Current Trends and Applications of Food Derived Antihypertensive Peptides for the Management of Cardiovascular Disease

Food derived Antihypertensive peptides is considered as a natural supplement for controlling the hypertension. Food protein not only serve as a macronutrient but also act as raw material for biosynthesis of physiologically active peptides. Food sources like milk and milk products, animal protein such as meat, chicken, fish, eggs and plant derived proteins from soy, rice, wheat, mushroom, pumpkins contain high amount of antihypertensive peptides. The food derived antihypertensive peptides has ability to supress the action of rennin and Angiotesin converting enzyme (ACE) which is mainly involved in regulation of blood pressure by RAS. The biosynthesis of endothelial nitric oxide synthase is also improved by ACE inhibitory peptides which increase the production of nitric oxide in vascular walls and encourage vasodilation. Interaction between the angiotensin II and its receptor is also inhibited by the peptides which help to reduce hypertension. This review will explore the novel sources and applications of food derived peptides for the management of hypertension.

SynB3 conjugated QBP1 passes blood-brain barrier models and inhibits polyQ protein aggregation

Background: Polyglutamine diseases are degenerative diseases in the central nervous system caused by CAG trinucleotide repeat expansion which encodes polyglutamine tracts, leading to the misfolding of pathological proteins. Small peptides can be designed to prevent polyglutamine diseases by inhibiting the polyglutamine protein aggregation, for example, polyglutamine binding peptide 1(QBP1). However, the transportation capability of polyglutamine binding peptide 1 across the blood-brain barrier is less efficient. We hypothesized whether its therapeutic effect could be improved by increasing the rate of membrane penetration. Objectives: The objective of the study was to explore whether polyglutamine binding peptide 1 conjugated cell-penetrating peptides could pass through the blood-brain barrier and inhibit the aggregation of polyglutamine proteins. Methods: n order to investigate the toxic effects, we constructed a novel stable inducible PC12 cells to express Huntington protein that either has 11 glutamine repeats or 63 glutamine repeats to mimic wild type and polyglutamine expand Huntington protein, respectively. Both SynB3 and TAT conjugated polyglutamine binding peptide 1 was synthesized, respectively, and we tested their capabilities to pass through a Trans-well system and subsequently studied the counteractive effects on polyglutamine protein aggregation. Results: The conjugation of cell-penetrating peptides to SynB3 and TAT enhanced the transportation of polyglutamine binding peptide 1 across the mono-cell layer and ameliorated polyglutamine-expanded Huntington protein aggregation; moreover, SynB3 showed better delivery efficiency than TAT. Interestingly, it has been observed that polyglutamine binding peptide 1 specifically inhibited polyglutamine-expanded protein aggregation rather than affected other amyloidosis proteins, for example, β-Amyloid. Conclusion: Our study indicated that SynB3 could be an effective carrier for polyglutamine binding peptide 1 distribution through the blood-brain barrier model and ameliorate the formation of polyglutamine inclusions, thus SynB3 conjugated polyglutamine binding peptide 1 could be considered as a therapeutic candidate for polyglutamine diseases.

Repeated administration of orexin into the thalamic paraventricular nucleus inhibits the development of morphine-induced analgesia

Background: Hypothalamic neuropeptides, orexins, play pivotal roles in nociception and pain modulation. Objective: In this study, we investigated the effect of the administration of orexin into the paraventricular nucleus (PVT) on the development of morphine-induced analgesia in rats. Method. Male Wistar rats weighing 250-300 g received subcutaneous (s.c.) chronic morphine (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two experimental groups in which the orexin (100 μM, 200 nl) and its vehicle were microinjected into the PVT nucleus for 7 days before each morphine injection. Then, the formalin test was performed for the assessment of pain-related behaviors. Results: The results demonstrated that the rats pretreated by intra-PVT orexin exhibited higher pain-related behaviors than the morphine-treated group. The analgesic effects of morphine were significantly lower in orexin plus morphine-treated rats than the vehicle plus morphine-treated ones. Conclusion: Our findings suggested that the animals receiving the prolonged intra-PVT application of orexin before morphine injection demonstrated a significant increase in the development of nociceptive behaviors in all phases. Therefore, the present study highlighted a new area of the brain involved in the effect of orexin on analgesia induced by morphine.

Identification of glutamine synthetase as a contryphan-Bt binding protein by His-tag pull-down

Background: Contryphan-Bt is a D-tryptophan-containing disulfide-constrained decapeptide recently isolated from the venom of Conus betulinus. The molecular targets of contryphans are controversial, and the identification of its interacting proteins may be of great importance. Methods: His-tag pull-down assays were performed to investigate intracellular binding proteins of contryphan-Bt from rat brain lysate. Bt-Acp-[His]6, a contryphan-Bt derivative containing hexahistidine tag, was synthesized and used as the bait. As a control, Acp-[His]6 was used to exclude nonspecific bindings. Results: Glutamine synthetase was identified as a potential contryphan-Bt binding protein by pull-down assays and subsequent LC-MS/MS. The binding of contryphan-Bt to glutamine synthetase was confirmed and determined using microscale thermophoresis, with a Kd of 74.02 ± 2.8 μM. The binding did not affect glutamine synthetase activity, suggesting that the interaction site was distinct from the catalytic center. Conclusions: Glutamine synthetase was identified as a novel contryphan-Bt binding protein. This is the first report in which the conopeptide binds to an intracellular protein.

Dose Dependent Degeneration of Leydig Cells Following Kisspeptin-10 Administration: An Ultrastructural Study

Background: The discovery of kisspeptin signaling as a key regulator of gonadotropin releasing hormone (GnRH) secretion from the hypothalamus enhanced our understanding of the neuroendocrine regulation of mammalian reproduction. Effects of central and peripheral administration of kisspeptin on plasma gonadotropins, testosterone and spermatogenesis are studied in detail. Objective: The present study was conducted to check the ultrastructure of Leydig cells in prepubertal male rats in response to the administration of a range of kisspeptin doses. Method: To this end, we administered a range of kisspeptin-10 doses (1µg, 1ηg and 10ρg) intraperitoneally, to prepubertal male Sprague-Dawley rats (PND 35) twice daily after every 12 hours. Control rats were injected with physiological saline in parallel. Results: At the end of the treatment, plasma concentrations of testosterone was measured by competitive binding radioimmunoassay and small pieces of rat testicular tissue were processed for electron microscopy to examine the ultrastructure of Leydig cells. Plasma testosterone concentration was reduced significantly at 1ηg (P<0.05) and 1μg (P<0.01) doses as compared to control. Distinct ultrastructural changes categorized as dilatation of cytoplasmic organelles, irregular shaped nuclei with nuclear membrane invaginations, reduced nuclear sizes, degeneration and vacuolation were observed in the kisspeptin-10 treated Leydig cells as compared to control. Quantification of the data showed reduced Leydig cell indices and hyperplasia of the interstitial cells. Conclusion: It is concluded that chronic intermittent administration of kisspeptin-10 has a dose dependent degenerative effect on the plasma testosterone levels and Leydig cells ultrastructure in prepubertal male rats.

Structural Analysis Revealed the Interaction of Cardenolides from Calotropis procera with Na+/K+ ATPases from Herbivores

Background : The herbivores Danaus plexippus (Lepidoptera), Oncopeltus fasciatus and Aphis nerii (Hemiptera) are specialist insects that feed on Calotropis procera (Apocynaceae) (Sodom Apple). At least 35 chemically distinct cardenolides have been reported in C. procera. Objective We aimed to evaluate the interaction between cardenolides and Na+/K+ ATPases from herbivores. Methods : The Na+/K+ ATPases from these insects were modeled and docking studies were performed with cardenolides from C. procera. Results : The replacement of serine in sensitive Na+/K+ ATPase with histidine, phenylalanine and tyrosine in the structures examined suggests spatial impairment caused by interaction, probably making the herbivorous insects resistant against the cardenolides of C. procera. In addition, the ability of the insects to avoid cardenolide toxicity was not correlated with cardenolide polarity. Therefore, the plant fights predation through molecular diversity and the insects, regardless of their taxonomy, face this molecular diversity through amino acid replacements at key positions of the enzyme targeted by the cardenolides. Conclusions : The results show the arsenal of chemically distinct cardenolides synthesized by C. procera.

Construction and Evaluation of Recombinant Chimeric Fibrillin and Elastin Fragment in Human Mesenchymal Stem Cells

Background: Diverse extracellular matrix (ECM) proteins physically interact with stem cells and regulate stem cell function. However, the large molecular weight of the natural ECM renders large-scale fabrication of a similar functional structure challenging. Objective: The objective of this study was to construct a low molecular weight and multifunctional chimeric form of recombinant ECM to stimulate mesenchymal stem cell (MSC) for tissue repair. We engineered Fibrillin-1PF14 fused to an elastin-like polypeptide to develop a new biomimetic ECM for stem cell differentiation and investigated whether this recombinant chimeric Fibrillin-Elastin fragment (rcFE) was effective on human nasal inferior turbinate-derived mesenchymal stem cells (hTMSCs). Methods: hTMSCs were grown in the medium supplemented with rcFE, then the effect of the protein was confirmed through cell adhesion assay, proliferation assay, and real-time PCR. Results: rcFE enhanced the adhesion activity of hTMSCs by 2.7-fold at the optimal concentration, and the proliferation activity was 2.6-fold higher than that of the control group (non-treatment rcFE). In addition, when smooth muscle cell differentiation markers were identified by real-time PCR, Calponin increased about 6-fold, α-actin about 9-fold, and MYH11 about 10-fold compared to the control group. Conclusion: Chimeric rcFE enhanced cellular functions such as cell adhesion, proliferation, and smooth muscle differentiation of hTMSCs, suggesting that the rcFE can facilitate the induction of tissue regeneration.

Truncated Lactoferricin peptide controls cervical cancer cell proliferation via lncRNA-NKILA/NF-κB feedback loop

Background : Lactoferricin peptide (LP) has been reported to control cancer cell proliferation. NF‐κB interacting lncRNA (NKILA) is a tumor suppressor in several cancers. Objective: We aimed to explore the potential function of the truncated LP (TLP) in the prevention of cervical cancer cell proliferation. Methods: Bioinformatics analysis via PPA-Pred2 showed that 18-aa N-terminus of truncated lactoferricin peptide (TLP18, FKCRRWQWRMKKLGAPSI) shows higher affinity with nuclear factor kappaB (NF-κB) than LP. The effects of LP and TLP18 on cervical cancer cells SiHa and HeLa and the related mechanisms were explored by investigating NF‐κB and lncRNA-NKILA. Results : TLP18 shows an inhibitory rate up to 0.4-fold higher than LP on the growth of cervical cancer cells (P<0.05). NKILA siRNA promoted cell growth whether LP or TLP18 treatment (P<0.05). TLP18 treatment increases the level of lncRNA-NKILA and reduces the level of NF‐κB up to 0.2-fold and 0.6-fold higher than LP (P<0.05), respectively. NKILA siRNA increased the levels of NF‐κB, cleaved caspase-3, and BAX (P<0.05). TLP18 increased apoptotic cell rate up to 0.2-fold higher than LP, while NKILA siRNA inhibited cell apoptosis cell growth even LP or TLP18 treatment. Conclusion: Truncated Lactoferricin peptide controls cervical cancer cell proliferation via lncRNA-NKILA/NF‐κB feedback loop.

Proteomic analysis of the colistin-resistant E. coli clinical isolate: Explorations of the resistome

Background: Antimicrobial resistance is a worldwide problem after the emergence of colistin resistance since it was the last option left to treat carbapenemase-resistant bacterial infections. The mcr gene and its variants are one of the causes for colistin resistance. Besides mcr genes, some other intrinsic genes are also involved in colistin resistance but still need to be explored. Objective: The aim of this study was to investigate differential proteins expression of colistin-resistant E. coli clinical isolate and to understand their interactive partners as future drug targets. Methods: In this study, we have employed the whole proteome analysis through LC-MS/MS. The advance proteomics tools were used to find differentially expressed proteins in the colistin-resistant Escherichia coli clinical isolate compared to susceptible isolate. Gene ontology and STRING were used for functional annotation and protein-protein interaction networks, respectively. Results: LC-MS/MS analysis showed overexpression of 47 proteins and underexpression of 74 proteins in colistin-resistant E. coli. These proteins belong to DNA replication, transcription and translational process; defense and stress related proteins; proteins of phosphoenol pyruvate phosphotransferase system (PTS) and sugar metabolism. Functional annotation and protein-protein interaction showed translational and cellular metabolic process, sugar metabolism and metabolite interconversion. Conclusion: We conclude that these protein targets and their pathways might be used to develop novel therapeutics against colistin-resistant infections. These proteins could unveil the mechanism of colistin resistance.