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Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects. SGLT2 inhibitors, a class of type 2 diabetes medication, reduce cardiovascular events in patients beyond expectation from blood sugar control. Here the authors report a randomized controlled trial showing that SGLT2 inhibitors reduce inflammasome activation in peripheral macrophages, which may contribute to the cardiovascular protection.

Type 2 diabetes mellitus (T2DM) is associated with metabolic dysregulation and chronic inflammation, and regular exercise may provide a strong stimulus for improving both. In this review, we first discuss the link between inflammation and metabolism. Next, we give an update on the clinical metabolic effects of exercise in T2DM patients with special focus on which parameters to consider for optimizing metabolic improvements. We then discuss the mechanisms whereby exercise exerts its anti‐inflammatory and related metabolic effects. Evidence exists that interleukin (IL)‐1β is involved in pancreatic β‐cell damage, whereas tumor necrosis factor (TNF)‐α appears to be a key molecule in peripheral insulin resistance. Mechanistic studies in humans suggest that moderate acute elevations in IL‐6, as provoked by exercise, exert direct anti‐inflammatory effects by an inhibition of TNF‐α and by stimulating IL‐1ra (IL‐1 receptor antagonist), thereby limiting IL‐1β signaling. In addition, IL‐6 has direct impact on glucose and lipid metabolism. Moreover, indirect anti‐inflammatory effects of exercise may be mediated via improvements in, for example, body composition. While waiting for the outcome of long‐term randomized clinical training studies with hard end points, it should be emphasized that physical activity represents a natural strong anti‐inflammatory and metabolism‐improving strategy with minor side effects. The February 2016 issue contains a Special Feature on the Effects of exercise on the immune system and metabolism coming into the Olympic year. The role of the immune system in exercise is complex and challenging. Too little exercise can depress the immune system. In contrast, too much exercise can also lead to a compromised immune system. This is a challenge that athletes face as they prepare for competition. Immunology & Cell Biology thanks the coordinators of this Special Feature ‐ Mark Febbraio and Graeme Lancaster ‐ for their planning and input.

This first‐in‐human study evaluated the safety, tolerability, single‐ and multiple‐dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three‐part trial including single and 2‐week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (3:1) to DFV890 or placebo (SAD [3–600 mg] and MAD [fasted: 10–200 mg, once‐daily or fed: 25 and 50 mg, twice‐daily]). DFV890 was generally well‐tolerated. Neither deaths nor serious adverse events were reported. A less than dose‐proportional increase in exposure was observed with the initially used crystalline suspension (3–300 mg); however, an adjusted suspension formulation using spray‐dried dispersion (SDD; 100–600 mg) confirmed dose‐proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, Cmax of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05‐ and 1.49‐fold increase in Cmax and AUC0–last compared with the fasting condition. The median IC50 and IC90 for ex‐vivo lipopolysaccharide‐stimulated interleukin IL‐1β release inhibition (PD) were 61 (90% CI: 50, 70) and 1340 ng/mL (90% CI: 1190, 1490). Crystalline tablets of 100 mg once‐daily or 25 mg twice‐daily were sufficient to maintain ~90% of the IL‐1β release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology.

ObjectiveTo evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19.MethodsWe present a post hoc analysis from a double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products—active caspase-1 (Casp1p20), IL-1β, and IL-18—were assessed at enrollment and after 48–72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days.ResultsThirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2–3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1β.ConclusionTreatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the ‘cytokine storm’ in COVID-19.Trial registration numbersRBR-8jyhxh

Research question In a randomized, triple-blind, placebo-controlled clinical trial (RCT), we investigated the effect of astaxanthin (AST) on pro-inflammatory cytokines, oxidative stress (OS) markers, and assisted reproductive technology (ART) outcomes in 44 infertile Polycystic Ovary Syndrome (PCOS) patients. Design Patients with PCOS were randomly divided into two groups. The intervention group received 6 mg AST, and the control group received placebo daily for 8 weeks. Blood samples were obtained from all patients before and after intervention and follicular fluid (FF) was collected during the ART procedure. Interleukin (IL) ‐6, IL‐1β were evaluated from serum samples and FF and OS markers (malondialdehyde [MDA], catalase [CAT], superoxide dismutase [SOD], and reactive oxygen species [ROS]) were measured from FF. The groups were compared for ART outcomes as well. Results A significant decrease in IL-6 and IL-1β concentrations (both, P = < 0.01) serum levels was found following AST treatment. FF cytokine levels and OS markers did not differ significantly between the groups. Reproductive outcomes, including the number of oocytes retrieved (P = 0.01), the MII oocyte count (P = 0.007), oocyte maturity rate (MII %) (P = 0.02) and number of frozen embryos (P = 0.03) significantly improved after intervention. No significant differences were found in chemical, clinical and multiple pregnancies between the groups. Conclusions AST pretreatment may modify inflammation and improve ART outcomes in PCOS infertile patients. Further investigations are recommended to verify these findings.

Background The protective effect of Coenzyme Q10 (CoQ10) on the cardiovascular system has been reported, however, whether it can promote early recovery of cardiac function and alleviate cardiac remodeling after myocardial infarction (MI) remains to be elucidated. Whether CoQ10 may regulate the macrophage-mediated pro-inflammatory response after MI and its potential mechanism are worth further exploration. Methods To determine the baseline plasma levels of CoQ10 by LC-MS/MS, healthy controls and MI patients ( n  = 11 each) with age- and gender-matched were randomly enrolled. Additional MI patients were consecutively enrolled and randomized into the blank control ( n  = 59) or CoQ10 group ( n  = 61). Follow-ups were performed at 1- and 3-month to assess cardiac function after percutaneous coronary intervention (PCI). In the animal study, mice were orally administered CoQ10/vehicle daily and were subjected to left anterior descending coronary artery (LAD) ligation or sham operation. Echocardiography and serum BNP measured by ELISA were analyzed to evaluate cardiac function. Masson staining and WGA staining were performed to analyze the myocardial fibrosis and cardiomyocyte hypertrophy, respectively. Immunofluorescence staining was performed to assess the infiltration of IL1β/ROS-positive macrophages into the ischemic myocardium. Flow cytometry was employed to analyze the recruitment of myeloid immune cells to the ischemic myocardium post-MI. The expression of inflammatory indicators was assessed through RNA-seq, qPCR, and western blotting (WB). Results Compared to controls, MI patients showed a plasma deficiency of CoQ10 (0.76 ± 0.31 vs. 0.46 ± 0.10 µg/ml). CoQ10 supplementation significantly promoted the recovery of cardiac function in MI patients at 1 and 3 months after PCI. In mice study, compared to vehicle-treated MI mice, CoQ10-treated MI mice showed a favorable trend in survival rate (42.85% vs. 61.90%), as well as significantly alleviated cardiac dysfunction, myocardial fibrosis, and cardiac hypertrophy. Notably, CoQ10 administration significantly suppressed the recruitment of pro-inflammatory CCR2 + macrophages into infarct myocardium and their mediated inflammatory response, partially by attenuating the activation of the NLR family pyrin domain containing 3 (NLRP3)/Interleukin-1 beta (IL1β) signaling pathway. Conclusions These findings suggest that CoQ10 can significantly promote early recovery of cardiac function after MI. CoQ10 may function by inhibiting the recruitment of CCR2 + macrophages and suppressing the activation of the NLRP3/IL1β pathway in macrophages. Trial registration Date of registration 09/04/2021 (number: ChiCTR2100045256).

An underlying pro-inflammatory status is related to recurrence and persistence of inflammatory susceptibility in obesity and periodontitis, two of the most prevalent chronic inflammatory diseases. Elevated levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), part of the inflammatory network linking these two conditions, persist even after periodontal treatment, with high salivary cytokine levels being linked to overweight and obesity risk. This trial assessed the effect of a novel composition comprising olive oil, trimethylglycine and xylitol, delivered topically to the oral mucosa, on salivary cytokines in periodontally healthy normal and overweight/pre-obese individuals. In a randomized placebo-controlled double-blind clinical trial, adult patients were randomly assigned to use a test toothpaste (intervention group, IG) or a placebo toothpaste (control group, CG) three times a day for 1 month. Primary outcomes were levels of salivary cytokines IL-1β, TNF-α and interleukin-4 (IL-4). Significant differences between IG and CG were observed for IL-1β (p = 0.003; Z = 2.901; r = 0.62) and TNF-α (p = 0.001; Z = 3.23; r = 0.69), but not for IL-4 (p = 0.203; Z = 1.321; r = 0.28). A significant reduction in IL-1β (p = 0.008) and a near significant reduction in TNF-α (p = 0.059) was found in the IG at the end of the trial. Additionally, the effect of body mass index on cytokine levels response was analyzed. A significantly different behavior was shown between IG and CG in the overweight/pre-obesity subgroup for IL-1β (p = 0.014; Z = 2.430; r = 0.63) and TNF-α (p = 0.029; Z = 2.199; r = 0.57). Moreover, a significant decrease in IL-1β in the IG (p = 0.028) was observed. The rapid reduction in IL-1β and TNF-α after 1 month of use of the intervention composition suggests a safe and effective novel strategy for reducing pro-inflammatory cytokines that may offer an opportunity to diminish the inflammatory status in patients with overweight/pre-obesity.

Background Accelerating orthodontic treatment is crucial in reducing complications such as root resorption, caries, and oral hygiene compromise, especially in adults. Piezocision and corticotomy are surgical techniques that accelerate tooth movement by causing bone remodelling. This study compares and evaluates changes in Interleukin-1β (IL-1β) levels in gingival crevicular fluid (GCF) following piezocision and corticotomy-facilitated orthodontics in adults. Aim To assess and compare IL-1β fluctuations in GCF of adult patients undergoing corticotomy and piezocision-assisted orthodontic treatment. Materials & methods This split-mouth study consisted of 16 adult patients (18–25 years) who needed premolar extractions. One half of the maxilla was randomly assigned for piezocision and the other half for corticotomy. GCF samples were taken from maxillary canines at varying time intervals: pre-treatment (T0), before surgery (T1), and 24 h (T2), 7 days (T3), and 21 days (T4) following surgery. IL-1β concentrations were quantified using an ELISA kit, and statistical analysis was done. Results IL-1β concentrations were highest at 24 h after surgery (T2) in both groups and decreased steadily by day 21 (T4), but were still elevated above pre-treatment levels. IL-1β concentrations were significantly greater in the piezocision group at all time points after surgery than in the corticotomy group ( p  < 0.001), reflecting a more intense inflammatory reaction and greater bone cell metabolism. Conclusion This study suggests that piezocision elicits a more intense biological response than corticotomy, as reflected by higher IL-1β levels in gingival crevicular fluid. While this may indicate a potential for enhanced bone remodelling and accelerated tooth movement, further research is needed to directly correlate cytokine expression with the rate of orthodontic tooth movement.

Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1 β . This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases.

Objectives Postoperative cognitive dysfunction (POCD) is a common clinical complication, with an underlying pathophysiology linked to heightened levels of neuroinflammation. However, it requires clarification as to whether the depth of anesthesia modulates postoperative cognitive dysfunction. This study investigated the association between depth of anesthesia and POCD in elderly patients undergoing abdominal surgery. Methods A total of 120 patients aged 60 years or older who were planned for abdominal surgery under total intravenous anesthesia were included in this study. The depth of anesthesia was guided by monitoring Bispectral Index (BIS) data. All study participants completed a battery of nine neuropsychological tests before surgery and at 7 days and 3 months after surgery. POCD was calculated by using the reliable change index. Plasma concentration of C‐reactive protein (CRP), interleukin (IL)‐1β, IL‐10, S‐100β, and norepinephrine (NE) were measured. Results The incidence of POCD at 7 days after surgery in the deep anesthesia group was 19.2% (10/52), which was significantly lower (p = 0.032) than the light anesthesia group 39.6% (21/53). The depth of anesthesia had no effect on POCD at 3 months after surgery (10.3% vs 14.6%, respectively, p = 0.558). Similarly, plasma levels of CRP and IL‐1β in deep anesthesia group were lower than that in light anesthesia group at 7 days after surgery (p < 0.05), but not at 3 months after surgery (p > 0.05). There were no significant differences in the plasma concentration of IL‐10, S‐100β, and NE between the groups (p > 0.05). Conclusions Deep anesthesia under total intravenous anesthesia could decrease the occurrence of short‐term POCD and inhibit postoperative peripheral inflammation in elderly patients undergoing abdominal surgery, compared with light anesthesia. Deep anesthesia under total intravenous anesthesia could decrease the occurrence of short‐term POCD and inhibit postoperative peripheral inflammation in elderly patients undergoing abdominal surgery, compared with light anesthesia.