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Marine Drugs Jul 2023In reviewing a selection of recent case studies from our laboratory, we revealed some lessons learned and benefits accrued from the application of mass spectrometry...
In reviewing a selection of recent case studies from our laboratory, we revealed some lessons learned and benefits accrued from the application of mass spectrometry (MS/MS) molecular networking in the field of marine sponge natural products. Molecular networking proved pivotal to our discovery of many new natural products and even new classes of natural product, some of which were opaque to alternate dereplication and prioritization strategies. Case studies included the discovery of: (i) trachycladindoles, an exceptionally rare class of bioactive indole alkaloid previously only known from a single southern Australia sample of ; (ii) dysidealactams, an unprecedented class of sesquiterpene glycinyl-lactam and glycinyl-imide from a sp., a sponge genera often discounted as having been exhaustively studied; (iii) cacolides, an unprecedented family of sesterterpene α-methyl-γ-hydroxybutenolides from a sp., all too easily mischaracterized and deprioritized during dereplication as a well-known class of sponge sesterterpene tetronic acids; and (iv) thorectandrins, a new class of indole alkaloid which revealed unexpected insights into the chemical and biological properties of the aplysinopsins, one of the earliest and more extensively reported class of sponge natural products.
Topics: Animals; Tandem Mass Spectrometry; Sesterterpenes; Porifera; Biological Products; Indole Alkaloids
PubMed: 37504944
DOI: 10.3390/md21070413 -
Phytomedicine : International Journal... Apr 2024Stomach diseases have become global health concerns. Protoberberine alkaloids (PBAs) are a group of quaternary isoquinoline alkaloids from abundant natural sources and... (Review)
Review
BACKGROUND
Stomach diseases have become global health concerns. Protoberberine alkaloids (PBAs) are a group of quaternary isoquinoline alkaloids from abundant natural sources and have been shown to improve gastric disorders in preclinical and clinical studies. The finding that PBAs exhibit low oral bioavailability but potent pharmacological activity has attracted great interest.
PURPOSE
This review aims to provide a systematic review of the molecular mechanisms of PBAs in the treatment of gastric disorders and to discuss the current understanding of the pharmacokinetics and toxicity of PBAs.
METHODS
The articles related to PBAs were collected from the Web of Science, Pubmed, and China National Knowledge Infrastructure databases using relevant keywords. The collected articles were screened and categorized according to their research content to focus on the gastroprotective effects, pharmacokinetics, and toxicity of PBAs.
RESULTS
Based on the results of preclinical studies, PBAs have demonstrated therapeutic effects on chronic atrophic gastritis and gastric cancer by activating interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (STAT6) pathway and suppressing transforming growth factor-beta 1 (TGF-β1)/phosphoinositide 3-kinase (PI3K), Janus kinase-2 (JAK2)/signal transducers and activators of transcription 3 (STAT3), and mitogen-activated protein kinase (MAPK) pathways. The major PBAs exhibit similar pharmacokinetic properties, including rapid absorption, slow elimination, and low bioavailability. Notably, the natural organ-targeting property of PBAs may account for the finding of their low blood levels and high pharmacological activity. PBAs interact with other compounds, including conventional drugs and natural products, by modulation of metabolic enzymes and transporters. The potential tissue toxicity of PBAs should be emphasized due to their high tissue accumulation.
CONCLUSION
This review highlights the gastroprotective effects, pharmacokinetics, and toxicity of PBAs and will contribute to the evaluation of drug properties and clinical translational studies of PBAs, accelerating their transfer from the laboratory to the bedside.
Topics: Phosphatidylinositol 3-Kinases; Alkaloids; Berberine Alkaloids; Drugs, Chinese Herbal
PubMed: 38367423
DOI: 10.1016/j.phymed.2024.155444 -
Molecules (Basel, Switzerland) Nov 2023Neurological ailments, including stroke, Alzheimer's disease (AD), epilepsy, Parkinson's disease (PD), and other related diseases, have affected around 1 billion people... (Review)
Review
Neurological ailments, including stroke, Alzheimer's disease (AD), epilepsy, Parkinson's disease (PD), and other related diseases, have affected around 1 billion people globally to date. PD stands second among the common neurodegenerative diseases caused as a result of dopaminergic neuron loss in the midbrain's substantia nigra regions. It affects cognitive and motor activities, resulting in tremors during rest, slow movement, and muscle stiffness. There are various traditional approaches for the management of PD, but they provide only symptomatic relief. Thus, a survey for finding new biomolecules or substances exhibiting the therapeutic potential to patients with PD is the main focus of present-day research. Medicinal plants, herbal formulations, and natural bioactive molecules have been gaining much more attention in recent years as synthetic molecules orchestrate a number of undesired effects. Several in vitro, in vivo, and in silico studies in the recent past have demonstrated the therapeutic potential of medicinal plants, herbal formulations, and plant-based bioactives. Among the plant-based bioactives, polyphenols, terpenes, and alkaloids are of particular interest due to their potent anti-inflammatory, antioxidant, and brain-health-promoting properties. Further, there are no concise, elaborated articles comprising updated mechanism-of-action-based reviews of the published literature on potent, recently investigated (2019-2023) medicinal plants, herbal formulations, and plant based-bioactive molecules, including polyphenols, terpenes, and alkaloids, as a method for the management of PD. Therefore, we designed the current review to provide an illustration of the efficacious role of various medicinal plants, herbal formulations, and bioactives (polyphenols, terpenes, and alkaloids) that can become potential therapeutics against PD with greater specificity, target approachability, bioavailability, and safety to the host. This information can be further utilized in the future to develop several value-added formulations and nutraceutical products to achieve the desired safety and efficacy for the management of PD.
Topics: Humans; Parkinson Disease; Plants, Medicinal; Neurodegenerative Diseases; Alkaloids; Terpenes
PubMed: 38005310
DOI: 10.3390/molecules28227588 -
International Journal of Molecular... Nov 2023Palmatine, a natural alkaloid found in various plants, has been reported to have diverse pharmacological and biological effects, including anti-inflammatory,...
Palmatine, a natural alkaloid found in various plants, has been reported to have diverse pharmacological and biological effects, including anti-inflammatory, antioxidant, and cardiovascular effects. However, the role of palmatine in mitophagy, a fundamental process crucial for maintaining mitochondrial function, remains elusive. In this study, we found that palmatine efficiently induces mitophagy in various human cell lines. Palmatine specifically induces mitophagy and subsequently stimulates mitochondrial biogenesis. Palmatine did not interfere with mitochondrial function, similar to CCCP, suggesting that palmatine is not toxic to mitochondria. Importantly, palmatine treatment alleviated mitochondrial dysfunction in PINK1-knockout MEFs. Moreover, the administration of palmatine resulted in significant improvements in cognitive function and restored mitochondrial function in an Alzheimer's disease mouse model. This study identifies palmatine as a novel inducer of selective mitophagy. Our results suggest that palmatine-mediated mitophagy induction could be a potential strategy for Alzheimer's disease treatment and that natural alkaloids are potential sources of mitophagy inducers.
Topics: Mice; Animals; Humans; Mitophagy; Alzheimer Disease; Mitochondria; Alkaloids; Ubiquitin-Protein Ligases
PubMed: 38003731
DOI: 10.3390/ijms242216542 -
International Journal of Molecular... Mar 2024Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple... (Review)
Review
Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-β peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.
Topics: Humans; NF-E2-Related Factor 2; Alkaloids; Diabetes Mellitus; Oxidative Stress
PubMed: 38542359
DOI: 10.3390/ijms25063385 -
International Journal of Molecular... Aug 2023Furoquinoline alkaloids exhibit a diverse range of effects, making them potential candidates for medicinal applications. Several compounds within this group have... (Review)
Review
Furoquinoline alkaloids exhibit a diverse range of effects, making them potential candidates for medicinal applications. Several compounds within this group have demonstrated antimicrobial and antiprotozoal properties. Of great interest is their potential as acetylcholinesterase inhibitors and anti-inflammatory agents in neurodegenerative diseases. The promising biological properties of furoquinoline alkaloids have motivated extensive research in this field. As a result, new compounds have been isolated from this group of secondary metabolites, and numerous pharmacological studies have been conducted to investigate their activity. It is crucial to understand the mechanisms of action of furoquinoline alkaloids due to their potential toxicity. Further research is required to elucidate their mechanisms of action and metabolism. Additionally, the exploration of derivative compounds holds significant potential in enhancing their pharmacological benefits. In vitro plant cultures offer an alternative approach to obtaining alkaloids from plant material, presenting a promising avenue for future investigations.
Topics: Acetylcholinesterase; Alkaloids; Cholinesterase Inhibitors; Radiopharmaceuticals
PubMed: 37628986
DOI: 10.3390/ijms241612811 -
Pharmaceutical Biology Dec 2023Alkaloid-enriched extract of (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders.
CONTEXT
Alkaloid-enriched extract of (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders.
OBJECTIVE
This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms.
MATERIALS AND METHODS
BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting.
RESULTS
HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1β compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway.
DISCUSSION AND CONCLUSIONS
HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases.
Topics: Lipopolysaccharides; Huperzia; Interleukin-6; Neuroinflammatory Diseases; Dinoprostone; Microglia; Tumor Necrosis Factor-alpha; Extracellular Signal-Regulated MAP Kinases; Alkaloids; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II
PubMed: 36617895
DOI: 10.1080/13880209.2022.2159450 -
Journal of Medicinal Chemistry Aug 2023Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new...
Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.
Topics: Animals; Alkaloids; Antineoplastic Agents; Ferroptosis; Neoplasms; Tumor Suppressor Protein p53
PubMed: 37578947
DOI: 10.1021/acs.jmedchem.3c00659 -
Toxins Mar 2024Alkaloids play an essential role in protecting plants against herbivores. Humans can also benefit from the pharmacological effects of these compounds. Plants produce an... (Review)
Review
Alkaloids play an essential role in protecting plants against herbivores. Humans can also benefit from the pharmacological effects of these compounds. Plants produce an immense variety of structurally different alkaloids, including quinolizidine alkaloids, a group of bi-, tri-, and tetracyclic compounds produced by species. Various lupin species produce different alkaloid profiles. To study the composition of quinolizidine alkaloids in lupin seeds, we collected 31 populations of two wild species native to Israel, and , and analyzed their quinolizidine alkaloid contents. Our goal was to study the alkaloid profiles of these two wild species to better understand the challenges and prospective uses of wild lupins. We compared their profiles with those of other commercial and wild lupin species. To this end, a straightforward method for extracting alkaloids from seeds and determining the quinolizidine alkaloid profile by LC-MS/MS was developed and validated in-house. For the quantification of quinolizidine alkaloids, 15 analytical reference standards were used. We used GC-MS to verify and cross-reference the identity of certain alkaloids for which no analytical standards were available. The results enabled further exploration of quinolizidine alkaloid biosynthesis. We reviewed and re-analyzed the suggested quinolizidine alkaloid biosynthesis pathway, including the relationship between the amino acid precursor l-lysine and the different quinolizidine alkaloids occurring in seeds of lupin species. Revealing alkaloid compositions and highlighting some aspects of their formation pathway are important steps in evaluating the use of wild lupins as a novel legume crop.
Topics: Humans; Quinolizidine Alkaloids; Lupinus; Chromatography, Liquid; Tandem Mass Spectrometry; Seeds
PubMed: 38535829
DOI: 10.3390/toxins16030163 -
Phytochemistry Sep 2023Four undescribed tryptamine-derived alkaloids, hunteriasines A - D, were isolated and identified from Hunteria umbellata (Apocynaceae), together with fifteen known...
Four undescribed tryptamine-derived alkaloids, hunteriasines A - D, were isolated and identified from Hunteria umbellata (Apocynaceae), together with fifteen known indole alkaloids. The chemical structure and absolute configuration of hunteriasine A were determined by spectroscopic and X-ray crystallographic data analyses. Hunteriasine A, featuring with a unique scaffold comprised of tryptamine and an unprecedented "12-carbon unit" moiety, is a zwitterionic indole-derived and pyridinium-containing alkaloid. Hunteriasines B - D were identified by spectroscopic data analyses and theoretical calculations. A plausible biogenetic pathway for hunteriasines A and B was proposed. The lipopolysaccharide-stimulated mouse macrophage cell line J774A.1 cell-based bioactivity assays revealed that (+)-eburnamine, strictosidinic acid, and (S)-decarbomethoxydihydrogambirtannine enhance the release of interleukin-1β.
Topics: Mice; Animals; Alkaloids; Indole Alkaloids; Apocynaceae; Plant Extracts; Tryptamines; Molecular Structure; Secologanin Tryptamine Alkaloids
PubMed: 37330032
DOI: 10.1016/j.phytochem.2023.113752