Machine intelligence in peptide therapeutics: A next-generation tool for rapid disease screening

Discovery and development of biopeptides are time-consuming, laborious, and dependent on various factors. Data-driven computational methods, especially machine learning (ML) approach, can rapidly and efficiently predict the utility of therapeutic peptides. ML methods offer an array of tools that can accelerate and enhance decision making and discovery for well-defined queries with ample and sophisticated data quality. Various ML approaches, such as support vector machines, random forest, extremely randomized tree, and more recently deep learning methods, are useful in peptide-based drug discovery. These approaches leverage the peptide data sets, created via high-throughput sequencing and computational methods, and enable the prediction of functional peptides with increased levels of accuracy. The use of ML approaches in the development of peptide-based therapeutics is relatively recent; however, these techniques are already revolutionizing protein research by unraveling their novel therapeutic peptide functions. In this review, we discuss several ML-based state-of-the-art peptide-prediction tools and compare these methods in terms of their algorithms, feature encodings, prediction scores, evaluation methodologies, and software utilities. We also assessed the prediction performance of these methods using well-constructed independent data sets. In addition, we discuss the common pitfalls and challenges of using ML approaches for peptide therapeutics. Overall, we show that using ML models in peptide research can streamline the development of targeted peptide therapies.     

Roles of toll-like receptors in Cancer: A double-edged sword for defense and offense

Toll-like receptors (TLRs) belong to a class of pattern-recognition receptors that play an important role in host defense against pathogens by recognizing a wide variety of pathogen-associated molecular patterns (PAMPs). Besides driving inflammatory responses, TLRs also regulate cell proliferation and survival by expanding useful immune cells and integrating inflammatory responses and tissue repair processes. TLR signaling, which is centrally involved in the initiation of both innate and adaptive immune responses, has been thought to be restricted to immune cells. However, recent studies have shown that functional TLRs are expressed not only on immune cells, but also on cancer cells, thus implicating a role of TLRs in tumor biology. Increasing bodies of evidence have suggested that TLRs act as a double-edged sword in cancer cells because uncontrolled TLR signaling provides a microenvironment that is necessary for tumor cells to proliferate and evade the immune response. Alternatively, TLRs can induce an antitumor immune response in order to inhibit tumor progression. In this review, we summarize the dual roles of TLRs in tumor cells and, more importantly, delve into the therapeutic potential of TLRs in the context of tumorigenesis.     

Keratinocyte regulation of TGF-β and connective tissue growth factor expression: A role in suppression of scar tissue formation

Allogeneic keratinocytes applied to large full-thickness wounds promote healing while suppressing scar tissue formation. This effect may be mediated in part by their effect on the levels of transforming growth factor-betas (TGF-betas) and connective tissue growth factor (CTGF) in the wound and subsequent modulation of fibroblast activity. We have examined the levels of TGF-beta and CTGF produced by keratinocytes and fibroblasts, and the effect of keratinocyte-conditioned medium using monolayer and living skin-equivalent cultures. Keratinocyte monolayers did not release any detectable TGF-beta1, but released moderate levels of TGF-beta2 into culture medium, and stained strongly for TGF-beta1, but only weakly for TGF-beta2. Fibroblasts released large amounts of TGF-beta1, no TGF-beta2, and stained strongly for TGF-beta1. Neither cell type released TGF-beta3, but both stained strongly for TGF-beta3. Keratinocyte-conditioned medium suppressed the levels of TGF-betas and CTGF associated with the fibroblasts compared with fibroblasts incubated in Dulbecco's minimal essential medium and fibroblast-conditioned medium. In living skin equivalents, keratinocytes stained very strongly for TGF-beta1 and CTGF, moderately strongly for TGF-beta3, and only weakly for TGF-beta2. Fibroblasts stained strongly for TGF-beta1 and 3 and CTGF. These observations suggest that keratinocytes may affect the TGF-beta profile in such a way as to suppress the formation of scar tissue.     

BNP directly immunoregulates the innate immune system of cardiac transplant recipients in vitro

BACKGROUND: The innate immune system plays an important role in cardiac allograft rejection. BNP has frequently been reported to elevate during acute cardiac rejection, yet the explanation behind this phenomenon is unclear. We hypothesized that BNP might interact with the innate immune system in cardiac transplant recipients and devised a series of in vitro culture experiments to explore this phenomena. METHODS: PBMCs were isolated from whole blood of (total n = 40) cardiac transplant recipients. Short (24h, n = 20) and long term (72h, n = 20) co-cultures of innate cells in the presence or absence of BNP were performed. BNP was added at two specific concentrations and compared to placebo control. Innate cells were immunophenotyped using flow cytometry. RESULTS: BNP dose dependently reduced the total number of monocytes, B cells and NK cells. Furthermore, BNP co-culture impaired NK cell cytotoxicity and adhesion of non-classical monocytes (via down-regulation of CD11c). DISCUSSION: BNP has an additional physiological role of moderating components of the innate immune system. Although speculative, this could be beneficial to cardiac transplant recipients as the innate immune system is involved in allograft rejection. Further investigation is required to elucidate the mechanism behind how BNP affects immune cells and whether the same effects are consistent with the adaptive immune system.     

Low temperature synthesis of BiFeO3 nanoparticles with enhanced magnetization and promising photocatalytic performance in dye degradation and hydrogen evolution

In this investigation, we have synthesized BiFeO₃ nanoparticles by varying hydrothermal reaction temperatures from 200 °C to 120 °C to assess their visible-light driven photocatalytic activity along with their applicability for hydrogen production via water splitting. The rhombohedral perovskite structure of BiFeO₃ is formed for hydrothermal reaction temperature up to 160 °C. However, for a further decrement of hydrothermal reaction temperature a mixed sillenite phase is observed. The XRD Rietveld analysis, XPS analysis and FESEM imaging ensure the formation of single-phase and well crystalline nanoparticles at 160 °C reaction temperature with 20 nm of average size. The nanoparticles fabricated at this particular reaction temperature also exhibit improved magnetization, reduced leakage current density and excellent ferroelectric behavior. These nanoparticles demonstrate considerably high absorbance in the visible range with a low band gap (2.1 eV). The experimentally observed band gap is in excellent agreement with the calculated band gap using first-principles calculations. The favorable photocatalytic performance of these nanoparticles has been able to generate more than two times of solar hydrogen compared to that produced by bulk BiFeO₃ as well as commercially available Degussa P25 titania. Notably, the experimentally observed band gap is almost equal for both bulk material and nanoparticles prepared at different reaction temperatures. Therefore, in solar energy applications, the superiority of BiFeO₃ nanoparticles prepared at 160 °C reaction temperature may be attributed not only to their band gap but also to other factors, such as reduced particle size, excellent morphology, good crystallinity, large surface to volume ratio, ferroelectricity and so on.

Multiferroic BiFeO₃ nanoparticles were synthesized using low temperature hydrothermal technique to assess their visible-light driven photocatalytic activity along with their applicability for the production of hydrogen via water splitting.     

Toll-like receptor modulators: a patent review (2006-2010)

INTRODUCTION: The immune response is mediated via two parallel immune components, innate and adaptive, whose effector functions are highly integrated and coordinated for the protection of the human body against invading pathogens and transformed cells. The discovery of pathogen recognition receptors (PRRs), most notably toll-like receptors (TLRs), in innate immunity has evoked increased interest in the therapeutic handling of the innate immune system. TLRs are germ line-encoded receptors that play a potent role in the recognition of a diverse variety of ligands ranging from hydrophilic nucleic acids to lipopolysaccharide (LPS) or peptidoglycan (PGN) structures in pathogens. AREAS COVERED: This review discusses recent updates (2006-2010) in completed, ongoing and planned clinical trials of TLR immunomodulator-based therapies for the treatment of infectious diseases, inflammatory disorders and cancer. EXPERT OPINION: Since the discovery of human TLRs, modulating immune responses using TLR agonists or antagonists for therapeutic purposes has provoked intense activity in the pharmaceutical industry. The ability of TLRs to initiate and propagate inflammation makes them attractive therapeutic targets. We are now at the stage of evaluating such molecules in human diseases. Additionally, there is also extensive literature available on TLRs in diseased states. These data provide a basis for the identification of novel immunomodulators (agonists and antagonists) for the therapeutic targeting of TLRs.