This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN and AITC (5, 10 and 20 mg/kg) or CRV (25, 100, 300, and 600 mg/kg) were administered intraperitoneally (i.p.), and glycemia was measured. In the intestine, Glucagon-like peptide-1 (GLP-1) and disaccharidase activity were evaluated (in vivo and in vitro, respectively). Furthermore, in vivo and in vitro insulin secretion was determined. Islets were used to measure insulin secretion and calcium influx. CIN and AITC improved glucose tolerance and increased insulin secretion in vivo and in vitro. CRV was unable to reduce glycemia. Electrophilic agonists, CIN and AITC, inhibited disaccharidases and acted as secretagogues in the intestine by inducing GLP-1 release in vivo and in vitro and contributed to insulin secretion and glycemia. The effect of CIN on calcium influx in pancreatic islets (insulin secretion) involves voltage-dependent calcium channels and calcium from stores. TRPA1 triggers calcium influx and potentiates intracellular calcium release to induce insulin secretion, suggesting that electrophilic agonists mediate this signaling transduction for the control of glycemia.

Diabetes mellitus is a metabolic syndrome that has grown globally to become a significant public health challenge. Hypothesizing that the plasma membrane protein, transient receptor potential ankyrin-1, is a pivotal target in insulin resistance, we investigated the mechanism of action of cinnamaldehyde (CIN), an electrophilic TRPA1 agonist, in skeletal muscle, a primary insulin target. Specifically, we evaluated the effect of CIN on insulin resistance, hepatic glycogen accumulation and muscle and adipose tissue glucose uptake. Furthermore, the in vitro role of CIN in glucose uptake and intracellular signaling was determined in insulin-resistant rats whose calcium influx was analyzed. Moreover, the serum lipid profile was assessed following short-term CIN treatment in rats, and lipid tolerance was analyzed. The effects of CIN on insulin resistance were mediated by TRPA1, with downstream signaling involving the activation of PI3-K, MAPK, PKC, as well as extracellular calcium and calcium release from intracellular stores. Additionally, cytoskeleton integrity was required for the complete action of CIN on glucose uptake in muscle. CIN also ameliorated the serum lipid profile and improved triglyceride tolerance following acute vivo exposure.

Aim: To evaluate the effects of whey protein (WP) supplementation (1.24 mg/g, 24 days) in rats with autism spectrum disorder (ASD) induced by valproic acid (400 mg/kg, single dose). Materials & met... Plain language summary Thousands of bacteria live in the human intestine. These bacteria help with many functions in the body and are so important that they can communicate with the brain. When the... Tweetable abstract In an animal model of autism, supplementation with whey protein improved gut microbiota composition and memory. These results suggest the beneficial effects of whey protein on th... Graphical abstract

Type 2 diabetes mellitus remains a major global health challenge, and natural hypoglycemic compounds are of increasing interest. Aqueous extracts from five Brazilian medicinal plants (Lippia origanoides Kunth, Amburana cearensis (Allemão) A.C. Smith, Justicia pectoralis Jacq., Libidibia ferrea (Mart. ex Tul.) L.P. Queiroz, and Spondias mombin L.) were evaluated for α-glucosidase and intestinal disaccharidase inhibition; next, they were chemically profiled by UPLC-HRMS. Extracts of L. origanoides, A. cearensis, and J. pectoralis exhibited the strongest activities, attributed to flavonoids, iridoid and cinnamic acid derivatives, phenolic acids, and saponins. Molecular docking identified hyperoside, eudesmic acid and isoquercitrin as their main α-glucosidase inhibitors, respectively. In vitro testing confirmed that isoquercitrin effectively inhibited α-glucosidase (IC₅₀ = 0.09 mg mL⁻¹), showing stronger activity than acarbose. ADME simulations indicated low gastrointestinal absorption but favorable intestinal enzyme-targeted properties, consistent with their pharmacological profiles. Acute toxicity in zebrafish showed low toxicity for L. origanoides and A. cearensis and moderate levels for J. pectoralis, supporting their overall safety. These findings highlight these species as promising sources of bioactive compounds for developing safe, plant-based antidiabetic agents.

LASSBio-1920 was synthesized due to the poor solubility of its natural precursor, combretastatin A4 (CA4). The cytotoxic potential of the compound against human colorectal cancer cells (HCT-116) and non-small cell lung cancer cells (PC-9) was evaluated, yielding IC₅₀ values of 0.06 and 0.07 μM, respectively. Its mechanism of action was analyzed by microscopy and flow cytometry, where LASSBio-1920 was found to induce apoptosis. Molecular docking simulations and the enzymatic inhibition study with wild-type (wt) EGFR indicated enzyme-substrate interactions similar to other tyrosine kinase inhibitors. We suggest that LASSBio-1920 is metabolized by O-demethylation and NADPH generation. LASSBio-1920 demonstrated excellent absorption in the gastrointestinal tract and high central nervous system (CNS) permeability. The pharmacokinetic parameters obtained by predictions indicated that the compound presents zero-order kinetics and, in a human module simulation, accumulates in the liver, heart, gut, and spleen. The pharmacokinetic parameters obtained will serve as the basis to initiate in vivo studies regarding LASSBio-1920’s antitumor potential.

Background/Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents that regulate blood glucose by preventing the degradation of active incretin hormones. Although clinically effective, this drug class is associated with adverse effects, creating the need for new molecular scaffolds with improved safety and efficacy. Methods: We evaluated the antihyperglycemic activity of β-aminohydrazine and β-amino-N-acylhydrazone derivatives (LASSBio-2123, 2125, 2129, and 2130) using a combined in vivo and in silico approach. Male C57BL/6 mice underwent glucose tolerance tests (GTT) and dexamethasone-induced insulin resistance protocols. Hepatic and skeletal muscle glycogen levels, as well as GLUT4 mRNA expression, were quantified. In silico studies included ADMET predictions and molecular docking analyses against aldose reductase and glucokinase enzymes. MTT was performed on the pancreatic cell line MIN6 (Mus musculus). Results: Among the compounds tested, LASSBio-2129 demonstrated the most promising profile, with favorable ADMET parameters, metabolic stability, and high docking affinity for aldose reductase and glucokinase. In vivo, LASSBio-2129 (10 mg/kg, i.p.) reduced blood glucose, increased hepatic and muscle glycogen storage, and upregulated GLUT4 mRNA expression in skeletal muscle. Additionally, LASSBio-2129 improved insulin sensitivity in the dexamethasone-induced insulin resistance model, with effects comparable to sitagliptin. Conclusions: The combined pharmacological, docking, and ADMET analyses identified LASSBio-2129 as aldose reductase inhibitor candidate and glucokinase activator. Its ability to improve glucose tolerance, enhance glycogen storage, and increase GLUT4 expression highlights its potential as a promising molecule for the treatment of type 2 diabetes mellitus.