Diabetic neuropathy: A NRF2 disease?

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has multifarious action with its target genes having redox-regulating functions and being involved in inflammation control, proteostasis, autophagy, and metabolic pathways. Therefore, the genes controlled by NRF2 are involved in the pathogenesis of myriad diseases, such as cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, autoimmune disorders, and cancer. Amidst this large array of diseases, diabetic neuropathy (DN) occurs in half of patients diagnosed with diabetes and appears as an injury inflicted upon peripheral and autonomic nervous systems. As a complex effector factor, NRF2 has entered the spotlight during the search of new biomarkers and/or new therapy targets in DN. Due to the growing attention for NRF2 as a modulating factor in several diseases, including DN, this paper aims to update the recently discovered regulatory pathways of NRF2 in oxidative stress, inflammation and immunity. It presents the animal models that further facilitated the human studies in regard to NRF2 modulation and the possibilities of using NRF2 as DN biomarker and/or as target therapy.

Immune Portrayal of a New Therapy Targeting Microbiota in an Animal Model of Psoriasis.

BACKGROUND: Despite all the available treatments, psoriasis remains incurable; therefore, finding personalized therapies is a continuous challenge. Psoriasis is linked to a gut microbiota imbalance, highlighting the importance of the gut-skin axis and its inflammatory mediators. Restoring this imbalance can open new perspectives in psoriasis therapy. We investigated the effect of purified IgY raised against pathological human bacteria antibiotic-resistant in induced murine psoriatic dermatitis (PSO). METHODS: To evaluate the immune portrayal in an imiquimod experimental model, before and after IgY treatment, xMAP array and flow cytometry were used. RESULTS: There were significant changes in IL-1α,ß, IL-5, IL-6, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17a, IFN-γ, TNF-α, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, MIP-1ß/CCL4, MIG/CXCL9, and KC/CXCL1 serum levels. T (CD3ε+), B (CD19+) and NK (NK1.1+) cells were also quantified. In our model, TNF-α, IL-6, and IL-1ß cytokines and CXCL1 chemokine have extremely high circulatory levels in the PSO group. Upon experimental therapy, the cytokine serum values were not different between IgY-treated groups and spontaneously remitted PSO. CONCLUSIONS: Using the murine model of psoriatic dermatitis, we show that the orally purified IgY treatment can lead to an improvement in skin lesion healing along with the normalization of cellular and humoral immune parameters.

Insights into Nutritional Strategies in Psoriasis.

Psoriasis, an autoimmune chronic inflammatory skin condition, has a high incidence in the general population, reaching 2-4%. Its pathogenesis involves an interplay of genetic factors, immune disturbances, and environmental factors. Within the environmental factors that aid the appearance of this autoimmune skin disease, the Western lifestyle and overall diet play important roles in the steady growth in psoriasis prevalence. Furthermore, psoriasis is associated with comorbidities such as psoriatic arthritis, cardiovascular disease, metabolic syndrome, and obesity. Accumulating evidence suggests that obesity is an important risk factor for psoriasis. Moreover, obesity aggravates established psoriasis, and a reduction in the body mass index can improve the clinical outcomes of psoriasis and increase the efficacy of standard psoriasis therapies. The possible connection between this autoimmune disease and obesity relies on the fact that white adipose tissue is an essential endocrine organ that secretes an array of immune mediators and inflammatory and metabolic factors with pro-inflammatory action. Thus, immune-mediated mechanisms in both psoriasis and obesity conditions are common factors. This paper describes the factors that link obesity with skin autoimmune disease and highlights the importance of the stimulatory or regulatory effects of nutrients and food in psoriasis and the possible improvement of psoriasis through nutritional strategies.

Innovative Collagen Based Biopolymers Tested as Fertilizers for Poor Soils Amendment.

Improving soil quality is of growing interest and, among optimal solutions, the reuse and recycling of biopolymers of pelt waste from the tannery industry have been proposed, one of them being for collagen hydrolysate with micronutrients and polymers incorporated, to be used as fertilizers for poor soils rehabilitation. As functionalization agents, polyacrylamide, starch and dolomite were included into biopolymer matrixes in order to enhance their specific efficiency. These fertilizers were adequately characterized for their physical-chemical properties, including nutrient content, and tested on three poor soils, while a fourth sample of normal soil was chosen for comparative purposes. These soils were also characterized for their texture and physical-chemical properties in order to establish the fertility state of the soils as a function of nutrient content. In this respect, a series of agrochemical tests were developed at laboratory scale, simulating real agriculture environments in a vegetation room, where a significant plant growth in height was observed for all the agro-hydrogels with nutrients encapsulated, and multiplication of the nodosities number was observed in the case of the soybean culture. The most significant effect was obtained in the case of the fertilizer functionalized with starch. Finally, the application dose of the organic fertilizers for specific culture plants was estimated, such as field cultures (cereals, corn), field vegetables, vineyards or fruit-growing plantations. These agro-collagen fertilizers are particularly recommended for amendment of field cereals and vegetables. The novelty of this study mainly consists of the recovery and recycling of the pelt waste as efficient fertilizers after their adequate functionalization with synthetic or natural biopolymers.

Skin Cancer Pathobiology at a Glance: A Focus on Imaging Techniques and Their Potential for Improved Diagnosis and Surveillance in Clinical Cohorts.

Early diagnosis is essential for completely eradicating skin cancer and maximizing patients' clinical benefits. Emerging optical imaging modalities such as reflectance confocal microscopy (RCM), optical coherence tomography (OCT), magnetic resonance imaging (MRI), near-infrared (NIR) bioimaging, positron emission tomography (PET), and their combinations provide non-invasive imaging data that may help in the early detection of cutaneous tumors and surgical planning. Hence, they seem appropriate for observing dynamic processes such as blood flow, immune cell activation, and tumor energy metabolism, which may be relevant for disease evolution. This review discusses the latest technological and methodological advances in imaging techniques that may be applied for skin cancer detection and monitoring. In the first instance, we will describe the principle and prospective clinical applications of the most commonly used imaging techniques, highlighting the challenges and opportunities of their implementation in the clinical setting. We will also highlight how imaging techniques may complement the molecular and histological approaches in sharpening the non-invasive skin characterization, laying the ground for more personalized approaches in skin cancer patients.

Langerhans Cells-Revising Their Role in Skin Pathologies.

Langerhans cells (LCs) constitute a cellular immune network across the epidermis. Because they are located at the skin barrier, they are considered immune sentinels of the skin. These antigen-presenting cells are capable of migrating to skin draining lymph nodes to prime adaptive immune cells, namely T- and B-lymphocytes, which will ultimately lead to a broad range of immune responses. Moreover, LCs have been shown to possess important roles in the anti-cancer immune responses. Indeed, the literature nicely highlights the role of LCs in melanoma. In line with this, LCs have been found in melanoma tissues where they contribute to the local immune response. Moreover, the immunogenic properties of LCs render them attractive targets for designing vaccines to treat melanoma and autoimmune diseases. Overall, future studies will help to enlarge the portfolio of immune properties of LCs, and aid the prognosis and development of novel therapeutic approaches to treating skin pathologies, including cancers.

U(VI) removal from diluted aqueous systems by sorption-flotation.

The legacies of past uranium mining and milling activities for nuclear fuel fabrication continue to be a cause of concern and require assessment and remedial action for researchers worldwide. The discharge of uranium contaminated water into the environment is a matter of regulation (World Health Organization, WHO-15 µg/L, Romanian Legislation, RO-21 µg/L), environment and health. Therefore, various removal technologies of U(VI) from diluted aqueous solutions include chemical precipitation, ion exchange, adsorption, immobilization on zero-valent iron nanoparticles, etc. have been extensively applied. Our previous research has studied the removal of U(VI) from diluted aqueous systems such as mine waters using Fe0-based nanomaterials synthesized in the laboratory (NMS) (Crane et al. in Water Res 45:2391-2942, 2011). The carbonate rich aqueous system was treated with NMS to remove U(VI). It was observed that after half an hour of reacting time only about 50% was removed due to its high tendency to form stable soluble carbonated complexes. Considering that, the present article aims to investigate the Sorption/Flotation technique, by using a sorbent generated in situ Fe2O3· nH2O and sodium oleate surfactant to remove U(VI) from diluted aqueous systems and to update the knowledge on the mechanism of process. In order to determine the removal efficiency of U(VI), the influencing factors were studied: pH, sorbent dose, surfactant concentration, contact time, stirring rate, the U(VI) concentration, air pressure in pressurized water recipient, and the effect of some accompanying heavy metals ions (Cu(II), Cr(VI), and Mo(VI)). The removal efficiency (%R) was monitored and its maximum values allowed to establish the optimal separation parameters (the established process parameters), which were validated on real mine water samples (MW). High U (VI) removal efficiencies %R > 98% were obtained. The Sorption/ Flotation technique was applied to remove U(VI) from two types of real mine water samples, namely "simple" and "pre-treated with NMS", respectively. For the mine water samples pre-treated with NMS, it worked in two variants: with and without pH correction. For pH range = 7.5-9.5, molar ratios [U(VI)] : [Fe(III)] = 1 : 75, [U(VI)] : [NaOL] = 1 : 1 × 10-2, contact time 30 min., stirring speed 250 RPM, initial concentration of U(VI) 10 mg·L-1, air pressure in pressurized water recipient p = 4 × 105 N·m-2 is obtained %R > 98%. It has been found that Sorption / Flotation can function with good %R values as a stand-alone operation or in tandem with NMS pre-treatment of mine water and pH adjustment proved to be highly efficiency (CU(VI) < 1·10-3 mg·L-1).

Healthy Ageing Reflected in Innate and Adaptive Immune Parameters.

Purpose: The aim of the paper is to establish and quantify the relation between healthy ageing and the innate and adaptive immune parameters as indicators of age-related diseases. Patients: In order to observe the immunological changes that occur according to age, several humoral and cellular immune parameters were investigated for 288 healthy donors (30-80 years). Subjects' selection was done using clinical, biochemical and immunological parameters of inclusion/exclusion criteria from SENIEUR protocol. Results: Age-related changes were observed for both humoral and cellular immune parameters. Lymphocyte immunophenotyping revealed several significant differences in the distribution of cells, both intra- and inter-age groups, namely decreased values of T-CD3+, T-CD8+ and NK cells, and elevated values for T-CD4+, T-CD4+/T-CD8+ ratio and B cells. The percentages of unstimulated neutrophils that show basal oxidative activity and the intensity of this activity had an increasing tendency age-related. The percentage of N-Formyl-Methionyl-Leucyl-Phenylalanine stimulated neutrophils clearly decreases with age, and is associated with an increasing intensity of oxidative activity. Our data also have shown an increased percentage of oxidative neutrophils after phorbol 12-myristate 13-acetate stimulation and an elevated oxidative activity with age. Conclusion: Overall healthy ageing is governed by some immune-related deregulations that account for immune exhaustion due to numerous developed immune processes during a life-time and the age-related diseases.

Skin Inflammation-A Cornerstone in Dermatological Conditions.

The skin provides more than a simple mechanical barrier against external aggressors; it is an array of effector cells and molecules that constitute the skin's immune system, as defined by Bos and Kapsenberg in 1986 [...].

Apprising Diagnostic and Prognostic Biomarkers in Cutaneous Melanoma-Persistent Updating.

The incidence of melanoma, a very aggressive skin cancer, has increased over the past few decades. Although there are well-established clinical, dermoscopic and histopathological criteria, the diagnosis is often performed late, which has important implications on the patient's clinical outcome. Unfortunately, melanoma is one of the most challenging tumors to diagnose because it is a heterogeneous neoplasm at the clinical, histopathological, and molecular level. The use of reliable biomarkers for the diagnosis and monitoring of disease progression is becoming a standard of care in modern medicine. In this review, we discuss the latest studies, which highlight findings from the genomics, epitranscriptomics, proteomics and metabolomics areas, pointing out different genes, molecules and cells as potential diagnostic and prognostic biomarkers in cutaneous melanoma.

Skin Cancer Research Goes Digital: Looking for Biomarkers within the Droplets.

Skin cancer, which includes the most frequent malignant non-melanoma carcinomas (basal cell carcinoma, BCC, and squamous cell carcinoma, SCC), along with the difficult to treat cutaneous melanoma (CM), pose important worldwide issues for the health care system. Despite the improved anti-cancer armamentarium and the latest scientific achievements, many skin cancer patients fail to respond to therapies, due to the remarkable heterogeneity of cutaneous tumors, calling for even more sophisticated biomarker discovery and patient monitoring approaches. Droplet digital polymerase chain reaction (ddPCR), a robust method for detecting and quantifying low-abundance nucleic acids, has recently emerged as a powerful technology for skin cancer analysis in tissue and liquid biopsies (LBs). The ddPCR method, being capable of analyzing various biological samples, has proved to be efficient in studying variations in gene sequences, including copy number variations (CNVs) and point mutations, DNA methylation, circulatory miRNome, and transcriptome dynamics. Moreover, ddPCR can be designed as a dynamic platform for individualized cancer detection and monitoring therapy efficacy. Here, we present the latest scientific studies applying ddPCR in dermato-oncology, highlighting the potential of this technology for skin cancer biomarker discovery and validation in the context of personalized medicine. The benefits and challenges associated with ddPCR implementation in the clinical setting, mainly when analyzing LBs, are also discussed.

Immunogenicity evaluation after BNT162b2 booster vaccination in healthcare workers.

Waning of the immune response upon vaccination in SARS-CoV-2 infection is an important subject of evaluation in this pandemic, mostly in healthcare workers (HCW) that are constantly in contact with infected samples and patients. Therefore, our study aimed to establish the specific humoral response of specific IgG and IgA antibodies upon vaccination, during the second year of pandemic and evaluating the booster shot with the same vaccine type. A group of 103 HCW with documented exposure to the virus were monitored for specific IgG and IgA levels prior to vaccination, after the first vaccination round, during the following 8 months and after the booster shot with the same vaccine type. After 8 months post-vaccination the humoral response in both IgG and IgA decreased, 2.4 times for IgG, and 2.7 times for IgA. Although the antibodies levels significantly decreased, no documented infection was registered in the group. After the booster shot, the entire group, displayed IgG increased levels, immediately after booster followed by the increase in specific IgA. IgG levels post-second round of vaccination are statistically higher compared to the first round, while IgA is restored at the same levels. Within the vaccination or booster routine for a multiple waves' pandemic that is generating new virus variants, populational immunity remains an important issue for future implementation of prevention/control measures.

Matrix Effectors in the Pathogenesis of Keratinocyte-Derived Carcinomas.

Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), referred to as keratinocyte carcinomas, are skin cancer with the highest incidence. BCCs, rarely metastasize; whereas, though generally not characterized by high lethality, approximately 2-4% of primary cSCCs metastasize with patients exhibiting poor prognosis. The extracellular matrix (ECM) serves as a scaffold that provides structural and biological support to cells in all human tissues. The main components of the ECM, including fibrillar proteins, proteoglycans (PGs), glycosaminoglycans (GAGs), and adhesion proteins such as fibronectin, are secreted by the cells in a tissue-specific manner, critical for the proper function of each organ. The skin compartmentalization to the epidermis and dermis compartments is based on a basement membrane (BM), a highly specialized network of ECM proteins that separate and unify the two compartments. The stiffness and assembly of BM and tensile forces affect tumor progenitors' invasion at the stratified epithelium's stromal border. Likewise, the mechanical properties of the stroma, e.g., stiffness, are directly correlated to the pathogenesis of the keratinocyte carcinomas. Since the ECM is a pool for various growth factors, cytokines, and chemokines, its' intense remodeling in the aberrant cancer tissue milieu affects biological functions, such as angiogenesis, adhesion, proliferation, or cell motility by regulating specific signaling pathways. This review discusses the structural and functional modulations of the keratinocyte carcinoma microenvironment. Furthermore, we debate how ECM remodeling affects the pathogenesis of these skin cancers.

Effectiveness of Platelet-Rich Plasma Therapy in Androgenic Alopecia-A Meta-Analysis.

Platelet-rich plasma (PRP) represents a novel therapy tested and is used more and more frequently in dermatology and cosmetic surgery for a variety of conditions, including androgenic alopecia (AGA), a common condition with a complex pathogenesis involving genetic factors, hormonal status and inflammation. We performed an extensive literature search which retrieved 15 clinical trials concerning the use in AGA of PRP therapy, alone or in combination, in male, female or mixed patient groups. A quantitative statistical meta-analysis of n = 17 trial groups proved significant increases in hair density from 141.9 ± 108.2 to 177.5 ± 129.7 hairs/cm2 (mean ± SD) following PRP (p = 0.0004). To the best of our knowledge, this is the first meta-analysis that proved a statistically significant correlation between the number of PRP treatments per month and the percentage change in hair density (r = 0.5, p = 0.03), as well as a negative correlation between the mean age of treatment group and the percentage change in hair density (r = -0.56, p = 0.016). Other factors considered for analysis were the PRP preparation method, amount used per treatment, hair diameter, terminal hairs and pull test. We conclude that PRP represents a valuable and effective therapy for AGA in both males and females if patients are rigorously selected.

Persistent Changes of Peripheral Blood Lymphocyte Subsets in Patients with Oral Squamous Cell Carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common cancer with high morbidity and mortality. Alterations of antitumor immune responses are involved in the development of this malignancy, and investigation of immune changes in the peripheral blood of OSCC patients has aroused the interest of researchers. METHODS: In our study, we assessed the proportions of CD3+ total T lymphocytes, CD3+CD4+ helper T lymphocytes, CD3+CD8+ suppressor/cytotoxic T lymphocytes, CD3-CD19+ total B lymphocytes, and CD3-CD16+CD56+ NK cells in the peripheral blood of OSCC patients. RESULTS: The data obtained both pre- and post-therapy showed a similar level of total CD3+ T lymphocytes in OSCC patients and control subjects, pinpointing the stability of this immune parameter. On the other hand, pre-therapeutic data showed a lower proportion of helper T lymphocytes (CD4+), a significantly higher level of cytotoxic/suppressive T lymphocytes (CD8+), and a much lower CD4+ T lymphocyte/CD8+ T lymphocyte ratio compared to control subjects. Conversely, evaluation of circulating NK (CD16+) cells showed a markedly higher pre-therapeutic level compared to the control group. CONCLUSIONS: Our results related to immune changes in the peripheral blood add new information to this complex universe of connections between immuno-inflammatory processes and carcinogenesis.

Testing Antigens, Antibodies, and Immune Cells in COVID-19 as a Public Health Topic-Experience and Outlines.

The current COVID-19 pandemic has triggered an accelerated pace in all research domains, including reliable diagnostics methodology. Molecular diagnostics of the virus and its presence in biological samples relies on the RT-PCR method, the most used and validated worldwide. Nonconventional tests with improved parameters that are in the development stages will be presented, such as droplet digital PCR or CRISPR-based assays. These molecular tests were followed by rapid antigen testing along with the development of antibody tests, whether based on ELISA platform or on a chemiluminescent microparticle immunoassay. Less-conventional methods of testing antibodies (e.g., lateral flow immunoassay) are presented as well. Left somewhere in the backstage of COVID-19 research, immune cells and, furthermore, immune memory cells, are gaining the spotlight, more so in the vaccination context. Recently, methodologies using flow-cytometry evaluate circulating immune cells in infected/recovered patients. The appearance of new virus variants has triggered a surge for tests improvement. As the pandemic has entered an ongoing or postvaccination era, all methodologies that are used to monitor public health focus on diagnostic strategies and this review points out where gaps should be filled in both clinical and research settings.

Nano-carriers of COVID-19 vaccines: the main pillars of efficacy.

As the current COVID-19 pandemic illustrates, vaccination is the most powerful method of disease prevention and public confidence in vaccines depends on their safety and efficacy. The information gathered in the current pandemic is growing at an accelerated pace. Both the key vital protein DNA/RNA messengers and the delivery carriers are the elements of a puzzle including their interactions with the immune system to suppress SARS-CoV-2 infection. A new nano-era is beginning in the vaccine development field and an array of side applications for diagnostic and antiviral tools will likely emerge. This review focuses on the evolution of vaccine carriers up to COVID-19-aimed nanoparticles and the immune-related adverse effects imposed by these nanocarriers.

Assessment of Immune Cell Populations in Tumor Tissue and Peripheral Blood Samples from Head and Neck Squamous Cell Carcinoma Patients.

Head and neck squamous cell carcinoma (HNSCC) is a common type of cancer worldwide. Strong connections have been revealed between immune cells and the pathogenesis of HNSCC. Important differences regarding the levels of immune cell subpopulations in both peripheral circulation and tumor microenvironment were emphasized, with some of them having prognostic significance. In our study, we performed an analysis of immune changes in the tumor tissue and the peripheral blood of untreated HNSCC patients, investigating the proportions of different immune cell populations in these two compartments. The local infiltrating lymphocytes were mainly cytotoxic T cells (CD8+). We have also revealed an increased level of B lymphocytes (CD19+) in the tumor microenvironment. In peripheral blood, the most important lymphocyte subtype was represented by the helper T lymphocytes (CD4+). We also found an increased proportion of circulating NK cells (CD56+). Our results showed significant differences between all investigated lymphocyte subtypes in the peripheral blood and the tumor tissue of untreated HNSCC patients, suggesting that the local and systemic expressions of antitumor immune responses are different and that investigation of immune cell proportions in peripheral circulation has different cues that do not reflect the immune infiltrate pattern within the tumor microenvironment. Further studies are necessary to unveil the complex interplay involving local and systemic events in the immune system's fight against cancer.

Safety and efficacy assessment of aerogels for biomedical applications.

The unique physicochemical properties of aerogels have made them an attractive class of materials for biomedical applications such as drug delivery, regenerative medicine, and wound healing. Their low density, high porosity, and ability to regulate the pore structure makes aerogels ideal nano/micro-structures for loading of drugs and active biomolecules. As a result of this, the number of in vitro and in vivo studies on the therapeutic efficacy of these porous materials has increased substantially in recent years and continues to be an area of great interest. However, data about their in vivo performance and safety is limited. Studies have shown that polymer-based, silica-based and some hybrid aerogels are generally regarded as safe but given that studies on the acute, subacute, and chronic toxicity for the majority of aerogel types is missing, more work is still needed. This review presents a comprehensive summary of different biomedical applications of aerogels proposed to date as well as new and innovative applications of aerogels in other areas such as decontamination. We have also reviewed their biological effect on cells and living organisms with a focus on therapeutic efficacy and overall safety (in vivo and in vitro).

Unconventional Therapy with IgY in a Psoriatic Mouse Model Targeting Gut Microbiome.

Psoriasis has a multifactorial pathogenesis and recently it was shown that alterations in the skin and intestinal microbiome are involved in the pathogenesis of psoriasis. Therefore, microbiome restoration becomes a promising preventive/therapy strategy in psoriasis. In our pre-clinical study design using a mice model of induced psoriatic dermatitis (Ps) we have tested the proof-of-concept that IgY raised against pathological human bacteria resistant to antibiotics can alleviate psoriatic lesions and restore deregulated immune cell parameters. Besides clinical evaluation of the mice and histology of the developed psoriatic lesions, cellular immune parameters were monitored. Immune cells populations/subpopulations from peripheral blood and spleen cell suspensions that follow the clinical improvement were assessed using flow cytometry. We have quantified T lymphocytes (CD3ε+) with T-helper (CD4+CD8-) and T-suppressor/cytotoxic (CD8a+CD4-) subsets, B lymphocytes (CD3ε-CD19+) and NK cells (CD3ε-NK1.1+). Improved clinical evolution of the induced Ps along with the restoration of immune cells parameters were obtained when orally IgY was administered. We pin-point that IgY specific compound can be used as a possible pre-biotic-like alternative adjuvant in psoriasis.