Guglielmina Froldi

This review provides a comprehensive overview of the modulatory actions of plant-derived constituents on membrane ion channels in various cell types. Among their diverse bioactivities, ion channel regulation—governing membrane excitability, signal transduction, and cellular homeostasis—has emerged as a critical mechanistic basis for their pharmacological effects. Twenty-four representative phytoconstituents are discussed and classified into five major categories based on their structural features: alkaloids, terpenoids, lignans and acetogenins, polyphenols, and other aromatic and conjugated compounds. Across these categories, the reviewed compounds exhibit distinct and often highly specific effects on the amplitude and gating kinetics of multiple ionic currents, including voltage-gated Na⁺ currents (I_Na), delayed-rectifier K⁺ currents (I_K(DR)), M-type K⁺ currents (I_K(M)), hyperpolarization-activated cation currents (I_h), erg-mediated K⁺ currents (I_K(erg)), inwardly rectifying K⁺ currents, and Ca²⁺-activated K⁺ currents (I_K(Ca)). Alkaloids predominantly suppress voltage-gated K⁺ currents, with notable exceptions such as aconitine, which alters the properties of both I_Na and I_K(DR), thereby contributing to its proarrhythmic toxicity. Terpenoids, including cannabidiol, croton diterpenoids, lutein, thymol, and triptolide, exert multifaceted effects on I_K(M), I_h, inwardly rectifying K⁺ currents, and Ca²⁺-activated K⁺ channels. Lignans and acetogenins, such as gomisin A, honokiol, sesamin, and squamocin, primarily modulate I_Na, I_h, and I_K(Ca), with several compounds demonstrating strong links between ion-channel modulation and anti-neoplastic or neuroprotective actions. Polyphenolic compounds, including curcumin, eugenol, resveratrol, gastrodigenin, gastrodin, and pterostilbene, display diverse ion-channel targeting profiles, influencing multiple Na⁺ and K⁺ channel subtypes. Other aromatic or conjugated compounds, such as isoplumbagin, plumbagin, and verteporfin, regulate I_K(erg) and I_K(Ca), potentially contributing to both therapeutic efficacy and adverse effects. Collectively, the compound-specific modulation of current amplitude and gating kinetics offers valuable mechanistic insight into the pharmacological and toxicological significance of plant-derived natural products, highlighting the functional role of ion channel evaluation in guiding their therapeutic development and ensuring safety assessment.

This review provides a comprehensive overview of the modulatory actions of plant-derived constituents on membrane ion channels in various cell types. Among their diverse bioactivities, ion channel regulation—governing membrane excitability, signal transduction, and cellular homeostasis—has emerged as a critical mechanistic basis for their pharmacological effects. Twenty-four representative phytoconstituents are discussed and classified into five major categories based on their structural features: alkaloids, terpenoids, lignans and acetogenins, polyphenols, and other aromatic and conjugated compounds. Across these categories, the reviewed compounds exhibit distinct and often highly specific effects on the amplitude and gating kinetics of multiple ionic currents, including voltage-gated Na+ currents (INa), delayed-rectifier K+ currents (IK(DR)), M-type K+ currents (IK(M)), hyperpolarization-activated cation currents (Ih), erg-mediated K+ currents (IK(erg)), inwardly rectifying K+ currents, and Ca2+-activated K⁺ currents (IK(Ca)). Alkaloids predominantly suppress voltage-gated K+ currents, with notable exceptions such as aconitine, which alters the properties of both INa and IK(DR), thereby contributing to its proarrhythmic toxicity. Terpenoids, including cannabidiol, croton diterpenoids, lutein, thymol, and triptolide, exert multifaceted effects on IK(M), Ih, inwardly rectifying K+ currents, and Ca2+-activated K⁺ channels. Lignans and acetogenins, such as gomisin A, honokiol, sesamin, and squamocin, primarily modulate INa, Ih, and IK(Ca), with several compounds demonstrating strong links between ion-channel modulation and anti-neoplastic or neuroprotective actions. Polyphenolic compounds, including curcumin, eugenol, resveratrol, gastrodigenin, gastrodin, and pterostilbene, display diverse ion-channel targeting profiles, influencing multiple Na⁺ and K⁺ channel subtypes. Other aromatic or conjugated compounds, such as isoplumbagin, plumbagin, and verteporfin, regulate IK(erg) and IK(Ca), potentially contributing to both therapeutic efficacy and adverse effects. Collectively, the compound-specific modulation of current amplitude and gating kinetics offers valuable mechanistic insight into the pharmacological and toxicological significance of plant-derived natural products, highlighting the functional role of ion channel evaluation in guiding their therapeutic development and ensuring safety assessment.

Thanks to advancements in biochemistry, biology, and pathology, natural products (NPs) continue to be a subject of intense scientific investigation

Polyalthia longifolia, a member of the Annonaceae family, is traditionally used for its medicinal properties, including as an antidiabetic remedy, primarily in Asia and sub-Saharan Africa. This study investigated the potential of six P. longifolia extracts in counteracting hyperglycemia and diabetes-related complications. Aqueous, ethanol, and methanol extracts from leaves and stems were evaluated for their antihyperglycemic, antiglycation, and antiradical properties using α-glucosidase, BSA, and ORAC assays, respectively. Phytochemical characterization was conducted using TPC and TFC assays, and HPLC analysis identified specific bioactive compounds, including various phenolic compounds (gallic acid, (+)-catechin, epicatechin, caffeic acid, ellagic acid and rosmarinic acid) and flavonoids (luteolin, kaempferol and baicalein). The MTT assay on the human cell line HT-29 assessed the activity of extracts on cell viability, showing slight cytotoxicity. Results demonstrated significant antidiabetic activity of the ethanol and methanol extracts from P. longifolia leaves. This study provides new insights into the potential use of P. longifolia in diabetes mellitus and supports the valorization of traditional medicinal plants.

Polyalthia longifolia, a member of the Annonaceae family, is traditionally used for its medicinal properties, including as an antidiabetic remedy, primarily in Asia and sub-Saharan Africa. This study investigated the potential of six P. longifolia extracts in counteracting hyperglycemia and diabetes-related complications. Aqueous, ethanol, and methanol extracts from leaves and stems were evaluated for their antihyperglycemic, antiglycation, and antiradical properties using α-glucosidase, BSA, and ORAC assays, respectively. Phytochemical characterization was conducted using TPC and TFC assays, and HPLC analysis identified specific bioactive compounds, including various phenolic compounds and flavonoids (mainly baicalein). The MTT assay on the human cell line HT-29 assessed the activity of extracts on cell viability, showing slight cytotoxicity. Results demonstrated significant antidiabetic activity of the ethanol and methanol extracts from P. longifolia leaves. This study provides new insights into the potential use of P. longifolia in diabetes mellitus and supports the valorization of traditional medicinal plants.

trans-Tiliroside and (+)-pinoresinol, a flavonoid and a lignan found in plants traditionally used for diabetes mellitus care, were investigated for antidiabetic properties through in vitro and in silico studies. Four assays were conducted: Bovine Serum Albumin (BSA) assay to assess inhibition of albumin glycation, α-glucosidase assay to evaluate decrease of carbohydrate digestion, Oxygen Radical Absorbance Capacity (ORAC) assay for antioxidant activity and cytotoxicity evaluation on HT-29 cells. trans-Tiliroside showed higher inhibition of protein glycation, with IC₅₀ values of 113.6, 71.03 and 95.73 µM against glucose, fructose and ribose-induced glycation, respectively. Moreover, trans-tiliroside demonstrated higher antioxidant capacity than (+)-pinoresinol. Both compounds showed slight α-glucosidase inhibitory activity and no cytotoxicity in HT-29 cells at 0.1-100 µM. An in silico pharmacokinetic study evaluated their bioavailability. Results suggest trans-tiliroside can act as an inhibitor of protein glycation, potentially reducing unwanted glycation reactions and preventing hyperglycaemia-related diseases.

Objective: This research studied two extracts from Treculia africana leaves for their potential against hyperglycaemia-related disorders. Methods: The influence of the extracts on α-glucosidase activity and albumin glycation was investigated, and cell viability was estimated in HT-29 human colorectal cells. Phenolic and flavonoid contents and antiradical activity were also detected. The extracts were examined using HPLC-DAD analysis. Key findings: The methanol and dichloromethane leaf extracts showed a significant concentration-dependent inhibition of α-glucosidase activity (IC50= 3.73 and 21.28 µg/ml, respectively). Both extracts also inhibited ribose-induced glycation of bovine serum albumin from 250 µg/ml. Phytochemical analysis revealed the presence of chlorogenic acid and α-mangostin in the extracts. The extracts did not change HT-29 cell viability up to 250 µg/ml, thus showing very low cytotoxicity. Conclusions: The methanol leaf extract of T. africana inhibited α-glucosidase activity in a concentration-dependent manner, supporting the use of the leaves in traditional medicine to control hyperglycaemia. Chlorogenic acid and α-mangostin, the latter identified for the first time in this species, were found in the T. africana leaves. Further, in vivo studies and pilot clinical trials should be conducted using standardized T. africana leaf extracts to evaluate their potential effectiveness in diabetes mellitus.

Metformin is a synthetic biguanide used as an antidiabetic drug in type 2 diabetes mellitus, achieved by studying the bioactive metabolites of Galega officinalis L. It is also used off-label for various other diseases, such as subclinical diabetes, obesity, polycystic ovary syndrome, etc. In addition, metformin is proposed as an add-on therapy for several conditions, including autoimmune diseases, neurodegenerative diseases, and cancer. Although metformin has been used for many decades, it is still the subject of many pharmacodynamic and pharmacokinetic studies in light of its extensive use. Metformin acts at the mitochondrial level by inhibiting the respiratory chain, thus increasing the AMP/ATP ratio and, subsequently, activating the AMP-activated protein kinase. However, several other mechanisms have been proposed, including binding to presenilin enhancer 2, increasing GLP1 release, and modification of microRNA expression. Regarding its pharmacokinetics, after oral administration, metformin is absorbed, distributed, and eliminated, mainly through the renal route, using transporters for cationic solutes, since it exists as an ionic molecule at physiological pH. In this review, particular consideration has been paid to literature data from the last 10 years, deepening the study of clinical trials inherent to new uses of metformin, the differences in effectiveness and safety observed between the sexes, and the unwanted side effects. For this last objective, metformin safety was also evaluated using both VigiBase and EudraVigilance, respectively, the WHO and European databases of the reported adverse drug reactions, to assess the extent of metformin side effects in real-life use.

The study of medicinal plants and their active compounds is relevant to maintaining knowledge of traditional medicine and to the development of new drugs of natural origin with lower environmental impact. From the seeds of the Brazilian plant Pterodon emarginatus, six different preparations were obtained: essential oil (EO), ethanol extract (EthE) prepared using the traditional method, and four extracts using solvents at different polarities, such as n-hexane, chloroform, ethyl acetate, and methanol (HexE, ChlE, EtAE, and MetE). Chemical characterization was carried out with gas chromatography, allowing the identification of several terpenoids as characteristic components. The two sesquiterpenes β-caryophyllene and farnesol were identified in all preparations of Pterodon emarginatus, and their amounts were also evaluated. Furthermore, the total flavonoid and phenolic contents of the extracts were assessed. Successively, the antiradical activity with DPPH and ORAC assays and the influence on cell proliferation by the MTT test on the human colorectal adenocarcinoma (HT-29) cell line of the preparations and the two compounds were evaluated. Lastly, an in silico study of adsorption, distribution, metabolism, excretion, and toxicity (ADMET) showed that β-caryophyllene and farnesol could be suitable candidates for development as drugs. The set of data obtained highlights the potential medicinal use of Pterodon emarginatus seeds and supports further studies of both plant preparations and isolated compounds, β-caryophyllene and farnesol, for their potential use in disease with free radical involvement as age-related chronic disorders.

The aqueous decoctions of Vernonia amygdalina (VA) leaves and roots are widely used in traditional African medicine as an antidiabetic remedy. The amount of luteolin and vernodalol in leaf and root extracts was detected, and their role was studied regarding α-glucosidase activity, bovine serum albumin glycation (BSA), reactive oxygen species (ROS) formation, and cell viability, together with in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Vernodalol did not affect α-glucosidase activity, whereas luteolin did. Furthermore, luteolin inhibited the formation of advanced glycation end products (AGEs) in a concentration-dependent manner, whereas vernodalol did not reduce it. Additionally, luteolin exhibited high antiradical activity, while vernodalol demonstrated a lower scavenger effect, although similar to that of ascorbic acid. Both luteolin and vernodalol inhibited HT-29 cell viability, showing a half-maximum inhibitory concentration (IC₅₀) of 22.2 µM (−Log IC₅₀ = 4.65 ± 0.05) and 5.7 µM (−Log IC₅₀ = 5.24 ± 0.16), respectively. Finally, an in silico ADMET study showed that both compounds are suitable candidates as drugs, with appropriate pharmacokinetics. This research underlines for the first time the greater presence of vernodalol in VA roots compared to leaves, while luteolin is prevalent in the latter, suggesting that the former could be used as a natural source of vernodalol. Consequently, root extracts could be proposed for vernodalol-dependent antiproliferative activity, while leaf extracts could be suggested for luteolin-dependent effects, such as antioxidant and antidiabetic effects.