Lipoteichoic Acid Induces Unique Inflammatory Responses when Compared to Other Toll-Like Receptor 2 Ligands

Toll-like receptors (TLRs) recognize evolutionarily-conserved molecular patterns originating from invading microbes. In this study, we were interested in determining if microbial ligands, which use distinct TLR2-containing receptor complexes, represent unique signals to the cell and can thereby stimulate unique cellular responses. Using the TLR2 ligands, R-FSL1, S-FSL1, Pam2CSK4, Pam3CSK4, and lipoteichoic acid (LTA), we demonstrate that these ligands activate NF-κB and MAP Kinase pathways with ligand-specific differential kinetics in murine macrophages. Most strikingly, LTA stimulation of these pathways was substantially delayed when compared with the other TLR2 ligands. These kinetics differences were associated with a delay in the LTA-induced expression of a subset of genes as compared with another TLR2 ligand, R-FSL1. However, this did not translate to overall differences in gene expression patterns four hours following stimulation with different TLR2 ligands. We extended this study to evaluate the in vivo responses to distinct TLR2 ligands using a murine model of acute inflammation, which employs intravital microscopy to monitor leukocyte recruitment into the cremaster muscle. We found that, although R-FSL1, S-FSL1, Pam2CSK4, and Pam3CSK4 were all able to stimulate robust leukocyte recruitment in vivo, LTA remained functionally inert in this in vivo model. Therefore distinct TLR2 ligands elicit unique cellular responses, as evidenced by differences in the kinetic profiles of signaling and gene expression responses in vitro, as well as the physiologically relevant differences in the in vivo responses to these ligands

Induction of protein citrullination and auto-antibodies production in murine exposed to nickel

Abstract Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity

New approaches in the diagnosis and treatment of latent tuberculosis infection

With nearly 9 million new active disease cases and 2 million deaths occurring worldwide every year, tuberculosis continues to remain a major public health problem. Exposure to Mycobacterium tuberculosis leads to active disease in only ~10% people. An effective immune response in remaining individuals stops M. tuberculosis multiplication. However, the pathogen is completely eradicated in ~10% people while others only succeed in containment of infection as some bacilli escape killing and remain in non-replicating (dormant) state (latent tuberculosis infection) in old lesions. The dormant bacilli can resuscitate and cause active disease if a disruption of immune response occurs. Nearly one-third of world population is latently infected with M. tuberculosis and 5%-10% of infected individuals will develop active disease during their life time. However, the risk of developing active disease is greatly increased (5%-15% every year and ~50% over lifetime) by human immunodeficiency virus-coinfection. While active transmission is a significant contributor of active disease cases in high tuberculosis burden countries, most active disease cases in low tuberculosis incidence countries arise from this pool of latently infected individuals. A positive tuberculin skin test or a more recent and specific interferon-gamma release assay in a person without overt signs of active disease indicates latent tuberculosis infection. Two commercial interferon-gamma release assays, QFT-G-IT and T-SPOT.TB have been developed. The standard treatment for latent tuberculosis infection is daily therapy with isoniazid for nine months. Other options include therapy with rifampicin for 4 months or isoniazid + rifampicin for 3 months or rifampicin + pyrazinamide for 2 months or isoniazid + rifapentine for 3 months. Identification of latently infected individuals and their treatment has lowered tuberculosis incidence in rich, advanced countries. Similar approaches also hold great promise for other countries with low-intermediate rates of tuberculosis incidence

Nanostructured materials for drug delivery and tissue engineering applications

Nanotechnology and nanostructured materials for drug delivery and tissue engineering applications are relatively new field that is constantly advancing and expanding. The materials used are at the nanoscale level. Recently, great discoveries and applications have been made (Agents for use in chemotherapy, biological agents and immunotherapy agents) in the treatment of diseases in various areas. Tissue engineering is based on the regeneration and repair of damaged organs and tissues by developing biological substitutes that restore, maintain or improve the function of tissues and organs. Cells isolated from patients are used to seed 3D nanoparticles that can be synthetic or natural biomaterials. For the development of new tissue in tissue engineering, it is necessary to meet the conditions for connecting cells. This paper will present the ways of connecting cells and creating new tissues. Some recent discoveries and advances in the field of nanomedicine and the application of nanotechnology in drug delivery will be presented. Furthermore, the improvement of the effectiveness of new and old drugs based on the application of nanotechnology will be shown

Functional biotransformation of phytoestrogens by gut microbiota with impact on cancer treatment

The human gut is a host for trillions of microorganisms, divided into more than 3,000 heterogeneous species that is called the gut microbiota. The gut microbiota composition can be altered by many different endogenous and exogenous factors, especially diet and nutrition. A diet rich in phytoestrogens, a variable group of chemical compounds similar to 17-β-estradiol (E2), the essential female steroid sex hormone is potent to change the composition of gut microbiota. However, the metabolism of phytoestrogens also highly depends on the action of enzymes produced by gut microbiota. Novel studies have shown that phytoestrogens could play an important role in the treatment of different types of cancers, such as breast cancer in women, due to their potential to decrease estrogen levels. This review aims to summarize recent findings about the lively dialogue between phytoestrogens and gut microbiota and to address their possible future application, especially in treating patients with diagnosed breast cancer. A potential therapeutic approach for the prevention and improving outcomes in breast cancer patients could be based on targeted probiotic supplementation with the use of soy phytoestrogens. A positive effect of probiotics on the outcome and survival of patients with breast cancer has been established. However, more in vivo scientific studies are needed to pave the way for the use of probiotics and phytoestrogens in the clinical practice of breast cancer treatment

Effect of diabetic neuropathy on reparative ability and immune response system

The effects of diabetes can be divided into short, medium and long term and various human organ systems can be effected. The present study aimed to determine how much the duration of diabetes mellitus (DM) affect the reparative ability of the body, immune response and the development of DM complications. Interleukin 1-β (IL-1β) and Interleukin 6 (IL-6) were monitored as specific indicators of inflammatory reaction and C-reactive protein (CRP), leukocyte count (WBC) and sedimentation rate (ESR) as general markers of inflammatory reaction. Tumour necrosis factor α (TNF-α) and transforming growth factor β1 (TGF-β1) were observed as indicators of reparative ability and polyneuropathy. All interleukins were determined by ELISA and evaluated spectrophotometrically. Michigan Neuropathy Screening Instrument (MNSI) is performed for neuropathy examination. Patients with diabetes mellitus were divided into 3 groups, according to duration of diabetes mellitus. IL-6 levels correlated with clinical stage of diabetic polyneuropathy at p = 0.025 R = 0.402; with CRP at p = 0.0001, R = 0.784 as well as correlation of CRP and MNSI score (R = 0.500, p = 0.034) in a group of patients with DM lasting up to 10 years. The reparative ability of the body is reduced by physiological age and ages of DM duration. The immune response is weakened in DM additionally. The dual activity of cytokines IL-6 and TGF-β1 is present in long-duration Diabetes Mellitus

Covid-19 a triggering factor of autoimmune and multi-inflammatory diseases

SARS-CoV-2 virus has attracted a lot of attention globally due to the autoimmune and inflammatory processes that were observed during the development of Covid-19 disease. Excessive activation of immune response and triggering of autoantibodies synthesis as well as an excessive synthesis of inflammatory cytokines and the onset of cytokine storm has a vital role in the disease outcome and the occurring autoimmune complications. This scenario is reminiscent of infiltration of lymphocytes and monocytes in specific organs and the increased production of autoantibodies and chemoattractants noted in other inflammatory and autoimmune diseases. The main goal of this study is to investigate the complex inflammatory processes that occur in Covid-19 disease and to find similarities with other inflammatory diseases such as multiple sclerosis (MS), acute respiratory distress syndrome (ARDS), rheumatoid arthritis (RA) and Kawasaki syndrome to advance existing diagnostic and therapeutic protocols. The therapy with Interferon-gamma (IFN-γ) and the use of S1P receptor modulators showed promising results. However, there are many unknowns about these mechanisms and possible novel therapies. Therefore, the inflammation and autoimmunity triggered by Covid-19 should be further investigated to improve existing diagnostic procedures and therapeutic protocols for Covid-19

Novel therapeutical approaches based on neurobiological and genetic strategies for diabetic polyneuropathy – a review

Background: Neuropathy is among the most often reported consequences of diabetes and the biggest cause of morbidity and mortality in people suffering from this life-long disease. Although different therapeutic methods are available for diabetic neuropathy, it is still the leading cause of limb amputations, and it significantly decreases patients’ quality of life. Aim: This study investigates potential novel therapeutic options that could ameliorate symptoms of DN. Methodology: Research and review papers from the last 10 years were taken into consideration. Results: There are various traditional drugs and non-pharmacological methods used to treat this health condition. However, the research in the area of pathogenic-oriented drugs in the treatment of DN showed no recent breakthroughs, mostly due to the limited evidence about their effectiveness and safety obtained through clinical trials. Consequently, there is an urgent demand for the development of novel therapeutic options for diabetic neuropathy. Conclusion: Some of the latest novel diagnostic methods for diagnosing diabetic neuropathy are discussed as well as the new therapeutic approaches, such as the fusion of neuronal cells with stem cells, targeting gene delivery and novel drugs