Clinical Utility of Rilonacept for the Treatment of Recurrent Pericarditis: Design, Development, and Place in Therapy.

Recurrent pericarditis (RP) has been traditionally regarded as a "nightmare" for both clinicians and patients. Until approximately a decade ago, available treatments were thin on the ground with non-steroidal anti-inflammatory medications, glucocorticoids, colchicine, and classical immunosuppressants being the only options. The first important step in the tale of RP was the advent of colchicine in clinical practice, which has been shown to halve the rate of first and subsequent pericarditis recurrences. The second major breakthrough advance in this setting was the introduction of interleukin-1 inhibitors based on the recently unveiled autoinflammatory nature of pericarditis. At present, anti-interleukin-1 inhibitors available for clinical use in patients with refractory RP include anakinra and rilonacept, with the latter having obtained FDA approval for this indication. Apart from the remarkable efficacy and good safety profile which is a common feature of all anti-interleukin-1 compounds, rilonacept has the advantage of weekly administration (instead of daily compared to anakinra) which is important in terms of adherence to treatment and improved quality of life albeit at the expense of a higher cost. This review aims to summarize the available evidence on the role of rilonacept in the treatment of RP and the reduction of the recurrences risk.

Majeed syndrome: first description in a patient of central-European ancestry.

OBJECTIVES: We present the first case of a Majeed syndrome in a girl of central-European ancestry. METHODS: : Patient's medical records were reviewed. A NGS panel for autoinflammatory diseases was performed and the mutation was confirmed by Sanger analysis. Freshly isolated monocytes were activated with LPS +/- ATP. The concentration of inflammatory cytokines was assessed in monocytes supernatants. RESULTS: A 2-year-old girl presented with pain in the lower limbs, increase of acute phase reactants and persistent microcytic anaemia. The MRI showed bilateral STIR hyper-intensity of the spongy osseous tissue of femur, tibia, radius, ulna, and astragalus. Bone marrow analysis revealed increased trilinear cellularity with signs of dyserythropoietic anaemia. NGS panel detected the presence of two novel compound heterozygous mutations in the LPIN2 gene, confirmed by Sanger analysis. Treatment with anakinra was started with a prompt resolution of the clinical picture. Increased kinetics and concentration of IL-1ß was observed in the patient's monocytes compared with healthy controls, with a marked drop following the start of therapy. About six months after the start of the therapy, resolution of MRI findings, microcytic anaemia and dyserythropoiesis at bone marrow aspirate was observed. CONCLUSION: We describe the first case of Majeed syndrome in a patient of central-European ancestry. The functional test on circulating monocytes before and after therapy with anakinra confirmed pathogenicity of the mutation and the role of LPIN2 in the NLRP3 inflammasome activation. Anti-IL1 agents were effective, leading not only to the resolution of bone lesion but also to an improvement of dyserythropoiesis.

Elastin-specific MR probe for visualization and evaluation of an interleukin-1ß targeted therapy for atherosclerosis.

Atherosclerosis is a chronic inflammatory condition of the arteries and represents the primary cause of various cardiovascular diseases. Despite ongoing progress, finding effective anti-inflammatory therapeutic strategies for atherosclerosis remains a challenge. Here, we assessed the potential of molecular magnetic resonance imaging (MRI) to visualize the effects of 01BSUR, an anti-interleukin-1ß monoclonal antibody, for treating atherosclerosis in a murine model. Male apolipoprotein E-deficient mice were divided into a therapy group (01BSUR, 2 × 0.3 mg/kg subcutaneously, n = 10) and control group (no treatment, n = 10) and received a high-fat diet for eight weeks. The plaque burden was assessed using an elastin-targeted gadolinium-based contrast probe (0.2 mmol/kg intravenously) on a 3 T MRI scanner. T1-weighted imaging showed a significantly lower contrast-to-noise (CNR) ratio in the 01BSUR group (pre: 3.93042664; post: 8.4007067) compared to the control group (pre: 3.70679168; post: 13.2982156) following administration of the elastin-specific MRI probe (p < 0.05). Histological examinations demonstrated a significant reduction in plaque size (p < 0.05) and a significant decrease in plaque elastin content (p < 0.05) in the treatment group compared to control animals. This study demonstrated that 01BSUR hinders the progression of atherosclerosis in a mouse model. Using an elastin-targeted MRI probe, we could quantify these therapeutic effects in MRI.

Evidence on Hidradenitis Suppurativa as an Autoinflammatory Skin Disease.

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory skin disease that often exhibits heterogeneity in its clinical presentation, especially in the context of its rare syndromic forms. The pathogenesis of HS results from a complex interplay of genetic predisposition, innate and adaptive immunity dysregulation, smoking, obesity and environmental factors. In the early phase of the disease, the innate immune system is hyperactivated, contributing to tissue damage and triggering the activation and amplification of the adaptive immune response, which plays a pivotal role in the chronic stages of the disease. Recent studies focused on elucidating the importance of innate immunity impairment and autoinflammation in HS and increasing evidence has emerged on the occurrence of the disease in the context of well-known monogenic and polygenic autoinflammatory syndromes (AIDs). This review provides a comprehensive examination of the current scientific background supporting the contribution of autoinflammation to HS etiology, including genetic data, molecular studies and clinical evidence, as well as the association between HS and AIDs. However, further research is needed to shed light on the pathogenic mechanism of this challenging condition and to identify potential perspectives for future therapeutic approaches.

Investigating the Prognostic Potential of Plasma ST2 in Patients with Peripheral Artery Disease: Identification and Evaluation.

Soluble interleukin 1 receptor-like 1 (ST2) is a circulating protein demonstrated to be associated with cardiovascular diseases; however, it has not been studied as a biomarker for peripheral artery disease (PAD). Using a prospectively recruited cohort of 476 patients (312 with PAD and 164 without PAD), we conducted a prognostic study of PAD using clinical/biomarker data. Plasma concentrations of three circulating proteins [ST2, cytokine-responsive gene-2 (CRG-2), vascular endothelial growth factor (VEGF)] were measured at baseline and the cohort was followed for 2 years. The outcome of interest was a 2-year major adverse limb event (MALE; composite of major amputation, vascular intervention, or acute limb ischemia). Using 10-fold cross-validation, a random forest model was trained using clinical characteristics and plasma ST2 levels. The primary model evaluation metric was the F1 score. Out of the three circulating proteins analyzed, ST2 was the only one that was statistically significantly higher in individuals with PAD compared to patients without PAD (mean concentration in plasma of 9.57 [SD 5.86] vs. 11.39 [SD 6.43] pg/mL, p < 0.001). Over a 2-year period, 28 (9%) patients with PAD experienced MALE. Our predictive model, incorporating clinical features and plasma ST2 levels, achieved an F1 score of 0.713 for forecasting 2-year MALE outcomes. Patients identified as high-risk by this model showed a significantly increased likelihood of developing MALE (HR 1.06, 95% CI 1.02-1.13, p = 0.003). By combining clinical characteristics and plasma ST2 levels, our proposed predictive model offers accurate risk assessment for 2-year MALE in PAD patients. This algorithm supports risk stratification in PAD, guiding clinical decisions regarding further vascular evaluation, specialist referrals, and appropriate medical or surgical interventions, thereby potentially enhancing patient outcomes.

Inflammasome activation aggravates choroidal neovascularization.

Inflammasome activation is implicated in diseases of aberrant angiogenesis such as age-related macular degeneration (AMD), though its precise role in choroidal neovascularization (CNV), a characteristic pathology of advanced AMD, is ill-defined. Reports on inhibition of inflammasome constituents on CNV are variable and the precise role of inflammasome in mediating pathological angiogenesis is unclear. Historically, subretinal injection of inflammasome agonists alone has been used to investigate retinal pigmented epithelium (RPE) degeneration, while the laser photocoagulation model has been used to study pathological angiogenesis in a model of CNV. Here, we report that the simultaneous introduction of any of several disease-relevant inflammasome agonists (Alu or B2 RNA, Alu cDNA, or oligomerized amyloid ß (1-40)) exacerbates laser-induced CNV. These activities were diminished or abrogated by genetic or pharmacological targeting of inflammasome signaling constituents including P2rx7, Nlrp3, caspase-1, caspase-11, and Myd88, as well as in myeloid-specific caspase-1 knockout mice. Alu RNA treatment induced inflammasome activation in macrophages within the CNV lesion, and increased accumulation of macrophages in an inflammasome-dependent manner. Finally, IL-1ß neutralization prevented inflammasome agonist-induced chemotaxis, macrophage trafficking, and angiogenesis. Collectively, these observations support a model wherein inflammasome stimulation promotes and exacerbates CNV and may be a therapeutic target for diseases of angiogenesis such as neovascular AMD.

Association of Serum Biomarkers With Neurocognitive Decline After PCI in Small Cell Lung Cancer: An Exploratory Study of the Phase III NCT01780675 Trial.

INTRODUCTION: Blood samples were collected to explore potential serum biomarkers associated with neurocognitive function in small-cell lung cancer (SCLC) patients who received prophylactic cranial irradiation (PCI). METHODS: This pre-specified study included patients with blood samples available, who participated in a phase III trial (NCT01780675). Blood samples were collected before PCI and 3-days post-initiating PCI. Neurocognitive decline was defined as a decrease of ≥ 5 points on total recall in the Hopkins Verbal Learning Test-Revised (HVLT-R) assessed from pre-PCI to 4-months post-PCI. Biomarkers were screened using univariate logistic regression analysis. P < .1 was considered statistically significant. RESULTS: Forty-eight enrolled patients who had blood samples at baseline were included and 27 were available for analysis as the other 21 did not assess neurocognitive function at 4-months. Lower levels of Tie-2 (OR = 0.999, 90% CI 0.998-1.000, P = .062), and higher levels of MIP-1b (OR = 1.022, 90% CI 1.000-1.044, P = .093), CCL-17 (OR = 1.004, 90% CI 1.001-1.006, P = .029), and IL-1α (OR = 1.597, 90% CI 1.077-2.367, P = .05) before PCI were correlated with neurocognitive decline at 4-months. Decrease of VEGF-C (OR = 0.972, 90% CI 0.949-0.996, P = .055), CCL-17 (OR = 0.993, 90% CI 0.988-0.999, P = .036), IL-1α (OR = 0.788, 90% CI 0.635-0.979, P = .071), and VEGF (OR = 0.981, 90% CI 0.965-0.997, P = .051) 3-days post-initiating PCI were also associated with neurocognitive decline at 4-months. CONCLUSIONS: Biomarker levels before PCI and changes in their levels 3-days post-initiating PCI may be linked to subsequent neurocognitive decline at 4-months. If validated, these biomarkers could be used to predict the risk of neurocognitive decline and act as a decision aid for personalized PCI in SCLC.

Microcrystal electron diffraction structure of Toll-like receptor 2 TIR-domain-nucleated MyD88 TIR-domain higher-order assembly.

Eukaryotic TIR (Toll/interleukin-1 receptor protein) domains signal via TIR-TIR interactions, either by self-association or by interaction with other TIR domains. In mammals, TIR domains are found in Toll-like receptors (TLRs) and cytoplasmic adaptor proteins involved in pro-inflammatory signaling. Previous work revealed that the MAL TIR domain (MALTIR) nucleates the assembly of MyD88TIR into crystalline arrays in vitro. A microcrystal electron diffraction (MicroED) structure of the MyD88TIR assembly has previously been solved, revealing a two-stranded higher-order assembly of TIR domains. In this work, it is demonstrated that the TIR domain of TLR2, which is reported to signal as a heterodimer with either TLR1 or TLR6, induces the formation of crystalline higher-order assemblies of MyD88TIR in vitro, whereas TLR1TIR and TLR6TIR do not. Using an improved data-collection protocol, the MicroED structure of TLR2TIR-induced MyD88TIR microcrystals was determined at a higher resolution (2.85 Å) and with higher completeness (89%) compared with the previous structure of the MALTIR-induced MyD88TIR assembly. Both assemblies exhibit conformational differences in several areas that are important for signaling (for example the BB loop and CD loop) compared with their monomeric structures. These data suggest that TLR2TIR and MALTIR interact with MyD88 in an analogous manner during signaling, nucleating MyD88TIR assemblies unidirectionally.

MicroRNAs as Epigenetic Regulators of Obesity.

In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective micro-ribonucleic acids (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block the expression of master regulators of adipogenesis. Since the specific miRNAs display different expressions during adipogenesis, in mature adipocytes and permanent obesity, their use as biomarkers or therapeutic targets is feasible. Upregulated miRNAs in persistent obesity are downregulated during adipogenesis. Moreover, some of the downregulated miRNAs in obese individuals are upregulated in mature adipocytes. Induction of adipocyte stress and hypertrophy leads to the release of adipocyte-derived exosomes (AdEXs) that contain the cargo molecules, miRNAs. miRNAs are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. While each miRNA targets multiple messenger RNAs (mRNAs), which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. Deletion of the miRNA-processing enzyme DICER in pro-opiomelanocortin-expressing cells results in obesity, which is characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism, and alterations in the pituitary-adrenal axis. In recent years, RNA-based therapeutical approaches have entered clinical trials as novel therapies against overweight and its complications. Development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity, and insulin resistance are effectively controlled by miRNAs. Thereby, miRNAs as epigenetic regulators are used to determine the new gene transcripts and therapeutic targets.

Rapid cleavage of IL-1ß in DRG neurons produces tissue injury-induced pain hypersensitivity.

Background: IL-1ß plays a critical role in the pathophysiology of neuroinflammation. The presence of cleaved IL-1ß (cIL-1ß) in the neurons of the dorsal root ganglion (DRG) implicates its function in biological signaling arising from the sensory neuron. This study was conducted to analyze the role of IL-1ß in nociceptive transduction after tissue injury. Methods: A plantar incision was made in C57BL/6 mice, following which immunohistochemistry and RNA scope in situ hybridization were performed at various time points to analyze cIL-1ß, caspase-1, and IL-1 receptor 1 (IL-1R1) expression in the DRG. The effect of intrathecal administration of a caspase-1 inhibitor or regional anesthesia using local anesthetics on cIL-1ß expression and pain hypersensitivity was analyzed by immunohistochemistry and behavioral analysis. ERK phosphorylation was also analyzed to investigate the effect of IL-1ß on the activity of spinal dorsal horn neurons. Results: cIL-1ß expression was significantly increased in caspase-1-positive DRG neurons 5 min after the plantar incision. Intrathecal caspase-1 inhibitor treatment inhibited IL-1ß cleavage and pain hypersensitivity after the plantar incision. IL-1R1 was also detected in the DRG neurons, although the majority of IL-1R1-expressing neurons lacked cIL-1ß expression. Regional anesthesia using local anesthetics prevented cIL-1ß processing. Plantar incision-induced phosphorylation of ERK was inhibited by the caspase-1 inhibitor. Conclusion: IL-1ß in the DRG neuron undergoes rapid cleavage in response to tissue injury in an activity-dependent manner. Cleaved IL-1ß causes injury-induced functional activation of sensory neurons and pain hypersensitivity. IL-1ß in the primary afferent neurons is involved in physiological nociceptive signal transduction.

Constitutive DAMPs in CNS injury: From preclinical insights to clinical perspectives.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways.

Conservative management of spinal pathology with autologous conditioned serum: A systematic review of the literature.

BACKGROUND: Chronic inflammatory pain is associated with increased expression of interleukin (IL)-1, an inflammatory cytokine, and activity on its receptor (IL-1R). In response, the body produces IL-1R antagonist (IL-1Ra) to reduce this signaling. Autologous conditioned serum (ACS) is the only biologic therapy for spinal pathologies that enhances the action of endogenous IL-1Ra reserves to improve symptoms. This systematic review investigates the effectiveness of ACS in treating pain and disability caused by spinal pathologies. AIM: To evaluate the use of ACS as a conservative management option for spinal pathology. METHODS: A systematic review of PubMed/Medline was performed to identify studies investigating administration of ACS for treatment of any spinal pathology. RESULTS: Six articles were included, comprising 684 patients treated with epidural (n = 133) or transforaminal (n = 551) ACS injections. Patients had an average age of 54.0 years with slight female predominance (53.2%). The lumbar spine was most commonly treated, with 567 patients (82.9%) receiving injections for lumbar radiculopathy (n = 67), degenerative disc disease (DDD) (n = 372), or spinal stenosis (n = 128); cervical injections were performed in 109 patients (15.9%). Mean (SD) follow-up was 21.7 (4.8) weeks from first ACS injection. All studies investigating mechanical lumbar and lumbar or cervical radicular pain reported significant pain reduction at final follow-up compared to baseline. ACS achieved comparable or superior results to lumbar epidural steroid injections. Adverse events were reported in 21 patients (3.1%), with no serious adverse events. CONCLUSION: ACS injection is a safe and effective intervention for pain reduction in many spinal pathologies, including cervical and lumbar radiculopathies.

Correlation of sputum inflammatory markers with severity and blood inflammatory markers in bronchiectasis.

Background: As a disease characterized by chronic neutrophilic inflammation, various sputum biomarkers have been investigated in the association with the severity and prognosis of bronchiectasis. However, there is lack of data on the association between sputum interleukin-1beta (IL-1ß), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) levels at clinical stable state and the clinical, spirometric and blood inflammatory parameters, as well as prognostic scores. The purpose of the study is to assess the association between sputum IL-1ß, IL-8 and TNF-α levels at clinical stable state and various clinical and laboratory parameters in bronchiectasis. Methods: A prospective study was conducted in a major regional hospital and tertiary respiratory referral centre in Hong Kong, including 44 Chinese patients with bronchiectasis. The correlation between stable state sputum IL-1ß, IL-8 and TNF-α levels with various clinical, laboratory and spirometric parameters in bronchiectasis, as well as FACED [forced expiratory volume in one second (FEV1), age, chronic colonisation by Pseudomonas aeruginosa, radiological extension and dyspnoea]/E-FACED (FACED plus exacerbations) scores were assessed. Results: Baseline sputum IL-1ß level was found to have significant moderate positive correlation with baseline blood high sensitivity C-reactive protein (hs-CRP) level with Pearson correlation coefficient (r) of 0.529 (P=0.001). Baseline sputum IL-8 level was found to have significant moderate positive correlation with baseline FACED and E-FACED score with r of 0.574 (P<0.001) and 0.539 (P<0.001) respectively. Baseline sputum TNF-α level was found to have significant moderate positive correlation with baseline FACED score with r of 0.520 (P<0.001). Conclusions: Sputum IL-1ß and, IL-8 and TNF-α levels were shown to have significant correlation with various clinical, laboratory and spirometry parameters in bronchiectasis, as well as more severe disease as measured by FACED and E-FACED scores.

Effects of interleukin-1 receptor antagonism in women with polycystic ovary syndrome-the FertIL trial.

Introduction: Chronic low-grade inflammation might contribute to hyperandrogenemia and metabolic complications in polycystic ovary syndrome (PCOS). The proinflammatory cytokine interleukin (IL)-1 stimulates androgen production from ovarian cells, whereas blockade of the IL-1 pathway improves cardiometabolic health. We aimed to investigate whether blocking the IL-1 pathway ameliorates hyperandrogenemia in patients with PCOS. Methods: This is a prospective, interventional, single-arm, proof-of-concept trial performed at a tertiary hospital in Switzerland (August 2018 to July 2020) in 18 premenopausal women with a diagnosis of PCOS according to the Rotterdam criteria, total testosterone levels ≥ 1.7 nmol/L, and C-reactive protein (CRP) ≥ 1.0 mg/L. Patients received 100 mg/day of the IL-1-receptor antagonist anakinra for 28 days and underwent weekly blood sampling until 1 week after the end of treatment. The primary endpoint was the change in serum androstenedione levels on day 7 of treatment, assessed with liquid chromatography-tandem mass spectrometry. Seven of these women participated in a subsequent observational sub-study (May 2021 to December 2021). Results: Median [interquartile range (IQR)] androstenedione increased by 0.5 [-0.1, 1.6] nmol/L (p = 0.048) with anakinra and by 1.3 [0.08, 2.4] nmol/L [p = 0.38] without anakinra between baseline and day 7. Anakinra reduced CRP levels on days 7, 21, and 28 (p < 0.001) but did not lead to an absolute reduction in androgens. However, four of six patients (67%) had smaller areas under the curves for androstenedione and/or testosterone during the 28-day intervention with anakinra as compared to 28 days without treatment. Discussion: Our findings suggest that anakinra suppresses IL-1-mediated chronic low-grade inflammation in PCOS and might attenuate biochemical hyperandrogenemia.

The role of inflammasomes as central inflammatory hubs in Mycobacterium tuberculosis infection.

Mycobacterium tuberculosis (Mtb) infection represents a global health problem and is characterized by formation of granuloma with a necrotic center and a systemic inflammatory response. Inflammasomes have a crucial role in the host immune response towards Mtb. These intracellular multi-protein complexes are assembled in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Inflammasome platforms activate caspases, leading to the maturation of the proinflammatory cytokines interleukin (IL)-1 and 18 and the cleavage of gasdermin D (GSDMD), a pore-forming protein responsible for cytokine release and pyroptotic cell death. Recent in vitro and in vivo findings have highlighted the importance of inflammasome signaling and subsequent necrotic cell death in Mtb-infected innate immune cells. However, we are just beginning to understand how inflammasomes contribute to disease or to a protective immune response in tuberculosis (TB). A detailed molecular understanding of inflammasome-associated pathomechanisms may foster the development of novel host-directed therapeutics or vaccines with improved activity. In this mini-review, we discuss the regulatory and molecular aspects of inflammasome activation and the associated immunological consequences for Mtb pathogenesis.

Structural characterization of TIR-domain signalosomes through a combination of structural biology approaches.

The TIR (Toll/interleukin-1 receptor) domain represents a vital structural element shared by proteins with roles in immunity signalling pathways across phyla (from humans and plants to bacteria). Decades of research have finally led to identifying the key features of the molecular basis of signalling by these domains, including the formation of open-ended (filamentous) assemblies (responsible for the signalling by cooperative assembly formation mechanism, SCAF) and enzymatic activities involving the cleavage of nucleotides. We present a historical perspective of the research that led to this understanding, highlighting the roles that different structural methods played in this process: X-ray crystallography (including serial crystallography), microED (micro-crystal electron diffraction), NMR (nuclear magnetic resonance) spectroscopy and cryo-EM (cryogenic electron microscopy) involving helical reconstruction and single-particle analysis. This perspective emphasizes the complementarity of different structural approaches.

Spirulina platensis shields the submandibular gland from cadmium toxicity by bolstering antioxidant defenses and maintaining its structural integrity.

Cadmium (Cd), an element categorized as a non-essential transitional metal, has potential hazards to the health of both human beings and animals. Spirulina platensis (SP), a type of blue-green algae, possesses a high concentration of essential antioxidants. The present study aimed to explore the possible defensive role of SP against Cd-induced submandibular gland injury in rats by assessment of biomarkers related to both oxidative stress and inflammatory processes, which were further explored through histopathological examination of submandibular gland tissue. Consequently, the study included 32 mature rats, subdivided into four different groups as follows: control, SP, Cadmium chloride (CdCl2), and CdCl2/SP. The duration of the study was 24days. The results revealed that CdCl2 induced submandibular gland injury as shown by the oxidant/antioxidant imbalance and increased inflammatory reactions, in addition to, histopathological changes and overexpression of BAX immunostaining. Concurrent SP administration to CdCl2-treated rats significantly improved all these effects. We concluded that concurrent SP supplement improved the submandibular gland injury provoked by CdCl2.

Citrus Flavanone Effects on the Nrf2-Keap1/GSK3/NF-κB/NLRP3 Regulation and Corticotroph-Stress Hormone Loop in the Old Pituitary.

Oxidative stress and inflammation are significant causes of aging. At the same time, citrus flavanones, naringenin (NAR), and hesperetin (HES) are bioactives with proven antioxidant and anti-inflammatory properties. Nevertheless, there are still no data about flavanone's influence and its potential effects on the healthy aging process and improving pituitary functioning. Thus, using qPCR, immunoblot, histological techniques, and biochemical assays, our study aimed to elucidate how citrus flavanones (15 mg/kg b.m. per os) affect antioxidant defense, inflammation, and stress hormone output in the old rat model. Our results showed that HES restores the redox environment in the pituitary by down-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein while increasing kelch-like ECH-associated protein 1 (Keap1), thioredoxin reductase (TrxR1), and superoxide dismutase 2 (SOD2) protein expression. Immunofluorescent analysis confirmed Nrf2 and Keap1 down- and up-regulation, respectively. Supplementation with NAR increased Keap1, Trxr1, glutathione peroxidase (Gpx), and glutathione reductase (Gr) mRNA expression. Decreased oxidative stress aligned with NLRP3 decrement after both flavanones and glycogen synthase kinase-3 (GSK3) only after HES. The signal intensity of adrenocorticotropic hormone (ACTH) cells did not change, while corticosterone levels in serum decreased after both flavanones. HES showed higher potential than NAR in affecting a redox environment without increasing the inflammatory response, while a decrease in corticosterone level has a solid link to longevity. Our findings suggest that HES could improve and facilitate redox and inflammatory dysregulation in the rat's old pituitary.

Novel Treatments in Refractory Recurrent Pericarditis.

Refractory recurrent pericarditis is a troublesome condition that severely impairs the quality of life of affected patients and significantly increases healthcare spending. Until recently, therapeutic options included only a few medications and most of the patients resorted to chronic glucocorticoid treatment with steroid dependence. In the most recent decade, the introduction of interleukin-1 blockers in clinical practice has revolutionized the treatment of glucocorticoid-dependent and colchicine-resistant recurrent pericarditis due to their excellent efficacy and good safety profile. The rationale for the introduction of this class of medications in clinical practice is the autoinflammatory nature of recurrent pericarditis in a substantial rate of cases, with interleukin-1 being the main pro-inflammatory cytokine involved in this context. This review aims to discuss the contemporary available evidence from original research and real-world data on interleukin-1 blocker use in refractory recurrent pericarditis, in terms of indications, mechanism of action, efficacy, side effects, and recommended treatment protocols. Moreover, novel treatment proposals, such as hydroxychloroquine, beta blockers, and cannabidiol, which showed encouraging preliminary results, are addressed. Finally, gaps in knowledge, unmet needs, and future perspectives related to recurrent pericarditis are thoroughly discussed.

Anti-Interferon-γ Therapy for Cytokine Storm Syndromes.

A vast body of evidence provides support to a central role of exaggerated production of interferon-γ (IFN-γ) in causing hypercytokinemia and signs and symptoms of hemophagocytic lymphohistiocytosis (HLH). In this chapter, we will describe briefly the roles of IFN-γ in innate and adaptive immunity and in host defense, summarize results from animal models of primary HLH and secondary HLH with particular emphasis on targeted therapeutic approaches, review data on biomarkers associated with activation of the IFN-γ pathway, and discuss initial efficacy and safety results of IFN-γ neutralization in humans.