Plant Alkaloid Research Articles

Pharmacokinetic and Phytochemical Appraisal of Trigonella foenum and Andrographis lineata in Dimethylnitrosamine Induced Injury in Albino Rats

Trigonelline is a plant alkaloid and Andrographolide is a diterpene lactone, both exhibiting anti-inflammatory, antioxidant and neuroprotective activities. The present study was designed to evaluate the antioxidative and anti-inflammatory activity of the above said compounds in Dimethylnitrosamine induced toxicity in albino rats. Extraction of Trigonella foenum and Andrographis lineata was carried out by using methanol, petroleum ether, ethyl acetate and ethanol assisted with suitable temperature, followed by DPPH scavenging activity (IC-50) of these extracts.Cmax, Tmax, t1/2, CL, Vd and AUC were evaluated as pharmacokinetic parameters by using calibration curves of Andrographolide and Trigonelline. Extracts of T. foenum-graecum and A. lineate have antioxidant activity by inhibiting DPPH (IC50 value was 69.04±3.65% and 71.76±6.99%, respectively) comparable with ascorbic acid (53.99±4.88%). Phytochemical analysis of T. foenum-graecum and A. lineate was found with maximum number of phenols in them, with least recovery in the ethyl acetate extract while maximum phenols were found in T. foenum graecum. All the pharmacokinetic parameters of trigonelline and andrographolide administered in low dose (200 mg/kg and 50 mg/kg respectively) confirmed the better antioxidative activity than that of ascorbic acid used as a potent antioxidant.

Plant Alkaloids Inhibit Membrane Fusion Mediated by Calcium and Fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 Fusion Peptides.

To rationalize the antiviral actions of plant alkaloids, the ability of 20 compounds to inhibit calcium-mediated fusion of lipid vesicles composed of phosphatidylglycerol and cholesterol was investigated using the calcein release assay and dynamic light scattering. Piperine, tabersonine, hordenine, lupinine, quinine, and 3-isobutyl-1-methylxanthine demonstrated the most potent effects (inhibition index greater than 50%). The introduction of phosphatidylcholine into the phosphatidylglycerol/cholesterol mixture led to significant changes in quinine, hordenine, and 3-isobutyl-1-methylxanthine efficiency. Comparison of the fusion inhibitory ability of the tested alkaloids, and the results of the measurements of alkaloid-induced alterations in the physical properties of model membranes indicated a potent relationship between a decrease in the cooperativity of the phase transition of lipids and the ability of alkaloids to prevent calcium-mediated vesicle fusion. In order to use this knowledge to combat the novel coronavirus pandemic, the ability of the most effective compounds to suppress membrane fusion induced by fragments of MERS-CoV and SARS-CoV/SARS-CoV-2 fusion peptides was studied using the calcein release assay and confocal fluorescence microscopy. Piperine was shown to inhibit vesicle fusion mediated by both coronavirus peptides. Moreover, piperine was shown to significantly reduce the titer of SARS-CoV2 progeny in vitro in Vero cells when used in non-toxic concentrations.

Antitumor activity of solamargine in mouse melanoma model: relevance to clinical safety

ABSTRACT Melanoma is the most aggressive type of skin cancer, and thus it is important to develop new drugs for its treatment. The present study aimed to examine the antitumor effects of solamargine a major alkaloid heteroside present in Solanum lycocarpum fruit. In addition solamargine was incorporated into nanoparticles (NP) of yttrium vanadate functionalized with 3-chloropropyltrimethoxysilane (YVO4:Eu3+:CPTES:SM) to determine antitumor activity. The anti-melanoma assessment was performed using a syngeneic mouse melanoma model B16F10 cell line. In addition, systemic toxicity, nephrotoxic, and genotoxic parameters were assessed. Solamargine, at doses of 5 or 10 mg/kg/day administered subcutaneously to male C57BL/6 mice for 5 days, decreased tumor size and frequency of mitoses in tumor tissue, indicative of a decrease in cell proliferation. Treatments with YVO4:Eu3+:CPTES:SM significantly reduced the number of mitoses in tumor tissue, associated with no change in tumor size. There were no apparent signs of systemic toxicity, nephrotoxicity, and genotoxicity initiated by treatments either with solamargine alone or plant alkaloid incorporated into NP. The animals treated with YVO4:Eu3+:CPTES:SM exhibited significant increase in spleen weight accompanied by no apparent histological changes in all tissues examined. In addition, animals treated with solamargine (10 mg/kg/day) and YVO4:Eu3+:CPTES:SM demonstrated significant reduction in hepatic DNA damage which was induced by tumor growth. Therefore, data suggest that solamargine may be considered a promising candidate in cancer therapy with no apparent toxic effects.

Anti-inflammatory efficacy of Berberine Nanomicelle for improvement of cerebral ischemia: formulation, characterization and evaluation in bilateral common carotid artery occlusion rat model

BackgroundBerberine (BBR) is a plant alkaloid that possesses anti-inflammatory and anti-oxidant effects with low oral bioavailability. In this study, micelle formulation of BBR was investigated to improve therapeutic efficacy and examined its effect on the secretion of inflammatory cytokines in cerebral ischemia in the animal model.Material and methodsNano formulation was prepared by thin-film hydration method, and characterized by particle size, zeta potential, morphology, encapsulation efficacy, and drug release in Simulated Gastric Fluid (SGF) and Simulated Intestine Fluid (SIF). Then, Wistar rats were pretreated with the drug (100 mg/kg) and nano-drug (25, 50, 75, 100 mg/kg) for 14 days. Then, on the fourteenth day, stroke induction was accomplished by Bilateral Common Carotid Artery Occlusion (BCCAO); after that, Tumor Necrosis Factor - Alpha (TNF-α), Interleukin – 1 Beta (IL-1ß), and Malondialdehyde (MDA) levels were measured in the supernatant of the whole brain, then the anti-inflammatory effect of BBR formulations was examined.Result and discussionMicelles were successfully formed with appropriate characteristics and smaller sizes than 20 nm. The Poly Dispersity Index (PDI), zeta potential, encapsulation efficacy of micelles was 0.227, − 22 mV, 81%, respectively. Also, the stability of nano micelles was higher in SGF as compared to SIF. Our outcomes of TNF-a, IL-1B, and MDA evaluation show a significant ameliorating effect of the Berberine (BBR) and BBR-loaded micelles in pretreated groups.ConclusionOur experimental data show that pretreated groups in different doses (nano BBR 100, 75, 50 mg/kg, and BBR 100 mg/kg) successfully showed decreased levels of the inflammatory factors in cerebral ischemia compared with the stroke group and pretreated group with nano BBR in the dose of 25 mg/kg. Nano BBR formulation with a lower dose can be a better candidate than conventional BBR formulation to reduce oxidative and inflammatory factors in cerebral ischemia. Therefore, BBR-loaded micelle formulation could be a promising protective agent on cerebral ischemia.

Risk factors for ED visits and admissions during outpatient chemotherapy in head and neck cancer.

223 Background: Despite the recent introduction of the CMS metric, OP-35, which tracks 30-day inpatient admissions and ED visits after outpatient chemotherapy administration, the risk factors driving acute care utilization (ACU) in the head and neck cancer treatment setting are not yet well understood. Further characterization of these risk factors could allow for improved care quality and reduce preventable inpatient and ED admissions. Methods: This was a retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked cancer registry-claims database. The study cohort consisted of patients aged 66 years or older diagnosed with head and neck cancer between 2004-2015 who received outpatient chemotherapy within the first two years after diagnosis. Multivariable logistic regression modeling was utilized to characterize the risk factors associated with an inpatient or ED admission within 30 days after receiving chemotherapy. Results: Of the 2,236 eligible patients, 735 (32.9%) had at least one inpatient or ED admission within 30 days of receiving outpatient chemotherapy. On multivariable analysis, cancer of the oral cavity [odds ratio (OR) 1.43; 95% confidence interval (CI) 1.04-1.96] and oropharynx/hypopharynx [OR 1.34; 95% CI 1.06-1.70] were associated with an increased odds of ACU. Other factors associated with ACU included NCI comorbidity index [OR 1.10; 95% CI 1.03-1.18], prior ACU [OR 1.06; 95% CI 1.02-1.09], second cycle of chemotherapy relative to the first cycle [OR 0.38, 95% CI 0.29-0.50], and third or greater cycle of chemotherapy [OR 0.17; 95% CI 0.13-0.21]. Certain chemotherapeutic agents also modified risk: use of an angiogenesis inhibitor [OR 0.18; 95% CI 0.06-0.45], alkylating agent [OR 1.24; 95% 1.01-1.53], plant alkaloid [OR 1.63; 95% CI 1.25-2.10], or antimetabolite [OR 2.69; 95% CI 1.78-4.09]. The most common admission diagnosis was pain (n = 243; 33.1%) followed by dehydration (n = 167; 22.7%). Conclusions: Multiple clinical variables modify risk of acute care utilization after outpatient chemotherapy in the head and neck cancer setting, providing several potential avenues of intervention for providers.

An Efficient Access to 3,5‐Disubstituted Isoxazoles with Anthranilate Ester Moiety: Alkaloid Lappaconitine – Aryl Conjugates with an Isoxazole Linker

AbstractAlkynones have gained great attention as useful building blocks in organic synthesis. They have been emerged as key intermediates in the synthesis of various heterocycles. In the present study, the alkynylketones derived from antranylic acids esters or alkaloid lappaconitine were employed as a platform for late‐stage derivatisation. The synthesis of regioisomeric 3,5‐diarylisoxazoles was achieved starting from ethyl N‐acetyl‐5‐iodoanthranilate. A range of 3,5‐disubstituted isoxazoles, containing the plant alkaloid lappaconitine moiety at the C‐3 position were convenience synthesized by a consecutive three‐component alkynylation‐cyclocondensation sequence starting from of 5′‐ethynyllappaconitine, aroyl chlorides, and hydroxylamine hydrochloride. Notably, several 5‐hydroxy‐4,5‐dihydroisoxazoles were obtained in good yields as main products in this three component reaction by using Et3N as the base and i‐PrOH as the solvent in cyclocondensation step.

NIC1 cloning and gene editing generates low-nicotine tobacco plants.

Nicotine is the predominant alkaloid in tobacco plants, accounting for ~90% of their total alkaloid content. It is the main addictive substance in cigarettes. Reducing nicotine content in tobacco leaves will aid the development of low nicotine tobacco products. Prior work has shown that manipulation of genes involved in nicotine biosynthesis can achieve this purpose (Hidalgo Martinez et al., 2020). Here, we focused on the long-sought major regulator of nicotine biosynthesis, NIC1 (A).

Berberine Photo-Activation Potentiates Cytotoxicity in Human Astrocytoma Cells through Apoptosis Induction

Photodynamic therapy (PDT) has recently attracted interest as an innovative and adjuvant treatment for different cancers including malignant gliomas. Among these, Glioblastoma (GBM) is the most prevalent neoplasm in the central nervous system. Despite conventional therapeutic approaches that include surgical removal, radiation, and chemotherapy, GBM is characterized by an extremely poor prognosis and a high rate of recurrence. PDT is a physical process that induces tumor cell death through the genesis and accumulation of reactive oxygen species (ROS) produced by light energy interaction with a photosensitizing agent. In this contribution, we explored the potentiality of the plant alkaloid berberine (BBR) as a photosensitizing and cytotoxic agent coupled with a PDT scheme using a blue light source in human established astrocytoma cell lines. Our data mainly indicated for the combined BBR-PDT scheme a potent activation of the apoptosis pathway, through a massive ROS production, a great extent of mitochondria depolarization, and the sub-sequent activation of caspases. Altogether, these results demonstrated that BBR is an efficient photosensitizer agent and that its association with PDT may be a potential anticancer strategy for high malignant gliomas.

Berberine Alleviates Non-alcoholic Steatohepatitis Through Modulating Gut Microbiota Mediated Intestinal FXR Activation.

Berberine is a natural plant alkaloid isolated from a diverse range of genera, it obtains anti-inflammatory, anti-obesity, and hepatoprotective properties, and is a promising agent for non-alcoholic steatohepatitis (NASH). Farnesoid X receptor (FXR) is a bile acid receptor and a drug target for NASH, however, the underlying mechanisms of berberine on regulating FXR are still unknown. In the present study, we feed mice with a 12-week high-fat diet with interval dextran sulfate sodium (0.5% in drinking water) diet to induce NASH, and treat the mice with berberine (100 mg/kg per day) via oral gavage for additional 4 weeks. We demonstrate that administration of berberine alleviates steatosis and infiltration of inflammatory cells in the liver of NASH mice. We apply 16S ribosomal DNA sequencing to screen the structure of gut microbiota, and ultra-performance liquid chromatography-tandem mass spectrometry analysis to determine the bile acid profiles. The results show that berberine modulates gut dysbiosis, and specifically increases the relative abundance of Clostridiales, Lactobacillaceae, and Bacteroidale. Berberine modulated microbiomes are associated with bile acid de-conjugation and transformation, which are consistent with the altered bile acid species (e.g., deoxycholic acid, ursodeoxycholic acid) upon berberine treatment. BA species that respond to berberine treatment are known FXR agonists, thus we performed quantitative Real Time-PCR and western blot to examine the FXR pathway, and find that berberine up-regulates intestinal FXR and fibroblast growth factor 15 (FGF15) expression, and the secretion of FGF15 further inhibits lipogenesis and nuclear factor-κB activation in the liver. Whereas the beneficial effects of berberine are blunted in FXR knockout mice. Our results reveal that berberine alleviates NASH by modulating the interplay of gut microbiota and bile acid metabolism, as well as the subsequent intestinal FXR activation.

The impact of chirality on the analysis of alkaloids in plant

Most of the alkaloids are chiral compounds and are clinically administered as the racemic mixture, even though its enantiomers have been known to exert different pharmacological activity. The determination of the enantiomeric composition of alkaloid-containing plants is subject to severe attention from pharmacological and toxicological points of view. This review gives an overview of the chiral analysis of alkaloids that were used in theoretical studies and applications for plants in recent years.

Screening of natural product extracts for fly repellent and larvicide

Fly is one of the vectors of foodborne pathogenic vectors and causes myiasis in humans and animals. To prevent the contamination of food and myiasis, various chemical products are commonly used. However, eco-friendly is now a trend all over the world so natural products are the alternative ways to reduce the chemical residue in the environment. The present study was screened the 12 natural products in 4 groups; the essential oil plants, the alkaloid plants, the cyanogenic plant, and the inorganic compounds which use a simple extraction on the fly repelling and larvicide. The fly repelling efficacy with 2 criteria consist of the time of the first swarm and percent repelling (PR) in the first 15 min. The larvicidal efficacy was determined by the mortality rate within 24 h. The Kaffir lime peels aqueous crude extract exhibited the best result on fly repelling from both criteria with no significant difference. The bamboo shoots aqueous crude extract gave the best result on larvicide with significantly different from other groups (P < 0.001) which was faster than the positive control group (Coumaphos & Propoxur). Moreover, the high mortality rate reached 73.33 ± 15.28% within 24 h, higher than the positive control group. The present study indicates the power of common natural products on fly repellent and larvicide that may apply for fly repellant to reduce the food contamination especially fresh materials and prevention or treatment of animal and human myiasis in rural areas

NEUROTROPIC ACTIVITY OF PLANT ALKALOIDS

Natural alkaloids are promising compounds for the development of new domestic neurotropic drugs based on them. The article presents the results of a study of the neurotropic effect of plant alkaloids (harmine, delphinifolin, echinopsin, zongoramine). The assessment of the neurotropic effect of the samples of alkaloids was carried out on the model of experimental stress using the tests «Open field» and «Raised cross-shaped maze».. As a result of the conducted studies, it was found that samples of plant alkaloids delphinifolin, harmine, echinopsin and zongoramin at a dose of 10 mg / kg exhibit a neurotropic effect, increasing the level of research activity, reducing the level of anxiety, fear and anxiety in animals in the tests «Open Field» and «Raised cross-shaped maze». The presence of an aryl group in the molecules of harmine, delphinifolin, zongoramine, and echinopsin is important for their neurotropic activity.

Effects of Berberine on the Chondrogenic Differentiation of Embryonic Limb Skeletal Progenitors.

IntroductionBerberine (BBR) is an isoquinoline plant alkaloid with demonstrated anti-inflammatory, anti-tumor and immunosuppressive pharmacological properties that functions via multiple signaling pathways and epigenetic modulators. Numerous studies have proposed BBR as a promising therapeutic agent for joint cartilage degeneration, and other connective tissue diseases.Purpose and MethodsThis work aimed to evaluate the effects of BBR on the growth and differentiation of embryonic skeletal progenitors using the limb mesoderm micromass culture assay.ResultsOur findings show that at difference of its apoptotic influence on a variety of tumor tissues, cell death was not induced in skeletal progenitors by the addition of 12 or 25 µM BBR concentration to the culture medium. Morphological and transcriptional analysis revealed dual and opposite effects of BBR treatments on chondrogenesis depending on the stage of differentiation of the cultured progenitors. At early stage of culture, BBR was a potent chondrogenic inhibitor, while chondrogenesis was intensified in treatments at advanced stages of culture. The chondrogenic promoting effect was accompanied by a moderate upregulation of gene markers of prehypertrophic cartilage, including ColXa1, alkaline phosphatase Alpl, Runx2, and Indian Hedgehog Ihh. We further observed a positive transcriptional influence of BBR in the expression of DNA methyltransferase genes, Dnmt1, Dnmt3a and Dnmt3b, suggesting a potential involvement of epigenetic factors in its effects.ConclusionOur study uncovers a new pharmacological influence of BBR in cartilage differentiation that must be taken into account in designing clinical protocols for its employment in the treatment of cartilage degenerative diseases.

Toxicity and mode of action of the aporphine plant alkaloid liriodenine on the insect GABA receptor

Liriodenine is a biologically active plant alkaloid with multiple effects on mammals, fungi, and bacteria, but has never been evaluated for insecticidal activity. Accordingly, liriodenine was applied topically in ethanolic solutions to adult female Anopheles gambiae, and found to be mildly toxic. Its lethality was synergized in mixtures with dimethyl sulfoxide and piperonyl butoxide. Recordings from the ventral nerve cord of larval Drosophila melanogaster showed that liriodenine was neuroexcitatory and reversed the inhibitory effect of 1 mM GABA at effective concentrations of 20–30 μM. GABA antagonism on the larval nervous system was equally expressed on both susceptible and cyclodiene-resistant rdl preparations. Acutely isolated neurons from Periplaneta americana were studied under patch clamp and inhibition of GABA-induced currents with an IC50 value of about 1 μM were observed. In contrast, bicuculline did not reverse the effects of GABA on cockroach neurons, as expected. In silico molecular models suggested reasonable structural concordance of liriodenine and bicuculline and isosteric hydrogen bond acceptor sites. This study is the first assessing of the toxicology of liriodenine on insects and implicates the GABA receptor as one likely neuronal target, where liriodenine might be considered an active chemical analog of bicuculline.

Мінливість елементів насіннєвої продуктивності у люпину білого кормового

Goal. To assess varieties and selection numbers of white fodder lupin, and to identify their genetic diversity by the main structural elements of seed productivity. Methods. Field — to assess the vegetative development of plants, the content of alkaloids in green plants, measuring and mathematical and statistical analysis — to make structural analysis with elements of seed productivity. Results. Seed yields of varieties and selection numbers of white lupin on average for 2016-2019 varied from 3.42 to 4.53 t/ha, and the weight of seeds from one plant — from 9.8 to 12.9 g. The number of beans varied from 10.7 to 15.6 pieces for a plant. In favorable weather conditions, the share of beans from the central panicles did not exceed 45%, in unfavorable years it increased to 60%. The number of seeds from the plant ranged from 38.2 to 44.6 pieces. In case of deterioration of growing conditions, most of the seeds were formed on the central panicles and reached 64% of their total number. The number of seeds in one bean averaged 3.7 pieces per plant, and on the central and lateral panicles — 4.1 and 3.3 pieces. The weight of 1000 seeds was at the level of 312 g, with seeds from the central panicles — 328 g, from the lateral — 286 g. On average for 4 years, the share of central panicles in ensuring plant productivity was 61% by weight of seeds from the plant, the number of seeds — 57, and beans — 51%, which is explained by the formation of larger seeds on the central panicles and more seeds in one bean than on the side panicles. The greatest genetic diversity of the studied selection material was found by the following traits: seed weight, number of beans and seeds from the plant, the coefficients of variation of which were 11.8%; 11.6 and 11.2% of the central panicles and 21.9%; 22.8 and 21.1% of the lateral, respectively. Less genotypic variability was found on the basis of the average number of seeds in one bean and the weight of 1000 seeds: coefficients of variation — 5.3 and 3.7% of the central and 7.8 and 4.2% of the lateral panicles. The indicators of lateral panicles revealed much greater variability compared to the central by weight of seeds and the number of beans and seeds from the plant. Conclusions. Under unfavorable growing conditions, the share of central panicles in the formation of seed productivity increased significantly. The greatest genotypic variability in the studied varieties and selection numbers was found by seed weight and number of beans and seeds from the plant.

Berberine, A Phytoalkaloid, Inhibits Inflammatory Response Induced by LPS through NF-Kappaβ Pathway: Possible Involvement of the IKKα.

Berberine (BBR), a plant alkaloid, is known for its therapeutic properties of anticancer, cardioprotective, antidiabetic, hypolipidemic, neuroprotective, and hepatoprotective activities. The present study was to determine the molecular mechanism of BBR’s pharmacological activity in human monocytic (THP-1) cells induced by arachidonic acid (AA) or lipopolysaccharide (LPS). The effect of BBR on AA/LPS activated proinflammatory markers including TNF-α, MCP-1, IL-8 and COX-2 was measured by ELISA or quantitative real-time PCR. Furthermore, the effect of BBR on LPS-induced NF-κB translocation was determined by immunoblotting and confocal microscopy. AA/ LPS-induced TNF-α, MCP-1, IL-6, IL-8, and COX-2 markers were markedly attenuated by BBR treatment in THP-1 cells by inhibiting NF-κB translocation into the nucleus. Molecular modeling studies suggested the direct interaction of BBR to IKKα at its ligand binding site, which led to the inhibition of the LPS-induced NF-κB translocation to the nucleus. Thus, the present study demonstrated the anti-inflammatory potential of BBR via NF-κB in activated monocytes, whose interplay is key in health and in the pathophysiology of atherosclerotic development in blood vessel walls. The present study findings suggest that BBR has the potential for treating various chronic inflammatory disorders.

Nuclear Factor Erythroid 2-Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression.

As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated aldehyde dehydrogenase 3a1 (ALDH3A1) in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers. SIGNIFICANCE STATEMENT: We identified nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target aldehyde dehydrogenase 3a1 (ALDH3A1) as novel therapeutic targets in pancreatic cancer. They negatively affect the efficacy of a conventional chemotherapeutic agent, gemcitabine. We confirmed that Nrf2 plays a pivotal role in the induction of ALDH3A1.

Updates on Anticancer Therapy-Mediated Vascular Toxicity and New Horizons in Therapeutic Strategies.

Vascular toxicity is a frequent adverse effect of current anticancer chemotherapies and often results from endothelial dysfunction. Vascular endothelial growth factor inhibitors (VEGFi), anthracyclines, plant alkaloids, alkylating agents, antimetabolites, and radiation therapy evoke vascular toxicity. These anticancer treatments not only affect tumor vascularization in a beneficial manner, they also damage ECs in the heart. Cardiac ECs have a vital role in cardiovascular functions including hemostasis, inflammatory and coagulation responses, vasculogenesis, and angiogenesis. EC damage can be resulted from capturing angiogenic factors, inhibiting EC proliferation, survival and signal transduction, or altering vascular tone. EC dysfunction accounts for the pathogenesis of myocardial infarction, atherothrombosis, microangiopathies, and hypertension. In this review, we provide a comprehensive overview of the effects of chemotherapeutic agents on vascular toxicity leading to hypertension, microvascular rarefaction thrombosis and atherosclerosis, and affecting drug delivery. We also describe the potential therapeutic approaches such as vascular endothelial growth factor (VEGF)-B and prokineticin receptor-1 agonists to maintain endothelial function during or following treatments with chemotherapeutic agents, without affecting anti-tumor effectiveness.

High-Throughput Detection of an Alkaloidal Plant Metabolome in Plant Extracts Using LC-ESI-QTOF-MS.

Plant alkaloids represent a diverse group of nitrogen-containing natural products. These compounds are considered valuable in drug discovery and development. High-throughput identification of such plant secondary metabolites in complex plant extracts is essential for drug discovery, lead optimization, and understanding the biological pathway. The present study aims to rapidly identify different classes of alkaloids in plant extracts through the liquid chromatography with electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) approach using 161 isolated and purified alkaloids. These are biologically important unique alkaloids belonging to different sub-classes such as isoquinoline, quinoline, indole, tropane, pyridine, piperidine, quinolizidine, aporphine, steroidal, and terpenoid. The majority of these are not available commercially and are known to manifest valuable biological activities. Four pools of a maximum of 50 phytostandards each were prepared, based on their log P value to minimize co-elution for rapid and cost-effective analyses. MS/MS spectra were acquired in the positive ionization mode by using their [M + H]+ and/or [M + Na]+ with both the average collisional energy (25.5-62 eV) and individual collisional energies (10, 20, 30, and 40 eV). Accurate mass, high-resolution mass spectrometry (HR-MS) data, MS/MS data, and retention times were curated for each compound. The developed LC-MS/MS method was successfully used to interrogate and fast dereplicate alkaloids in 13 medicinal plant extracts and a herbal formulation. A total of 56 alkaloids were identified based on the reference standard retention times (RTs), HR-MS spectra, and/or MS/MS spectra. The MS data have been submitted to the MetaboLights online database (MTBLS2914). The mass spectrometric and chromatographic data will be useful for the discovery of new congeners and the study of biological pathways of alkaloids in the plant kingdom.

Rational design of novel N‐alkyl amine analogues of noscapine, their chemical synthesis and cellular activity as potent anticancer agents

The scaffold structure of noscapine (an antitussive plant alkaloid) was modified by inducting N-aryl methyl pharmacophore at C-9 position of the isoquinoline ring to rationally design and screened three novel 9-(N-arylmethylamino) noscapinoids, 15-17 with robust binding affinity with tubulin. The selected 9-(N-arylmethylamino) noscapinoids revealed improved predicted binding energy of -6.694kcal/mol for 15, -7.118kcal/mol for 16 and -7.732kcal/mol for 17, respectively in comparison to the lead molecule (-5.135kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDA-MB-231, as well as with a panel of primary breast tumor cells. These derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.2 and 32.2μM, which is 11.9 to 1.8 fold lower than that of noscapine. These novel derivatives effectively arrest the cell cycle in the G2/M phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 9-(N-arylmethyl amino) noscapinoids, 15-17 have a high probability to be a novel therapeutic agent for breast cancers.