Bruton's tyrosine kinase (BTK) inhibitors alter blood glucose and insulin in obese mice but reduce inflammation independent of BTK.

Obesity is associated with metabolic inflammation, which can contribute to insulin resistance, higher blood glucose and higher insulin indicative of prediabetes progression. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a metabolic danger sensor implicated in metabolic inflammation. Many features of metabolic disease can activate of the NLRP3 inflammasome; however, it is not yet clear which upstream trigger to target, and there are no clinically approved NLRP3 inflammasome inhibitors for metabolic disease. Bruton's tyrosine kinase (BTK) mediates activation of the NLRP3 inflammasome. Ibrutinib is the most-studied pharmacological inhibitor of BTK and it can improve blood glucose control in obese mice. However, inhibitors of tyrosine kinases are permissive, and it is unknown if BTK inhibitors require BTK to alter endocrine control of metabolism or metabolic inflammation. We tested whether ibrutinib and acalabrutinib, a new generation BTK inhibitor with higher selectivity, require BTK to inhibit the NLRP3 inflammasome, metabolic inflammation and blood glucose in obese mice. Chronic ibrutinib administration lowered fasting blood glucose and improved glycemia, while acalabrutinib increased blood insulin levels and increased markers of insulin resistance in high-fat fed CBA/J mice with intact Btk. These metabolic effects of BTK inhibitors were absent in CBA/CaHN-Btkxid/J mice with mutant Btk. However, ibrutinib and acalabrutinib reduced NF-κB activity pro-inflammatory gene expression and NLRP3 inflammasome activation in macrophages with and without functional BTK. These data highlight the BTK inhibitors can have divergent effect on metabolism and separate effects on metabolic inflammation that can occur independently of actions on BTK.

Microbiota and Nod-like receptors balance inflammation and metabolism during obesity and diabetes.

Gut microbiota influence host immunity and metabolism during obesity. Bacterial sensors of the innate immune system relay signals from specific bacterial components (i.e., postbiotics) that can have opposing outcomes on host metabolic inflammation. NOD-like receptors (NLRs) such as Nod1 and Nod2 both recruit receptor-interacting protein kinase 2 (RIPK2) but have opposite effects on blood glucose control. Nod1 connects bacterial cell wall-derived signals to metabolic inflammation and insulin resistance, whereas Nod2 can promote immune tolerance, insulin sensitivity, and better blood glucose control during obesity. NLR family pyrin domain containing (NLRP) inflammasomes can also generate divergent metabolic outcomes. NLRP1 protects against obesity and metabolic inflammation potentially because of a bias toward IL-18 regulation, whereas NLRP3 appears to have a bias toward IL-1ß-mediated metabolic inflammation and insulin resistance. Targeting specific postbiotics that improve immunometabolism is a key goal. The Nod2 ligand, muramyl dipeptide (MDP) is a short-acting insulin sensitizer during obesity or during inflammatory lipopolysaccharide (LPS) stress. LPS with underacylated lipid-A antagonizes TLR4 and counteracts the metabolic effects of inflammatory LPS. Providing underacylated LPS derived from Rhodobacter sphaeroides improved insulin sensitivity in obese mice. Therefore, certain types of LPS can generate metabolically beneficial metabolic endotoxemia. Engaging protective adaptive immunoglobulin immune responses can also improve blood glucose during obesity. A bacterial vaccine approach using an extract of the entire bacterial community in the upper gut promotes protective adaptive immune response and long-lasting improvements in blood glucose control. A key future goal is to identify and combine postbiotics that cooperate to improve blood glucose control.

Antibacterial and hemolytic activity of a new lectin purified from the seeds of Sterculia foetida L.

The aim of this study was to isolate, characterize, and verify possible antibacterial and hemolytic activity for a lectin found in the seeds of Sterculia foetida L. Purification of the lectin from S. foetida (SFL) was realized with ion exchange chromatography DEAE-Sephacel coupled to HPLC. The purity and the molecular weight was determined by SDS-PAGE. The isolated SFL was characterized as to its glycoprotein nature, and sugar specificity, as well as resistance to pH, temperature, denaturing agents, reduction, oxidation, and chelation. A microdilution method was used to determine antibacterial activity, and hemolytic activity was observed in human erythrocytes. The SFL has a molecular weight of 17 kDa, and a carbohydrate content of 53 µg/mL, specific for arabinose and xylose, and is resistant to treatment with urea, sensitive to treatment with sodium metaperiodate and ß-mercaptoethanol, and in the presence of EDTA lost its hemagglutinating activity (HA). However, in the presence of divalent cations (Ca(2 +) and Mn(2 +)) the HA was increased. The SFL remained active even after incubation at 80 °C, and, within pH values of between 5 and 11. The SFL inhibited the bacterial growth of all the tested strains and caused little hemolysis in human erythrocytes when compared to the positive control Triton X-100.