The worldwide prevalence of diabetes has reached 8.5% among adults, and this is characterised by elevated glucose concentrations and failing insulin secretion. Furthermore, most people with type 2 diabetes are either obese or overweight, with the associated dyslipidaemia contributing to the development of insulin resistance and increased cardiovascular risk. Here we incubated INS-1 pancreatic β-cells for 72 h in RPMI-1640 media, or media supplemented with 28 mM glucose, 200 µM palmitic acid, and 200 µM oleic acid as a cellular model of diabetic glucolipotoxicity. Illumina HiSeq gene expression analysis showed the trace amine-associated receptor (TAAR) family to be among the most highly downregulated by glucolipotoxicity. Importantly, MetaCore integrated knowledge database, from Clarivate Analytics, indicated potential TAAR impact on insulin secretion through adenylyl cyclase signalling pathways. We therefore investigated the effect of TAAR ligands on cAMP signalling and insulin secretion, and found that only the branch of the TAAR family tree that is activated by isopentylamine, 2-phenylethylamine, p-tyramine, and agmatine significantly increased intracellular cAMP and resulted in increased insulin secretion from INS-1 cells and primary mouse islets under normal conditions. Crucially however, this enhancement was not evident when the receptor family was downregulated by glucolipotoxic conditions. This data indicates that a subset of TAARs are regulators of insulin secretion in pancreatic β-cells, and that their downregulation contributes to glucolipotoxic inhibition of insulin secretion. As such they may be potential targets for treatment of type 2 diabetes.

No abstract

Crescentia cujete Linn. is a fast-growing evergreen tree in the Philippines. Folklore says C. cujete Linn. has been used as an alternative medicine to treat ailments such as hematoma and tumors. In this study, air-dried leaves of C. cujete Linn. was prepared and partitioned using hexane, and ethyl acetate as solvents and was qualitatively assessed for the presence of phytochemical constituents. Secondary metabolites like flavonoids, tannins, reducing sugar, and steroids were observed in the preliminary phytochemical screening of hexane, ethyl acetate and aqueous extracts. Cytotoxicity of the different extracts were determined using brine shrimp lethality test (BSLT). Median lethal concentration (LC50) of the hexane, aqueous, and crude ethanolic extracts were determined after 6 hours of exposure showing 572, 3048 and 220 ppm, respectively. Moreover, LC50 of the hexane, aqueous, and crude ethanolic extract, after 24 hours of exposure, were also determined showing 0, 0.184, and 6.47 ppm, respectively. The hexane, aqueous, and crude ethanolic extracts of C. cujete Linn. were also tested for its mutagenicity, antimutagenicity, and protective potentials using peripheral blood micronucleus test. The number of micronucleated polychromatic erythrocyte (MNPCE) observed from the mutagenicity test of hexane, aqueous, and crude ethanolic extract administered at a dose of 50mg/kg and 100mg/kg showed an average mean of 16.7,14.6 and 14.7, respectively, are lower compared to that of the positive control, methyl methanesulfonate (MMS), showing 49.5 number of MNPCE. Also, results for the antimutagenicity and protective potentials of hexane, aqueous, and crude ethanolic extract administered at a dose of 50mg/kg and 100mg reduced the number of MNPCEs produced by the MMS.

No abstract

1. Diabetic chronic wounds, mainly foot ulcers, constitute one of the most common complications of poorly managed diabetes mellitus. The most typical reasons are insufficient glycemic management, latent neuropathy, peripheral vascular disease, and neglected foot care. In addition, it is a common cause of foot osteomyelitis and amputation of the lower extremities. Patients are admitted in larger numbers attributable to chronic wounds compared to any other diabetic disease. In the United States, diabetes is currently the most common cause of non-traumatic amputations. Approximately five percent of diabetics develop foot ulcers, and one percent require amputation. Therefore, it is necessary to identify sources of lead with wound-healing properties. Redox imbalance due to excessive oxidative stress is one of the causes for the development of diabetic wounds. Antioxidants have been shown to decrease the progression of diabetic neuropathy by scavenging ROS, regenerating endogenous and exogenous antioxidants, and reversing redox imbalance. Matrix metalloproteinases (MMPs) play vital roles in numerous phases of the wound healing process. Antioxidant and fibroblast cell migration activity of Marantodes pumilum (MP) crude extract has previously been reported. Through their antioxidant, epithelialization, collagen synthesis, and fibroblast migration activities, the authors hypothesise that naringin, eicosane and octacosane identified in the MP extract may have wound-healing properties. 2. The present study aims to identify the bioactive components present in the dichloromethane (DCM) extract of M. pumilum and evaluate their antioxidant and wound healing activity. Bioactive components were identified using LCMS, HPTLC and GCMS. Excision wound on STZ-induced diabetic rat model, human dermal fibroblast (HDF) cell line and colorimetric antioxidant assays were used to evaluate wound healing and antioxidant activities, respectively. Molecular docking and pkCMS software would be utilised to predict binding energy and affinity, as well as ADME parameters. 3. Naringin (NAR), eicosane (EIC), and octacosane (OCT) present in MP displayed antioxidant action and wound excision closure. Histological examination HDF cell line demonstrates epithelialization, collagen production, fibroblast migration, polymorphonuclear leukocyte migration (PNML), and fibroblast movement. The results of molecular docking indicate a substantial attraction and contact between MMPs. pkCMS prediction indicates inadequate blood-brain barrier permeability, low toxicity, and absence of hepatotoxicity. 4. Wound healing properties of (NEO) naringin, eicosane and octacosane may be the result of their antioxidant properties and possible interactions with MMP.

No abstract

(1) Insulin resistance, a symptom of type 2 diabetes mellitus (T2DM), is caused by the inactivation of the insulin signaling pathway, which includes IRS-PI3K-IRS-1-PKC-AKT2 and GLUT4. Metformin (biguanide) and glimepiride (sulfonylurea) are both drugs that are derivatives of urea, and they are widely used as first-line drugs for the treatment of type 2 diabetes mellitus. Palmatine has been previously reported to possess antidiabetic and antioxidant properties. (2) The current study compared palmatine to metformin and glimepiride in a type 2 diabetes model for ADME and insulin resistance via the PI3K/Akt/GLUT4 signaling pathway: in vitro, in vivo, ex vivo, and in silico molecular docking. (3) Methods: Differentiated L6 skeletal muscle cells and soleus muscle tissue were incubated in standard tissue culture media supplemented with high insulin and high glucose as a cellular model of insulin resistance, whilst streptozotocin (STZ)-induced Sprague Dawley rats were used as the diabetic model. The cells/tissue/animals were treated with palmatine, while glimepiride and metformin were used as standard drugs. The differential gene expression of PI3K, IRS-1, PKC-α, AKT2, and GLUT4 was evaluated using qPCR. (4) Results: The results revealed that the genes IRS-PI3K-IRS-1-PKC-AKT2 were significantly down-regulated, whilst PKC-α was upregulated significantly in both insulin-resistant cells and tissue animals. Interestingly, palmatine-treated cells/tissue/animals were able to reverse these effects. (5) Conclusion: Palmatine appears to have rejuvenated the impaired insulin signaling pathway through upregulation of the gene expression of IRS-1, PI3K, AKT2, and GLUT4 and downregulation of PKC-expression, according to in vitro, in vivo, and ex vivo studies.

In this study, Crescentia cujete Linn. fruit was extracted using 95% ethanol and was concentrated in vacuo. The crude ethanolic extract (CEE) was then subjected to solvent partitioning using hexane and water. Fresh (FE) and decocted (DE) extracts were also prepared by m/v ratio of sample:water. Among the plants samples in vitro hypoglycemic assay, 10000ppm hexane extract possessed the highest ability to inhibit (55.21%) the activity of alphaamylase. Also, 10000ppm AE and CEE exhibited 32.87% and 32.64% inhibition, respectively. FE, DE, HE, AE and CEE were administered to the 24-hour starved Mus musculus via oral gavage for eight consecutive days. The initial blood glucose level (BGL) of the test organisms was recorder and determined using one-touch glucometer. Twenty four hours after the eightday treatment, the blood glucose level was determined. In vivo hypoglycemic assay revealed positive BGL lowering in the FE, 10000ppm of HE, AE and CEE upon comparison to the inducer, Alloxan. Protective potential assay also revealed significant lowering of BGL in the previously mentioned extracts with the addition of 1:1 m/v decocted and 5000ppm CEE. Moreover, Alloxan group was monitored for five days after its administration on the third day thus proving Alloxan's degradation. Colorimetric determination of glucose concentration in the plant sample was performed and it shows the increase in sample extract concentration is proportional to the amount of glucose in it. The pure decoction 4:0 m/v ratio revealed the highest glucose concentration (453.30ppm), while the 100ppm of CEE has the lowest glucose content (55.66ppm). The extracts of Crescentia cujete Linn. reveals hypoglycemic potential and its utilization before the occurrence of the metabolic disorder diabetes mellitus can help in regulating BGL in the blood.