Inhibition of key enzymes linked to type 2 diabetes by compounds isolated from Aframomum melegueta fruit

Context: The use of Aframomum melegueta K. Schum. (Zingiberaceae) fruit for treatment of diabetes has recently been established in Nigeria. However, compounds responsible for the antidiabetic action have not been identified.

Objective: The present study carried out the bioassay-guided isolation of possible bioactive compounds responsible for the antidiabetic action of A. melegueta fruit.

Materials and methods: The A. melegueta fruit was sequentially extracted using ethyl acetate (EtOAc), ethanol and water, and the most active extract (EtOAc) was subjected to column chromatography on a silica gel column using solvent gradient systems of hexane (HEX):EtOAc and EtOAc:MeOH and the isolation of compounds was guided by α-glycosidase and α-amylase inhibitory activities at various concentrations (30–240?μg/mL).

Results: According to the results, 3 arylalkanes, 6-paradol (1), 6-shogaol (2) and 6-gingerol (3) and a pentacyclic triterpene, oleanolic acid (4) were isolated from A. melegueta fruit. All the compounds exhibited inhibitory effects against α-amylase and α-glucosidase. 6-Gingerol (3) and oleanolic acid (4) showed higher inhibitory activity against α-amylase (IC₅₀: 6-gingerol: 81.78?±?7.79?μM; oleanolic acid: 91.72?±?1.63?μM) and α-glucosidase (IC₅₀: 6-gingerol: 21.55?±?0.45?μM; oleanolic acid: 17.35?±?0.88?μM) compared to the standard drug, acarbose and other isolated compounds. The kinetics of the enzyme action of the compounds showed a noncompetitive mode of inhibition.

Conclusion: The data of this study suggest that the 6-gingerol (3) and oleanolic acid (4) showed higher α-amylase and α-glucosidase inhibitory action and therefore could be responsible for the antidiabetic activity of A. melegueta fruit.     

Bioactive compounds from endemic plants of Southwest Portugal: Inhibition of acetylcholinesterase and radical scavenging activities

Context: Natural products are reported to have substantial neuroprotective activity due to their radical scavenging capacity, and also acetylcholinesterase (AChE) inhibitory capacity, both activities important in neurodegeneration.

Objective: The undesirable side effects of compounds in pharmacological use make it important to identify natural neuroprotective molecules. This work assesses the potential of five endemic Portuguese plants as sources of neuroprotective compounds.

Materials and methods: Antioxidant capacity for peroxyl radical was determined by Oxygen Radical Absorbance Capacity method and for hydroxyl by Electron Paramagnetic Resonance, as well as AChE inhibitory capacity of the plant hydroethanolic extracts. The molecules responsible for these valuable properties were also tentatively identified by HPLC.

Results and discussion: Armeria rouyana and Thymus capitellatus presented some of the highest phenolic contents (76.60?±?7.19 and 12.82?±?0.24?mg GAE g^?1 dw, respectively) and antioxidant capacities (592?±?116 and 449?±?57 μmol TE g^?1 dw, respectively). The flavonoids were identified as the phytomolecules related to the antioxidant capacity of these plant extracts; in the case of A. rouyana, l-ascorbic acid also made an important contribution (3.27?±?0.26?mg g^?1 dw). Plant extracts clearly demonstrated effective AChE inhibitory activity (480?±?98 and 490?±?46 μg mL^?1, respectively), that could be associated to polyphenols.

Conclusions: The extracts of A. rouyana and T. capitellatus and their active components, especially polyphenols, demonstrate interesting neuroprotective potential. They, therefore, deserve further study as their phytomolecules are promising sources of either natural neuroprotective products and/or novel lead compounds.     

Inhibition of key enzymes linked to type 2 diabetes and sodium nitroprusside-induced lipid peroxidation in rat pancreas by water extractable phytochemicals from some tropical spices

Context: Spices have been used as food adjuncts and in folklore for ages. Inhibition of key enzymes (α-amylase and α-glucosidase) involved in the digestion of starch and protection against free radicals and lipid peroxidation in pancreas could be part of the therapeutic approach towards the management of hyperglycemia and dietary phenolics have shown promising potentials.

Objective: This study investigated and compared the inhibitory properties of aqueous extracts of some tropical spices: Xylopia aethiopica [Dun.] A. Rich (Annonaceae), Monodora myristica (Gaertn.) Dunal (Annonaceae), Syzygium aromaticum [L.] Merr. et Perry (Myrtaceae), Piper guineense Schumach. et Thonn (Piperaceae), Aframomum danielli K. Schum (Zingiberaceae) and Aframomum melegueta (Rosc.) K. Schum (Zingiberaceae) against α-amylase, α-glucosidase, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and sodium nitroprusside (SNP)-induced lipid peroxidation in rat pancreas - in vitro using different spectrophotometric method.

Materials and methods: Aqueous extract of the spices was prepared and the ability of the spice extracts to inhibit α-amylase, α-glucosidase, DPPH radicals and SNP-induced lipid peroxidation in rat pancreas - in vitro was investigated using various spectrophotometric methods.

Result: All the spice extracts inhibited α-amylase (IC₅₀?=?2.81–4.83?mg/mL), α-glucosidase (IC₅₀?=?2.02–3.52?mg/mL), DPPH radicals (EC₅₀?=?15.47–17.38?mg/mL) and SNP-induced lipid peroxidation (14.17–94.38%), with the highest α-amylase & α-glucosidase inhibitory actions and DPPH radical scavenging ability exhibited by X. aethiopica, A. danielli and S. aromaticum, respectively. Also, the spices possess high total phenol (0.88–1.3?mg/mL) and flavonoid (0.24–0.52?mg/mL) contents with A. melegueta having the highest total phenolic and flavonoid contents.

Discussion and conclusion: The inhibitory effects of the spice extracts on α-amylase, α-glucosidase, DPPH radicals and SNP-induced lipid peroxidation in pancreas (in vitro) could be attributed to the presence of biologically active phytochemicals such as phenolics and some non-phenolic constituents of the spices. Furthermore, these spices may exert their anti-diabetic properties through the mechanism of enzyme inhibition, free radicals scavenging ability and prevention of lipid peroxidation.     

In vitro antioxidant and inhibitory potential of Terminalia bellerica and Emblica officinalis fruits against LDL oxidation and key enzymes linked to type 2 diabetes

The present study evaluated the free radical scavenging capacity and antioxidant potential of different solvent extracts (Hexane (HE), ethyl acetate (EA), methanol (ME), 70% methanol (MW) and Water (WA)) of Terminalia bellerica (TB) and Emblica officinalis (EB) fruits. Methanol extract (ME) of TB and EB fruits exhibited maximum scavenging activity against DPPH, superoxide, hydroxyl and nitric oxide radicals. Cell based antioxidant activity was assayed by flow cytometry using DCFH-DA as probe. Methanol extracts were also screened for their antidiabetic activity via inhibition of α-amylase, α-glucosidase and antiglycation assays. Results showed that ME of TB and EB can act as potent α-amylase and α-glucosidase inhibitor. Significant antiglycation activity also confirms the therapeutic potential of these extracts against diabetes. Both the extracts significantly inhibited the oxidation of LDL under in vitro conditions. Liquid chromatography-mass spectroscopy (LC-MS) analysis revealed that methanol extract of TB and EB contains ellagic acid and ascorbic acid as the major compound respectively.     

Biochemical and pharmacological characterization of isatin and its derivatives: from structure to activity

Isatin, 1H-indole-2,3-dione, is a heterocyclic compound of significant importance in medicinal chemistry. It is a synthetically versatile molecule, a precursor for a large number of pharmacologically active compounds. Isatin and its derivatives have aroused great attention in recent years due to their wide variety of biological activities, relevant to application as insecticides and fungicides and in a broad range of drug therapies, including anticancer drugs, antibiotics and antidepressants. The purpose of this review is to provide an overview of the pharmacological activities of isatin and its synthetic and natural derivatives. Molecular modifications to tailor the properties of isatin and its derivatives are also discussed.     

Bisphosphonic acids and related compounds as inhibitors of nucleotide‐ and polyphosphate‐processing enzymes: A PPK1 and PPK2 case study

Bisphosphonic acids, which are structural analogs of pyrophosphate, constitute a class of compounds with very high potential for the construction of effective inhibitors of enzymes operating on oligo‐ and polyphosphates. The bisphosphonate‐based methodology was applied for the discovery of inhibitors of two families of polyphosphate kinases (PPK1 and PPK2). Screening of thirty‐two structurally diverse bisphosphonic acids and related compounds revealed several micromolar inhibitors of both enzymes. Importantly, selectivity of bisphosphonates could be achieved by application of the appropriate side chain.     

Contribution of momilactones A and B to diabetes inhibitory potential of rice bran: Evidence from in vitro assays

This study was the first to detect the presence of the two compounds momilactone A (MA) and momilactone B (MB) in rice bran using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). By in vitro assays, both MA and MB exhibited potent inhibitory activities on pancreatic α-amylase and α-glucosidase which were significantly higher than γ-oryzanol, a well-known diabetes inhibitor. Remarkably, MA and MB indicated an effective inhibition on trypsin with the IC₅₀ values of 921.55 and 884.03 µg/mL, respectively. By high-performance liquid chromatography (HPLC), quantities of MA (6.65 µg/g dry weight) and MB (6.24 µg/g dry weight) in rice bran were determined. Findings of this study revealed the α-amylase, α-glucosidase and trypsin inhibitors MA and MB contributed an active role to the diabetes inhibitory potential of rice bran.     

Dapagliflozin: potential beneficial effects in the prevention and treatment of renal and cardiovascular complications in patients with type 2 diabetes

Introduction: Diabetic kidney disease is the leading cause of end-stage renal disease, a significant contributor to cardiovascular (CV) disease, responsible for much of the morbidity and mortality in patients with type 2 diabetes (T2DM). Strategies to slow or prevent the onset and progression of diabetic kidney disease are critical for effectively managing T2DM and reducing CV risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic agents, which may provide nephroprotective and CV protective effects.

Areas covered: This review examines the role of the kidney in glucose homeostasis, discusses renal hemodynamic changes in diabetes, and outlines the major hypotheses regarding the mechanisms underlying renal injury in diabetes. The potential benefits of SGLT2 inhibitors in the prevention and treatment of CV complications in patients with T2DM are reviewed, with particular focus on dapagliflozin.

Expert opinion: Dapagliflozin and other SGLT2 inhibitors have the capacity to decrease hyperglycemia and visceral fat, components of the metabolic syndrome particularly associated with the progression of CV disease. However, the mechanisms of action of SGLT2 inhibitors resulting in their positive CV effects remain unclear. Furthermore, the mechanism of action of SGLT2 inhibitors on heart function in non-diabetic patients with decompensated heart failure remains to be explored.     

AaeAP1 and AaeAP2: Novel Antimicrobial Peptides from the Venom of the Scorpion,Androctonus aeneas: Structural Characterisation,Molecular Cloning of Biosynthetic Precursor-Encoding cDNAs and Engineering of Analogues with Enhanced Antimicrobial and Anticancer Activities

The main functions of the abundant polypeptide toxins present in scorpion venoms are the debilitation of arthropod prey or defence against predators. These effects are achieved mainly through the blocking of an array of ion channel types within the membranes of excitable cells. However, while these ion channel-blocking toxins are tightly-folded by multiple disulphide bridges between cysteine residues, there are additional groups of peptides in the venoms that are devoid of cysteine residues. These non-disulphide bridged peptides are the subject of much research interest, and among these are peptides that exhibit antimicrobial activity. Here, we describe two novel non-disulphide-bridged antimicrobial peptides that are present in the venom of the North African scorpion, Androctonus aeneas. The cDNAs encoding the biosynthetic precursors of both peptides were cloned from a venom-derived cDNA library using 3''- and 5''-RACE strategies. Both translated precursors contained open-reading frames of 74 amino acid residues, each encoding one copy of a putative novel nonadecapeptide, whose primary structures were FLFSLIPSVIAGLVSAIRN and FLFSLIPSAIAGLVSAIRN, respectively. Both peptides were C-terminally amidated. Synthetic versions of each natural peptide displayed broad-spectrum antimicrobial activities, but were devoid of antiproliferative activity against human cancer cell lines. However, synthetic analogues of each peptide, engineered for enhanced cationicity and amphipathicity, exhibited increases in antimicrobial potency and acquired antiproliferative activity against a range of human cancer cell lines. These data clearly illustrate the potential that natural peptide templates provide towards the design of synthetic analogues for therapeutic exploitation.     

Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: a sub-analysis of data from a randomised clinical trial

Abstract

Objectives:

To evaluate the efficacy and safety of linagliptin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin and sulphonylurea.     

Novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds as small key organic molecules for the potential treatment of type‐2 diabetes mellitus: In vitro studies against yeast α‐ and β‐glucosidase and in silico molecular modeling

A range of novel pyridine‐2,4,6‐tricarbohydrazide thiourea compounds ( 4a–i ) were synthesized in good to excellent yields (63–92%). The enzyme inhibitory potentials of these compounds were investigated against α‐ and β‐glucosidases because these enzymes play a crucial role in treating type‐2 diabetes mellitus (T2DM). As compared to the reference compound acarbose (IC₅₀ 38.22 ± 0.12 μM), compounds 4i (IC₅₀ 25.49 ± 0.67 μM), 4f (IC₅₀ 28.91 ± 0.43 μM), 4h (IC₅₀ 30.66 ± 0.52 μM), and 4e (IC₅₀ 35.01 ± 0.45 μM) delivered better inhibition against α‐glucosidase and were quite inactive/completely inactive against β‐glucosidase. The structure–activity relationship of these compounds was developed and elaborated with the help of molecular docking studies.     

The efficacy and safety of teneligliptin added to ongoing metformin monotherapy in patients with type 2 diabetes: a randomized study with open label extension

Objective: The study investigated the efficacy and tolerability of teneligliptin co-administered to patients with type 2 diabetes mellitus (T2DM) who were inadequately controlled by stable metformin monotherapy ≥ 1000 mg/day.

Methods: A total of 447 patients from 55 European centers who completed a 14-day screening and 14-day run-in phase, received randomized double-blind treatment with 5, 10, 20 or 40 mg teneligliptin or placebo once daily, for 24 weeks. 364 patients continued treatment in a 28-week open label extension during which they received teneligliptin 20 mg once daily.

Results: Co-administration of teneligliptin (5 to 40 mg) with metformin demonstrated dose-related and statistically significant reductions in HbA_1c after 24 weeks (-0.30 to -0.63% placebo adjusted) of double-blind treatment. The greatest reduction in HbA_1c was seen with teneligliptin at 40 mg (-0.63%) at Week 24. There was also a dose-dependent increase in proportion of responders achieving HbA_1c < 7.0% at this endpoint. Responses were maintained throughout 28 weeks open label treatment with 20 mg teneligliptin. Treatment was well tolerated to Week 52 and the overall incidence of hypoglycemia during 52 weeks was 2.3%.

Conclusions: Teneligliptin co-administered with metformin produced significant reductions in HbA_1c in patients with T2DM without increasing the risk of hypoglycemia.     

Adherence to oral glucose lowering drugs,quality of life,treatment satisfaction and illness perception: A cross-sectional study in patients with type 2 diabetes

Objective

To evaluate treatment adherence to oral glucose lowering drugs (OGLD) and health related quality of life in Lebanese diabetics. Secondary objectives were to examine associations between treatment adherence, quality of life (QOL), treatment satisfaction and illness perception.