Anthelmintic screening of Bangladeshi medicinal plants and related phytochemicals using in vitro and in silico methods: An ethnobotanical perspective.

ETHNOPHARMACOLOGICAL RELEVANCE: Infections caused by parasitic worms or helminth continue to pose a great burden on human and animal health, particularly in underdeveloped tropical and subtropical countries where they are endemic. Current anthelmintic drugs present serious limitations and the emergence of drug resistance has made it increasingly challenging to combat such infections (helminthiases). In Bangladesh, medicinal plants are often used by indigenous communities for the treatment of helminthiases. Knowledge on such plants along with screening for their anthelmintic activity has the potential to lead to the discovery of phytochemicals that could serve as novel molecular scaffolds for the development of new anthelminthic drugs. AIM OF THE STUDY: The purpose of this study was i) to conduct an ethnobotanical survey to gather data on Bangladeshi medicinal plants used in the treatment of helminthiases, ii) to test plants with the highest use values for their in vitro anthelmintic activity, and iii) to carry out in silico screening on phytochemicals present in the most active plant extract to investigate their ability to disrupt ß-tubulin function in helminths. METHODS: The ethnobotanical survey was conducted across three sub-districts of Bangladesh, namely Mathbaria, Phultala and Khan Jahan Ali. The in vitro screening for anthelmintic activity was performed in a motility test using adult Haemonchus contortus worms. Virtual screening using PyRx was performed on the phytochemicals reported from the most active plant, exploring their interactions with the colchicine binding site of the ß-tubulin protein target (PDB ID: 1SA0). RESULTS: The survey respondents reported a total of 32 plants for treating helminthiases. Based on their use values, the most popular choices were Ananas comosus (L.) Merr., Azadirachta indica A.Juss., Carica papaya L., Citrus maxima (Burm.) Merr., Curcuma longa L., Momordica charantia L., Nigella sativa L. and Syzygium cumini (L.) Skeels. In vitro anthelmintic testing revealed that A. indica leaves and bark had the highest activity with LC50 values of 16 mg/mL in both cases. Other plant extracts also exhibited good anthelmintic activity with LC50 values ranging from 16 to 52 mg/mL, while the value for albendazole (positive control) was 8.39 mg/mL. The limonoids nimbolide and 28-deoxonimbolide showed a binding affinity of -8.9 kcal/mol, and satisfied all drug-likeness parameters. The control ligand N-deacetyl-N-(2-mercaptoacetyl)colchicine had a binding affinity of -6.9 kcal/mol. CONCLUSION: Further in silico and in vitro studies are warranted on the identified limonoids to confirm the potential of these derivatives as novel drug templates for helminthiases. The current study supports the need for an ethnobotanical survey-based approach to discover novel drug templates for helminthiases.

In silico studies on the anti-acne potential of Garcinia mangostana xanthones and benzophenones.

Garcinia mangostana fruits are used traditionally for inflammatory skin conditions, including acne. In this study, an in silico approach was employed to predict the interactions of G. mangostana xanthones and benzophenones with three proteins involved in the pathogenicity of acne, namely the human JNK1, Cutibacterium acnes KAS III and exo-ß-1,4-mannosidase. Molecular docking analysis was performed using Autodock Vina. The highest docking scores and size-independent ligand efficiency values towards JNK1, C. acnes KAS III and exo-ß-1,4-mannosidase were obtained for garcinoxanthone T, gentisein/2,4,6,3',5'-pentahydroxybenzophenone and mangostanaxanthone VI, respectively. To the best of our knowledge, this is the first report of the potential of xanthones and benzophenones to interact with C. acnes KAS III. Molecular dynamics simulations using GROMACS indicated that the JNK1-garcinoxanthone T complex had the highest stability of all ligand-protein complexes, with a high number of hydrogen bonds predicted to form between this ligand and its target. Petra/Osiris/Molinspiration (POM) analysis was also conducted to determine pharmacophore sites and predict the molecular properties of ligands influencing ADMET. All ligands, except for mangostanaxanthone VI, showed good membrane permeability. Garcinoxanthone T, gentisein and 2,4,6,3',5'-pentahydroxybenzophenone were identified as the most promising compounds to explore further, including in experimental studies, for their anti-acne potential.

Anticancer and chemopreventive potential of Morinda citrifolia L. bioactive compounds: A comprehensive update.

Morinda citrifolia L., commonly known as Noni, has a longstanding history in traditional medicine for treating various diseases. Recently, there has been an increased focus on exploring Noni extracts and phytoconstituents, particularly for their effectiveness against cancers such as lung, esophageal, liver, and breast cancer, and their potential in cancer chemoprevention. This study aims to provide a comprehensive review of in vitro and in vivo studies assessing Noni's impact on cancer, alongside an exploration of its bioactive compounds. A systematic review was conducted, encompassing a wide range of scientific databases to gather pertinent literature. This review focused on in vitro and in vivo studies, as well as clinical trials that explore the effects of Noni fruit and its phytoconstituents-including anthraquinones, flavonoids, sugar derivatives, and neolignans-on cancer. The search was meticulously structured around specific keywords and criteria to ensure a thorough analysis. The compiled studies highlight Noni's multifaceted role in cancer therapy, showcasing its various bioactive components and their modes of action. This includes mechanisms such as apoptosis induction, cell cycle arrest, antiangiogenesis, and immune system modulation, demonstrating significant anticancer and chemopreventive potential. The findings reinforce Noni's potential as a safe and effective option in cancer prevention and treatment. This review underscores the need for further research into Noni's anticancer properties, with the hope of stimulating additional studies and clinical trials to validate and expand upon these promising findings.

Antiviral and antibacterial properties of phloroglucinols: a review on naturally occurring and (semi)synthetic derivatives with potential therapeutic interest.

Phloroglucinol and derived compounds comprise a huge class of secondary metabolites widely distributed in plants and brown algae. A vast array of biological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer has been associated to this class of compounds. In this review, the available data on the antiviral and antibacterial capacity of phloroglucinols have been analyzed. Some of these compounds and derivatives show important antimicrobial properties in vitro. Phloroglucinols have been shown to be effective against viruses, such as human immunodeficiency virus (HIV), herpes or enterovirus, and preliminary data through docking analysis suggest that they can be effective against SARS-CoV-19. Also, some phloroglucinols derivatives have shown antibacterial effects against diverse bacteria strains, including Bacillus subtilis and Staphylococcus aureus, and (semi)synthetic development of novel compounds have led to phloroglucinols with a significantly increased biological activity. However, therapeutic use of these compounds is hindered by the absence of in vivo studies and scarcity of information on their mechanisms of action, and hence further research efforts are required. On the basis of this consideration, our work aims to gather data regarding the efficacy of natural-occurring and synthetic phloroglucinol derivatives as antiviral and antibacterial agents against human pathogens, which have been published during the last three decades. The recollection of results reported in this review represents a valuable source of updated information that will potentially help researchers in the development of novel antimicrobial agents.

Antimicrobial and cytotoxic naphthoquinones from microbial origin: An updated review.

Naphthoquinones (NQs) are small molecules bearing two carbonyl groups. They have been the subject of much research due to their significant biological activities such as antiproliferative, antimicrobial, anti-inflammatory, antioxidant, and antimalarial effects. NQs are produced mainly by bacteria, fungi and higher plants. Among them, microorganisms are a treasure of NQs with diverse skeletons and pharmacological properties. The purpose of the present study is to provide a comprehensive update on the structural diversity and biological activities of 91 microbial naphthoquinones isolated from 2015 to 2022, with a special focus on antimicrobial and cytotoxic activities. During this period, potent cytotoxic NQs such as naphthablin B (46) and hygrocin C (30) against HeLa (IC50=0.23 µg/ml) and MDA-MB-431 (IC50=0.5 µg/ml) cell lines was reported, respectively. In addition, rubromycin CA1 (39), exhibited strong antibacterial activity against Staphylococcus aureus (MIC of 0.2 µg/ml). As importance bioactive compounds, NQs may open new horizon for treatment of cancer and drug resistant bacteria. As such, it is hoped that this review article may stimulates further research into the isolation of further NQs from microbial, and other sources as well as the screening of such compounds for biological activity and beneficial uses.

Protective Effects of Medicinal Plant-Based Foods against Diabetes: A Review on Pharmacology, Phytochemistry, and Molecular Mechanisms.

Diabetes mellitus (DM) comprises a range of metabolic disorders characterized by high blood glucose levels caused by defects in insulin release, insulin action, or both. DM is a widespread condition that affects a substantial portion of the global population, causing high morbidity and mortality rates. The prevalence of this major public health crisis is predicted to increase in the forthcoming years. Although several drugs are available to manage DM, these are associated with adverse side effects, which limits their use. In underdeveloped countries, where such drugs are often costly and not widely available, many people continue to rely on alternative traditional medicine, including medicinal plants. The latter serves as a source of primary healthcare and plant-based foods in many low- and middle-income countries. Interestingly, many of the phytochemicals they contain have been demonstrated to possess antidiabetic activity such as lowering blood glucose levels, stimulating insulin secretion, and alleviating diabetic complications. Therefore, such plants may provide protective effects that could be used in the management of DM. The purpose of this article was to review the medicinal plant-based foods traditionally used for the management of DM, including their therapeutic effects, pharmacologically active phytoconstituents, and antidiabetic mode of action at the molecular level. It also presents future avenues for research in this field.

Phenolic compounds as Nrf2 inhibitors: potential applications in cancer therapy.

Cancer is a leading cause of death worldwide and involves an oxidative stress mechanism. The transcription factor Nrf2 has a crucial role in cytoprotective response against oxidative stress, including cancer growth and progression and therapy resistance. For this reason, inhibitors of Nrf2 are new targets to be studied. Traditional plant-based remedies rich in phytochemicals have been used against human cancers and phenolic compounds are known for their chemopreventive properties. This comprehensive review offers an updated review of the role of phenolic compounds as anticancer agents due to their action on Nrf2 inhibition. In addition, the role of naturally-occurring bioactive anticancer agents are covered in the clinical applications of polyphenols as Nrf2 inhibitors. Video Abstract.

Role of the Dietary Phytochemical Curcumin in Targeting Cancer Cell Signalling Pathways.

The diarylheptanoid curcumin [(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione] is one of the phenolic pigments responsible for the yellow colour of turmeric (Curcuma longa L.). This phytochemical has gained much attention in recent years due to its therapeutic potential in cancer. A range of drug delivery approaches have been developed to optimise the pharmacokinetic profile of curcumin and ensure that it reaches its target sites. Curcumin exhibits numerous biological effects, including anti-inflammatory, cardioprotective, antidiabetic, and anti-aging activities. It has also been extensively studied for its role as a cancer chemopreventive and anticancer agent. This review focusses on the role of curcumin in targeting the cell signalling pathways involved in cancer, particularly via modulation of growth factors, transcription factors, kinases and other enzymes, pro-inflammatory cytokines, and pro-apoptotic and anti-apoptotic proteins. It is hoped that this study will help future work on the potential of curcumin to fight cancer.

Cancer Protective Role of Selected Dietary Polyphenols via Modulating Keap1/Nrf2/ARE and Interconnected Signaling Pathways.

The Kelch-like ECH associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathway is considered a master regulator of the cellular response against oxidative stress. Numerous studies have investigated the role of Keap1/Nrf2/ARE in the different stages of cancer development. A comprehensive literature search using the Google Scholar, PubMed and Science Direct databases was performed to retrieve information related to the cancer protective role of 21 selected dietary polyphenols via modulation of Keap1/Nrf2/ARE and interconnected signaling pathways/proteins (MAPK/ERK1/2, PI3K/Akt, PKD, JNKs, AMPK, NF-κB). Information on the anti-inflammatory and cytoprotective effects caused by the selected dietary polyphenols following Keap1/Nrf2/ARE modulation was also collected. The majority of the studies analyzed in this review demonstrated the cancer protective role of the selected polyphenols mostly in-vitro. Limited work was performed in-vivo and only one of the selected polyphenols was subjected to a clinical trial. It is hoped that this review will encourage further in-vivo studies to confirm the cancer protective role of methyleugenol, carnosol, and catechin, as well as further clinical trials to unambiguously establish whether the consumption of dietary polyphenols impacts on the incidence and progression of cancers in humans.

Allium vegetables: Traditional uses, phytoconstituents, and beneficial effects in inflammation and cancer.

The genus Allium comprises of at least 918 species; the majority grown for dietary and medicinal purposes. This review describes the traditional uses, phytoconstituents, anti-inflammatory and anticancer activity, and safety profile of six main species, namely Allium sativum L. (garlic), Allium cepa L. (onions), Allium ampeloprasum L. (leek), Allium fistulosum L. (scallion), Allium schoenoprasum L. (chives) and Allium tuberosum Rottler (garlic chives). These species contain at least 260 phytoconstituents; mainly volatile compounds-including 63 organosulfur molecules-, saponins, flavonoids, anthocyanins, phenolic compounds, amino acids, organic acids, fatty acids, steroids, vitamins and nucleosides. They have prominent in vitro anti-inflammatory activity, and in vivo replications of such results have been achieved for all except for A. schoenoprasum. They also exert cytotoxicity against different cancer cell lines. Several anticancer phytoconstituents have been characterized from all except for A. fistulosum. Organosulfur constituents, saponins and flavonoid glycosides have demonstrated anti-inflammatory and anticancer activity. Extensive work has been conducted mainly on the anti-inflammatory and anticancer activity of A. sativum and A. cepa. The presence of anti-inflammatory and anticancer constituents in these two species suggests that similar bioactive constituents could be found in other species. This provides future avenues for identifying new Allium-derived anti-inflammatory and anticancer agents.

Evaluation of potential bacterial protease inhibitor properties of selected hydroxyquinoline derivatives: an in silico docking and molecular dynamics simulation approach.

Antimicrobial drug resistance (AMR) is a severe global threat to public health. The increasing emergence of drug-resistant bacteria requires the discovery of novel antibacterial agents. Quinoline derivatives have previously been reported to exhibit antimalarial, antiviral, antitumor, antiulcer, antioxidant and, most interestingly, antibacterial properties. In this study, we evaluated the binding affinity of three newly designed hydroxyquinolines derived from sulfanilamide (1), 4-amino benzoic acid (2) and sulfanilic acid (3) towards five bacterial protein targets (PDB ID: 1JIJ, 3VOB, 1ZI0, 6F86, 4CJN). The three derivatives were designed considering the amino acid residues identified at the active site of each protein involved in the binding of each co-crystallized ligand and drug-likeness properties. The ligands displayed binding energy values with the target proteins ranging from -2.17 to -8.45 kcal/mol. Compounds (1) and (3) showed the best binding scores towards 1ZI0/3VOB and 1JIJ/4CJN, respectively, which may serve as new antibiotic scaffolds. Our in silico results suggest that sulfanilamide (1) or sulfanilic acid (3) hydroxyquinoline derivatives have the potential to be developed as bacterial inhibitors, particularly MRSA inhibitors. But before that, it must go through the proper preclinical and clinical trials for further scientific validation. Further experimental studies are warranted to explore the antibacterial potential of these compounds through preclinical and clinical studies.Communicated by Ramaswamy H. Sarma.

Phytochemical study and immunomodulatory activity of Fraxinus excelsior L.

OBJECTIVES: Fraxinus excelsior L. (FE) is traditionally used to treat inflammatory and pain disorders. This study aimed to identify the constituents of FE leaves and evaluate the effects of its n-hexane (FEH), ethyl acetate (FEE), methanol (FEM) extracts and constituents on the viability of THP-1 cells and their ability to release pro-inflammatory cytokines. METHODS: THP-1 cell viability was assessed using an MTT assay. The immunomodulatory activity was evaluated by measuring tumour necrosis factor-alpha (TNF-α) and interleukin 12 (IL-12) released by lipopolysaccharide-stimulated THP-1 cells using enzyme-linked immunosorbent assays. KEY FINDINGS: Triterpenes, tyrosol esters, alkanes, phytyl and steryl esters, pinocembrin and bis(2-ethylhexyl)phthalate were isolated from FE. The tyrosol esters showed no significant effect on THP-1 cell viability. FEH, FEE, FEM, and pinocembrin, ursolic acid, oleanolic acid had IC50 values of 56.9, 39.9, 124.7 µg/ml and 178.6, 61.5 and 199.8 µM, respectively. FE extracts, ursolic acid, oleanolic acid and pinocembrin significantly reduced TNF-α/IL-12 levels. The tyrosol esters did not significantly affect TNF-α/IL-12 production. CONCLUSIONS: FE was able to reduce pro-inflammatory cytokine production indicating a mechanistic focus in its use for inflammation and pain. Further investigations are warranted to unravel the mode of action of the tested constituents and discover other potentially active compounds in FE extracts.

An updated and comprehensive review on the ethnomedicinal uses, phytochemistry, pharmacological activity and toxicological profile of Tinospora crispa (L.) Hook. f. & Thomson.

Tinospora crispa (L.) Hook. f. & Thomson (Menispermaceae) is a plant indigenous to Africa and South-East Asia. It is widely used in ethnomedicine to alleviate various diseases including hypertension, diabetes, rheumatism, jaundice, inflammation, fever, fractures, scabies, and urinary disorders. A total of 167 phytoconstituents, belonging to 12 different chemical categories, including alkaloids, flavonoids, terpenoids, and phenolic compounds have thus far been isolated from various parts of T. crispa. Numerous in vitro and in vivo investigations have already established the antidiabetic, anticancer, antiparasitic, antimicrobial, immunomodulatory, hepatoprotective, analgesic, antipyretic, antihyperuricemic, and pesticidal activity of this plant, as well as its effects on the cardiac and the central nervous system. Most pharmacological investigations to date have been carried out on plant extracts and fractions. The exact identity of the phytoconstituents responsible for the observed biological effects and their mode of action at the molecular level are yet to be ascertained. Toxicological studies have demonstrated that T. crispa is relatively safe, although dose-dependent hepatotoxicity is a concern at high doses. This review presents a comprehensive update and analysis on studies related to the ethnomedicinal uses, phytochemistry, pharmacological activity and toxicological profile of T. crispa. It provides some critical insights into the current scientific knowledge on this plant and its future potential in pharmaceutical research.

Anxiolytic, antidepressant and antioxidant activity of the methanol extract of Canarium resiniferum leaves.

Background and aim: This study evaluated the anxiolytic, antidepressant, and antioxidant activity of the methanol extract of Canarium resiniferum (MECR) leaves, and determined the total phenolic and flavonoid contents in this extract. Experimental procedure: The anxiolytic effect of MECR (100, 200, 400 mg/kg, p. o.) was tested in mice using the elevated plus-maze (EPM) test, the hole-board test (HBT), and the light-dark box (LDB) test. Its antidepressant effect was evaluated in the tail suspension (TST) and the forced swim (FST) tests. The total phenolic (TPC) and flavonoid (TFC) content was measured using standard colorimetric assays. Antioxidant activity was determined using the DPPH radical scavenging and ferric reducing antioxidant power (FRAP) assays. Results and conclusion: MECR, at all doses, showed dose-dependent anxiolytic activity. At 400 mg/kg, it significantly increased the time spent and number of entries in the open arms (EPM test), the number of head-dips (HBT), and the time spent into the light compartment (LDB) test compared to the control. In the TST and FST, MECR dose-dependently reduced the duration of immobility compared to untreated animals. This was significant for all doses except for 100 mg/kg in the FST model. MECR showed high TPC and TFC (90.94 ± 0.75 mg GAE/g and 51.54 ± 0.78 mg QE/g of dried extract, respectively) and displayed potent activity in the DPPH radical scavenging (IC50 = 177.82 µg/mL) and FRAP assays. These findings indicate that C. resiniferum has the potential to alleviate anxiety and depression disorders, which merits further exploration.

Antidiabetic Actions of Ethanol Extract of Camellia sinensis Leaf Ameliorates Insulin Secretion, Inhibits the DPP-IV Enzyme, Improves Glucose Tolerance, and Increases Active GLP-1 (7-36) Levels in High-Fat-Diet-Fed Rats.

Camellia sinensis (green tea) is used in traditional medicine to treat a wide range of ailments. In the present study, the insulin-releasing and glucose-lowering effects of the ethanol extract of Camellia sinensis (EECS), along with molecular mechanism/s of action, were investigated in vitro and in vivo. The insulin secretion was measured using clonal pancreatic BRIN BD11 ß cells, and mouse islets. In vitro models examined the additional glucose-lowering properties of EECS, and 3T3L1 adipocytes were used to assess glucose uptake and insulin action. Non-toxic doses of EECS increased insulin secretion in a concentration-dependent manner, and this regulatory effect was similar to that of glucagon-like peptide 1 (GLP-1). The insulin release was further enhanced when combined with isobutylmethylxanthine (IBMX), tolbutamide or 30 mM KCl, but was decreased in the presence of verapamil, diazoxide and Ca2+ chelation. EECS also depolarized the ß-cell membrane and elevated intracellular Ca2+, suggesting the involvement of a KATP-dependent pathway. Furthermore, EECS increased glucose uptake and insulin action in 3T3-L1 cells and inhibited dipeptidyl peptidase IV (DPP-IV) enzyme activity, starch digestion and protein glycation in vitro. Oral administration of EECS improved glucose tolerance and plasma insulin as well as inhibited plasma DPP-IV and increased active GLP-1 (7-36) levels in high-fat-diet-fed rats. Flavonoids and other phytochemicals present in EECS could be responsible for these effects. Further research on the mechanism of action of EECS compounds could lead to the development of cost-effective treatments for type 2 diabetes.

Theoretical exploration on structures, bonding aspects and molecular docking of α-aminophosphonate ligated copper complexes against SARS-CoV-2 proteases.

Recent years have witnessed a growing interest in the biological activity of metal complexes of α-aminophosphonates. Here for the first time, a detailed DFT study on five α-aminophosphonate ligated mononuclear/dinuclear CuII complexes is reported using the dispersion corrected density functional (B3LYP-D2) method. The electronic structures spin densities, FMO analysis, energetic description of spin states, and theoretical reactivity behaviour using molecular electrostatic potential (MEP) maps of all five species are reported. All possible spin states of the dinuclear species were computed and their ground state S values were determined along with the computation of their magnetic coupling constants. NBO analysis was also performed to provide details on stabilization energies. A molecular docking study was performed for the five complexes against two SARS-CoV-2 coronavirus protein targets (PDB ID: 6LU7 and 7T9K). The docking results indicated that the mononuclear species had a higher binding affinity for the targets compared to the dinuclear species. Among the species investigated, species I showed the highest binding affinity with the SARS-CoV-2 Omicron protease. NPA charge analysis showed that the heteroatoms of model species III had a more nucleophilic nature. A comparative study was performed to observe any variations and/or correlations in properties among all species.