Incidence Of Inflammatory Disease Research Articles

Emerging Role of NAT10 as ac4C Writer in Inflammatory Diseases: Mechanisms and Therapeutic Applications.

The incidence of inflammatory diseases, including infections, autoimmune disorders, and tumors, is consistently increasing year by year, posing a significant and growing threat to human health on a global scale. Recent research has indicated that RNA acetylation modification, a specific type of post-transcriptional modification, may play a critical role in the pathogenesis of these diseases. Among the various mechanisms of RNA modification, N-acetyltransferase 10 (NAT10) has been identified as the sole cytidine acetyltransferase in eukaryotes. NAT10 is responsible for acetylating mRNA cytosine, which leads to the formation of N4-acetylcytidine (ac4C), a modification that subsequently influences mRNA stability and translation efficiency. Despite these insights, the specific roles and underlying mechanisms by which RNA acetylation contributes to the onset and progression of inflammatory diseases remain largely unclear. This review aimed to elucidate the alterations in NAT10 expression, the modifications it induces in target genes, and its overall contribution to the pathogenesis of various inflammatory conditions. It has been observed that NAT10 expression tends to increase in most inflammatory conditions, thereby affecting the expression and function of target genes through the formation of ac4C. Furthermore, inhibitors targeting NAT10 present promising therapeutic avenues for treating inflammatory diseases by selectively blocking NAT10 activity, thereby preventing the modification of target genes and suppressing immune cell activation and inflammatory responses. This potential for therapeutic intervention underscores the critical importance of further research on NAT10's role in inflammatory disease pathogenesis, as understanding these mechanisms could lead to significant advancements in treatment strategies, potentially transforming the therapeutic landscape for these conditions.

Role of alternative activation of macrophages in hookworm therapy for inflammatory diseases: a review

As a type of highly plastic innate immune cells, macrophages may be differentiated into M1 and M2 macrophages upon different stimuli, and M2 macrophages are involved in immune regulation, tissue remodeling and regeneration, and wound healing. Previous epidemiological studies have shown a significant negative correlation between the prevalence of helminth infections and the incidence of inflammatory diseases, such as allergy and autoimmune diseases. As a common type of intestinal helminths, hookworm infection may trigger high levels of type II host immune responses, with alternative activation of macrophages, which are effective to inhibit the development and progression of inflammatory diseases. This review summarizes the advances in alternative activation of macrophages in hookworm therapy for inflammatory diseases.

THE ROLE OF THE INFECTIOUS FACTOR IN MISCARRIAGE

Abstract: The article considers the pathogenetic role of the infectious factor in miscarriage. In the Russian Federation, one of the main causes of low fertility is reproductive losses. The main causes of miscarriage have been identified, among which infectious and inflammatory processes of the genitals play an important role. It is noted that every year there is an increase in the incidence of inflammatory diseases of the pelvic organs among women of reproductive age. It is proved that among women with a history of miscarriage, the incidence of endometritis is several times higher than among women without a burdened gynecological and obstetric history. The pathogenetic aspects of chronic endometritis during miscarriage are diverse, but it has been determined with accuracy that this pathology can lead to further reproductive losses. It was revealed that not only an infectious lesion of the endometrium is a risk factor for miscarriage. Infectious and dysbiotic processes of other genitals also negatively affect the course of pregnancy, and can lead to reproductive losses. The systemic effect of pathogenic microflora on the reproductive system, which is realized by systemic endotoxinemia, is considered. The main pathogens of gram-positive and gram-negative microflora and the pathogenesis of their effects leading to miscarriage are shown. The main directions of prevention of the development of inflammatory diseases of the pelvic organs and their complications are shown. The importance of carrying out sanitary and educational work among women, especially teenage girls, was noted.

Physical exercise increases global and gene-specific (interleukin-17 and interferon-γ) DNA methylation in lymphocytes from aged women.

What is the central question of this study? Is lymphocyte DNA methylation differentially modulated by resistance training and aerobic exercise in older women? What is the main finding and its importance? The practice of resistance training led to an increased global DNA methylation in lymphocytes. The exercise-induced increase of inflammatory genes methylation may be associated with immune function impairment during ageing. Ageing-induced increase in inflammatory gene expression through a reduction in DNA methylation might contribute to chronic diseases. Regular physical exercise practices, in turn, are associated with a decrease in the incidence of inflammatory diseases. We herein evaluated the effects of three exercise modalities on lymphocyte global and gene-specific (interferon γ (IFN-γ) and interleukin 17A (IL-17A) DNA methylation in aged women (68±7.5years). This cross-sectional study included 86 women, divided into four groups according to the physical exercise practice: 20 were practicing resistance training (RT); 24 were practicing water aerobics exercise (W); 22 were practicing water aerobics and resistance exercise (RWT), and 20 did not practice any physical exercise (CON). We evaluated volunteer functional capability using the Timed Up and Go (TUG) test, global lymphocyte DNA methylation by enzyme-linked immunosorbent assay, IFN-γ and IL-17A methylation by qPCR and CD4+ IFN-γ+ and CD4+ IL-17+ cell percentage by flow cytometry. The three physically exercised groups performed functional capability tests in a shorter period and showed a higher global lymphocyte DNA methylation and methylated CpGs of IL-17A and IFN-γ promoter regions than the control group. The practice of resistance training (RT and RWT groups) lead to high global DNA methylation. The combination of resistance training and aerobic exercise led to the increase of lymphocyte IL-17A and IFN-γ gene methylation induced by each separately. However, the percentage of IFN-γ+ and IL-17+ cells was lower only in the RT group. The exercise-induced increase of inflammatory-gene methylation may be associated with gene expression changes and immune function impairment during ageing.

Effects of Inflammatory Disease on Clinical Progression and Treatment of Ischiogluteal Bursitis: A Retrospective Observational Study.

Introduction:The symptoms of Ischiogluteal Bursitis (IGB) are often nonspecific and atypical, and its diagnosis is more challenging. Moreover, it is difficult to predict cases of chronic progression or poor treatment response. Therefore, the aim of this study was to investigate the clinical course of IGB patients and identify factors that are predictive of failure of conservative treatment.Materials and Methods:Our study consisted of IGB patients diagnosed between 2010 March and 2016 December who had been followed-up for at least one year. Structured questionnaires and medical records were reviewed to analyse demographic characteristics, lifestyle patterns, blood tests, and imaging studies. We categorized the cases into two groups based on the response to conservative treatment and the need for surgical intervention.Results:The most common initial chief symptoms were buttock pains in 24 patients (37.5%). Physical examinations showed the tenderness of ischial tuberosity area in 59 (92.2%) patients, but no specific findings were confirmed in 5 patients (7.8%). 51 patients (79.7%) responded well to the conservative management, 11 patients (17.2%) needed injection, and 2 patients (3.1%) had surgical treatment performed due to continuous recurrence. There was no difference in demographic and blood lab data between the two groups. However, the incidence of inflammatory diseases (response group: 10.3% vs non-response group: 66.7%, p=0.004) was significantly different between the two groups.Conclusion:The diagnosis of IGB can be missed due to variations in clinical symptoms, and cautions should be exercised in patients with inflammatory diseases as conservative treatment is less effective in them, leading to chronic progression of IGB.

Клініко-статистичний аналіз особливостей репродуктивного здоров’я жінок при повторних невдалих спробах застосування допоміжних репродуктивних технологій

The objective: to conduct a clinical and statistical analysis of the characteristics of the somatic and reproductive history in women with repeated unsuccessful attempts of assisted reproductive technologies and to determine significant medical and social factors in the formation of chronic endometritis. Materials and methods. A clinical and statistical analysis of 177 outpatient cards was carried out: Group I – 127 women under the age of 45 with a history of two or more ineffective attempts at in vitro fertilization; Group II – there were 50 healthy women without reproductive disorders. The comprehensive examination included data from anamnesis, general clinical and gynecological examination, laboratory and instrumental methods according to the data of outpatient observation cards at the MC LLC «Isida – IVF». The diagnosis of chronic endometritis was verified by the data of the histological examination of the endometrium obtained by the pipel biopsy method on days 4 –9 of the menstrual cycle. Results. The incidence of inflammatory diseases of the uterine appendages in patients of group I was 47.2%, inflammatory diseases of the endometrium – 41.7%; р1.2<0.01. The incidence of acute endometritis among patients of group I was 6.3%; р1.2>0.05 and was due to the implementation of the infectious process after abortion. In the first group, sexually transmitted infections were noted in 67.7% of patients, р1.2>0.05; bacterial vaginosis was recorded 1.5 times more often – 28.4%; р1.2<0.05. In the first group, one-time artificial termination of pregnancy appeared in 15.0%, twice – in 15.7% (р1.2<0.05). Laparoscopies were previously performed in 59.8% of women, laparotomies – in 62.2%, while operations were repeated in 25.4% of women. Unilateral tubectomy for ectopic pregnancy was performed in 25.4% of women, bilateral in 12.7%. Removal of fallopian tubes due to sactosalpinxes in 25.4% of women, unilateral removal of appendages appeared in patients in 3.9% of cases. The most significant risk factors for the development of chronic endometritis in the studied groups are acute post-abortion endometritis VR (relative risk) = 1.439, p=0.029 and postoperative peritonitis, which was caused by complications of appendectomy – RR=1.430, p=0.084. We did not reveal a significant effect of inflammatory diseases of the uterine appendages on the implementation of chronic endometritis (RR=45.132, CI (6.151-31.167), p=0.001. Analysis of reproductive failures as a risk factor for the development of chronic endometritis in women of group I showed a significant relative risk: with a history of PR RR=1.44, p=0.039, with repeated artifactual abortions RR=1.5, p<0.001, SV RR=1.572, p=0.001. A higher relative risk of developing XE was observed during pregnancy – RR=1.597, p=0.001. Conclusions. Clinical and statistical analysis of the reproductive health of women with repeated unsuccessful attempts at ART has shown that these women have a high frequency of intrauterine interventions, a low frequency of using alternative and safe methods of abortion, and there is no system of health measures after reproductive failures. There is a significant increase in spontaneous abortion in the early stages and the absence of a decrease in premature birth. Preserving the reproductive health of women is an important medical and social problem, the solution of which depends on the joint efforts of state and public organizations and health authorities, as well as on the responsibility of the population for their health. The development and implementation of pregravid health improvement and pregnancy planning programs for women with repeated unsuccessful attempts at ART against the background of chronic endometritis should be a priority in the health care system. Keywords: assisted reproductive technologies, chronic endometritis, ineffective attempts at fertilization, reproductive health, pregnancy.

Analysis of gynecological morbidity and the trend of development of stationary gynecological care in the Russian Federation

Background: Due to a quantitative decrease in the demographic reserve and a qualitative decrease in the reproductive potential of the country, protecting the reproductive health of women in Russia has now become an emergency situation. The obstetric and gynecological service is of major importance in maintaining reproductive health and conducting a comprehensive demographic policy. This study aimed to assess the dynamics of gynecological morbidity in the Russian Federation, the Central Federal District, the city of Moscow, and the organization of stationary gynecological care. Material and methods: The official statistics of the Federal State Statistics Service and the Ministry of Health of Russia for 20092018, as well as data from copies of the medical records (medical history, records of patients discharged from the hospital) of patients who received treatment in a gynecological day patient facility between 2015 and 2017. Results: A decrease in the number of gynecological beds by 32.2% over 10 years was noted. At the same time, the level of primary and general incidence of inflammatory diseases of the female pelvic organs did not decrease; between 2014 and 2018, there has been an increase in the incidence of primary female infertility. Non-inflammatory diseases of the female genital organs prevail (76.6%) as reason for admission in the day patient facility. Conclusion: The gynecological day patient facility manages female health; however, the nationwide and regional incidence rate of gynecological morbidity follows a negative trend and is increasing annually.

\u03b2-hydroxybutyrate and hydroxycarboxylic acid receptor 2 agonists activate the AKT, ERK and AMPK pathways, which are involved in bovine neutrophil chemotaxis

Elevated plasma concentrations of the ketone body β-hydroxybutyrate (BHB), an endogenous agonist of the hydroxycarboxylic acid receptor 2 (HCA2), is associated with an increased incidence of inflammatory diseases during lactation in dairy cows. In the early stages of this pathology, an increase in neutrophil recruitment is observed; however, the role of BHB remains elusive. This study characterized the effect of BHB and synthetic agonists of the HCA2 receptor on bovine neutrophil chemotaxis and the signaling pathways involved in this process. We demonstrated that treatment with BHB concentrations between 1.2 and 10 mM and two full selective agonists of the HCA2 receptor, MK-1903 and nicotinic acid, increased bovine neutrophil chemotaxis. We also observed that BHB and HCA2 agonists induced calcium release and phosphorylation of AKT, ERK 1/2 and AMPKα. To evaluate the role of these pathways in bovine neutrophil chemotaxis, we used the pharmacological inhibitors BAPTA-AM, pertussis toxin, U73122, LY294002, U0126 and compound C. Our results suggest that these pathways are required for HCA2 agonist-induced bovine neutrophil chemotaxis in non-physiological condition. Concentrations around 1.4 mM of BHB after calving may exert a chemoattractant effect that is key during the onset of the inflammatory process associated with metabolic disorders in dairy cows.

Сучасний стан репродуктивного здоров’я подружньої пари з урогенітальними інфекціями в анамнезі

This article highlights the actual problem of reproductive health in a married couple with a history of urogenital infections. The main trigger for the development of inflammation of the uterine adnexas is microbial invasion. In recent years, there have been significant changes in the etiological structure of inflammatory diseases of the reproductive system: the incidence of inflammatory diseases caused by the agents of the «second generation» – chlamydia, ureaplasmas, mycoplasmas, viruses significantly increased. The untimely and inadequate treatment of acute inflammatory processes of the internal genital organs, as well as the lack of their prevention explains the high incidence of chronic salpingoophoritis. Recently, give considerable attention to the study of the prevalence and role of viruses in the structure of sexually transmitted diseases. Today, inflammatory diseases of the urogenital sphere in men and women are the leading among the problems that have to deal with urologists, andrologists, gynecologists, reproductologists. This pathology is most common among patients of reproductive and working age. It has a negative effect on sexual function, ability to conceive, family relationships, social adaptation and efficiency. Marriage infertility is a worldwide prevalent pathology that is a significant personal, medical, biological, social and demographic problem of today. According to the latest data from the European Society for Human Reproductology and Embryology (ESHRE), about 1 million married couples suffer from infertility in Ukraine, ie 15–17%. The overview of current research summarizes the theoretical and statistical data of recent years. The modern ideas about the etiopathogenesis of male and female infertility, namely the effect of transmitted urogenital infections on the occurrence of disorders in the female and male genitourinary systems are considered. Accent is placed on the analysis of the problem of complications regarding further planned pregnancy in a couple who has a history of urogenital infections. Key words: reproductive health, urogenital infections, infertility, pregnancy, mixed infections, married couple, sexually transmitted diseases (STDs).

Unmet need in rheumatology: reports from the Targeted Therapies meeting 2019

ObjectivesTo detail the greatest areas of unmet scientific and clinical needs in rheumatology.MethodsThe 21st annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and...

Клінічні аспекти асоційованих кандидозно-герпетичних вульвовагінітів

Inflammatory processes of the female genital organs account for 55-70% of cases in the structure of all gynecological diseases, of which 40-50% are vaginal infections. Despite a significant amount of scientific research and the latest antibacterial agents, the incidence of inflammatory diseases does not tend to decrease. Candidiasis and herpes are one of the most widespread infections of the person with the chronic nature of a current and a long persistence of the agent. It is important to consider psychological consequences of infection. The objective: of the study was to study the features of a clinical current and also psychoemotional state of women with a chronically candidiasis-herpetic vulvovaginitis. Materials and methods. A total of 138 women with the associated candida-herpetic infection of a vagina (the main group) and 20 gynecologic healthy women (control group). Everything surveyed carried out all-clinical, cytological, mycological and virological researches . The psychoemotional state is studied according to the method by L.I. Wasserman’s. Results. At all examined women clinical manifestations of the vulvovaginitis of the mixed etiology were observed. 92.4% of patients had long and heavy discharges’ from a vagina. Results of virological and mycological researches correlated with a frequency of a recurrence of a disease and weight of their clinical manifestations. The research of psychological state showed that most of women with a mixed-infection (76.6%) had an increased level of psycho-emotional pressure in comparison with women of control group. Conclusions. It was established that women at the age of 20-30 years (67.4%) are at risk of having a candidiasis-herpetic infection. In most patients, the elements of the lesion occupy several anatomical areas. In patients with candidiasis- herpetic infection of the vagina, immunological dysfunction has been established at the level of the humoral link. Particularities attention should be paid to the relationship of psycho-emotional state and state of somatic health. Key words: associated infection, vulvovaginitis, candidiasis, genital herpes, psycho-emotional state.

Sepsis in obstetrics and gynecology

Despite certain advances in modern medicine, the incidence of inflammatory diseases in women does not decrease, and infectious complications continue to occupy a leading place in the structure of obstetric and gynecological pathology. Moreover, the incidence of such dangerous complications as septic shock tends to increase. Over the past 25 years, the definition of sepsis and septic shock has changed three times; an international intensive care protocol is updated every four years with the participation of dozens of leading organizations and experts. Thus, the urgency of the problem is obvious and requires from doctors of all specialty’s modern knowledge on early detection and timely, early targeted therapy for sepsis and septic shock in obstetrics.

Pustulosis palmoplantar: características epidemiológicas, clínicas y genéticas de una serie de 41 casos

IntroductionPalmoplantar pustulosis (PPP) is characterised by the presence of sterile association with other diseases differ among published studies. IL36RN gene mutation has recently been identified in patients with mainly generalised pustular forms, but also in some patients with PPP. The objective of this study is to describe clinical and epidemiological characteristics, the incidence of inflammatory diseases in PPP, and to study the frequency of IL36RN gene mutations. MethodsAn observational, retrospective, longitudinal study is presented, which includes all patients attended in our centre between 2009 and 2017 with a PPP diagnosis if only they were controlled by photography. Results41 patients were included (90% women; average age of 55, 8). 94% were smokers or ex-smokers, 24% had a history of plaque psoriasis, 39% ungueal psoriasis and 27% a positive familiar background. On analysing IMIDs (immune mediated inflammatory disorders) incidence in PPP patients, 7% had inflammatory bowel disease, 10% psoriatic arthritis, and 22% other types of arthritis. No IL36RN gene mutations were found in any of the 11 patients in whom a genetic study was performed. ConclusionsPatients with PPP are mostly women who smoke, in the fifth decade of life, with an incidence of IMIDs higher than expected, as well as with a high prevalence of personal and family history of psoriasis.

Role of Lactobacillus reuteri in Human Health and Diseases.

Lactobacillus reuteri (L. reuteri) is a well-studied probiotic bacterium that can colonize a large number of mammals. In humans, L. reuteri is found in different body sites, including the gastrointestinal tract, urinary tract, skin, and breast milk. The abundance of L. reuteri varies among different individuals. Several beneficial effects of L. reuteri have been noted. First, L. reuteri can produce antimicrobial molecules, such as organic acids, ethanol, and reuterin. Due to its antimicrobial activity, L. reuteri is able to inhibit the colonization of pathogenic microbes and remodel the commensal microbiota composition in the host. Second, L. reuteri can benefit the host immune system. For instance, some L. reuteri strains can reduce the production of pro-inflammatory cytokines while promoting regulatory T cell development and function. Third, bearing the ability to strengthen the intestinal barrier, the colonization of L. reuteri may decrease the microbial translocation from the gut lumen to the tissues. Microbial translocation across the intestinal epithelium has been hypothesized as an initiator of inflammation. Therefore, inflammatory diseases, including those located in the gut as well as in remote tissues, may be ameliorated by increasing the colonization of L. reuteri. Notably, the decrease in the abundance of L. reuteri in humans in the past decades is correlated with an increase in the incidences of inflammatory diseases over the same period of time. Direct supplementation or prebiotic modulation of L. reuteri may be an attractive preventive and/or therapeutic avenue against inflammatory diseases.

Репродуктивний анамнез жінок із післяпологовими гнійно-септичними ускладненнями

Postpartum purulent-septic complications are considered to be one of the main causes of maternal loss, hence, this is why they continue to maintain their relevance and priority in modern obstetrics. The incidence of this disease remains high and aggravates the extension of the postpartum period in 5–26% of cases. Mostly postpartum purulent-septic complications are caused by not one, but a combination of several reasons that can act simultaneously or sequentially and are often caused by a combination of medical and social factors. These factors require the necessity of diligent analysis of the reproductive anamnesis of women who suffered from complications of septic nature during the postpartum period, in order to highlight the risk factors for these complications. The objective: to explore the possibility of formation of high-risk groups based on the analysis of reproductive anamnesis in women with postpartum purulent-septic complications as part of preventive measures. Patients and methods. According to the purpose of this research a detailed retrospective analysis was made of anamnesis histories of 89 women (study group) with postpartum septic complications, namely, 58 women with postpartum purulent-septic complications who bore through natural birth canal; 31 women with postpartum purulent-septic complications after cesarean section. The control group consisted of 40 women recently confined within uncomplicated maternal postpartum process. Results. It was investigated that in the group of women with postpartum complications prevailed women who were pregnant for the second time (especially after cesarean section).It is important to highlight the fact that significant percentage of menstrual disorders and the commencement of early sexual live of women in the study group. Analysis of an illness revealed a significant incidence of inflammatory diseases of the female reproductive organs, cervical pathology, chronic tonsillitis, chronic pyelonephritis, cystitis, anemia clinical history in the main group. Significant percentage is noticed of the women with thyroid disorders. Significantly higher frequency was noticed with regards to pregnancies that had negative consequences in anamnesis, the presence of gynecological pathology, surgery and vaginal microbiota disturbances before and during pregnancy in women with postpartum purulent-septic complications. A combination of two or more selected factors, especially in women with extragenital pathology and transferred infectious diseases in anamnesis, greatly increases the risk of septic complications in the postpartum period. Conclusions. Current analysis has provided implicit evidences to ensure that it is important to select a separate group at high risk of postpartum septic complications on the stage which precedes pregnancy for the development of an individual plan for diagnostic and preventive measures to prevent this disease. Key words: postpartum purulent-septic complications, risk factors, reproductive anamnesis.

Functional morphology of the placental villous tree at term singleton pregnancies, achieved by methods of assisted reproductive technology

Introduction. Of special interest in the use of assisted reproductive technology techniques (ART) is the placenta as the main authority responsible for the formation and growth of the fetus. Purpose and objectives. The aim of our research is to study the morpho-functional state of placenta after pregnancy achieved by means of ART. Research objectives: histological and immunohistochemical study using the CD34, NOS-3 and HIF in these placentas. Methods. Total 98 placentas from full-term singleton pregnancies with gestational age were examined. Two study groups were formed: a basic group - the placenta from pregnancy induced methods of ART (n = 60) was divided into I subgroup, which included 30 placentas from women with primary infertility and II subgroup - 30 placentas from women with secondary infertility comparison group consisted of the placenta from the naturally ensuing pregnancy (12 placentas from primigravidae and 26 placentas from multiparous patients). Results. Histological examination of the morphological structure of the placenta was found that the incidence of chronic placental insufficiency was 1.4 times higher than in the subgroup with secondary infertility. Immunohistochemical study of placentas in the basic group, there was a significant decrease in the expression of cell adhesion marker (CD34) in the vascular epithelium chorionic villi, decreased expression of vascular tone marker (NOS-3) and increase the expression of hypoxia-inducible factor (HIF-1α) in the basic group compared to placenta s from children born naturally. Changes in the expression of the studied markers are most pronounced in the placentas from children born with secondary infertility, which is likely due to the high incidence of inflammatory diseases of the pelvic organs in this subgroup. Conclusions. Endometrial pathology in primary and secondary infertility, can cause the formation of functional disorders and morphological structure of placental complex and occurrence in the future placental insufficiency.

Bugging inflammation: role of the gut microbiota

The advent of vaccination and improved hygiene have eliminated many of the deadly infectious pathogens in developed nations. However, the incidences of inflammatory diseases, such as inflammatory bowel disease, asthma, obesity and diabetes are increasing dramatically. Research in the recent decades revealed that it is indeed the lack of early childhood microbial exposure, increase use of antibiotics, as well as increase consumption of processed foods high in carbohydrates and fats, and lacking fibre, which wreak havoc on the proper development of immunity and predispose the host to elevated inflammatory conditions. Although largely unexplored and under-appreciated until recent years, these factors impact significantly on the composition of the gut microbiota (a collection of microorganisms that live within the host mucosal tissue) and inadvertently play intricate and pivotal roles in modulating an appropriate host immune response. The suggestion that shifts in the composition of host microbiota is a risk factor for inflammatory disease raises an exciting opportunity whereby the microbiota may also present as a potential modifiable component or therapeutic target for inflammatory diseases. This review provides insights into the interactions between the microbiota and the immune system, how these affect disease phenotypes, and explore current and emerging therapies that target the gut microbiota as potential treatment for inflammatory diseases.

Abstract C281: The carcinogen cadmium promotes activation of lysine 63 (K63)-linked ubiquitin-dependent signaling by inhibiting selective autophagy and CYLD K63 deubiquitination.

Abstract K63-linked ubiquitination– i.e. conjugation of a chain of ubiquitins (Ub) linked through lysine 63– has emerged as a key mechanism regulating signaling transduction pathways. Although critical, very little information is currently available about how subversion of K63 ubiquitination might contribute to inflammatory diseases and cancers. The present study provides the first evidence that cadmium (Cd), a widespread environmental carcinogen, is a powerful activator of K63 ubiquitination. Indeed, Cd induces accumulation of K63 polyubiquitinated proteins, independently of oxidative damage, activation of ubiquitin ligase or proteasome impairment. Rather, we demonstrate that Cd activates K63 ubiquitination by inhibiting both CYLD and autophagy, two tumor suppressors that selectively deubiquitinate and degrade K63-linked ubiquitinated proteins, respectively. As a result, we found that cadmium treatment induces sustained activation of NF-κB, a pathway critically dependent on K63 ubiquitination. Given the role of NF-κB in survival, proliferation, and inflammation, these findings provide a potential molecular link between cadmium exposure and the increased incidences of inflammatory diseases and cancers. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C281. Citation Format: Abderrahman Chargui, Amine Belaid, Véronique Imbert-Rezzonico, Michel Samson, Jean-Marie Guigonis, Sebastien L'hoste, Michel Tauc, Jean François Peyron, Philippe Poujeol, Paul Hofman, Baharia Mograbi. The carcinogen cadmium promotes activation of lysine 63 (K63)-linked ubiquitin-dependent signaling by inhibiting selective autophagy and CYLD K63 deubiquitination. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C281.

Manipulation of Regulatory T-Cell Function by Immunomodulators: A Boon or a Curse?

Regulatory T cells (Tregs) constitute a subset of lymphocytes that have the capability of suppressing immune responses in vivo and in vitro both directly by cell-cell contact and indirectly through the production of anti-inflammatory cytokines, such as interleukin-10 and tumor growth factor-β. Tregs constitute a small subset of T lymphocytes, yet their presence can prevent and control autoimmune disease and organ transplant rejection and contribute to maternal tolerance of fetal alloantigens, whereas their absence results in uncontrolled inflammation. But Treg function may not always be considered beneficial: There is growing evidence that the immunosuppressive effects of Tregs are also associated with growth of tumor cells. Thus, Tregs are of considerable medical interest as targets for the treatment of both inflammatory diseases and cancer. In this review of published literature, we describe some well-characterized immunomodulatory drugs and environmental toxicants that can either positively or negatively affect the number and/or function of Tregs in animal models and/or human patients. The targeted suppression or enhancement of Treg function needs to be carefully considered in immunotoxicity evaluations as manipulation of this immune cell population could result in undesired consequences, including decreased host resistance, decreased fertility, or increased incidence of inflammatory disease.

David Artis: Fear no worm

As the incidence of inflammatory disease and food allergies increases in the industrialized world, David Artis wonders if something is wrong with the little friends in our guts.