Inflammatory Reactivity Research Articles

Использование интегральных лейкоцитарных индексов для оценки воспалительного процесса, эндогенной интоксикации и иммунологической реактивности у поросят при желудочно-кишечных болезнях и эффективности проводимой терапии

The article presents the results of studying the possibility of using integral leukocyte indices to assess the inflammatory process, endogenous intoxication and immunological reactivity in piglets with gastrointestinal infections on industrial pig breeding farms and the efficacy of therapy of sick animals with an interferon-containing drug. It was found that in sick piglets, compared with clinically healthy animals, the values of integral leukocyte indices of endogenous intoxication were higher, and the lymphocytic-granulocytic index, which characterized the severity of inflammation and the degree of intoxication associated with the infectious process, was lower. At the same time, changes in the indices of nonspecific reactivity were revealed, indicating a decrease in the activity of the monocyte-macrophage system, the adaptive capabilities of the organism and a pronounced stress reaction. The use of propig ensured the recovery of 97,5 % of sick animals. In recovered piglets, the values of integral leukocyte indices, which characterize endogenous intoxication, decreased, there were changes in the values of nonspecific reactivity indices, indicating an increase in the immune status, there was a tendency to an increase in the lymphocytic-granulocytic index, which indicated the extinction of the inflammatory process and the efficacy of treatment. The conducted studies have established the possibility of using integral leukocyte indices for an objective assessment of the presence of an inflammatory process, endogenous intoxication and the state of immunological reactivity in piglets with gastrointestinal diseases and the efficacy of therapy.

Integrated indices as a criterion for evaluation of the level of endogenous intoxication for leptospirosis in dogs

One of the most important directions in the development of modern veterinary medicine is the improvement and implementation of modern methods of diagnosis and prognosis of diseases based on determining the degree of dysfunction and the possibility of correcting the protective functions of the body. for most veterinary clinics, the study of the immunological status of animals is not available, and clinical blood tests make it possible to determine the assessment of the functional state of the immune system by integrated hematological parameters. In the article on the basis of blood formulas that reflect the state of neurohumoral homeostasis and immunological reactivity of the organism, for the first time investigated and established violations of humoral and cellular immune systems, micro- and macrophage systems, reduced nonspecific protection and found relationships between immunity in 23 dogs with leptospirosis, which calculated 19 markers of inflammatory activity, endogenous intoxication, adaptation, nonspecific and immune reactivity. The study was conducted in veterinary clinics in zhytomyr and kyiv, blood for the study was taken from the superficial vein of the forearm v. anterbrachium, medial subcutaneous vein or subcutaneous tibial vein v. saphena. Diagnostic studies to confirm leptospirosis were performed using rapid tests Combo Test IgG Ab/IgM Ab, vetlaboratories and elisa on the basis of a private veterinary laboratory of Llc “Bald” in Kiev. The interpretation of integrated leukocyte blood parameters revealed the development of autoimmune processes with suppression of cellular immunity and the development of endogenous intoxication, which indicates an increase in total (P < 0.01), leukocyte (P < 0.05) and nuclear index (P< 0.001). Suppression of the immune response and increased hypersensitivity of the immediate type based on a decrease in non-specific reactivity by P < 0.001 and inflammation index by P < 0.05. It is proved that integrated hematological parameters of peripheral blood increase the informativeness of the general analysis of blood in dogs with infectious diseases and allow to determine not only the degree of reactivity of the organism, but also to assess the level of endogenous intoxication.

Frequent Interpersonal Stress and Inflammatory Reactivity Predict Depressive-Symptom Increases: Two Tests of the Social-Signal-Transduction Theory of Depression

The social-signal-transduction theory of depression asserts that people who experience ongoing interpersonal stressors and mount a greater inflammatory response to social stress are at higher risk for depression. The current study tested this theory in two adult samples. In Study 1, physically healthy adults (N = 76) who reported more frequent interpersonal tension had heightened depressive symptoms at Visit 2, but only if they had greater inflammatory reactivity to a marital conflict at Visit 1. Similarly, in Study 2, depressive symptoms increased among lonelier and less socially supported breast-cancer survivors (N = 79). This effect was most pronounced among participants with higher inflammatory reactivity to a social-evaluative stressor at Visit 1. In both studies, noninterpersonal stress did not interact with inflammatory reactivity to predict later depressive symptoms.

Expression of Emotions and Genes: Proinflammatory Gene Expression Rises With Spousal Distress

Marital quality shares ties to inflammation-related conditions like cardiovascular disease and diabetes. Lab-based studies implicate hostility during marital conflict as a mechanism via inflammatory reactivity. However, developmental theories suggest that conflict declines with age. Spousal distress is an important but overlooked context for aging couples as networks shrink and assistance needs increase. To examine the effects of spousal distress on changes in proinflammatory gene expression, 38 adults ages 40-81 witnessed their spouse relive an upsetting personal memory aloud, rated their mood before and after, and provided blood samples at baseline and twice post-task. Those whose negative mood increased more in response to spousal disclosure showed larger elevations in proinflammatory gene expression 40 (p=.022) and 80 minutes (p<.0001) after the task. Effects were robust to race, gender, age, alcohol, smoking, and body mass index. These novel findings identify spousal distress as a key marital context that may escalate inflammation-related health risks.

Immune Characteristics of IgA Nephropathy With Minimal Change Disease

Background: IgA nephropathy (IgAN) has a high degree of heterogeneity in clinical and pathological features. Among all subsets of IgAN, the pathogenesis of IgAN with minimal change disease (MCD-IgAN) remained controversial. Methods: We analyzed the clinical and pathological characteristics of MCD-IgAN patients in a retrospective cohort. Patients diagnosed with IgAN, excluding MCD-IgAN, were randomly selected as controls. Levels of plasma galactose-deficient IgA1 (GdIgA1), IgG autoantibodies against GdIgA1, GdIgA1 deposition in the glomerulus, and inflammatory reactivity of circulating poly-IgA1 complexes to cultured mesangial cells were evaluated. Results: Patients with MCD-IgAN had significantly higher levels of proteinuria and estimated glomerular filtration rate (eGFR), lower levels of albumin and urine blood cells, and milder histological lesions by a light microscope compared to IgAN patients, which bears a resemblance to MCD. Lower levels of GdIgA1 (3.41 ± 1.68 vs. 4.92 ± 2.30 μg/ml, p = 0.009) and IgG antiglycan autoantibodies (23.25 ± 22.59 vs. 76.58 ± 71.22 IU/ml, p < 0.001) were found in MCD-IgAN patients than those in IgAN controls. Meanwhile, weaker fluorescence intensities of both IgA and GdIgA1 were observed in the glomerulus of MCD-IgAN patients compared to those in IgAN patients. Furthermore, poly-IgA1 complexes from MCD-IgAN patients induced weaker inflammatory effects on cultured mesangial cells than those from IgAN patients in vitro. Conclusion: The results demonstrated that MCD-IgAN cases represent a dual glomerulopathy, namely, mild IgAN with superimposed MCD, which furthermore provides substantial evidence for the corticosteroids therapy in MCD-IgAN patients as the guidelines recommended.

Inflammatory reactivity to the influenza vaccine is associated with changes in automatic social behavior

Recent evidence suggests differential patterns of social behavior following an inflammatory challenge, such that increases in inflammation may not uniformly lead to social withdrawal. Indeed, increases in inflammation have been associated with enhanced self-reported motivation to approach a specific close other, and greater neural sensitivity to positive social cues. However, no known studies have examined the association between inflammation in response to an inflammatory challenge and social behavior in humans, nor has past research examined specifically how approach and withdrawal behavior may differ based on whether the target is a close other or stranger. To address this, 31 participants (ages 18–24) received the influenza vaccine to elicit a low-grade inflammatory response. The morning before and approximately 24 h after the vaccine, participants provided a blood sample and completed a computer task assessing automatic (implicit) approach and withdrawal behavior toward a social support figure and strangers. Greater increases in the inflammatory cytokine interleukin-6 (IL-6) in response to the vaccine were associated with an increase in accuracy in avoiding strangers and a decrease in accuracy in approaching them. Increases in IL-6 were also associated with a decrease in reaction time to approach a support figure, but only when controlling for baseline IL-6 levels. There were no associations between change in IL-6 and changes in self-reported motivation to engage in social behavior with either close others, or strangers. Together, these findings reveal that increases in inflammation following the influenza vaccine are associated with automatic social behavior, especially behavior suggesting avoidance of unfamiliar social targets and ease in approaching a support figure. These data add to the growing literature suggesting that the association between inflammation and social behavior includes both social withdrawal and social approach, depending on the specific target.

Inflammatory reactivity to the influenza vaccine is associated with avoiding strangers and approaching close others

Recent pre-clinical data suggest that increases in inflammation may not uniformly lead to social withdrawal. However, no known human research has examined the association between inflammation and approach and withdrawal behavior, nor how that behavior may differ based on whether the target is a close other or stranger. 31 adult participants received the influenza vaccine to elicit a mild inflammatory response. Participants provided blood samples before and 24 hours after the vaccine, and completed a computer task assessing automatic approach and withdrawal behavior toward a close other and strangers. Greater increases in interleukin-6 (IL-6) following the vaccine were associated with more accurately avoiding strangers, b = .13, p = .06, and less accurately approaching them, b = -.15, p = .02. IL-6 increases were also associated with faster reaction times approaching a close other, b = -411.64, p = .03. These findings reveal that increases in IL-6 following the influenza vaccine are associated with behavior suggesting vigilance in avoiding unfamiliar social targets and approaching close others. This adds to a growing literature suggesting that inflammation is linked with both social withdrawal and social approach, depending on the target.

Abstract 105: Chronic Stress Primes Innate Immune Responses In Mice And Humans

Psychological stress is associated with elevated circulating markers of inflammation, including inflammatory cytokines and acute phase reactants that accelerate progression of chronic inflammatory diseases (e.g., atherosclerosis, metabolic syndrome, autoimmune diseases and cancer). However, the mechanisms underlying inflammatory reactivity to stress and how it confers future health risk are poorly understood. Monocyte-derived macrophages play key roles in sustaining tissue inflammation, and recent studies show that they can maintain epigenetic memory of pathogen or sterile inflammatory insults, leading to a heightened inflammatory state upon secondary stimulation. We show herein that psychological stress induces transcriptomic and epigenomic reprogramming of monocytes which primes them for a heightened inflammatory immune response following challenge. Monocytes isolated from stressed mice or humans with high reported levels of psychological stress exhibit a common signature of heightened inflammatory gene expression and produce increased levels of proinflammatory cytokines upon ex vivo stimulation with Toll-like receptor ligands. RNA and ATAC sequencing studies revealed that monocytes from stressed mice and humans exhibit activation of cellular metabolic pathways, including mTOR and PI3Kinase pathways, and reduced chromatin accessibility at loci associated with mitochondrial respiration. Taken together, our findings suggest that psychological stress primes the reprogramming of innate immune cells resulting in a hyperresponsive inflammatory state, which may explain its deleterious association with inflammatory disease risk.

Amyotrophic lateral sclerosis is a systemic disease: peripheral contributions to inflammation-mediated neurodegeneration.

Neuroinflammation is an important mediator of the pathogenesis of disease in amyotrophic lateral sclerosis (ALS). Genetic mutations such as C9orf72 have begun to define the numerous cell autonomous pathways that initiate motor neuron injury. Yet, it is the signalling to surrounding glia and peripherally derived immune cells that initiates the noncell autonomous inflammatory process and promotes self-propagating motor neuron cell death. The purpose of this review is to explore the systemic immune/inflammatory contributions to the pathogenesis of ALS: what are the peripheral pro-inflammatory signatures, what initiates their presence and do they represent potential therapeutic targets. In ALS, motor neuron cell death is initiated by multiple cell autonomous pathways leading to misfolded proteins, oxidative stress, altered mitochondria, impaired autophagy and altered RNA metabolism, which collectively promote noncell autonomous inflammatory reactivity. The resulting disease is characterized by activated microglia and astrocytes as well as peripherally derived pro-inflammatory innate and adaptive immune cells. In this unrelenting disorder, circulating blood monocytes and natural killer cells are pro-inflammatory. Furthermore, regulatory T lymphocytes are dysfunctional, and pro-inflammatory cytokines and acute phase proteins are elevated. The collective dysregulation of cells and cytokines in patients with ALS accurately reflect increased disease burdens, more rapid progression rates and reduced survival times, reinforcing the concept of ALS as a disorder with extensive systemic pro-inflammatory responses. These increased systemic pro-inflammatory immune constituents provide potentially meaningful therapeutic targets.

Repeated Neonatal Isoflurane Exposure is Associated with Higher Susceptibility to Chronic Variable Stress-induced Behavioural and Neuro-inflammatory Alterations

Numerous studies have reported that prolonged or multiple exposures to anaesthetics in early life lead to detrimental effects on brain function, most having focused on neurocognitive function, and relatively few on long term neuropsychiatric performance. The present study investigated the impact of repeated neonatal isoflurane exposure on chronic variable stress (CVS)-induced psychiatric and behavioural outcomes together with CVS-related neuronal activity and neuro-inflammatory reactivity in relevant brain circuits. In the present study, C57BL/6J mice received either three exposures to isoflurane at postnatal days 7, 8, and 9 or a control exposure. From postnatal day 45, mice were exposed to a mild, 3-week, CVS paradigm or none and the CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The neuronal activity in relevant brain regions was measured by ΔFosB immunopositivity and CVS-related neuroinflammation was assessed by analysing levels of pro-inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α. In mice experiencing serial neonatal isoflurane exposure, we detected a significant enhancement in anxiety levels following CVS procedures, together with enhanced neuronal activity, and exacerbated neuroinflammation in the basolateral amygdaloid nuclei (BLA) and hippocampal dentate gyrus (DG) regions. No such change was found in control mice. These results indicate an association between early multiple isoflurane exposures in infant mice and susceptibility to a CVS-evoked anxious phenotype accompanied by enhanced neuronal activity in BLA and DG regions and high inflammatory reactivity in response to CVS.

Ocular microvascular damage in autoimmune rheumatic diseases: The pathophysiological role of the immune system

Pathological eye involvement represents a quite common finding in a broad spectrum of autoimmune rheumatic diseases (ARDs). Ocular signs, often occur as early manifestations in ARDs, ranging from symptoms related to the mild dry eye disease to sight-threatening pathologies, linked to the immune response against retinal and choroidal vessels. Retinovascular damage driven by markedly inflammatory reactivity need a prompt diagnosis and treatment. Immune-complexes formation, complement activation and antibody-mediated endothelial damage seem to play a key role, particularly, in microvascular damage and ocular symptoms, occurring in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SS). Conversely, early alterations of retinal and choroidal vessels in the asymptomatic patient, often detectable coincidentally, might be indicators of widespread vascular injury in other connective tissue diseases. Particularly, endothelin-induced hypoperfusion and pathological peri-choroidal extracellular matrix deposition, might be responsible for the micro-architectural alterations and loss of capillaries detected in systemic sclerosis (SSc). Instead, interferon alpha-mediated microvascular rarefaction, combined with endothelial lesions caused by specific autoantibodies and immune-complexes, appear to play a significant role in retinal vasculopathy associated to inflammatory idiopathic myopathies (IIM). The immuno-pathophysiological mechanisms of ocular microcirculatory damage associated with the major ARDs will be discussed under the light of the most recent achievements.

Using the influenza vaccine as a mild, exogenous inflammatory challenge: When does inflammation peak?

BackgroundThe influenza vaccine has shown promise as a mild, exogenous inflammatory challenge, but use of this model is limited by lack of knowledge about the timing of the inflammatory response. This study was designed to characterize the time-course of the acute inflammatory response and explore psychological and behavioral predictors of that response. MethodsTwenty-one young, healthy individuals were recruited to receive the annual influenza vaccine. Serial blood samples were collected immediately before, and 24, 48, and 72 ​h following influenza vaccination. Interleukin (IL)-6 concentrations were assayed at each time-point and psychological and behavioral factors (anxiety and depressive symptoms, sleep disturbance, and childhood adversity) were assessed at baseline. ResultsSignificant elevations in IL-6 were observed at 24 ​h post-vaccination (mean increase ​= ​0.70 ​pg/mL, Cohen’s d ​= ​0.54, p ​= ​.018)), with 61.9% of participants exhibiting peak concentrations at that time point, χ2 ​= ​22.54, p ​< ​.001, η ​= ​0.52. In exploratory analyses, sleep disturbance was associated with greater increases in IL-6 at 24 ​h. ConclusionsBy identifying the peak IL-6 response to influenza vaccination among a sample of young, healthy individuals, these findings support the use of the influenza vaccine in future PNI research. This vaccine model can be used to examine the impact of mild inflammatory challenges on the brain and behavior, and to identify psychological and behavioral factors (e.g., anxiety, sleep) that modulate inflammatory reactivity.

Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation.

Alzheimer's disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer's disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer's disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer's disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer's disease fed a control (35 mg/kg zinc) or diet deficient in zinc (3 mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid β plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer's disease.SIGNIFICANCE STATEMENT Alzheimer's disease is a common condition mostly affecting the elderly. Zinc deficiency is also a global problem, especially in the elderly and also in people with Alzheimer's disease. Zinc deficiency contributes to many clinical disorders, including immune dysfunction. Inflammation is known to contribute to the risk and progression of Alzheimer's disease; thus, we hypothesized that zinc status would affect Alzheimer's disease progression. Here we show that zinc supplementation reduced the prevalence and symptomatic decline in people with Alzheimer's disease. In an animal model of Alzheimer's disease, zinc deficiency worsened cognitive decline because of an enhancement in NLRP3-driven inflammation. Overall, our data suggest that zinc status affects Alzheimer's disease progression, and that zinc supplementation could slow the rate of cognitive decline.

Potential for Cognitive Communication Impairment in COVID-19 Survivors: A Call to Action for Speech-Language Pathologists.

Purpose Severe acute respiratory syndrome coronavirus 2 is the virus resulting in COVID-19 infections in nearly 4.3 million Americans with COVID-19 in the United States as of July 29, 2020, with nearly 150,000 deaths and hundreds of thousands of survivors (https://www.coronavirus.jhu.edu/map.html). This tutorial reviews (a) what has been reported about neurological insults in cases of COVID-19 infection, (b) what is known from similar conditions in other disorders, and (c) how that combined information can inform clinical decision making. Method PubMed and the Cochrane Central Register of Controlled Trials were searched for COVID-19 or other coronavirus infections, cognitive impairment observed following critical care, and disorders for which intermittent or chronic hypoxia is characteristic. These were combined with searches relating to cognition, brain, and communication. All searches were conducted between April 8 and May 23, 2020. Meta-analyses and randomized clinical trials addressing other critical illnesses were also included to extend findings to potential cognitive communication outcomes following COVID-19. Results COVID-19 infection results in a combination of (a) respiratory infection with mechanical ventilation secondary to inadequate oxygenation, (b) inflammatory system reactivity, and (c) increased blood clotting factors. These affect central nervous system function incurring long-term cognitive communication impairment in a proportion of survivors. Diagnostic and intervention approaches for such impairments are discussed. Conclusions The existing literature on cognitive sequela of COVID-19 infection is small to date, but much can be learned from similar viral infections and disorders. Although COVID-19 is novel, the speech-language pathology approaches to evaluation and intervention of other populations of critical care patients are applicable. However, speech-language pathologists have not routinely been involved in these patients' acute care. As such, this is a call to action to speech-language pathologists to address the unprecedented numbers of patients who will need their services early in the disease process and throughout recovery.

Maternal dietary omega-3 deficiency worsens the deleterious effects of prenatal inflammation on the gut-brain axis in the offspring across lifetime.

Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD.

Suture and Needle Characteristics in Orthopaedic Surgery.

There remains a dearth of research on and general knowledge with regard to materials used for wound closure and soft-tissue repair and approximation. Critical suture properties include physical configuration, fluid absorption and capillarity, caliber or diameter, tensile strength, torsion, absorbability, elasticity, plasticity, memory, coefficient of friction, and knot security. The optimal ranges of each of these characteristics remain undefined for most sutures and indications. Needle types and basic design characteristics affect suture passage and require further consideration with regard to specific suture-needle selection. Suture must perform its intended purpose with a minimum of undesirable reaction and infectious potential, adequate duration of efficacy, and adequate strength. However, stronger, or high tensile strength, suture is not always better because of the requisite increase in suture caliber as well as the potential for inadvertent tissue strangulation, possibly increasing inflammatory reactivity. Sometimes, we seek stable, watertight fascial closure; occasionally, strong and durable tendon repair; and other times, gentle, cosmetically friendly, skin eversion and opposition. A variety of common suture types differ in these critical characteristics and may be optimally utilized for contrasting, but sometimes overlapping, indications.

Autonomic nervous system activity predicts increasing serum cytokines in children

Systemic inflammation is associated with increased risk for prevalent and costly diseases, and animal models implicate the autonomic nervous system in the control of inflammatory processes. In humans, research on autonomic-immune connections has been much more limited, and has focused on single branch autonomic measures (i.e., either parasympathetic or sympathetic). The current study utilized cardiac autonomic balance (CAB), derived from dual-branch cardiac autonomic recordings, to test the relation between resting autonomic function and inflammatory reactivity to challenge in children. MethodsParticipants included 96 children (51 boys, 45 girls) ages 9–11 years (mean age = 9.93 years, SD = 0.57 years). CAB values were calculated from standardized measures of parasympathetic and sympathetic activity, namely resting respiratory sinus arrhythmia and pre-ejection period data, respectively. Children provided two blood samples, one before and one following exposure to an acute social stressor or control condition. Serum was assayed for four cytokines that orchestrate inflammation: interleukin-6 (IL6), interleukin-8 (IL8), interleukin-10 (IL10), and tumor necrosis factor-alpha (TNFa). ResultsWe discovered large individual differences in inflammatory marker production across children, and no average main effect of stress condition. CAB significantly predicted these individual differences, such that children lower on CAB showed increasing serum cytokines from time 1 to time 2. In contrast, children with greater CAB tended to show declining inflammatory markers across the session. DiscussionLow cardiac autonomic balance (i.e., the combination of low parasympathetic and high sympathetic activity) may be a useful marker of proinflammatory tendencies in children, suggesting novel paths for early risk detection and intervention.

Tanshinone IIA Suppresses Proliferation and Inflammatory Cytokine Production of Synovial Fibroblasts from Rheumatoid Arthritis Patients Induced by TNF-α and Attenuates the Inflammatory Response in AIA Mice.

Rheumatoid arthritis (RA) is a chronic and progressive autoimmune disease in which activated RA fibroblast-1ike synoviocytes (RA-FLSs) are one of the main factors responsible for inducing morbidity. Previous reports have shown that RA-FLSs have proliferative features similar to cancer cells, in addition to causing cartilage erosion that eventually causes joint damage. Thus, new therapeutic strategies and drugs that can effectively contain the abnormal hyperplasia of RA-FLSs and restrain RA development are necessary for the treatment of RA. Tanshinone IIA (Tan IIA), one of the main phytochemicals isolated from Salvia miltiorrhiza Bunge, is capable of promoting RA-FLS apoptosis and inhibiting arthritis in an AIA mouse model. In addition, RA patients treated at our clinic with Tan IIA showed significant improvements in their clinical symptoms. However, the details of the molecular mechanism by which Tan IIA effects RA are unknown. To clarify this mechanism, we evaluated the antiproliferative and inhibitory effects of proinflammatory factor production caused by Tan IIA to RA-FLSs. We demonstrated that Tan IIA can restrict the proliferation, migration, and invasion of RA-FLSs in a time- and dose-dependent manner. Moreover, Tan IIA effectively suppressed the increase in mRNA expression of some matrix metalloproteinases and proinflammatory factors induced by TNF-α in RA-FLSs, resulting in inflammatory reactivity inhibition and blocking the destruction of the knee joint. Through the integration of network pharmacology analyses with the experimental data obtained, it is revealed that the effects of Tan IIA on RA can be attributed to its influence on different signaling pathways, including MAPK, AKT/mTOR, HIF-1, and NF-kB. Taken together, these data suggest that the compound Tan IIA has great therapeutic potential for RA treatment.

Epigenome-wide association study and multi-tissue replication of individuals with alcohol use disorder: evidence for abnormal glucocorticoid signaling pathway gene regulation

Alcohol use disorder (AUD) is a chronic debilitating disorder with limited treatment options and poorly defined pathophysiology. There are substantial genetic and epigenetic components; however, the underlying mechanisms contributing to AUD remain largely unknown. We conducted the largest DNA methylation epigenome-wide association study (EWAS) analyses currently available for AUD (total N = 625) and employed a top hit replication (N = 4798) using a cross-tissue/cross-phenotypic approach with the goal of identifying novel epigenetic targets relevant to AUD. Results show that a network of differentially methylated regions in glucocorticoid signaling and inflammation-related genes were associated with alcohol use behaviors. A top probe consistently associated across all cohorts was located in the long non-coding RNA growth arrest specific five gene (GAS5) (p < 10−24). GAS5 has been implicated in regulating transcriptional activity of the glucocorticoid receptor and has multiple functions related to apoptosis, immune function and various cancers. Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network-related probes were associated with stress phenotypes. Postmortem brain analyses documented increased GAS5 expression in the amygdala of individuals with AUD. Our data suggest that alcohol use is associated with differential methylation in the glucocorticoid system that might influence stress and inflammatory reactivity and subsequently risk for AUD.

Interpersonal life stress, inflammation, and depression in adolescence: Testing Social Signal Transduction Theory of Depression.

Depression rates increase markedly for girls across the adolescent transition, but the social-environmental and biological processes underlying this phenomenon remain unclear. To address this issue, we tested a key hypothesis from Social Signal Transduction Theory of Depression, which posits that individuals who mount stronger inflammatory responses to social stress should exhibit greater increases in depressive symptoms following interpersonal life stress exposure than those who mount weaker inflammatory responses to such stress. Participants were 116 adolescent girls (Mage = 14.71) at risk for psychopathology, defined as having a history of mental health concerns (e.g., psychiatric treatment, significant symptoms) over the past 2 years. At baseline, we characterized their inflammatory reactivity to social stress by quantifying their salivary proinflammatory cytokine responses to a laboratory-based social stressor. Then, 9 months later, we assessed the interpersonal and noninterpersonal stressful life events that they experienced over the prior 9 months using an interview-based measure of life stress. As hypothesized, greater interpersonal life stress exposure was associated with significant increases in depression over time, but only for girls exhibiting stronger salivary tumor necrosis factor-α and interleukin-1β reactivity to social stress. In contrast, noninterpersonal stress exposure was unrelated to changes in depression longitudinally, both alone and when combined with youths' cytokine reactivity scores. These results are consistent with Social Signal Transduction Theory of Depression and suggest that heightened inflammatory reactivity to social stress may increase adolescents' risk for depression. Consequently, it may be possible to reduce depression risk by modifying inflammatory responses to social stress.