium channels; regulation of pain receptor activity; modulation of immune cell activity; alteration of motor neuron activity; degradation or inhibition of ß-amyloid plaque formation; antibacterial, antifungal, antiviral, and antiprotozoal activities; increase in sperm motility and potentiation of erectile function; reduction of intraocular pressure; anticoagulation, fibrinolytic, and antithrombotic activities; etc. This systematic review compiles these biomedical properties and potential biomedical applications of synthesized animal venom-derived peptides reported in the latest research. In addition, the limitations and areas of opportunity in this research field are discussed so that new studies can be developed based on the data presented.

Effect of Ethanol Consumption on the Placenta and Liver of Partially IGF-1-Deficient Mice: The Role of Metabolism via CYP2E1 and the Antioxidant Enzyme System.

Ethanol use during pregnancy is a risk factor for developing adverse outcomes. Its metabolism by cytochrome P450 2E1 (CYP2E1) produces radical oxygen species (ROS), promoting cellular injury and apoptosis. To date, no studies have been conducted to elucidate the teratogenic effects due to both IGF-1 deficiency and ethanol consumption in mice placentas. The aim of this study is to determine the effect of ethanol consumption on the placenta and liver of partially IGF-1-deficient mice, the role of metabolism via CYP2E1, and the antioxidant enzyme system. Heterozygous (HZ, Igf1+/-) pregnant female mice were given water or 10% ethanol. Wild-type (WT, Igf1+/+) female mice were used as controls. At gestational day 19, pregnant dams were euthanized, and maternal liver and placentas were collected. Pregnant HZ dams were smaller than controls, and this effect was higher due to ethanol consumption. Cyp2e1 gene was overexpressed in the liver of HZ pregnant dams exposed to ethanol; at the protein level, CYP2E1 is reduced in placentas from all genotypes. The antioxidant enzymatic system was altered by ethanol consumption in both the maternal liver and placenta. The results in this work hint that IGF-1 is involved in intrauterine development because its deficiency exacerbates ethanol's effects on both metabolism and the placenta.

Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?

Gestational diabetes mellitus (GDM), is one of the most important pregnancy complications affecting approximately 15% of pregnant women. It is related to several gestational adverse outcomes in the fetus, e.g., macrosomia, shoulder dystocia, stillbirth, neonatal hypoglycemia, and respiratory distress. Women with GDM have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors could contribute to its development: ß-cell dysfunction and failure in insulin secretion in response to insulin resistance induced by gestation. Both processes, together with the physiological activities of the insulin-like growth factors (IGFs), play a crucial role in glucose transport to the fetus and hence, fetal growth and development. IGFs (both IGF-1 and IGF-2) and their binding proteins (IGFBPs) regulate glucose metabolism and insulin sensitivity. Maternal nutritional status determines the health of the newborn, as it has substantial effects on fetal growth and development. Maternal obesity and an energy-dense diet can cause an increase in insulin and IGF-1 serum levels, producing metabolic disorders, such as insulin resistance, GDM, and high birth weight (> 4,000 g) due to a higher level of body fat. In this way, in GDM pregnancies there is an increase in IGF-1 and IGF-2 serum levels, and a decrease in IGFBP-1 and 4 serum levels, suggesting the crucial role of the insulin/IGF system in this gestational outcome. Here, the present review tries to elucidate the role that energy-dense diets and the insulin/IGF-1 signaling pathway perform in GDM pregnancies.

The Placenta as a Target for Alcohol During Pregnancy: The Close Relation with IGFs Signaling Pathway.

Alcohol is one of the most consumed drugs in the world, even during pregnancy. Its use is a risk factor for developing adverse outcomes, e.g. fetal death, miscarriage, fetal growth restriction, and premature birth, also resulting in fetal alcohol spectrum disorders. Ethanol metabolism induces an oxidative environment that promotes the oxidation of lipids and proteins, triggers DNA damage, and advocates mitochondrial dysfunction, all of them leading to apoptosis and cellular injury. Several organs are altered due to this harmful behavior, the brain being one of the most affected. Throughout pregnancy, the human placenta is one of the most important organs for women's health and fetal development, as it secretes numerous hormones necessary for a suitable intrauterine environment. However, our understanding of the human placenta is very limited and even more restricted is the knowledge of the impact of toxic substances in its development and fetal growth. So, could ethanol consumption during this period have wounding effects in the placenta, compromising proper fetal organ development? Several studies have demonstrated that alcohol impairs various signaling cascades within G protein-coupled receptors and tyrosine kinase receptors, mainly through its action on insulin and insulin-like growth factor 1 (IGF-1) signaling pathway. This last cascade is involved in cell proliferation, migration, and differentiation and in placentation. This review tries to examine the current knowledge and gaps in our existing understanding of the ethanol effects in insulin/IGFs signaling pathway, which can explain the mechanism to elucidate the adverse actions of ethanol in the maternal-fetal interface of mammals.

Prenatal indole-3-carbinol administration activates aryl hydrocarbon receptor-responsive genes and attenuates lung injury in a bronchopulmonary dysplasia model.

Hyperoxia-hypoxia exposure is a proposed cause of alveolar developmental arrest in bronchopulmonary dysplasia in preterm infants, where mitochondrial reactive oxygen species and oxidative stress vulnerability are increased. The aryl hydrocarbon receptor (AhR) is one of the main activators of the antioxidant enzyme system that protects tissues and systems from damage. The present study aimed to determine if the activation of the AhR signaling pathway by prenatal administration of indole-3-carbinol (I3C) protects rat pups from hyperoxia-hypoxia-induced lung injury. To assess the activation of protein-encoding genes related to the AhR signaling pathway (Cyp1a1, Cyp1b1, Ugt1a6, Nqo1, and Gsta1), pup lungs were excised at 0, 24, and 72 h after birth, and mRNA expression levels were quantified by reverse transcription-quantitative polymerase chain reaction assays (RT-qPCR). An adapted Ratner's method was used in rats to evaluate radial alveolar counts (RACs) and the degree of fibrosis. The results reveal that the relative expression of AhR-related genes in rat pups of prenatally I3C-treated dams was significantly different from that of untreated dams. The RAC was significantly lower in the hyperoxia-hypoxia group (4.0 ± 1.0) than that in the unexposed control group (8.0 ± 2.0; P < 0.01). When rat pups of prenatally I3C-treated dams were exposed to hyperoxia-hypoxia, an RAC recovery was observed, and the fibrosis index was similar to that of the unexposed control group. A cytokine antibody array revealed an increase in the NF-κB signaling cascade in I3C-treated pups, suggesting that the pathway could regulate the inflammatory process under the stimulus of this compound. In conclusion, the present study demonstrates that I3C prenatal treatment activates AhR-responsive genes in pup's lungs and hence attenuates lung damage caused by hyperoxia-hypoxia exposure in newborns.

Metabolic impact of current therapeutic strategies in Polycystic Ovary Syndrome: a preliminary study.

PURPOSE: To investigate the metabolic impact of currently used therapies in polycystic ovary syndrome (PCOS). METHODS: This is an observational, retrospective and transversal protocol. A small cohort of 133 patients, aged 14-48 years, diagnosed with PCOS was divided into four experimental groups: 1) untreated PCOS patients (n = 51); 2) PCOS patients treated with one of the following therapies (n = 82): a) combined oral contraceptives (COC, n = 35); b) metformin (n = 11); and c) inositols (n = 36). RESULTS: Although only < 10% of patients included in this cohort can be strictly encompassed in the development of metabolic syndrome, approximately 20% had insulin resistance. In PCOS patients, COC treatment modified the hormonal profile and worsened lipid parameters (increasing cholesterol and triglyceride levels) and insulin resistance, whereas inositol therapies improved significantly insulin resistance and glycosylated hemoglobin, reducing cholesterol and triglyceride levels. In these women, obesity was associated with greater alterations in lipid and glycemic metabolism and with higher blood pressure levels. PCOS patients with phenotype A presented vaster alterations in lipid metabolism and higher values of glycosylated hemoglobin as well as blood pressure compared to other PCOS phenotypes. CONCLUSIONS: Results in this paper suggest that inositol therapies (alone or combined with COC) are the most useful therapies with the best benefits against PCOS symptoms. Thus, integrative treatment may become a more efficient long-term choice to control PCOS symptoms. Furthermore, obesity can be considered as an adverse symptom and calorie restriction a key element of combined treatment in PCOS, not only for fertility management but also in long-term metabolic sequelae.

Altered Body Composition and Increased Resting Metabolic Rate Associated with the Postural Instability/Gait Difficulty Parkinson's Disease Subtype.

BACKGROUND: Weight loss in Parkinson's disease (PD) patients is a common but poorly understood manifestation. Several studies have reported that weight changes could be related to motor symptoms, drug side effects, dysphagia, depression, and/or dementia. Weight loss in PD is not a benign phenomenon and it has several clinical and prognostic implications with increased morbidity and mortality. Thus, it is crucial to determine nutritional changes in PD patients in order to prevent malnutrition and improve their quality of life. OBJECTIVE: To compare body composition and resting metabolic rates between PD patients and controls. METHODS: A total of 64 PD patients and 52 controls were studied. The Hoehn-Yahr scale was used to determine the disease stage, clinical and epidemiological data were recorded from verbal questionnaire, Inbody S10® was used to collect corporal parameters, and FitMate system was used to assess the resting metabolic rate. RESULTS: No significant differences were found between both experimental groups in age, gender, height, cholesterol levels, and the presence of hypertension, diabetes, and hypo/hyperthyroidism. However, the PD group showed lower body fat mass, whole-body fat percentage, and greater resting metabolic rate compared to controls (p < 0.05), with no significant differences in musculoskeletal mass. Parkinson's disease postural instability/gait difficulty (PD-PIGD) subtype showed lower body fat parameters, increased fat-free mass, and higher resting metabolic rates. CONCLUSIONS: These results suggest that PD patients present an increased resting metabolic rate associated with the postural instability/gait difficulty PD subtype, allowing a selective decrease of body fat mass and not musculoskeletal mass. Of note, several disease-related factors may contribute to this weight loss in PD patients, being a complex and multifactorial consequence. Our findings could likely be one of the many contributing factors. However, present findings may further add to our understanding of the phenomenon of weight loss in patients with PD.

Is insulin-like growth factor-1 involved in Parkinson's disease development?

Parkinson's disease (PD) is a neurodegenerative disorder that results in the death of dopaminergic neurons within the substantia nigra pars compacta and the reduction in dopaminergic control over striatal output neurons, leading to a movement disorder most commonly characterized by akinesia or bradykinesia, rigidity and tremor. Also, PD is less frequently depicted by sensory symptoms (pain and tingling), hyposmia, sleep alterations, depression and anxiety, and abnormal executive and working memory related functions. On the other hand, insulin-like growth factor 1 (IGF-1) is an endocrine, paracrine and autocrine hormone with several functions including tissue growth and development, insulin-like activity, proliferation, pro-survival, anti-aging, antioxidant and neuroprotection, among others. Herein this review tries to summarize all experimental and clinical data to understand the pathophysiology and development of PD, as well as its clear association with IGF-1, supported by several lines of evidence: (1) IGF-1 decreases with age, while aging is the major risk for PD establishment and development; (2) numerous basic and translational data have appointed direct protective and homeostasis IGF-1 roles in all brain cells; (3) estrogens seem to confer women strong protection to PD via IGF-1; and (4) clinical correlations in PD cohorts have confirmed elevated IGF-1 levels at the onset of the disease, suggesting an ongoing compensatory or "fight-to-injury" mechanism.

Neurotrophic Factors and Their Receptors Are Altered by the Mere Partial IGF-1 Deficiency.

Neurotrophic factors (NTFs) are a relevant group of secreted proteins that modulate growth, differentiation, repair, and survival of neurons, playing a role in the maintenance of the synaptic unions, dendrites, and axons and also being crucial for peripheral nervous system development and regulating plasticity in the adult central nervous system. On the other hand, insulin-like growth factor 1 (IGF-1) has been ascertained multiple beneficial actions in the brain: neuro-development, -protection, -genesis and plasticity. To further investigate the possible mechanisms underlying IGF-1 deficiency in the establishment of neurological disease, microarray and reverse transcription polymerase chain reaction gene expression analyses coupled with in silico processing were performed in an experimental model of partial IGF-1 deficiency. Results show that the mere IGF-1 deficiency seems to be responsible for an altered expression of genes coding for neurotrophic factors (particularly ciliary neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor), their receptors and signaling pathways (specially RET). The presented findings support that IGF-1 deficiency might be involved in the establishment and progression of neurodegenerative disorders.

Primary growth hormone insensitivity and psychomotor delay.

We report a case of short stature irresponsive to growth hormone (GH) replacement therapy. Low GH response to provocative tests and undetectable IGF-1 levels had suggested GH deficiency, while response to therapy indicated GH insensitivity. Molecular evaluation of the GH/IGF-1 axis should be performed in these cases to improve diagnosis and therapy.

Mexican case report of a never-treated Laron syndrome patient evolving to metabolic syndrome, type 2 diabetes, and stroke.

Glucose and lipid profile together with blood pressure should always be considered for low sera-IGF-1 patients. Even when adulthood is reached, IGF-1 therapy in these patients should be pursued as metabolic and protective cellular effects could be triggered. Real incidence of growth hormone insensitivity is still to be uncovered.

Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins.

Circulating levels of IGF-1 may decrease under several circumstances like ageing, metabolic syndrome, and advanced cirrhosis. This reduction is associated with insulin resistance, dyslipidemia, progression to type 2 diabetes, and increased risk for cardiovascular diseases. However, underlying mechanisms between IGF-1 deficiency and cardiovascular disease remain elusive. The specific aim of the present work was to study whether the partial IGF-1 deficiency influences heart and/or coronary circulation, comparing vasoactive factors before and after of ischemia-reperfusion (I/R). In addition, histology of the heart was performed together with cardiac gene expression for proteins involved in structure and function (extracellular matrix, contractile proteins, active peptides); carried out using microarrays, followed by RT-qPCR confirmation of the three experimental groups. IGF-1 partial deficiency is associated to a reduction in contractility and angiotensin II sensitivity, interstitial fibrosis as well as altered expression pattern of genes involved in extracellular matrix proteins, calcium dynamics, and cardiac structure and function. Although this work is descriptive, it provides a clear insight of the impact that partial IGF-1 deficiency on the heart and establishes this experimental model as suitable for studying cardiac disease mechanisms and exploring therapeutic options for patients under IGF-1 deficiency conditions.

Insulin-Like Growth Factor-1 Deficiency and Cirrhosis Establishment.

Cirrhosis represents the final stage of chronic liver damage, which can be due to different factors such as alcohol, metabolic syndrome with liver steatosis, autoimmune diseases, drugs, toxins, and viral infection, among others. Nowadays, cirrhosis is an important health problem and it is an increasing cause of morbidity and mortality, being the 14th most common cause of death worldwide. The physiopathological pathways that lead to fibrosis and finally cirrhosis partly depend on the etiology. Nevertheless, some common features are shared in this complex mechanism. Recently, it has been demonstrated that cirrhosis is a dynamic process that can be altered in order to delay or revert fibrosis. In addition, when cirrhosis has been established, insulin-like growth factor-1 (IGF-1) deficiency or reduced availability is a common condition, independently of the etiology of chronic liver damage that leads to cirrhosis. IGF-1 deprivation seriously contributes to the progressive malnutrition of cirrhotic patient, increasing the vulnerability of the liver to establish an inflammatory and oxidative microenvironment with mitochondrial dysfunction. In this context, IGF-1 deficiency in cirrhotic patients can justify some of the common characteristics of these individuals. Several studies in animals and humans have been done in order to test the replacement of IGF-1 as a possible therapeutic option, with promising results.

Clinical and molecular diagnosis of a cartilage-hair hypoplasia with IGF-1 deficiency.

Cartilage-hair hypoplasia syndrome (CHH) is a rare autosomal recessive condition characterized by metaphyseal chondrodysplasia and characteristic hair, together with a myriad of other symptoms, being most common immunodeficiency and gastrointestinal complications. A 15-year-old Mexican male initially diagnosed with Hirschsprung disease and posterior immunodeficiency, presents to our department for genetic and complementary evaluation for suspected CHH. Physical, biochemical, and genetic studies confirmed CHH together with IGF-1 deficiency. For this reason, we propose IGF-1 replacement therapy for its well-known actions on hematopoiesis, immune function and maturation, and metabolism. © 2016 Wiley Periodicals, Inc.