Biology/Life Sciences
Neuropeptide Network of Polycystic Ovary Syndrome – A Review
Polycystic Ovary Syndrome (PCOS) the ubiquitous reproductive disorder has been documented as highly prevalent (6-9%) in India. 10% of women globally are predicted to have the disease. The highly mutable endocrinopathy with differential clinical criteria for each diagnosis of PCOS can mask the severity of the syndrome by influencing the incidence and occurrence of PCOS.
When there is a solid theoretical hypothesis between the neuroendocrine origin and ovarian origin of PCOS recent evidence supports the neuroendocrine derivation of the pathology. It is considered of neuroendocrine basis – as it controls the ovarian axis and acts as a delicate target because it possesses receptors for various gonadal hormones neurotransmitters & neuropeptides. Can these neuroendocrine alterations variations in central brain circuits and neuropeptide dysregulation be the tie that would link the pathophysiology of the disorder the occurrence of all the 1˚ and 2˚ symptoms like polycystic ovaries hyperandrogenism obesity insulin resistance etc. in PCOS?
This review anticipates providing a comprehensive overview of how neuropeptides such as Kisspeptin Neurokinin B Dynorphin A β-Endorphin Nesfatin Neuropeptide Y Phoenixin Leptin Ghrelin Orexin and Neudesin influence PCOS the understanding of which may help to establish potential drug candidates against precise targets in these central circuits.
Anionic Host Defence Peptides from the Plant Kingdom: Their Anticancer Activity and Mechanisms of Action
It is becoming increasingly clear that plants ranging across the plant kingdom produce anionic host defence peptides (AHDPs) with potent activity against a wide variety of human cancers cells. In general this activity involves membrane partitioning by AHDPs which leads to membranolysis and / or internalization to attack intracellular targets such as DNA. Several models have been proposed to describe these events including: the toroidal pore and Shai-Matsuzaki- Huang mechanisms but in general the mechanisms underpinning the membrane interactions and anticancer activity of these peptides are poorly understood. Plant AHDPs with anticancer activity can be conveniently discussed with reference to two groups: cyclotides which possess cyclic molecules stabilized by cysteine knot motifs and other ADHPs that adopt extended and -helical conformations. Here we review research into the anticancer action of these two groups of peptides along with current understanding of the mechanisms underpinning this action.
The Amazing World of Peptide Engineering: the Example of Antimicrobial Peptides from Frogs and Their Analogues
This review discusses the importance and properties of antimicrobial peptides from frogs and their synthetic analogues as potential therapeutic alternatives in fighting not only bacterial infections but also protozoans involved with the major neglected diseases which afflict human populations (e.g. Chagas disease African sleeping sickness Leishmaniasis and malaria). Here we emphasize their multifunctional properties such as promising broad-spectrum drugs that target protozoan parasites too.
Induced Folding Under Membrane Mimetic and Acidic Conditions Implies Undiscovered Biological Roles of Prokaryotic Ubiquitin-Like Protein Pup
Ubiquitin-like proteins play important roles in diverse biological processes. In Mycobacterium tuberculosis Pup (prokaryotic ubiquitin-like protein) a functional homologue of eukaryotic ubiquitin interacts with the proteasome ATPase subunit Mpa to recognize and unfold substrates and then translocate them into the proteasome core for degradation. Previous studies revealed that Pup an intrinsically disordered protein (IDP) adopts a helical structure upon binding to the N-terminal coiled-coil domain of Mpa at its disordered C-terminal region. In the present study using circular dichroism (CD) surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) we show that membrane mimetic and acidic conditions also induce Pup to adopt helical conformations. Moreover at low pH Pup via both of its N- and C-terminal regions binds to Mpa on sites from the N-terminal region in addition to the C-terminal region of the coiled-coil domain. Our results imply Pup may play undiscovered roles in some biological processes e.g. those involve in membrane.
C-terminal Lysine-Linked Magainin 2 with Increased Activity Against Multidrug-Resistant Bacteria
Due to the growing problem of antibiotic-resistant microorganisms the development of novel antimicrobial agents is a very important challenge. Dimerization of cationic antimicrobial peptides (cAMPs) is a potential strategy for enhancing antimicrobial activity. Here we studied the effects of magainin 2 (MG2) dimerization on its structure and biological activity. Lysine and glutamic acid were used to synthesize the C- and N-terminal dimers of MG2 respectively in order to evaluate the impact of linker position used to obtain the dimers. Both MG2 and its dimeric versions showed a random coil structure in aqueous solution. However in the presence of a structure-inducing solvent or a membrane mimetic all peptides acquired helical structure. N-terminal dimerization did not affect the biological activity of the peptide. On the other hand the C-terminal dimer (MG2)2K showed antimicrobial activity 8–16 times higher than that of MG2 and the time required to kill Escherichia coli was lower. The enhanced antimicrobial activity was related to membrane permeabilization. (MG2)2K was also more active against multidrug-resistant bacteria of clinical origin. Overall the results presented here demonstrate that C-terminal lysine-linked dimerization improve the activity of MG2 and (MG2)2K can be considered as a potential antimicrobial agent.
Ribosome-inactivating Proteins from Root Tubers and Seeds of Trichosan-thes kirilowii and Other Trichosanthes Species
Ribosome-inactivating proteins have been isolated from Trichosanthes kirilowii root tubers and seeds including trichosanthin karasurin and T 33 from root tubers and trichosanthrip trichokirin alpha-kirilowin beta-kirilowin and trichoanguin from seeds. The aforementioned proteins show structural and functional similarities. Among them trichosanthin is the best known and most intensely studied. Trichosanthin manifests anticancer activity in vitro and in tumor bearing mice against a variety of cancers/cancer cell lines. It also exhibits anti-HIV-1 and anti-HSV-1 activities. Trichosanthin has been found to be useful for treatment of cesarean scar pregnancies and ectopic pregnancy and for preventing acute rejection of major histocompatibility complex-mismatched mouse skin allograft. Trichosanthin selectively lesions some neurons and thus can be used in neuroscience research.
Wasp Venom Toxins as a Potential Therapeutic Agent
It is high time now to discover novel drugs due to the increasing rate of drug resistance by the pathogen organisms and target cells as well as the dependence or tolerance of the body towards the drug. As it is obvious that significant numbers of the modern day pharmaceuticals are derived from natural products it is equally astonishing to accept that venoms of various origins have therapeutic potentials. Wasp venoms are also a rich source of therapeutically important toxins which includes short cationic peptides kinins polyamines and polyDNA viruses to name a few indentified. Wasp venom cationic peptides namely mastoparan and its analogs show a very important potency as an antimicrobial and anticancer agents of the future. They have proven to be the better candidates due to their lesser toxic effects and higher selectivity upon chemical modification and charge optimization. They also have superiority over the conventional chemical drugs as the target cells very rarely develop resistance against them because these peptides primarily imparts its effect through biophysical interaction with the target cell membrane which is dependent upon the net charge of the peptide its hydrophobicity and anionicity and fluidity of the target cell membranes. Besides the other components of wasp venom such as kinins polyamines and polyDNA viruses show various pharmacological promise in the treatment of pain inflammatory disease and neurodegenerative diseases such as epilepsy and aversion.
Activities of Venom Proteins and Peptides with Possible Therapeutic Applications from Bees and WASPS
The variety of proteins and peptides isolated from honey bee venom and wasp venom includes melittin adiapin apamine bradykinin cardiopep mast cell degranulating peptide mastoparan phospholipase A2 and secapin. Some of the activities they demonstrate may find therapeutic applications.
Insights into Antimicrobial Peptides from Spiders and Scorpions
The venoms of spiders and scorpions contain a variety of chemical compounds. Antimicrobial peptides (AMPs) from these organisms were first discovered in the 1990s. As of May 2015 there were 42 spider's and 63 scorpion's AMPs in the Antimicrobial Peptide Database (http://aps.unmc.edu/AP). These peptides have demonstrated broad or narrow-spectrum activities against bacteria fungi viruses and parasites. In addition they can be toxic to cancer cells insects and erythrocytes. To provide insight into such an activity spectrum this article discusses the discovery classification structure and activity relationships bioinformatics analysis and potential applications of spider and scorpion AMPs. Our analysis reveals that in the case of linear peptides spiders use both glycine-rich and helical peptide models for defense whereas scorpions use two distinct helical peptide models with different amino acid compositions to exert the observed antimicrobial activities and hemolytic toxicity. Our structural bioinformatics study improves the knowledge in the field and can be used to design more selective peptides to combat tumors parasites and viruses.
High-Level Secretory Expression and Purification of Recombinant Human Interleukin 1 Beta in Pichia pastoris
As an important pro-inflammatory cytokine interleukin-1beta (IL-1β) participates in a variety of physiological and pathological responses. In order to obtain higher yielded recombinant human interleukin-1 beta (rhIL-1β) we cloned hIL-1β cDNA sequences based on the coding sequence of human mature IL-1. After recombinant pPICZA/hIL-1β was separated and sequenced we transformed recombinant pPICZA/hIL-1β into Pichia pastoris GS115 SMD1168 and X-33 strain via electroporation. The results showed that recombinant pPICZA/ hIL-1β had the highest expression level in X-33 Pichia pastoris. Subsequently rhIL-1β was purified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and identified by Western blot. Then the fermentation process was optimized to increase product yield. Under the fermentation conditions of the absorption value of fermentation liquor before induction of 600 oxygen concentration of 20% methanol concentration of 0.25% with pH 5.0 the yield of rhIL-1β reached to 250 mg/L after 72 h induction at 26°C. After aqueous two-phase extraction combined with chromatography the purity of rhIL-1β was 95% and the yield was up to 85%. The biological activity of rhIL-1β was detected by MTT assay and the result showed that rhIL-1 significantly inhibited the growth and proliferation of B16 melanoma cells.
Prognostic Value of CD34 Positive Cells in the Lumen of Tumor Vessels in Breast Cancer
Background/Objective: The role of circulating endothelial cells in tumor progression was noted by many researchers. The purpose of this research was to study the relationship of free (unrelated to the wall of vessel) CD34 positive cells (F-CD34+) located in the lumen of tumor vessels with features of angiogenesis clinical and morphological characteristics of breast cancer (BC). Materials and Methods: The tumor samples received from 45 patients with T1-T2 stages of ductal invasive carcinomas were included in this study. The sections were stained immunohistochemically using antibodies to CD34. The presence of F-CD34+ was assessed microscopically and compared with clinical characteristics of BC hormone receptors and HER2/neu status with the number of different tumor vessels and with the presence of lymphovascular invasion (LVI). Results: F-CD34+ were revealed in 35 cases (778%). Their presence correlated with the number of atypical dilated capillaries (p=0.00001) and “cavitary” structures (CS) type-1 (p=0001) having been described by us earlier with the presence of LVI (p=002) tumor grade (p=001) estrogen receptor (p=00002) and progesterone receptor (p=0002) status. FCD34+ were more often observed in the cases with multiple atypical dilated capillaries (p=0001) and CS type-1 (p=004) in the presence of LVI (p=01) in G2-G3 (p=009) in negative estrogen (p=001) and progesterone (p=003) receptors status. The correlations of F-CD34+ with Her2/new status microvessel density and other types of tumor vessels were not detected. Conclusion: The presence of F-CD34+ in tumor vessels is associated with clinical morphological and biological characteristics of BC and its evaluation may be important for the prognosis.
Vascular Endothelial Growth Factor: A New Paradigm for Targeting Various Diseases
Vascular endothelial growth factor is a signaling protein which is responsible for the angiogenesis process. Variation in its expression leads to various disorders like cancer diabetes psoriasis and neuronal imbalance (depression) etc. The abundance of VEGF (VEGF-A B C) concentration is present in the kidney heart lung ovary thyroid gland neurons embryonic tissue etc. The regulation of VEGF expression is controlled by the hypoxia condition hormonal regulation inflammatory mediator cytokines and growth hormone. The VEGF binds to the VEGFR1 and VEGFR2 tyrosine kinase receptors causing conformational changes resulting in the endothelial cell proliferation increased vascular permeability and formation of new blood vessel. The high level of VEGF- A activity found in the synovial fluid leads to rheumatoid arthritis whereas in the retinal cell it results in diabetic retinopathy. The tumor growth factor induced VEGF A expression in keratin cell lead to psoriasis. The higher level of VEGF activity increased neovascularization which is beneficial in cerebral ischemia as well as in the growth of the neurons. VEGF is also considered to be an important factor in tumor invasion and metastasis. Various growth factors stimulate or participated in tumor angiogenesis. Therefore the Anti-VEGF therapy can be a potential option for treatment of psoriasis rheumatoid arthritis diabetic retinopathy and cancer. The (VEGF) gene expression modulation will lead to the new therapeutic possibilities in the future.
Targeting Tumor Angiogenesis in Gastrointestinal Malignancies
Gastrointestinal [GI] malignancies are common and frequently lethal neoplasms. As our understanding of GI cancers deepens more pathways are discovered that play key roles in tumorigenesis and metastasis. Angiogenesis has emerged as a critical pathway in many cancers particularly in GI cancers. The discovery of a complex network of signals including vascular epithelial growth factor [VEGF] led to the emergence of a new class of cancer therapies targeting angiogenesis. Bevacizumab was the first to emerge gaining US Food and Drug Administration [FDA] approval in 2004 for the treatment of advanced colorectal cancer; since then several antiangiogenic agents have become clinically available and numerous others are in clinical or preclinical testing. This review will focus on anti-angiogenesis therapies in GI malignancies.
The State-of-Art in Angiogenic Properties of Latex from Different Plant Species
Background: The development of drugs capable of enhance or inhibit the cell proliferation is an area in expansion at modern biomedical sciences. Recent researches have shown that latex has strong angiogenic potential. Methods: We performed a bibliometric analysis on the global literature trying to identify: the main scientometrics data the botanical families and species the angiogenic or antiangiogenic properties and also discussed the results obtained on this topic up to now. Results: The different bibliometric approaches showed a continuous increase of both quantitative and qualitative parameters in the studies of latex utilization in the angiogenesis process. From more than 35000 lactiferous species existing only 29 have been studied and showed angiogenic potential. Then the potential for finding new therapeutic compounds in latex is a new and promising field that needs to be better explored. Regarding the biological activity 59% of articles have reported the angiogenic activity and 41% the antiangiogenic property. The most articles identified in this research have been used in their experimental analysis the crude latex (73.41%). Only 26.52% of the articles used biocompounds isolated from latex. Among the weaknesses in this field it is necessary to point: the molecular characterization of latex; the establishment of molecular mechanism of action; and demonstration of latex biocompunds safety and effectiveness in clinical trials. Conclusion: Those results are important to spread knowledge about the use of latex as a new biomaterial employed in medicine indicate trends point out the technical difficult on the development of new drugs.
Extracellular Matrix on the Phenotypic Switching of Vascular Smooth Muscle Cells
Background: Vascular smooth muscle cells (VSMCs) show eminently plasticity during physiological and pathological processes. VSMCs undergo from contractile phenotype to proliferative matrigenic inflammatory or osteogenic phenotype during the pathogenesis of hypertension atherosclerosis and vascular calcification etc. Methods: Here we reviewed the research papers regarding to the respective effects of extracellular matrix (ECM) on VSMC phenotypic switching. Results: The ECM including collagens elastins proteoglycans and glycoproteins etc via complex protein-protein interaction constitute a complicated microenvironment for VSMCs. Each component regulates VSMC phenotypic switching via various signaling pathways and cell surface receptor. On the other hand ECM can be dynamic degraded or proteolysed by a variety of extracellular proteinases such as matrix metalloproteinases (MMPs) and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS). Thus these extracellular proteinases are able to modulate VSMC phenotypes partially via degrading ECM. Moreover the ECM-modulated VSMC phenotypic switching also plays a critical role in various vascular diseases such as hypertension atherosclerosis and vascular calcification. Conclusion: Various ECM compositions including fibrous proteins glycoproteins and proteoglycans exhibit the ability to modulate the VSMC phenotypic switching.