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Annals of Medicine Dec 2022Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant... (Review)
Review
Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources. The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α-adrenergic receptors and has a moderate affinity for 1 and 2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors. The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.
Topics: Male; Humans; Yohimbine; Adrenergic alpha-Antagonists; Aphrodisiacs; Receptors, Adrenergic, alpha-2; Pharmaceutical Preparations
PubMed: 36263866
DOI: 10.1080/07853890.2022.2131330 -
Journal For Immunotherapy of Cancer Aug 2023Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be...
BACKGROUND
Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response.
METHOD
We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8 T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment.
RESULTS
Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8 T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages.
CONCLUSIONS
This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.
Topics: Animals; Mice; Tumor-Associated Macrophages; Vinblastine; CD8-Positive T-Lymphocytes; Macrophages; Immunity
PubMed: 37652576
DOI: 10.1136/jitc-2023-007253 -
Nature Sep 2022Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer...
Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine. As MIAs are difficult to chemically synthesize, the world's supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.
Topics: Antineoplastic Agents; Bioreactors; Biosynthetic Pathways; Catharanthus; Genes, Fungal; Genes, Plant; Metabolic Engineering; Polyisoprenyl Phosphates; Saccharomyces cerevisiae; Tryptophan; Vinblastine; Vinca Alkaloids
PubMed: 36045295
DOI: 10.1038/s41586-022-05157-3 -
International Journal of Molecular... May 2022Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most... (Review)
Review
Antimitotic agents such as the clinically approved vinca alkaloids, taxanes and epothilone can arrest cell growth during interphase and are therefore among the most important drugs available for treating cancer. These agents suppress microtubule dynamics and thus interfere with intracellular transport, inhibit cell proliferation and promote cell death. Because these drugs target biological processes that are essential to all cells, they face an additional challenge when compared to most other drug classes. General toxicity can limit the applicable dose and therefore reduce therapeutic benefits. Photopharmacology aims to avoid these side-effects by introducing compounds that can be applied globally to cells in their inactive form, then be selectively induced to bioactivity in targeted cells or tissue during a defined time window. This review discusses photoswitchable analogues of antimitotic agents that have been developed by combining different photoswitchable motifs with microtubule-stabilizing or microtubule-destabilizing agents.
Topics: Antimitotic Agents; Antineoplastic Agents; Humans; Microtubules; Neoplasms; Vinca Alkaloids
PubMed: 35628467
DOI: 10.3390/ijms23105657 -
Journal of Chromatography. B,... Apr 2021A simple, rapid, and sensitive LC-MS/MS method for determining concentrations of the anticancer alkaloid vincristine in micro volumes of mouse plasma was developed and...
A simple, rapid, and sensitive LC-MS/MS method for determining concentrations of the anticancer alkaloid vincristine in micro volumes of mouse plasma was developed and validated in positive ion mode. Separation of vincristine and the internal standard [H]-vincristine was achieved on an Accucore aQ column with a gradient mobile phase delivered at a flow rate of 0.4 mL/min and a run time of 2.2 min. Calibration curves were linear (r > 0.99, n = 8) up to 250 ng/mL, with a lower limit of quantitation of 2.5 ng/mL. The matrix effect and extraction recovery for vincristine were ranging 108-110% and 88.4-107%, respectively. The intra-day and inter-day precision of quality controls tested at 3 different concentrations were always less than 15%, and accuracy ranged from 91.7 to 107%. The method was successfully applied to evaluate the pharmacokinetic profile of vincristine in wild-type and CYP3A-deficient mice in support of a project to provide mechanistic insight into drug-drug interactions and to identify sources of inter-individual pharmacokinetic variability associated with vincristine-induced peripheral neuropathy.
Topics: Animals; Chromatography, High Pressure Liquid; Limit of Detection; Linear Models; Male; Mice; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Vincristine
PubMed: 33684722
DOI: 10.1016/j.jchromb.2021.122591 -
The Alkaloids. Chemistry and Biology 2016The sarpagine-related macroline and ajmaline alkaloids share a common biosynthetic origin, and bear important structural similarities, as expected. These indole... (Review)
Review
The sarpagine-related macroline and ajmaline alkaloids share a common biosynthetic origin, and bear important structural similarities, as expected. These indole alkaloids are widely dispersed in 25 plant genera, principally in the family Apocynaceae. Very diverse and interesting biological properties have been reported for this group of natural products. Isolation of new sarpagine-related alkaloids and the asymmetric synthesis of these structurally complex molecules are of paramount importance to the synthetic and medicinal chemists. A total of 115 newly isolated sarpagine-related macroline and ajmaline alkaloids, along with their physicochemical properties have been included in this chapter. A general and efficient strategy for the synthesis of these monomeric alkaloids, as well as bisindoles, has been presented, which involves application of the asymmetric Pictet-Spengler reaction (>98% ee) as a key step because of the ease of scale up of the tetracyclic template. Also included in this chapter are the syntheses of the sarpagine-related alkaloids, published since 2000.
Topics: Ajmaline; Indole Alkaloids; Magnetic Resonance Spectroscopy; Secologanin Tryptamine Alkaloids
PubMed: 26827883
DOI: 10.1016/bs.alkal.2015.08.002 -
Canadian Medical Association Journal Sep 1961
Topics: Alkaloids; Antineoplastic Agents; Vinblastine
PubMed: 13729372
DOI: No ID Found -
The Yale Journal of Biology and Medicine Jun 2020, otherwise known as kratom, is a plant in the coffee family (Rubiaceae) native to Southeast Asia and Thailand whose leaves have been shown to cause opioid-like and... (Review)
Review
, otherwise known as kratom, is a plant in the coffee family (Rubiaceae) native to Southeast Asia and Thailand whose leaves have been shown to cause opioid-like and stimulant responses upon ingestion. The major pharmacologically active compounds present in kratom, mitragynine and 7-hydroxymitragynine (7-HMG), are both indole alkaloids and are responsible for its opioid-like activity. While kratom is most commonly known for its affinity for mu-opioid receptors, research has shown one of its active components has effects on the same receptors to which some antipsychotics bind, such as D dopamine, serotonin (5-HT and 5-HT), and alpha-2 adrenergic receptors displaying possible indications of kratom to be used as both antipsychotics and antidepressants. Although studies to evaluate this effect are still lacking, several online and in-person surveys note relief of depression and anxiety symptoms among those who consume kratom products, and in fact identify it as a common reason for consumption. This then highlights the dire need for further research to be conducted on kratom, its mechanism of action and the constituents that elicit these antidepressant, anxiolytic, and antipsychotic properties.
Topics: Antidepressive Agents; Antipsychotic Agents; Behavioral Symptoms; Biological Products; Humans; Indole Alkaloids; Mitragyna; Receptors, Opioid; Secologanin Tryptamine Alkaloids; Treatment Outcome
PubMed: 32607089
DOI: No ID Found -
ACS Chemical Neuroscience Jan 2023Alkaloids from the botanical (commonly referred to as "kratom") interact with opioid, adrenergic, serotonergic, and other receptors to provide myriad reported effects,...
Alkaloids from the botanical (commonly referred to as "kratom") interact with opioid, adrenergic, serotonergic, and other receptors to provide myriad reported effects, including analgesia, energy, improved mood, and relaxation, among others. These alkaloids are complex and unique and may serve as a blueprint for the development of novel molecules to treat various substance use disorders.
Topics: Humans; Plant Extracts; Secologanin Tryptamine Alkaloids; Analgesics, Opioid; Substance-Related Disorders; Mitragyna
PubMed: 36594896
DOI: 10.1021/acschemneuro.2c00704 -
PloS One 2022Leaves harvested from kratom [Mitragyna speciosa (Korth.)] have a history of use as a traditional ethnobotanical medicine to combat fatigue and improve work productivity...
Leaves harvested from kratom [Mitragyna speciosa (Korth.)] have a history of use as a traditional ethnobotanical medicine to combat fatigue and improve work productivity in Southeast Asia. In recent years, increased interest in the application and use of kratom has emerged globally, including North America, for its potential application as an alternative source of medicine for pain management and opioid withdrawal syndrome mitigation. Although the chemistry and pharmacology of major kratom alkaloids, mitragynine and 7-hydroxymitragynine, are well documented, foundational information on the impact of plant production environment on growth and kratom alkaloids synthesis is unavailable. To directly address this need, kratom plant growth, leaf chlorophyll content, and alkaloid concentration were evaluated under three lighting conditions: field full sun (FLD-Sun), greenhouse unshaded (GH-Unshaded), and greenhouse shaded (GH-Shaded). Nine kratom alkaloids were quantified using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Greenhouse cultivation generally promoted kratom height and width extension by 93-114% and 53-57%, respectively, compared to FLD-Sun. Similarly, total leaf area and leaf number were increased by 118-160% and 54-80% under such conditions. Average leaf size of plants grown under GH-Shaded was 41 and 69% greater than GH-Unshaded and FLD-Sun, respectively; however, no differences were observed between GH-Unshaded and FLD-Sun treatments. At the termination of the study, total leaf chlorophyll a+b content of FLD-Sun was 17-23% less than those grown in the greenhouse. Total leaf dry mass was maximized when cultivated in the greenhouse and was 89-91% greater than in the field. Leaf content of four alkaloids to include speciociliatine, mitraphylline, corynantheidine, and isocorynantheidine were not significantly impacted by lighting conditions, whereas 7-hydroxymitragynine was below the lower limit of quantification across all treatments. However, mitragynine, paynantheine, and corynoxine concentration per leaf dry mass were increased by 40%, 35%, and 111%, respectively, when cultivated under GH-Shaded compared to FLD-Sun. Additionally, total alkaloid yield per plant was maximized and nearly tripled for several alkaloids when plants were cultivated under such conditions. Furthermore, rapid, non-destructive chlorophyll evaluation correlated well (r2 = 0.68) with extracted chlorophyll concentrations. Given these findings, production efforts where low-light conditions can be implemented are likely to maximize plant biomass and total leaf alkaloid production.
Topics: Chlorophyll A; Chromatography, Liquid; Mitragyna; Plant Extracts; Secologanin Tryptamine Alkaloids; Substance Withdrawal Syndrome; Tandem Mass Spectrometry
PubMed: 35472200
DOI: 10.1371/journal.pone.0259326