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Rheumatoid arthritis (RA) is a chronic autoimmune condition frequently found in rheumatological patients that sometimes raises diagnosis and management problems. The pathogenesis of the disease is complex and involves the activation of many cells and intracellular signaling pathways, ultimately leading to the activation of the innate and acquired immune system and producing extensive tissue damage. Along with joint involvement, RA can have numerous extra-articular manifestations (EAMs), among which lung damage, especially interstitial lung disease (ILD), negatively influences the evolution and survival of these patients. Although there are more and more RA-ILD cases, the pathogenesis is incompletely understood. In terms of genetic predisposition, external environmental factors act and subsequently determine the activation of immune system cells such as macrophages, neutrophils, B and T lymphocytes, fibroblasts, and dendritic cells. These, in turn, show the ability to secrete molecules with a proinflammatory role (cytokines, chemokines, growth factors) that will produce important visceral injuries, including pulmonary changes. Currently, there is new evidence that supports the initiation of the systemic immune response at the level of pulmonary mucosa where the citrullination process occurs, whereby the autoantibodies subsequently migrate from the lung to the synovial membrane. The aim of this paper is to provide current data regarding the pathogenesis of RA-associated ILD, starting from environmental triggers and reaching the cellular, humoral, and molecular changes involved in the onset of the disease. [ABSTRACT FROM AUTHOR]

Autism Spectrum Disorder (ASD) is a disturbance of neurodevelopment with a complicated pathogenesis and unidentified etiology. Many children with ASD have a history of "allergic symptoms", often in the absence of mast cell (MC)-positive tests. Activation of MCs by various stimuli may release molecules related to inflammation and neurotoxicity, contributing to the development of ASD. The aim of the present paper is to enrich the current knowledge on the relationship between MCs and ASD by discussing key molecules and immune pathways associated with MCs in the pathogenesis of autism. Cytokines, essential marker molecules for MC degranulation and therapeutic targets, are also highlighted. Understanding the relationship between ASD and the activation of MCs, as well as the involved molecules and interactions, are the main points contributing to solving the enigma. Key molecules, associated with MCs, may provide new insights to the discovery of drug targets for modeling inflammation in ASD. [ABSTRACT FROM AUTHOR]

Osteoporosis is a major public health concern affecting millions of people worldwide and resulting in significant economic costs. The condition is characterized by changes in bone homeostasis, which lead to reduced bone mass, impaired bone quality, and an increased risk of fractures. The pathophysiology of osteoporosis is complex and multifactorial, involving imbalances in hormones, cytokines, and growth factors. Understanding the cellular and molecular mechanisms underlying osteoporosis is essential for appropriate diagnosis and management of the condition. This paper provides a comprehensive review of the normal cellular and molecular mechanisms of bone homeostasis, followed by an in-depth discussion of the proposed pathophysiology of osteoporosis through the osteoimmunological, gut microbiome, and cellular senescence models. Furthermore, the diagnostic tools used to assess osteoporosis, including bone mineral density measurements, biochemical markers of bone turnover, and diagnostic imaging modalities, are also discussed. Finally, both the current pharmacological and non-pharmacological treatment algorithms and management options for osteoporosis, including an exploration of the management of osteoporotic fragility fractures, are highlighted. This review reveals the need for further research to fully elucidate the molecular mechanisms underlying the condition and to develop more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

The prevalence of metabolic-related disorders, such as non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (DM2), has been increasing. Therefore, developing improved methods for the prevention, treatment, and detection of these two conditions is also necessary. In this study, our primary focus was on examining the role of chronic inflammation as a potential link in the pathogenesis of these diseases and their interconnections. A comprehensive search of the PubMed database using keywords such as "non-alcoholic fatty liver disease", "type 2 diabetes mellitus", "chronic inflammation", "pathogenesis", and "progression" yielded 177 relevant papers for our analysis. The findings of our study revealed intricate relationships between the pathogenesis of NAFLD and DM2, emphasizing the crucial role of inflammatory processes. These connections involve various molecular functions, including altered signaling pathways, patterns of gene methylation, the expression of related peptides, and up- and downregulation of several genes. Our study is a foundational platform for future research into the intricate relationship between NAFLD and DM2, allowing for a better understanding of the underlying mechanisms and the potential for introducing new treatment standards. [ABSTRACT FROM AUTHOR]

Most diseases of older age have as their common denominator a dysfunctional immune system, wherein a low, chronic level of inflammation is present due to an imbalance of pro-inflammatory cytokines over anti-inflammatory cytokines that develops during aging ("inflamm-aging"). A gerotherapeutic that can restore the immune balance to that shared by young/middle-aged adults and many centenarians could reduce the risk of those age-related diseases and increase healthy longevity. In this perspectives paper, we discuss potential longevity interventions that are being evaluated and compare them to a novel gerotherapeutic currently being evaluated in humans—Transcranial Electromagnetic Wave Treatment (TEMT). TEMT is provided non-invasively and safety through a novel bioengineered medical device—the MemorEM—that allows for near complete mobility during in-home treatments. Daily TEMT to mild/moderate Alzheimer's Disease (AD) patients over a 2-month period rebalanced 11 of 12 cytokines in blood back to that of normal aged adults. A very similar TEMT-induced rebalancing of cytokines occurred in the CSF/brain for essentially all seven measurable cytokines. Overall inflammation in both blood and brain was dramatically reduced by TEMT over a 14–27 month period, as measured by C-Reactive Protein. In these same AD patients, a reversal of cognitive impairment was observed at 2 months into treatment, while cognitive decline was stopped over a 2½ year period of TEMT. Since most age-related diseases have the commonality of immune imbalance, it is reasonable to postulate that TEMT could rebalance the immune system in many age-related diseases as it appears to do in AD. We propose that TEMT has the potential to reduce the risk/severity of age-related diseases by rejuvenating the immune system to a younger age, resulting in reduced brain/body inflammation and a substantial increase in healthy longevity. [ABSTRACT FROM AUTHOR]

Subarachnoid hemorrhage (SAH) represents a severe acute event with high morbidity and mortality due to the development of early brain injury (EBI), secondary delayed cerebral ischemia (DCI), and shunt-related hydrocephalus. Secondary events (SSE) such as neuroinflammation, vasospasm, excitotoxicity, blood-brain barrier disruption, oxidative cascade, and neuronal apoptosis are related to DCI. Despite improvement in management strategies and therapeutic protocols, surviving patients frequently present neurological deficits with neurocognitive impairment. The aim of this paper is to offer to clinicians a practical review of the actually documented pathophysiological events following subarachnoid hemorrhage. To reach our goal we performed a literature review analyzing reported studies regarding the mediators involved in the pathophysiological events following SAH occurring in the cerebrospinal fluid (CSF) (hemoglobin degradation products, platelets, complement, cytokines, chemokines, leucocytes, endothelin-1, NO-synthase, osteopontin, matricellular proteins, blood-brain barrier disruption, microglia polarization). The cascade of pathophysiological events secondary to SAH is very complex and involves several interconnected, but also distinct pathways. The identification of single therapeutical targets or specific pharmacological agents may be a limited strategy able to block only selective pathophysiological paths, but not the global evolution of SAH-related events. We report furthermore on the role of heparin in SAH management and discuss the rationale for use of intrathecal heparin as a pleiotropic therapeutical agent. The combination of the anticoagulant effect and the ability to interfere with SSE theoretically make heparin a very interesting molecule for SAH management. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a cardiac disease marked by the stretching and thinning of the heart muscle and impaired left ventricular contractile function. While most patients do not develop significant cardiac diseases from myocarditis, disparate immune responses can affect pathological outcomes, including DCM progression. These altered immune responses, which may be caused by genetic variance, can prolong cytotoxicity, induce direct cleavage of host protein, or encourage atypical wound healing responses that result in tissue scarring and impaired mechanical and electrical heart function. However, it is unclear which alterations within host immune profiles are crucial to dictating the outcomes of myocarditis. Coxsackievirus B3 (CVB3) is a well-studied virus that has been identified as a causal agent of myocarditis in various models, along with other viruses such as adenovirus, parvovirus B19, and SARS-CoV-2. This paper takes CVB3 as a pathogenic example to review the recent advances in understanding virus-induced immune responses and differential gene expression that regulates iron, lipid, and glucose metabolic remodeling, the severity of cardiac tissue damage, and the development of DCM and heart failure. [ABSTRACT FROM AUTHOR]

Our understanding of the regulatory processes of reepithelialization during wound healing is incomplete. In an attempt to map the genes involved in epidermal regeneration and differentiation, we measured gene expression in formalin-fixed, paraffin-embedded standardized epidermal wounds induced by the suction-blister technique with associated nonwounded skin using NanoString technology. The transcripts of 139 selected genes involved in clotting, immune response to tissue injury, signaling pathways, cell adhesion and proliferation, extracellular matrix remodeling, zinc transport and keratinocyte differentiation were evaluated. We identified 22 upregulated differentially expressed genes (DEGs) in descending order of fold change (MMP1, MMP3, IL6, CXCL8, SERPINE1, IL1B, PTGS2, HBEGF, CXCL5, CXCL2, TIMP1, CYR61, CXCL1, MMP12, MMP9, HGF, CTGF, ITGB3, MT2A, FGF7, COL4A1 and PLAUR). The expression of the most upregulated gene, MMP1, correlated strongly with MMP3 followed by IL6 and IL1B. rhIL-1β, but not rhIL-6, exposure of cultured normal human epidermal keratinocytes and normal human dermal fibroblasts increased both MMP1 mRNA and MMP-1 protein levels, as well as TIMP1 mRNA levels. The increased TIMP1 in wounds was validated by immunohistochemistry. The six downregulated DEGs (COL7A1, MMP28, SLC39A2, FLG1, KRT10 and FLG2) were associated with epidermal maturation. KLK8 showed the strongest correlation with MKI67 mRNA levels and is a potential biomarker for keratinocyte proliferation. The observed gene expression changes correlate well with the current knowledge of physiological reepithelialization. Thus, the gene expression panel described in this paper could be used in patients with impaired healing to identify possible therapeutic targets. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea syndrome (OSAS) is a common but underdiagnosed condition with significant health and economic implications for society. Inflammatory mediators are proposed to be associated with the presence and severity of OSAS and contribute to morbidity and mortality. This paper details a prospective non-randomized case control study of a cohort of subjects, who underwent surgical treatment of OSAS and were enrolled to assess the sleep parameters and blood levels of selected inflammatory markers at pre-operative and post-operative time points, also comparing them to the levels in a control group. A total of 25 study subjects and 18 control subjects were enrolled. Median values and interquartile range (IQR) of the apnea–hypopnea index (AHI) in the study group pre-operatively and post-operatively were 34 (18.5–45.5) and 13.3 (7.5–27.3), while in the control group 1.4 (1.0–2.1) per hour. The mean (IQR) hs-CRP levels (mg/L) were 1.782 (0.941–5.594) and 1.980 (0.990–5.445) in the study group, pre-operatively and post-operatively, respectively, while 0.891 (0.767–1.436) in the control group. The mean (IQR) TNF-α levels (pg/mL) were 7.999 (6.137–9.216) and 6.614 (5.534–7.460) pre-and post-operatively, respectively, and were 6.000 (5.026–6.823) in the control group. Results demonstrated that both inflammatory markers, hs-CRP and TNF-α, are higher in subjects with OSAS compared to the controls, and their levels decrease, but are still higher than the controls, after successful surgical treatment. Further analysis including the body mass index and age demonstrated that these changes were significant for TNF-α, but not hs-CRP. [ABSTRACT FROM AUTHOR]

Stretching is one of the popular elements in physiotherapy and rehabilitation. When correctly guided, it can help minimize or slow down the disabling effects of chronic health conditions. Most likely, the benefits are associated with reducing inflammation; recent studies demonstrate that this effect from stretching is not just systemic but also local. In this review, we present the current body of knowledge on the anti-inflammatory properties of stretching at a molecular level. A total of 22 papers, focusing on anti-inflammatory and anti-cancer properties of stretching, have been selected and reviewed. We show the regulation of oxidative stress, the expression of pro- and anti-inflammatory genes and mediators, and remodeling of the extracellular matrix, expressed by changes in collagen and matrix metalloproteinases levels, in tissues subjected to stretching. We point out that a better understanding of the anti-inflammatory properties of stretching may result in increasing its importance in treatment and recovery from diseases such as osteoarthritis, systemic sclerosis, and cancer. [ABSTRACT FROM AUTHOR]

That the nervous system is the main target of lead (Pb) has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, we present recent literature reports on the effect of Pb on the inflammatory processes in the brain, particularly the expression of selected cytokines in the brain (interleukin 6, TGF-β1, interleukin 16, interleukin 18, and interleukin 10); expression and activity of enzymes participating in the inflammatory processes, such as cyclooxygenase 2, caspase 1, nitrogen oxide synthase (NOS 2) and proteases (carboxypeptidases, metalloproteinases and chymotrypsin); and the expression of purine receptors P2X4 and P2X7. A significant role in the development of inflammatory processes in the brain is also played by microglia (residual macrophages in the brain and the spinal cord), which act as the first line of defense in the central nervous system, and astrocytes--Whose most important function is to maintain homeostasis for the proper functioning of neurons. In this paper, we also present evidence that exposure to Pb may result in micro and astrogliosis by triggering TLR4-MyD88-NF-κB signaling cascade and the production of pro-inflammatory cytokines. [ABSTRACT FROM AUTHOR]

For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at low-doses. The disrupted balance between regulatory and effector T cells (Tregs and Teffs, respectively) is a characteristic of autoimmune diseases, and is dependent on homeostatic cytokines, including IL-2. Actually, inherent defects in the IL-2 signaling pathway and/or levels leading to Treg compromised function and numbers as well as Th17 expansion have been attributed to autoimmune disorders. In this review, we discuss the role of IL-2 in the pathogenesis of autoimmune diseases. In particular, we highlight the impact of the dysregulated IL-2 pathway on disruption of the Treg/Th17 balance, reversal of which appears to be a possible mechanism of the low-dose IL-2 treatment. The negative effects of IL-2 on the differentiation of follicular helper T cells (Tfh) and pathogenic Th17 cells, both of which contribute to autoimmunity, is emphasized in the paper as well. We also compare the current IL-2-based therapies of animal and human subjects with immune-mediated diseases aimed at boosting the Treg population, which is the most IL-2-dependent cell subset desirable for sufficient control of autoimmunity. New perspectives of therapeutic approaches focused on selective delivery of IL-2 to inflamed tissues, thus allowing local activity of IL-2 to be combined with its reduced systemic and pleiotropic toxicity, are also proposed in this paper. [ABSTRACT FROM AUTHOR]

Emerging evidence has demonstrated that microRNAs (miRs) play a role in the survival and amplification of viruses, bacteria and other pathogens. There are various ways in which pathogens can benefit from miR-directed alterations in protein translation and signal transduction. Members of the herpesviridae family have previously been shown to encode multiple miRs, while the production of miRs by viruses like HIV-1 remained controversial. Recently, novel techniques have facilitated the elucidation of true miR targets by establishing miR-argonaute association and the subsequent interactions with their cognate cellular mRNAs. This, in combination with miR reporter assays, has generated physiologically relevant evidence that miRs from the herpesviridae family have the potential to downregulate multiple cellular targets, which are involved in immune activation, cytokine signaling and apoptosis. In addition, viruses and bacteria have also been linked to the induction of host cellular miRs, which have the capacity to mitigate immune activation, cytokine signaling and apoptosis. Interfering with miR expression may be clinically relevant. In the case of hepatitis C infection, the cellular miR-122 is already targeted therapeutically. This not only exemplifies how important miRs can be for the survival of specific viruses, but it also delineates the potential to use miRs as drug targets. In this paper we will review the latest reports on viruses and bacteria that abuse miR regulation for their benefit, which may be of interest in the development of miR-directed therapies. [ABSTRACT FROM AUTHOR]

Background: Early and accurate diagnosis of endometriosis is crucial for the management of this benign, yet debilitating pathology. Despite the advances of modern medicine, there is no common ground regarding the pathophysiology of this disease as it continues to affect the quality of life of millions of women of reproductive age. The lack of specific symptoms often determines a belated diagnosis. The gold standard remains invasive, surgery followed by a histopathological exam. A biomarker or a panel of biomarkers is easy to measure, usually noninvasive, and could benefit the clinician in both diagnosing and monitoring the treatment response. Several studies have advanced the idea of biomarkers for endometriosis, thereby circumventing unnecessary invasive techniques. Our paper aims at harmonizing the results of these studies in the search of promising perspectives on early diagnosis. Methods: We selected the papers from Google Academic, PubMed, and CrossRef and reviewed recent articles from the literature, aiming to evaluate the effectiveness of various putative serum and urinary biomarkers for endometriosis. Results: The majority of studies focused on a panel of biomarkers, rather than a single biomarker and were unable to identify a single biomolecule or a panel of biomarkers with sufficient specificity and sensitivity in endometriosis. Conclusion: Noninvasive biomarkers, proteomics, genomics, and miRNA microarray may aid the diagnosis, but further research on larger datasets along with a better understanding of the pathophysiologic mechanisms are needed. [ABSTRACT FROM AUTHOR]

Psoriasis is a recurrent, chronic, immune-mediated, systemic inflammatory disease of the skin, joints, and other organic systems. After atopic dermatitis, chronic stationary psoriasis is the most common inflammatory skin disease, affecting an average of 2–4% of the world's population. The disease carries a significant burden due to its numerous comorbidities and the major impact on patients' social and emotional aspects of life. According to current knowledge, psoriasis is a multifactorial disease that occurs in genetically predisposed individuals under various environmental factors, which trigger an immune response disorder with a series of complex inflammatory cascades. The disease is initiated and maintained by mutual interaction of the innate and adaptive immune cells, primarily dendritic cells, T lymphocytes, and keratinocytes, whose leading role alternates at different stages of the disease, consisting mainly in the IL-23/Th17 pathway. Inflammatory events result in consequent epidermal and dermal changes and evolution of the characteristic psoriatic phenotype, respectively. This paper aims to present a comprehensive overview of current knowledge on psoriasis genetic and environmental etiological factors, immunopathogenesis, and the leading cellular and cytokine participants in the inflammatory pathways of this disease. [ABSTRACT FROM AUTHOR]

Melatonin modulates a wide range of physiological functions with pleiotropic effects on the immune system. Despite the large number of reports implicating melatonin as an immunomodulatory compound, it still remains unclear how melatonin regulates immunity. While some authors argue that melatonin is an immunostimulant, many studies have also described anti-inflammatory properties. The data reviewed in this paper support the idea of melatonin as an immune buffer, acting as a stimulant under basal or immunosuppressive conditions or as an anti-inflammatory compound in the presence of exacerbated immune responses, such as acute inflammation. The clinical relevance of the multiple functions of melatonin under different immune conditions, such as infection, autoimmunity, vaccination and immunosenescence, is also reviewed. [ABSTRACT FROM AUTHOR]

Biocompatible materials are of considerable interest in the development of cell/drug delivery carriers for therapeutic applications. This paper investigates the effects of the Bloom index of gelatin on its interaction with retinal pigment epithelial (RPE) cells. Following two days of culture of ARPE-19 cells with gelatin samples G75-100, G175, and G300, the in vitro biocompatibility was determined by cell proliferation and viability assays, and glutamate uptake measurements, as well as cytokine expression analyses. The mitochondrial dehydrogenase activity in the G300 groups was significantly lower than that of G75-100 and G175 groups. The Live/Dead assays also showed that the gelatin samples G300 induced mild cytotoxicity. In comparison with the treatment of gelatins with low Bloom index, the exposure to high Bloom strength gelatins markedly reduced the glutamate uptake capacity of ARPE-19 cells. One possible explanation for these observations is that the presence of gelatin samples G300 with high viscosity in the medium may affect the nutrient availability to cultured cells. The analyses of pro-inflammatory cytokine IL-6 expression at both mRNA and protein levels showed that the gelatins with low Bloom index caused less cellular inflammatory reaction and had more acceptable biocompatibility than their high Bloom strength counterparts. These findings suggest that the Bloom index gives influence on cellular responses to gelatin materials. [ABSTRACT FROM AUTHOR]

One of the ultimate goals of wound healing research is to find effective healing techniques that utilize the regeneration of similar tissues. This involves the modification of various wound dressing biomaterials for proper wound management. The biopolymer chitosan (β-1,4-D-glucosamine) has natural biocompatibility and biodegradability that render it suitable for wound management. By definition, a biocompatible biomaterial does not have toxic or injurious effects on biological systems. Chemical and physical modifications of chitosan influence its biocompatibility and biodegradability to an uncertain degree. Hence, the modified biomedical-grade of chitosan derivatives should be pre-examined in vitro in order to produce high-quality, biocompatible dressings. In vitro toxicity examinations are more favorable than those performed in vivo, as the results are more reproducible and predictive. In this paper, basic in vitro tools were used to evaluate cellular and molecular responses with regard to the biocompatibility of biomedical-grade chitosan. Three paramount experimental parameters of biocompatibility in vitro namely cytocompatibility, genotoxicity and skin pro-inflammatory cytokine expression, were generally reviewed for biomedical-grade chitosan as wound dressing. [ABSTRACT FROM AUTHOR]

There are a large number of remedies in traditional medicine focused on relieving pain and inflammation. Flavanones have been a potential source in the search for leading compounds and biologically active components, and they have been the focus of much research and development in recent years. Eysenhardtia platycarpa is used in traditional medicine for the treatment of kidney diseases, bladder infections, and diabetes mellitus. Many compounds have been isolated from this plant, such as flavones, flavanones, phenolic compounds, triterpenoid acids, chalcones, sugars, and fatty acids, among others. In this paper, natural flavanone 1 (extracted from Eysenhardtia platycarpa) as lead compound and flavanones 1a–1d as its structural analogues were screened for anti-inflammatory activity using Molinspiration® and PASS Online in a computational study. The hydro alcoholic solutions (FS) of flavanones 1, 1a–1d (FS1, FS1a–FS1d) were also assayed to investigate their in vivo anti-inflammatory cutaneous effect using two experimental models, a rat ear edema induced by arachidonic acid (AA) and a mouse ear edema induced by 12-O-tetradecanoylphorbol acetate (TPA). Histological studies and analysis of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were also assessed in AA-inflamed rat ear tissue. The results showed that the flavanone hydro alcoholic solutions (FS) caused edema inhibition in both evaluated models. This study suggests that the evaluated flavanones will be effective when used in the future in skin pathologies with inflammation, with the results showing 1b and 1d to be the best. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a very common chronic disease with progressively increasing prevalence. Besides the well-known autoimmune and inflammatory pathogenesis of type 1 diabetes, in many people, metabolic changes and inappropriate lifestyle favor a subtle chronic inflammatory state that contributes to development of insulin resistance and progressive loss of β-cell function and mass, eventually resulting in metabolic syndrome or overt type 2 diabetes. In this paper, we review the anti-inflammatory effects of the extract of Hypericum perforatum L. (St. John's wort, SJW) and its main active ingredients firstly in representative pathological situations on inflammatory basis and then in pancreatic β cells and in obese or diabetic animal models. The simultaneous and long-lasting inhibition of signal transducer and activator of transcription (STAT)-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs)/c-jun N-terminal kinase (JNK) signaling pathways involved in pro-inflammatory cytokine-induced β-cell dysfunction/death and insulin resistance make SJW particularly suitable for both preventive and therapeutic use in metabolic diseases. Hindrance of inflammatory cytokine signaling is likely dependent on the hyperforin content of SJW extract, but recent data reveal that hypericin can also exert relevant protective effects, mediated by activation of the cyclic adenosine monophosphate (cAMP)/protein kinase cAMP-dependent (PKA)/adenosine monophosphate activated protein kinase (AMPK) pathway, against high-fat-diet-induced metabolic abnormalities. Actually, the mechanisms of action of the two main components of SJW appear complementary, strengthening the efficacy of the plant extract. Careful quantitative analysis of SJW components and suitable dosage, with monitoring of possible drug–drug interaction in a context of remarkable tolerability, are easily achievable pre-requisites for forthcoming clinical applications. [ABSTRACT FROM AUTHOR]

Some coronavirus disease 2019 (COVID-19) patients develop acute pneumonia which can result in a cytokine storm syndrome in response to Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection. The most effective anti-inflammatory drugs employed so far in severe COVID-19 belong to the cytokine-directed biological agents, widely used in the management of many autoimmune diseases. In this paper we analyze the efficacy of epigallocatechin 3-gallate (EGCG), the most abundant ingredient in green tea leaves and a well-known antioxidant, in counteracting autoimmune diseases, which are dominated by a massive cytokines production. Indeed, many studies registered that EGCG inhibits signal transducer and activator of transcription (STAT)1/3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factors, whose activities are crucial in a multiplicity of downstream pro-inflammatory signaling pathways. Importantly, the safety of EGCG/green tea extract supplementation is well documented in many clinical trials, as discussed in this review. Since EGCG can restore the natural immunological homeostasis in many different autoimmune diseases, we propose here a supplementation therapy with EGCG in COVID-19 patients. Besides some antiviral and anti-sepsis actions, the major EGCG benefits lie in its anti-fibrotic effect and in the ability to simultaneously downregulate expression and signaling of many inflammatory mediators. In conclusion, EGCG can be considered a potential safe natural supplement to counteract hyper-inflammation growing in COVID-19. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAF) are the most abundant cells of the tumor stroma and they critically influence cancer growth through control of the surrounding tumor microenvironment (TME). CAF-orchestrated reactive stroma, composed of pro-tumorigenic cytokines and growth factors, matrix components, neovessels, and deregulated immune cells, is associated with poor prognosis in multiple carcinomas, including breast cancer. Therefore, beyond cancer cells killing, researchers are currently focusing on TME as strategy to fight breast cancer. In recent years, nanomedicine has provided a number of smart delivery systems based on active targeting of breast CAF and immune-mediated overcome of chemoresistance. Many efforts have been made both to eradicate breast CAF and to reshape their identity and function. Nano-strategies for CAF targeting profoundly contribute to enhance chemosensitivity of breast tumors, enabling access of cytotoxic T-cells and reducing immunosuppressive signals. TME rearrangement also includes reorganization of the extracellular matrix to enhance permeability to chemotherapeutics, and nano-systems for smart coupling of chemo- and immune-therapy, by increasing immunogenicity and stimulating antitumor immunity. The present paper reviews the current state-of-the-art on nano-strategies to target breast CAF and TME. Finally, we consider and discuss future translational perspectives of proposed nano-strategies for clinical application in breast cancer. [ABSTRACT FROM AUTHOR]

Natural Killer (NK) cells are innate lymphocytes that contribute to immune protection by cytosis, cytokine secretion, and regulation of adaptive responses of T cells. NK cells distinguish between healthy and ill cells, and generate a cytotoxic response, being cumulatively regulated by environmental signals delivered through their diverse receptors. Recent advances in biomaterials and device engineering paved the way to numerous artificial microenvironments for cells, which produce synthetic signals identical or similar to those provided by the physiological environment. In this paper, we review recent advances in materials and devices for artificial signaling, which have been applied to regulate NK cells, and systematically study the role of these signals in NK cell function. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common tumor and the second cause for cancer-related death in women worldwide, although combined treatments are well-established interventions. Several effects seem to be responsible for poor outcomes in advanced or triple-negative BC patients. Focusing on the interaction of ionizing radiation with tumor and normal tissues, the role of cytokine modulation as a surrogate of immunomodulation must still be explored. In this work, we carried out an overview of studies published in the last five years involving the cytokine profile in BC patients undergoing radiotherapy. The goal of this review was to evaluate the profile and modulation of major cytokines and interleukins as potential biomarkers of survival, treatment response, and toxicity in BC patient undergoing radiotherapy. Out of 47 retrieved papers selected using PubMed search, 15 fulfilled the inclusion criteria. Different studies reported that the modulation of specific cytokines was time- and treatment-dependent. Radiotherapy (RT) induces the modulation of inflammatory cytokines up to 6 months for most of the analyzed cytokines, which in some cases can persist up to several years post-treatment. The role of specific cytokines as prognostic and predictive of radiotherapy outcome is critically discussed. [ABSTRACT FROM AUTHOR]

Exosomes released by cells can serve as vehicles for delivery of biological materials and signals. Long non-coding RNAs (lncRNAs) are non-coding RNAs longer than 200 nt, which roles are increasingly appreciated in various biological content. Tumor-derived exosomal lncRNAs have been implicated as signaling mediators to orchestrate cell function among neighbor tumor cells. However, the role of tumor-derived lncRNAs in cross-talk with environmental macrophages has yet to be explored. In this paper, we demonstrated that hepatocellular carcinoma (HCC) cells–derived exosomes contain elevated levels of lncRNA TUC339 and that HCC-derived exosomes could be taken up by THP-1 cells. In seeking to dissect the biological function of tumor secreting TUC339 in macrophages, we applied loss-of-function and gain-of-function strategies. We observed increased pro-inflammatory cytokine production, increased co-stimulatory molecule expression, and enhanced phagocytosis upon suppression of TUC339 by siRNA in THP-1 cells, and the opposite effect upon over-expression of this lncRNA, which indicates that TUC339 was involved in the regulation of macrophage activation. Moreover, we detected an elevated level of TUC339 in M(IL-4) macrophages as compared to M(IFN-γ + LPS) macrophages and a down-regulation of TUC339 expression during M(IL-4)-to-M(IFN-γ + LPS) repolarization and vice versa. Furthermore, suppression of TUC339 in macrophages diminished the expression of M(IL-4) markers upon IL-4 treatment while overexpression of TUC339 in macrophages enhanced M(IL-4) markers upon IFN-γ + LPS treatment, which suggests a critical function of TUC339 in the regulation of macrophage M1/M2 polarization. Lastly, using microarray analysis, we identified cytokine-cytokine receptor interaction, CXCR chemokine receptor binding, Toll-like receptor signaling, FcγR-mediated phagocytosis, regulation of the actin cytoskeleton, and cell proliferation are related with TUC339 function in macrophages. Our results provide evidence for a novel regulatory function of tumor-derived exosomal lncRNA TUC339 in environmental macrophages and shed light on the complicated interactions between tumor and immune cells through exosomal lncRNAs. [ABSTRACT FROM AUTHOR]

An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia’s viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS-evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-β, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark. [ABSTRACT FROM AUTHOR]

Treatment with anti-TNF-α (tumor necrosis factor), one of the pivotal cytokines, was introduced to clinical practice at the end of last century and revolutionized the treatment of rheumatoid arthritis (RA) as well as many other inflammatory conditions. Such a treatment may however bring many safety issues regarding infections, tuberculosis, as well as cardiovascular diseases, including heart failure. Given the central role of proinflammatory cytokines in RA, atherosclerosis, and congestive heart failure (CHF), such a treatment might result in better control of the RA process on the one side and improvement of heart function on the other. Unfortunately, at the beginning of this century two randomized controlled trials failed to show any benefit of anti-TNF treatment in patients with heart failure (HF), suggesting direct negative impact of the treatment on morbidity and mortality in HF patients. As a result the anti-TNF treatment is contraindicated in all patients with heart failure and a substantial portion of patients with RA and impaired heart function are not able to benefit from the treatment. The role of TNF in CHF and RA differs substantially with regard to the source and pathophysiological function of the cytokine in both conditions, therefore negative data from CHF studies should be interpreted with caution. At least some of RA patients with heart failure may benefit from anti-TNF treatment, as it results not only in the reduction of inflammation but also contributes significantly to the improvement of cardiac function. The paper addresses the epidemiological data of safety of anti-TNF treatment in RA patients with the special emphasis to basic pathophysiological mechanisms via which TNF may act differently in both diseases. [ABSTRACT FROM AUTHOR]