Dental applications of Punica granatum L. in the treatment of gingivitis: A review of ethnomedicinal uses, randomized clinical trials, and antibacterial potential against Porphyromonas gingivalis.

ETHNOPHARMACOLOGICAL RELEVANCE: Mouthwashes based on medicinal plants have demonstrated benefits in controlling plaque and inflammation, acting positively on the oral hygiene of patients with gingivitis. In traditional medicine, Punica granatum L. has been used to treat oral diseases in countries in Europe, Asia, North America, and Africa. AIM OF THE STUDY: The present study aimed to conduct a comprehensive review on the dental applications of Punica granatum L. for the treatment of gingivitis, including ethnomedicinal uses, analysis of randomized clinical trials, antibacterial activity against Porphyromonas gingivalis, mechanisms of action of phytochemicals isolated from this plant, and preclinical toxicity. MATERIALS AND METHODS: The literature was retrieved from Google Scholar, PubMed®, SciELO, and ScienceDirect®, since the first report published on the topic in 2001 until March 2024. RESULTS: Several clinical trials have demonstrated that mouthwashes containing P. granatum have equal or better efficacy than chlorhexidine in treating patients with gingivitis, confirming the indications for use of this plant by traditional communities. However, reports on the in vitro antibacterial activity of extracts from the fruits of this plant have not shown clinical relevance against the pathogen P. gingivalis. The ellagitannin punicalagin isolated from P. granatum has shown potential against several strains of Gram-positive and Gram-negative bacteria, but, to date, this compound has not yet been tested against P. gingivalis. It is likely that the mechanisms of action of flavonoids, such as quercetin, are involved in the inhibition of the activities of the RgpA, RgpB, and Kgp proteases of P. gingivalis. CONCLUSIONS: In summary, natural products obtained from P. granatum do not present toxic side effects and can be considered as possible substitutes of commercial products recommended for the treatment of gingivitis and other oral diseases.

Bioactivity-based Analysis and Chemical Characterization of Hypoglycemic Components from Helicteres angustifolia L.

Helicteres angustifolia L. (H. angustifolia), a well-known traditional Chinese medicine, has been demonstrated to have hypoglycemic activity. We found that the EtOAc extract of H. angustifolia (HAEF) showed stronger α-glucosidase inhibitory activity than that of positive control. Furthermore, the hypoglycemic activity of HAEF was evaluated in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) rats. The results demonstrated that HAEF reduced the drinking quantity, feeding quantity, and controlled weight loss in diabetic rats. Besides, the fasting blood glucose (FBG), viscera index, and the area under time-blood glucose curve (AUC) were significantly decreased, and the oral glucose tolerance was also improved after 5 weeks. Then, the high-performance liquid chromatography with quadrupole time of flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS) method was performed for qualitative analysis of the chemical constituents in HAEF. Twenty-one compounds were identified from in HAEF. Four compounds were further isolated from HAEF and subjected to α-glucosidase inhibition experiments. At the end, molecular docking was empolyed simulate the interaction of three compounds with α-glucosidase. This is the first report on major hypoglycaemic components has been identified in the roots of H. angustifolia. These findings provide a material basis for the use of H. angustifolia in the treatment of diabetes.

Dyotropic Rearrangement of ß-Lactams: Reaction Development, Mechanistic Study, and Application to the Total Syntheses of Tricyclic Marine Alkaloids.

An unprecedented dyotropic rearrangement of ß-lactams has been developed, which provides an enabling tool for the synthesis of structurally diverse γ-butyrolactams. Unlike the well-established dyotropic rearrangements of ß-lactones, the present reaction probably proceeds through a dual-activation mode, and thus displays unusual reactivity and chemoselectivity. The combined computational and experimental results suggest that the dyotropic rearrangement of ß-lactams may proceed through different mechanisms depending on the nature of migrating groups (H, alkyl, or aryl). Hinging on a chemoselective H-migration dyotropic rearrangement of ß-lactams, we have completed the divergent synthesis of tricyclic marine alkaloids (-)-lepadiformine A, (+)-cylindricine C, and (-)-fasicularin within 11-12 longest linear steps.

The expanding antimicrobial diversity of the genus Pantoea.

With the rise of antimicrobial resistance, there is high demand for novel antimicrobials to combat multi-drug resistant pathogens. The bacterial genus Pantoea produces a diversity of antimicrobial natural products effective against a wide range of bacterial and fungal targets. These antimicrobials are synthesized by specialized biosynthetic gene clusters that have unique distributions across Pantoea as well as several other genera outside of the Erwiniaceae. Phylogenetic and genomic evidence shows that these clusters can mobilize within and between species and potentially between genera. Pantoea antimicrobials belong to unique structural classes with diverse mechanisms of action, but despite their potential in antagonizing a wide variety of plant, human, and animal pathogens, little is known about many of these metabolites and how they function. This review will explore the known antimicrobials produced by Pantoea: agglomerins, andrimid, D-alanylgriseoluteic acid, dapdiamide, herbicolins, pantocins, and the various Pantoea Natural Products (PNPs). It will include information on the structure of each compound, their genetic basis, biosynthesis, mechanism of action, spectrum of activity, and distribution, highlighting the significance of Pantoea antimicrobials as potential therapeutics and for applications in biocontrol.

Molecular modelling and experimental validation identified a new therapeutic inhibitor of toxoplasmosis.

Toxoplasmosis is a widespread parasitic disease, caused by Toxoplasma gondii, that affects nearly one-third of the human population. The lack of effective treatments drives the demand for novel anti-toxoplasmosis therapeutic options. In the present study, we used computational approaches and experimental validation to identify therapeutic inhibitors of toxoplasmosis. Initially, using the structure of the co-crystallized ligand of T. gondii calcium-dependent protein kinase 1 (TgCDPK1), we retrieved 3000 compounds from the database of COCONUT (COlleCtion of Open Natural ProdUcTs). These compounds were docked against the crystal structure of TgCDPK1 on the Glide Ligand Docking panel of Maestro 12.5 (Schrödinger Suite 2020-3). Based on the docking scores, we assessed promising molecules for toxicity potential on the ProTox-II online server, while the ADME profiling was done on the SwissADME server. Following the computational studies, we selected nine promising compounds for experimental validation against T. gondii in vitro. Of the compounds, C4, C5, C6, and C8 exhibited dose-dependent anti-T. gondii action with EC50 values ranging from 3.3 to 120.2 µg/mL. Host toxicity profiling revealed differential cytotoxic action with a selectivity index (SI) of <1 for the compounds except C5, which had an SI of 1.8. To validate our screening assay, we used sulfadiazine, a standard drug for toxoplasmosis and showed that it inhibited parasite growth. Further experiments showed that C5, an imidazole-based natural compound, has strong but reversible anti-parasitic action that peaks within the first 8 h. In addition, C5 exhibited similar toxic tendencies towards T. gondii within (intracellular) and outside (extracellular) the host, suggesting it likely has a parasite target(s). C5 showed no effect on host invasion but strongly impeded parasite replication and growth, thereby affecting the T. gondii lytic cycle. Furthermore, C5 treatment raised the reactive oxygen species level, but this may be a secondary effect because augmentation with Trolox antioxidant failed to block C5 anti-T. gondii action. In addition, molecular dynamics simulations of C5 and TgCDPK1 complex revealed relative stability within 100 ns run time. Collectively, our findings support the potential of imidazole-based compounds as novel, alternative anti-parasitic agents.

Natural synergy: Oleanolic acid-curcumin co-assembled nanoparticles combat osteoarthritis.

Curcumin (Cur) is a natural polyphenol that is one of the most valuable natural products. However, its use as a functional food is limited by low water solubility, chemical instability and poor bioavailability. In this study, a supramolecular co-assembly strategy was used to construct an oleanolic acid-curcumin (OLA-Cur) co-assembly composite nano-slow-release treatment system. As a co-assembled compound, OLA is a widely present pentacyclic triterpenoid compound with multiple biological activities in the plant kingdom, which is expected to jointly alleviate the damaging effects of papain-induced mouse osteoarthritis model. The OLA-Cur NPs shows the solid core-shell structure, which can effectively improve the water solubility of Cur and OLA, and has good stability and sustained release characteristics. The analysis results show that the two compounds are mainly assembled through hydrogen bonding interactions, hydrophobic interactions, and π - π stacking interactions. The OLA-Cur NPs can inhibit the release of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß induced by LPS in RAW264.7 mouse macrophages, promote the secretion of anti-inflammatory cytokine IL-10, and improve the oxidative stress index of hydrogen peroxide induced human rheumatoid arthritis synovial fibroblasts. In addition, it has a certain improvement effect on cartilage and subchondral bone damage in mouse osteoarthritis models. These findings suggest that constructing co-assembled composite nanoparticles based on pure natural compounds may break through the limitations of a variety of important nutritional ingredients in functional foods.

Chevalierlin: A spirocyclic alkaloid from a hydrothermal vent associated fungus Aspergillus chevalieri TW132-65.

A previously undescribed spirodiketopiperazine-indole alkaloid, chevalierlin (1), two pairs of previously undescribed dihydroisocoumarin enantiomers eurotiumides H-I (2-3), as well as six related known compounds (4-9) were isolated from the culture of a hydrothermal vent associated fungus Aspergillus chevalieri TW132-65. Their structures were unambiguously determined by NMR, mass spectrometry, and ECD calculations. Chevalierlin (1) exhibits moderate cytotoxic activities with IC50 values of 6.20 ± 0.05 µM and 7.68 ± 0.01 µM against Namalwa and Raji cell lines.

Harnessing natural inhibitors of protein synthesis for cancer therapy: A comprehensive review.

Cancer treatment remains a formidable challenge in modern medicine, necessitating a nuanced understanding of its molecular underpinnings and the identification of novel therapeutic modalities. Among the intricate web of cellular pathways implicated in oncogenesis, protein synthesis has emerged as a fundamental process warranting meticulous investigation. This review elucidates the multifaceted role of protein synthesis pathways in tumor initiation and progression, highlighting the potential of targeting key nodes within these pathways as viable therapeutic strategies. Natural products have long served as a source of bioactive compounds with therapeutic potential owing to their structural diversity and evolutionary honing. Within this framework, we provide a thorough examination of natural inhibitors of protein synthesis as promising candidates for cancer therapy, drawing upon recent advancements and mechanistic insights. By synthesizing current evidence and elucidating key challenges and opportunities, this review aims to galvanize further research into the development of natural product-based anticancer therapeutics, thereby advancing the clinical armamentarium against malignancies.

The National Center for Natural Products Research (NCNPR) at 30: A Legacy of Pioneering Research in Natural Products and Dietary Supplements.

Since its establishment in 1994, the National Center for Natural Products Research (NCNPR) at the University of Mississippi has made notable contributions to the field of natural product research, coinciding with the passage of the Dietary Supplement Health and Education Act. Over the past three decades, the Center has focused on studying plants, herbs, and other natural materials for applications in medicine, agriculture, and nutraceuticals, particularly in the area of botanical dietary supplements. NCNPR scientists have been actively engaged in developing and improving quality control measures to help ensure the safety of dietary supplements in response to a growing market. The Center's research efforts have led to its designation as a U.S. Food and Drug Administration Center of Excellence, reflecting its role in advancing scientific understanding of natural products. Through collaborations with various stakeholders and regulators, NCNPR has contributed to shaping the regulatory landscape for botanical dietary supplements, highlighting both their potential health benefits and associated risks, such as product adulteration. The Center's influence is also evident internationally, as demonstrated by its annual International Conference on the Science of Botanicals, which will mark its 26th year in April 2025. This overview outlines NCNPR's role in supporting research, regulation, and safety in the natural products field.

Advances in natural products modulating autophagy influenced by cellular stress conditions and their anticancer roles in the treatment of ovarian cancer.

Autophagy is a conservative catabolic process that typically serves a cell-protective function. Under stress conditions, when the cellular environment becomes unstable, autophagy is activated as an adaptive response for self-protection. Autophagy delivers damaged cellular components to lysosomes for degradation and recycling, thereby providing essential nutrients for cell survival. However, this function of promoting cell survival under stress conditions often leads to malignant progression and chemotherapy resistance in cancer. Consequently, autophagy is considered a potential target for cancer therapy. Herein, we aim to review how natural products act as key modulators of autophagy by regulating cellular stress conditions. We revisit various stressors, including starvation, hypoxia, endoplasmic reticulum stress, and oxidative stress, and their regulatory relationship with autophagy, focusing on recent advances in ovarian cancer research. Additionally, we explore how polyphenolic compounds, flavonoids, alkaloids, terpenoids, and other natural products modulate autophagy mediated by stress responses, affecting the malignant biological behavior of cancer. Furthermore, we discuss their roles in ovarian cancer therapy. This review emphasizes the importance of natural products as valuable resources in cancer therapeutics, highlighting the need for further exploration of their potential in regulating autophagy. Moreover, it provides novel insights and potential therapeutic strategies in ovarian cancer by utilizing natural products to modulate autophagy.

In Vitro Antioxidant Activity and Anticonvulsant Properties on Zebrafish PTZ-Induced Seizure Model of a Tilia viridis Aqueous Extract.

Objectives: Tilia viridis (Bayer) Simonk. (Malvaceae) is widely distributed in Argentina and employed for its tranquilizing properties. Other species of the genus (Tilia europaea L., Tilia cordata Mill., Tilia platyphyllos Scop.) have been traditionally used for the treatment of epilepsy. Epilepsy affects approximately 65 million people worldwide and is characterized by an imbalance between excitatory and inhibitory processes in the brain, leading to unpredictable, unprovoked, recurrent seizures. Current pharmacological interventions often present mild to moderately severe side effects. Epilepsy has been associated with oxidative and nitrative stress as well as neuroinflammation. Herbal medicine therapies may offer new treatment options with multi-target antioxidant and anticonvulsant effects for patients whose seizures remain uncontrolled, potentially providing cost-effective solutions for individuals worldwide suffering from uncontrolled epilepsy.The aim of this study was to demonstrate the anticonvulsant activity of a standardized T. viridis aqueous extract (TE). Methods: Study of the constituents of TE, TE's antioxidant and anticonvulsant activities and toxicity, and analysis of the possible relation between the potential activities and the compounds present in the extract. In order to demonstrate TE's anticonvulsant activity a zebrafish model was used. The study also assessed TE's toxicity and antioxidant activity. To standardize the extract, total polyphenols and flavonoids were quantified and specific flavonoids were identified and quantified using HPLC-MS/MS and HPLC-UV. Results: TE exhibited anticonvulsant activity at low concentrations and demonstrated antioxidant effects by scavenging free radicals, exhibiting superoxide dismutase and peroxidase-like activities, as well as inhibiting lipoperoxidation. These actions can be attributed to the presence of polyphenols, particularly flavonoids. Conclusion: TE holds promise as a complementary herbal medicine in the treatment of epilepsy and may also offer benefits for other neuropathies associated with oxidative stress, such as Parkinson's disease and Alzheimer's disease.

Repositioning Brusatol as a Transmission Blocker of Malaria Parasites.

Currently, primaquine is the only malaria transmission-blocking drug recommended by the WHO. Recent efforts have highlighted the importance of discovering new agents that regulate malarial transmission, with particular interest in agents that can be administered in a single low dose, ideally with a discrete and Plasmodium-selective mechanism of action. Here, our team demonstrates an approach to identify malaria transmission-blocking agents through a combination of in vitro screening and in vivo analyses. Using a panel of natural products, our approach identified potent transmission blockers, as illustrated by the discovery of the transmission-blocking efficacy of brusatol. As a member of a large family of biologically active natural products, this discovery provides a critical next step toward developing methods to rapidly identify quassinoids and related agents with valuable pharmacological therapeutic properties.

Low molecular weight acids differentially impact Fusarium verticillioides transcription.

Fusarium verticillioides is both an endophyte and pathogen of maize. During growth on maize, the fungus often synthesizes the mycotoxins fumonisins, which have been linked to a variety of diseases, including cancer in some animals. How F. verticillioides responds to other fungi, such as Fusarium proliferatum, Aspergillus flavus, Aspergillus niger, and Penicillium oxalicum, that coinfect maize, has potential to impact mycotoxin synthesis and disease. We hypothesize that low molecular weight acids produced by these fungi play a role in communication between the fungi in planta/nature. To address this hypothesis, we exposed 48-h maize kernel cultures of F. verticillioides to oxalic acid, citric acid, fusaric acid, or kojic acid and then compared transcriptomes after 30 min and 6 h. Transcription of some genes were affected by multiple chemicals and others were affected by only one chemical. The most significant positive response was observed after exposure to fusaric acid which resulted in >2-fold upregulation of 225 genes, including genes involved in fusaric acid synthesis. Exposure of cultures to the other three chemicals increased expression of only 3-15 genes. The predicted function and frequent co-localization of three sets of genes support a role in protecting the fungus from the chemical or a role in catabolism. These unique transcriptional responses support our hypothesis that these chemicals can act as signaling molecules. Studies with gene deletion mutants will further indicate if the initial transcriptional response to the chemicals benefit F. verticillioides.

Deep learning in template-free de novo biosynthetic pathway design of natural products.

Natural products (NPs) are indispensable in drug development, particularly in combating infections, cancer, and neurodegenerative diseases. However, their limited availability poses significant challenges. Template-free de novo biosynthetic pathway design provides a strategic solution for NP production, with deep learning standing out as a powerful tool in this domain. This review delves into state-of-the-art deep learning algorithms in NP biosynthesis pathway design. It provides an in-depth discussion of databases like Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, and UniProt, which are essential for model training, along with chemical databases such as Reaxys, SciFinder, and PubChem for transfer learning to expand models' understanding of the broader chemical space. It evaluates the potential and challenges of sequence-to-sequence and graph-to-graph translation models for accurate single-step prediction. Additionally, it discusses search algorithms for multistep prediction and deep learning algorithms for predicting enzyme function. The review also highlights the pivotal role of deep learning in improving catalytic efficiency through enzyme engineering, which is essential for enhancing NP production. Moreover, it examines the application of large language models in pathway design, enzyme discovery, and enzyme engineering. Finally, it addresses the challenges and prospects associated with template-free approaches, offering insights into potential advancements in NP biosynthesis pathway design.

Proanthocyanidin Regulates NETosis and Inhibits the Growth and Proliferation of Liver Cancer Cells - In Vivo, In Vitro and In Silico Investigation.

Liver cancer ranks third in global cancer-related mortality, with about 700,000 deaths recorded yearly, making it one of the most common cancers worldwide. Even though prognoses differ according to the severity of the diseases, many patients now exhibit an increased life cycle since the implementation of chemotherapy. In the current study, we investigated the effect of proanthocyanidin ‒a polyphenol molecule found in many plants‒ on the proliferation and invasion of liver cancer cells. In particular, we determined the effect of proanthocyanidin on the serum levels of four strategic liver cancer target, TNFα, IL-6, cfDNA, and IL-1ß. Further molecular insight on the inhibitory mechanism of proanthocyanidin against TNFα, IL-6, and IL-1ß was obtained via molecular docking, molecular dynamics simulations and binding free energy calculations. Results showed that proanthocyanidin inhibited the growth of HepG2 and HEP3B cells, and effectively reduced clonogenic survival and invasion potential when compared to control cells. Proanthocyanidin was also found to suppress the expression of Bcl-2 (26 kDa) protein in HepG2 cells, while increasing the expression of Bax (21 kDa). Molecular dynamics (MD) and thermodynamic binding free energy calculations showed that proanthocyanidin maintained stable binding within the active site of target proteins across the entire 100 ns MD simulation period, and its binding affinity outscored respective control molecules.In conclusion, the multifaceted analysis showcased in this study demonstrated promising anti-cancer effect of proanthocyanidin on HepG2 and HEP3B cancer cells, highlighting its potential as a viable liver cancer therapeutic alternative.

Medicinal activities of Tualang honey: a systematic review.

Natural products derived from various sources, including plants, have garnered significant interest as alternative therapeutic options. Among these, Tualang honey, extracted from the nectar of Tualang trees (Koompassia excelsa (Becc.) Taub.), has a long history of traditional use due to its therapeutic properties. This review aims to examine the pharmacological activities of Tualang honey, encompassing both in vitro and in vivo studies. A systematic search was conducted in multiple databases, including PubMed, Springer, Scopus, Wiley, and Science Direct, up until December 2022 to identify relevant studies on the pharmacological activities of Tualang honey. Two independent reviewers were involved in article selection, followed by data extraction and assessment of methodological quality using Syrcle's risk of bias tool. 123 articles were included, collectively describing the pharmacological activities of Tualang honey, including antimicrobial, anticancer, anti-inflammatory, antioxidant, antinociceptive, neuroprotective effects, and others. Tualang honey has significant promise as an alternative treatment option for treating a wide range of pathological diseases due to its wide range of pharmacological properties. Tualang honey's diverse array of pharmacological actions indicates its potential for multiple medicinal uses.

Potential benefits of marine-derived compounds for slowing the advancement of Alzheimer's disease.

The incidence of Alzheimer's is increasing and poses a significant social and economic burden. The pathogenesis involved in the expansion of AD includes neuronal oxidative damage, tau phosphorylation, amyloid beta aggregation, neuroinflammation, etc. Despite enormous efforts, there is currently no effective treatment or cure for this condition in the allopathic system. Marine compounds are appealing options and have a strong neuroprotective impact. Marine-derived compounds from sponges, algae, and marine invertebrates can be used for neuroprotection, with fewer adverse effects than synthetic drugs. Various compounds such as bryostatin-1, docosahexaenoic acid, spirolides, and astaxanthin, GV-971, have demonstrated outstanding activity and bioavailability.

Discovery of anti-infective compounds against Mycobacterium marinum after biotransformation of simple natural stilbenes by a fungal secretome.

Introduction: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains a serious threat to human health worldwide and the quest for new anti-tubercular drugs is an enduring and demanding journey. Natural products (NPs) have played a significant role in advancing drug therapy of infectious diseases. Methods: This study evaluated the suitability of a high-throughput infection system composed of the host amoeba Dictyostelium discoideum (Dd) and Mycobacterium marinum (Mm), a close relative of Mtb, to identify anti-infective compounds. Growth of Dd and intracellular Mm were quantified by using luminescence and fluorescence readouts in phenotypic assays. The system was first benchmarked with a set of therapeutic anti-Mtb antibiotics and then used to screen a library of biotransformed stilbenes. Results: The study confirmed both efficacy of established antibiotics such as rifampicin and bedaquiline, with activities below defined anti-mycobacterium susceptibility breakpoints, and the lack of activity of pyrazinamide against Mm. The screening revealed the promising anti-infective activities of trans-δ-viniferins and in particular of two compounds 17 and 19 with an IC50 of 18.1 µM, 9 µM, respectively. Both compounds had no activity on Mm in broth. Subsequent exploration via halogenation and structure-activity relationship studies led to the identification of derivatives with improved selectivity and potency. The modes of action of the anti-infective compounds may involve inhibition of mycobacterial virulence factors or boosting of host defense. Discussion: The study highlights the potential of biotransformation and NP-inspired derivatization approaches for drug discovery and underscores the utility of the Dd-Mm infection system in identifying novel anti-infective compounds.