Magnoflorine from Coptis chinese has the potential to treat DNCB-induced Atopic dermatits by inhibiting apoptosis of keratinocyte

AimsIn Sheng Nong’s herbal classic in China, Rhizoma coptidis ^a(RC) could be used to treat Atopic dermatits ^b(AD), but its core ingredient(s) and mechanism remains unknown. The present study aimed to find out the ingredients against AD and expound its mechanisms.Materials and methodsSeven alkaloids were isolated from RC to compare the inhibition against HaCaT cells by MTT assays and apoptosis of cells stimulated with TNF-α/IFN-γ by flow cytometry. The effects of target alkaloids against AD were evaluated on DNCB^c (2,4-dinitrochlorobenzene)-induced atopic dermatitis in mice.Key findingsSeven alkaloids were isolated from RC successfully. The results from MTT and flow cytometry indicated that among these alkaloids, only magnoflorine ^d(MAG) had no obvious toxicity on cells, but could inhibit the apoptosis of the cells stimulated with TNF-α/IFN-γ. Further animal experiments confirmed that MAG significantly attenuated the AD-like symptom and inhibited the AD-induced increases in IgE/IL-4, as compared with control (P < 0.01). Moreover, MAG reduced the low Δψ_m ^e(mitochondrial membrane potential) in HaCaT cells. The results of western blotting proved that MAG inhibited apoptosis of keratinocytes through decreasing the expressions of CTSB^f (cathepsin B), Cyte C^g (cytochrome C), Bid and caspase-3/7/8/9.SignificanceOverall, MAG inhibited apoptosis by decreasing the expression of apoptotic pathway-related proteins, and laid a foundation for the study of AD mechanisms.     

Therapeutic potential of indole alkaloids in respiratory diseases: A comprehensive review

BackgroundIndole alkaloids are very promising for potential therapeutic purposes and appear to be particularly effective against respiratory diseases. Several experimental studies have been performed, both in vivo and in vitro, to evaluate the effectiveness of indole alkaloids for the management of respiratory disorders, including asthma, emphysema, tuberculosis, cancer, and pulmonary fibrosis.PurposeThe fundamental objective of this review was to summarize the in-depth therapeutic potential of indole alkaloids against various respiratory disorders.Study designIn addition to describing the therapeutic potential, this review also evaluates the toxicity of these alkaloids, which have been utilized for therapeutic benefits but have demonstrated toxic consequences. Some indole alkaloids, including scholaricine, 19-epischolaricine, vallesamine, and picrinine, which are derived from the plant Alstonia scholaris, have shown toxic effects in non-rodent models.MethodsThis review also discusses clinical studies exploring the therapeutic efficacy of indole alkaloids, which have confirmed the promising benefits observed in vivo and in vitro.ResultsThe indole alkaloidal compounds have shown efficacy in subjects with respiratory diseases.ConclusionThe available data established both preclinical and clinical studies confirm the potential of indole alkaloids to treat the respiratory disorders.     

Structural diversity and defensive properties of diterpenoid alkaloids

Diterpenoid alkaloids are compounds of pharmacological interest. Forty four C₁₉ norditerpenoid (NDAs) and 23 C₂₀ diterpenoid (DAs) alkaloids isolated from Aconitum, Delphinium and Consolida species were tested for their insecticidal effects (antifeedant and toxic) on Spodoptera littoralis and Leptinotarsa decemlineata, their cytotoxicity on tumoral cell lines with several multidrug resistance mechanisms, and their antiparasitic effects against Trypanososma cruzi and Leishmania infantum. Overall, C₁₉ norditerpene alkaloids (NDAs) resulted better insect antifeedants and post-ingestive toxicants than the related C₂₀ diterpene alkaloids (DAs). Their antifeedant or insecticidal potencies did not parallel their reported nAChR binding activity, but did correlate␣with the␣agonist/antagonist insecticidal/ antifeedant model proposed for nicotininc insecticides.␣Among the most potent antifeedants (EC₅₀ < 0.2 μg/cm²) are␣the NDAs 1,14 diacetylcardiopetaline (10),␣18-hydroxy-14-O-methylgadesine (34) and 14-O-acetyldelectinine (28) (to CPB) and the DA 19-oxodihydroatisine (55) (to S.␣littoralis). DAs had strong antiparasitic effects with molecular selectivity while NDAs were inactive. Delphigraciline (53), 15,22-O-Diacetyl-19-oxo-dihydroatisine (56), azitine (64) and isoazitine (65) were active against L. infantum promastigotes and had a moderate effect on T. cruzi epimastigotes, while atisinium chloride (59) and 13-oxocardiopetamine (48) had a potent effect on T. cruzi epimastigotes. These compounds were not toxic to the host cell, significantly reduced parasite infection capacity and severely affected the multiplication of their extracellular forms. Several NDAs exhibited selective cytotoxicity to cancerous cells and some of these had irreversible effects on SW480, HeLa and SkMel25 cell lines (neoline 5, pubescenine 16, 14-deacetylajadine 26, lycoctonine 27, dehydrotakaosamine 35, and ajadelphinine 38). These cytotoxic effects could be related to the inhibition of ATP production.     

The bioactive alkaloids identified from Cortex Phellodendri ameliorate benign prostatic hyperplasia via LOX-5/COX-2 pathways

BackgroundThe bioactive alkaloids identified from Cortex Phellodendri (CP) were highly effective in treating rats with benign prostatic hyperplasia (BPH). Specifically, lipoxygenase-5 (LOX-5) and cyclooxygenase-2 (COX-2) were identified as two primary targets for alleviating inflammation in BPH rats. However, it remains unknown whether the alkaloid components in CP can interact with the two target proteins.PurposeTo further identify bioactive alkaloids targeting LOX/COX pathways.MethodsAn affinity-ultrafiltration mass spectrometry approach was employed to screen dual-target LOX-5/COX-2 ligands from alkaloid extract. The structures of bioactive alkaloids were characterized by high-resolution Fourier transform ion cyclotron resonance mass spectrometry. To understand the molecular mechanisms underlying the effects of bioactive alkaloids, the expression levels of LOX-5 and COX-2 in BPH model rats were investigated at both protein and mRNA levels. The LOX-5/COX-2 enzymes activity experiments and molecular docking analysis were performed to fully evaluate the interactions between bioactive alkaloids and LOX-5/COX-2.ResultsAfter comprehensive analysis, the results showed that bioactive alkaloids could suppress the expression of LOX-5 and COX-2 simultaneously to exert an anti-inflammatory effect on the progression of BPH. In addition, the screened protoberberine, demethyleneberberine was found to exhibit prominent inhibitory activities against both LOX-5 and COX-2 enzymes, palmatine and berberine with moderate inhibitory activities. Molecular docking analysis confirmed that demethyleneberberine could interact well with LOX-5/COX-2.ConclusionThis study is the first to explore the inhibitory effects of bioactive alkaloids from CP on LOX-5 and COX-2 activities in BPH rats. Our findings demonstrate that the bioactive alkaloids from CP can ameliorate BPH via dual LOX-5/COX-2 pathways, which serves as an efficient approach for the discovery of novel drug leads from natural products with reduced side effects.     

Isoquinoline alkaloids

Representatives of eleven different classes of isoquinoline alkaloids inhibit Na⁺, K⁺-ATPase and Mg²⁺-ATPase in rat brain microsomal preparations. In most cases the Na⁺, K⁺-ATPase is more sensitive than Mg²⁺-ATPase to inhibition by the alkaloids. The classes of alkaloids can be ranked according to potency of inhibition of Na⁺, K⁺-ATPase. Protoberberines are most effective, followed in decreasing order by benzophenanthridines, benzylisoquinolines, aporphines, tetrahydroprotoberberines, pavines, protopines, isoquinolines, tetrahydrobenzylisoquinolines, morphinanes, and tetrahydroisoquinolines. As specific representatives of each of the first four classes of alkaloids, berberine, sanguinarine, papaveroline and 1,2,10,11-tetrahydroxyaporphine, respectively, prove most valuable in kinetic studies because they exhibit the greatest inhibitory action on brain Na⁺, K⁺-ATPase. Kinetic analyses plotted in double reciprocal form reveal that berberine and 1,2,10,11-tetrahydroxyaporphine are simple linear competitive inhibitors with respect to ATP, whereas sanguinarine and papaveroline are simple linear noncompetitive inhibitors. These four representative alkaloids exhibit nonlinear competitive inhibition with respect to Na⁺-activation. Additionally, these alkaloids significantly inhibit rat brain microsomal K⁺-activatedpNPPase. The results demonstrate that certain members of several classes of isoquinoline alkaloids markedly affect various cation-dependent phosphohydrolases in vitro.     

Norditerpenoid alkaloids from the roots of Aconitum heterophyllum Wall with antibacterial activity

Two new aconitine-type norditerpenoid alkaloids 6-dehydroacetylsepaconitine (1) and 13-hydroxylappaconitine (2), along with three known norditerpenoid alkaloids lycoctonine, delphatine and lappaconitine were isolated from the roots of the Aconitum heterophyllum Wall. These compounds exhibited significant antibacterial activity. The structure of compound 1 and 2 were deduced on the basis of their spectral data.     

Uptake and metabolism of pyrrolizidine alkaloids in<Emphasis Type="Italic"> Longitarsus</Emphasis> flea beetles (Coleoptera: Chrysomelidae) adapted and non-adapted to alkaloid-containing host plants

Several Longitarsus flea beetle species sequester pyrrolizidine alkaloids acquired from their Asteraceae and Boraginaceae host plants. We carried out feeding and injection experiments using radioactively labeled pyrrolizidine alkaloids to investigate the physiological mechanisms of uptake, metabolism and storage of alkaloids in adult beetles. We examined six Longitarsus species belonging to different phylogenetic clades in a comparative approach. All species that accepted pyrrolizidine alkaloids in a preceding food choice study showed the ability both to store pyrrolizidine alkaloid N-oxides and to metabolize tertiary pyrrolizidine alkaloids into their N-oxides. Regardless of whether the beetles' natural host plants contain pyrrolizidine alkaloids or not, these species were found to possess an oxidizing enzyme. This oxygenase appears to be specific to pyrrolizidine alkaloids: [³H]Atropine and [¹⁴C]nicotine, two alkaloids not related to pyrrolizidine alkaloids, were neither stored nor N-oxidized by any of the tested species. One species, L. australis, that strictly avoids pyrrolizidine alkaloids behaviorally, exhibited a lack of adaptations to pyrrolizidine alkaloids on a physiological level as well. After injection of tertiary [¹⁴C]senecionine, beetles of this species neither N-oxidized nor stored the compounds, in contrast to L. jacobaeae, an adapted species that underwent the same treatment. L. jacobaeae demonstrated the same efficiency in N-oxidation and storage when fed or injected with tertiary [¹⁴C]senecionine.Communicated by G. Heldmaier     

The sequential appearance and metabolism of alkaloids in Heimia salicifolia

The seeds of Heimia salicifolia do not contain alkaloids. Two unidentified alkaloids were detected in 1-week-old seedlings; these alkaloids were absent from older plant samples. Lyfoline, cryogenine, and lythrine were first detected in 2-week-old plants. Sinicuichine was first observed in 3-week-old plants and nesodine in 2-month-old plants. The maximum rates of synthesis for most of these alkaloids occurred in 1- to 2-month-old plants. Following administration of ¹⁴CO₂ to H. salicifolia plants, small quantities of alkaloids were purified to constant specific activity without alkaloid dilution; 95.6% of the administered ¹⁴CO₂ was assimilated and up to 0.16% of this activity was incorporated into known alkaloids. Sinicuichine and lyfoline were shown to undergo catabolism, while cryogenine was degraded very slowly, if at all. Evidence is presented for the conversion of lyfoline to lythrine.     

Indole alkaloid biosynthesis : An investigation into leucine as a possible precursor of the monoterpene portion of vindoline

Because of the nonspecific incorporation of acetate into the monoterpenoid portion of the indole alkaloids, the amino acid leucine has been investigated as an alternative precursor. Incorporations of leucine into the alkaloids vindoline and catharanthine in Vinca rosea are found to be 0.07 and 0.02%, respectively, levels comparable with those of acetate. An equation is developed to calculate the quantity of [¹³C]leucine needed to be fed in order to obtain alkaloids with sufficient ¹³C enrichment to be analysed by ¹³C nmr spectroscopy. This equation assumes that percentage incorporations do not decrease with increasing quantities of leucine fed, an assumption found to be true. [2-¹³C]Leucine was synthesized from [2-¹³C]acetic acid in an eight-step procedure in 11.5% overall yield, and fed to Vinca rosea plants. Incorporations into vindoline obtained using both ¹⁴C and ¹³C were in reasonable agreement, and the activity was found to be spread over seven carbon atoms, none of which corresponded to the two atoms at which activity was expected. It is concluded that the leucine → mevalonate → monoterpene route does not operate in indole alkaloid biosynthesis, leaving open the question of the origin of the monoterpene portion of the alkaloids. An attempt to confirm these results by degradation of ¹⁴C-labelled alkaloids was unsuccessful, vindoline proving to be unexpectedly resistant to oxidation.     

Structure-activity relationships of alkaloids from mesquite (<Emphasis Type="Italic">Prosopis juliflora</Emphasis> (Sw.) DC.)

The structure–activity relationships of alkaloids (1–5) from mesquite were subjected to assessment of growth inhibition against the shoot and root growth of monocotyledonous plants, barnyard grass, rice and timothy, and dicotyledonous ones, amaranth, lettuce and cress. All alkaloids tested generally showed growth inhibitory against both monocotyledonous and dicotyledonous plants. Furthermore, these alkaloids exhibited higher activity against the growth of root than that of shoot of all plant species used, except that juliprosopine (5) showed higher activity against the shoot growth than the root growth of rice seedling. Among these alkaloids, the highest active compound appeared to be juliprosine (4), followed by a (1:1) mixture of 3-oxo- and 3-oxo-juliprosine (3a and 3b), and juliprosopine (5). The activity of juliprosine (4) containing 2-methyl piperidine bearing hydroxyl groups at C-3 and C-3 was higher than that of 3-oxo- and 3-oxo-juliprosine (3a and 3b) containing 3-oxo- and 3-oxo-2-methylpiperidine. Compound 3 and 4 containing dihydroindolizinium ring showed higher activity than compound 5 containing tetrahydroindolizine ring, whereas compound 1 containing tetrahydroindolizinone ring showed weaker activity. The activity of secojuliprosopinal (2) without indolizine ring was very weak. It was thus clarified that the active sites in the chemical structure of alkaloids from mesquite are the functional group at C-3 and C-3 of piperidine and indolizine skeleton.     

Pyrrolic Metabolites from Non-toxic Pyrrolizidine Alkaloids

THERE is evidence that some or all of the cytotoxic effects of unsaturated pyrrolizidine alkaloids are, in some animals, caused by pyrrolic metabolites formed by enzymatic dehydro-genation of the alkaloids in the liver^1,2. These metabolites are dihydropyrrolizine alcohols like I in Fig. 1 or their esters II; one such alcohol has been identified³. Compared with the parent alkaloids these metabolites are highly reactive alkylating agents, capable of reacting chemically with tissue constituents^1,2,4.     

New natural cholinesterase inhibiting and calcium channel blocking quinoline alkaloids

During this study, one new coumarin; 7-O-β-D-glucopyranoside-2H-1-benzopyran-2-one (1) and three quinoline alkaloids; 3-hydroxy, 2, 2, 6-trimethyl–3, 4, 5, 6-tetrahydro-2H-pyrano[3,2-c] quinoline 5-one (2), ribalinine (3) and methyl isoplatydesmine (4) were isolated from the aerial parts of Skimmia laureola and their structures established by spectroscopic studies. Compounds 2-4 were found to be linear mixed type inhibitors of acetylcholinesterase (K_i = 110.0, 30.0 and 30.0 μM, respectively). Compounds 2 and 3 were also found to be linear mixed type inhibitors of butyrylcholinesterase, while compound 4 was a noncompetitive inhibitor of the enzyme (K_i = 90.0, 70.0 and 19.0 μM, respectively). The inhibition of acetyl- and butyryl-cholinesterase enzymes persists as the most promising therapeutic strategy for activating the impaired cholinergic functions in Alzheimer's disease and related dementias.

Compound 4 also showed dose-dependent spasmolytic activity in the isolated rabbit jejunum intestinal preparation by relaxing the spontaneous (EC₅₀ = 0.1 mg/mL) and K⁺-induced contractions (EC₅₀ = 0.4 mg/mL), suggesting that the spasmolytic effect of compound 4 is mediated through the blockade of voltage-dependent Ca^{2 +} channels.     

Constituents from Chimonanthus praecox (wintersweet)

One new (1) and seven (2–8) known sesquiterpenoids, four dimeric tryptamine-related alkaloids (9–12) and six glycosides (13–18) were isolated from the fruits and leaves of Chimonanthus praecox (wintersweet). Based on its spectroscopic data, the new structure of compound 1, an oppositane-type sesquiterpenoid, was elucidated to be the C-4 epimer of bullatantriol (2). All isolated compounds were evaluated for their cytotoxicities against a small panel of human cancer cell lines, and only the chimonanthine-type alkaloids (10–12) were found to have cytotoxic effects against gastric carcinoma NUGC3 and hepatocarcinoma SNU739 cancer cells, with IC₅₀ values ranging from 10.3 to 19.7 μM.     

大花地不容块根生物碱成分的研究

为研究大花地不容块根的生物碱成分,该研究采用酸提碱沉法从大花地不容块根中提取出总生物碱,通过硅胶柱色谱法和制备液相色谱技术对大花地不容块根的总生物碱提取物进行分离纯化,并利用波谱学手段对化合物进行结构鉴定。结果表明:(1)从总生物碱提取物中分离得到11个化合物,分别鉴定为青藤碱(1)、青风藤碱(2)、斯帝酚灵碱(3)、瑞枯灵(4)、异紫堇定(5)、紫堇单酚碱(6)、巴婆碱(7)、sukhodianine(8)、荷包牡丹碱(9)、7-氧代克班宁(10)和巴马汀(11)。(2)体外细胞毒性测试显示,大花地不容总生物碱和其主成分青藤碱对人类肺癌细胞A549的IC₅₀值分别为7.5×10^-4 g·mL^-1和6.59×10^-9 g·mL^-1。化合物2、3、4、7、8、9和10系首次从大花地不容中分离得到。大花地不容块根中含有吗啡烷、原阿朴啡、阿朴啡、苄基四氢异喹啉和原小檗碱5种类型的生物碱。     

Effects of different elicitors on yield of tropane alkaloids in hairy roots of Anisodus acutangulus

The four tropane alkaloids have played a pivotal role in controlling diseases such as the toxic and septic shock, the organophosphorus poison and the acute lung injury. Here, the elicitation effect of different elicitors on the production of tropane alkaloids and the molecular mechanism of enzyme genes in the pathway was firstly demonstrated in hairy roots of Anisodus acutangulus. The results showed ethanol, methyl jasmonate and Ag⁺ could improve the accumulation of tropane alkaloids up to 1.51, 1.13 and 1.08 times after 24 h treatment, respectively (P < 0.05), whereas salicylic acid decreased the average content of tropane alkaloids. Furthermore, expression profile analysis results revealed that up-regulation of hyoscyamine-6b-hydroxylase (AaH6H) and little regulation of tropinone reducase II (AaTR2) elicited by ethanol, increased expression of putrescine N-methyltransferase I (AaPMT1) elicited by Ag⁺, elevated expression of tropinone reducase I (AaTR1) elicited by methyl jasmonate, respectively, resulted in tropane alkaloids improvement. Our results showed that hairy root culture of A. acutangulus in combination with elicitors was a promising way for production of tropane alkaloids in the future.     

Biosynthese und Stoffwechsel der chinolizidinalkaloide von Sophora alopecuroides

Administration of matrine-U-³H and sophocarpine-U-³H to Sophora alopecuroides seedlings shows that these compounds were incorporated into quinolizidine alkaloids such as matrine, sophacarpine, and their N-oxides, but not into sophoridine. It is suggested that there is no stereochemical conversion of alkaloids of matrine configuration into sophoridine by the plant. The incorporation of cadaverine-1,5-¹⁴C was so low that it cannot be regarded with certainty as a physiological precursor of the alkaloids. The N-oxides of matrine and sophocarpine were isolated and identified by their chromatographic and chemical properties.     

Media optimization for SHuffle T7 Escherichia coli expressing SUMO-Lispro proinsulin by response surface methodology

Background

The present study intends to optimize the processing technology for the wine-processing of Rhizoma Coptidis, using alkaloids as indicators.

Method

In the present study, the Box–Behnken design method was adopted to optimize the processing technology for Rhizoma Coptidis, using the alkaloid component quantities as the index. 100 g of Rhizoma Coptidis slices and 12.5 g of Rhizoma Coptidis wine were used. After full mixing, box-Behnken design method was used to optimize the processing time, processing temperature and processing time of coptis chinensis by taking alkaloid content as index. After mixing well, these components were fried in a container at 125 °C for 6 min and exhibited good parallelism.

Results

The content of alkaloids in coptis chinensis was the highest after roasting at 125 °C for 6 min. The characteristic components were berberine hydrochloride, and the relative content was about 15.96%. And showed good parallelism. The effective components of Rhizoma Coptidis were primarily alkaloids.

Conclusion

The optimized processing technology for Rhizoma Coptidis is good.

     

Effects ofPsychotria colorata alkaloids in brain opioid system

An ethnopharmacological survey showed that home remedies prepared with flowers and fruits ofPsychotria colorata are used by Amazonian peasants as pain killers. Psychopharmacological in vivo evaluation of alkaloids obtained from leaves and flowers of this species showed a marked dose-dependent naloxone-reversible analgesic activity, therefore suggesting an opioid-like pharmacological profile. This paper reports an inhibitory effect ofP. colorata flower alkaloids on [³H]naloxone binding in rat striata as well as a decrease in adenylate cyclase basal activity. The alkaloids did not affect [³H] GMP-PNP binding. These findings provide a neurochemical basis for the opioid-like activity previously detected in vivo and point toPsychotria alkaloids as a potential source of new bioactive opiate derivatives.     

Alkaloids of Uncaria attenuata from Thailand

The major alkaloids of a sample of leaves of Uncaria attenuata obtained from Thailand have been identified as the pentacyclic heteroyohimbine alkaloids tetrahydroalstonine, rauniticine and the novel 14-β-hydroxy-3-iso-rauniticine. Evidence for the structure of the new alkaloid was obtained from a study of UV, IR, MS, ¹H NMR and ¹C NMR spectra.