Combatting infectious diarrhea: innovations in treatment and vaccination strategies.

INTRODUCTION: The escalating prevalence of infectious diseases is an important cause of concern in society. Particularly in several developing countries, infectious diarrhea poses a major problem, with a high fatality rate, especially among young children. The condition is divided into four classes, namely, acute diarrhea, invasive diarrhea, acute bloody diarrhea, and chronic diarrhea. Various pathogenic agents, such as bacteria, viruses, protozoans, and helminths, contribute to the onset of this condition. AREAS COVERED: The review discusses the scenario of infectious diarrhea, the prevalent types, as well as approaches to management including preventive, therapeutic, and vaccination strategies. The vaccination techniques are extensively discussed including the available vaccines, their advantages as well as limitations. EXPERT OPINION: There are several approaches available to develop new-improved vaccines. In addition, route of immunization is important and aerosols/nasal sprays, oral route, skin patches, powders, and liquid jets to minimize needles can be used. Plant-based vaccines, such as rice, might save packing and refrigeration costs by being long-lasting, non-refrigerable, and immunogenic. Future research should utilize predetermined PCR testing intervals and symptom monitoring to identify persistent pathogens after therapy and symptom remission.

Dimethyl fumarate modulates the dystrophic disease program following short-term treatment.

New medicines are urgently required to treat the fatal neuromuscular disease Duchenne muscular dystrophy (DMD). Dimethyl fumarate (DMF) is a potent immunomodulatory small molecule nuclear erythroid 2-related factor 2 activator with current clinical utility in the treatment of multiple sclerosis and psoriasis that could be effective for DMD and rapidly translatable. Here, we tested 2 weeks of daily 100 mg/kg DMF versus 5 mg/kg standard-care prednisone (PRED) treatment in juvenile mdx mice with early symptomatic DMD. Both drugs modulated seed genes driving the DMD disease program and improved force production in fast-twitch muscle. However, only DMF showed pro-mitochondrial effects, protected contracting muscles from fatigue, improved histopathology, and augmented clinically compatible muscle function tests. DMF may be a more selective modulator of the DMD disease program than PRED, warranting follow-up longitudinal studies to evaluate disease-modifying impact.

High-Dose Vitamin B6 (Pyridoxine) Displays Strong Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated Monocytes.

Vitamin B6 is shown to have anti-inflammatory properties, which makes it an interesting nutraceutical agent. Vitamin B6 deficiency is well established as a contributor to inflammatory-related conditions, whilst B6 supplementation can reverse these inflammatory effects. There is less information available regarding the effects of high-dose vitamin B6 supplementation as a therapeutic agent. This study set out to examine the effects of high-dose vitamin B6 on an LPS-stimulated monocyte/macrophage cell population via an analysis of protein and gene expression using an RT2 profiler PCR array for Human Innate and Adaptive Immune responses. It was identified that high-dose vitamin B6 has a global anti-inflammatory effect on lipopolysaccharide-induced inflammation in monocyte/macrophage cells by downregulating the key broad-spectrum inflammatory mediators CCL2, CCL5, CXCL2, CXCL8, CXCL10, CCR4, CCR5, CXCR3, IL-1ß, IL-5, IL-6, IL-10, IL-18, IL-23-a, TNF-α, CSF2, DDX58, NLRP3, NOD1, NOD2, TLR-1 -2 -4 -5 -7 -8 -9, MYD88, C3, FOXP3, STAT1, STAT3, STAT6, LYZ, CASP-1, CD4, HLA-E, MAPK1, MAPK8 MPO, MX-1, NF-κß, NF-κß1A, CD14, CD40, CD40LG, CD86, Ly96, ICAM1, IRF3, ITGAM, and IFCAM2. The outcomes of this study show promise regarding vitamin B6 within the context of a potent broad-spectrum anti-inflammatory mediator and could prove useful as an adjunct treatment for inflammatory-related diseases.

Potent CCR3 Receptor Antagonist, SB328437, Suppresses Colonic Eosinophil Chemotaxis and Inflammation in the Winnie Murine Model of Spontaneous Chronic Colitis.

Eosinophils and their regulatory molecules have been associated with chronic intestinal inflammation and gastrointestinal dysfunctions; eosinophil accumulation in the gut is prominent in inflammatory bowel disease (IBD). The chemokine receptor CCR3 plays a pivotal role in local and systemic recruitment and activation of eosinophils. In this study, we targeted CCR3-ligand interactions with a potent CCR3 receptor antagonist, SB328437, to alleviate eosinophil-associated immunological responses in the Winnie model of spontaneous chronic colitis. Winnie and C57BL/6 mice were treated with SB328437 or vehicle. Clinical and histopathological parameters of chronic colitis were assessed. Flow cytometry was performed to discern changes in colonic, splenic, circulatory, and bone marrow-derived leukocytes. Changes to the serum levels of eosinophil-associated chemokines and cytokines were measured using BioPlex. Inhibition of CCR3 receptors with SB328437 attenuated disease activity and gross morphological damage to the inflamed intestines and reduced eosinophils and their regulatory molecules in the inflamed colon and circulation. SB328437 had no effect on eosinophils and their progenitor cells in the spleen and bone marrow. This study demonstrates that targeting eosinophils via the CCR3 axis has anti-inflammatory effects in the inflamed intestine, and also contributes to understanding the role of eosinophils as potential end-point targets for IBD treatment.

Leucocyte-Rich Platelet-Rich Plasma Enhances Fibroblast and Extracellular Matrix Activity: Implications in Wound Healing.

BACKGROUND: Platelet-rich plasma (PRP) is an autologous blood product that contains a high concentration of platelets and leucocytes, which are fundamental fibroblast proliferation agents. Literature has emerged that offers contradictory findings about leucocytes within PRP. Herein, we elucidated the effects of highly concentrated leucocytes and platelets on human fibroblasts. METHODS: Leucocyte-rich, PRP (LR-PRP) and leucocyte-poor, platelet-poor plasma (LP-PPP) were compared to identify their effects on human fibroblasts, including cell proliferation, wound healing and extracellular matrix and adhesion molecule gene expressions. RESULTS: The LR-PRP exhibited 1422.00 ± 317.21 × 103 platelets/µL and 16.36 ± 2.08 × 103 white blood cells/µL whilst the LP-PPP demonstrated lower concentrations of 55.33 ± 10.13 × 103 platelets/µL and 0.8 ± 0.02 × 103 white blood cells/µL. LR-PRP enhanced fibroblast cell proliferation and cell migration, and demonstrated either upregulation or down-regulation gene expression profile of the extracellular matrix and adhesion molecules. CONCLUSION: LR-PRP has a continuous stimulatory anabolic and ergogenic effect on human fibroblast cells.

Streptococcus thermophilus ST285 Alters Pro-Inflammatory to Anti-Inflammatory Cytokine Secretion against Multiple Sclerosis Peptide in Mice.

Probiotic bacteria have beneficial effects to the development and maintenance of a healthy microflora that subsequently has health benefits to humans. Some of the health benefits attributed to probiotics have been noted to be via their immune modulatory properties suppressing inflammatory conditions. Hence, probiotics have become prominent in recent years of investigation with regard to their health benefits. As such, in the current study, we determined the effects of Streptococcus thermophilus to agonist MBP83-99 peptide immunized mouse spleen cells. It was noted that Streptococcus thermophilus induced a significant increase in the expression of anti-inflammatory IL-4, IL-5, IL-10 cytokines, and decreased the secretion of pro-inflammatory IL-1ß and IFN-γ Regular consumption of Streptococcus thermophilus may therefore be beneficial in the management and treatment of autoimmune diseases such as multiple sclerosis.

Streptococcus thermophilus alters the expression of genes associated with innate and adaptive immunity in human peripheral blood mononuclear cells.

Consumption of probiotics contributes to a healthy microbiome of the GIT leading to many health benefits. They also contribute to the modulation of the immune system and are becoming popular for the treatment of a number of immune and inflammatory diseases. The main objective of this study was to evaluate anti-inflammatory and modulatory properties of Streptococcus thermophilus. We used peripheral blood mononuclear cells from healthy donors and assessed modifications in the mRNA expression of their genes related to innate and adaptive immune system. Our results showed strong immune modulatory effects of S. thermophilus 285 to human peripheral blood mononuclear cells with an array of anti-inflammatory properties. S. thermophilus 285 reduced mRNA expression in a number of inflammatory immune mediators and markers, and upregulated a few of immune markers. S. thermophilus is used in the dairy industry, survives during cold storage, tolerates well upon ingesting, and their consumption may have beneficial effects with potential implications in inflammatory and autoimmune disorders.

Immunomodulatory effects of probiotics: Can they be used to treat allergies and autoimmune diseases?

As a person ages, physiological, immunological and gut microbiome changes collectively result in an array of chronic conditions. According to the 'hygiene hypothesis' the increasing prevalence of immune-mediated disorders may be related to intestinal dysbiosis, leading to immune dysfunction and associated conditions such as eczema, asthma, allergies and autoimmune diseases. Beneficial probiotic bacteria can be utilized by increasing their abundance within the gastrointestinal lumen, which in turn will modulate immune cells, such as, T helper (Th)-1, Th2, Th17, regulatory T (Treg) cells and B cells, which have direct relevance to human health and the pathogenesis of immune disorders. Here, we describe the cross-talk between probiotics and the gastrointestinal immune system, and their effects in relation to inflammatory bowel disease, multiple sclerosis, allergies and atopic dermatitis.

Multiple Sclerosis: Immunopathology and Treatment Update.

The treatment of multiple sclerosis (MS) has changed over the last 20 years. All immunotherapeutic drugs target relapsing remitting MS (RRMS) and it still remains a medical challenge in MS to develop a treatment for progressive forms. The most common injectable disease-modifying therapies in RRMS include ß-interferons 1a or 1b and glatiramer acetate. However, one of the major challenges of injectable disease-modifying therapies has been poor treatment adherence with approximately 50% of patients discontinuing the therapy within the first year. Herein, we go back to the basics to understand the immunopathophysiology of MS to gain insights in the development of new improved drug treatments. We present current disease-modifying therapies (interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, mitoxantrone), humanized monoclonal antibodies (natalizumab, ofatumumb, ocrelizumab, alentuzumab, daclizumab) and emerging immune modulating approaches (stem cells, DNA vaccines, nanoparticles, altered peptide ligands) for the treatment of MS.

Design and Synthesis of Non-Peptide Mimetics Mapping the Immunodominant Myelin Basic Protein (MBP83-96) Epitope to Function as T-Cell Receptor Antagonists.

Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP83-96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP83-96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP83-99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS.