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International Journal of Molecular... Oct 2021bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from , is known to inhibit some voltage-dependent...
bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from , is known to inhibit some voltage-dependent ion channels and muscarinic receptors, but its interaction with ligand-gated ion channels remains unexplored. We have studied if Pm affects nicotinic acetylcholine receptors (nAChRs), since they play broad functional roles, both in the nervous system and non-neuronal tissues. Muscle-type nAChRs were incorporated to oocytes and the action of Pm on the membrane currents elicited by ACh (s) was assessed. Functional studies were combined with virtual docking and molecular dynamics assays. Co-application of ACh and Pm reversibly blocked , with an IC in the low micromolar range. Pm inhibited nAChR by: (i) open-channel blockade, evidenced by the voltage-dependent inhibition of , (ii) enhancement of nAChR desensitization, revealed by both an accelerated decay and a decelerated deactivation, and (iii) resting-nAChR blockade, deduced from the inhibition elicited by Pm when applied before ACh superfusion. In good concordance, virtual docking and molecular dynamics assays demonstrated that Pm binds to different sites at the nAChR, mostly at the transmembrane domain. Thus, Pm from bulbs, considered therapeutic herbs, targets nAChRs with high affinity, which might account for its anti-inflammatory actions.
Topics: Animals; Anti-Inflammatory Agents; Cevanes; Drugs, Chinese Herbal; Gene Expression Regulation; Muscles; Oocytes; Plant Extracts; Receptors, Nicotinic; Xenopus laevis
PubMed: 34681946
DOI: 10.3390/ijms222011287 -
Journal of Ethnopharmacology Jan 2022Fritillariae thunbergii Miq (FTM)exhibit versatile biological activities including the significant antitussive and expectorant activities. As a herbal medicine, the...
Chemical profiling of Fritillariae thunbergii Miq prepared by different processing methods reveals two new quality markers: Zhebeininoside and imperialine-3-β-D-glucoside.
ETHNOPHARMACOLOGICAL RELEVANCE
Fritillariae thunbergii Miq (FTM)exhibit versatile biological activities including the significant antitussive and expectorant activities. As a herbal medicine, the therapeutic effects of FTM may be expressed by multi-components which have complicated integration effects on multi-targets. With the time going, the different processing methods of FTM has been changed a lot. Thus,the study described the effect of processing methods to FTM and its quality.
MATERIAL AND METHOD
Studies were undertaken by using UHPLC-LTQ Orbitrap MS and pharmacodynamic models. All reagents were involved of analytical grade. While a HPLC-ELSD's method has been developed and validated, a certified Quality System is conformed to ICH requirements. The experimental animals followed the animal welfare guidelines.
AIM OF THE STUDY
We aimed to found the differences after the different processing methods of FTM, and to demonstrate the changes could be selected as quality control indicators, and established a method for simultaneous determination of these for quality control.
RESULTS
we have previously found two new steroidal alkaloids: zhebeininoside and imperialine-3-β-D-glucoside from the different processing methods of FTM, which is the difference between the different processing methods of FTM, mainly on the steroidal alkaloids. The activity analysis of zhebeininoside, imperialine-3-β-D-glucoside, verticine and verticinone showed that the mouse model of cough expectorant has antitussive effect. The positive drug selected was dextromethorphan syrup. The positive group showed biological activity, but the blank group showed nothing. The model group showed illness which means that the model was effective. There are two ways of the mechanism of action of the expectorant action which can make sputum thin, reduce its viscosity, and be easy to cough up, or can accelerate the movement of mucous cilia in the respiratory tract and promote the discharge of sputum. In our study, the content of phenol red was significantly reduced in the administration group.
CONCLUSIONS
To sum up, our results suggest that zhebeininoside and other three components cloud be selected as quality control indicators, and a method for simultaneous determination of zhebeininoside and other three components was established for quality control.
Topics: Animals; Mice; Ammonia; Antitussive Agents; Cevanes; Cough; Dextromethorphan; Drugs, Chinese Herbal; Fritillaria; Phytotherapy; Plant Stems; Quality Control; Random Allocation
PubMed: 34653522
DOI: 10.1016/j.jep.2021.114670 -
Molecules (Basel, Switzerland) Sep 2021spp. grow throughout the world and are especially prevalent in high mountain meadows of North America. All parts of plants have been used for the treatment of ailments... (Review)
Review
spp. grow throughout the world and are especially prevalent in high mountain meadows of North America. All parts of plants have been used for the treatment of ailments including injuries, hypertension, and rheumatic pain since as far back as the 1600s. Of the 17-45 spp., alkaloids have been proven to possess favorable medicinal properties associated with inhibition of hedgehog (Hh) pathway signaling. Aberrant Hh signaling leads to proliferation of over 20 cancers, including basal cell carcinoma, prostate and colon among others. Six of the most well-studied alkaloids are cyclopamine (), veratramine (), isorubijervine (), muldamine (), cycloposine (), and veratrosine (). Recent inspection of the ethanolic extract from root and rhizome via liquid chromatography-mass spectrometry has detected up to five additional alkaloids that are proposed to be verazine () etioline (), tetrahydrojervine () dihydrojervine (), 22-keto-26-aminocholesterol (). For each alkaloid identified or proposed in , this review surveys literature precedents for extraction methods, isolation, identification, characterization and bioactivity to guide natural product drug discovery associated with this medicinal plant.
Topics: Alkaloids; Animals; Antineoplastic Agents, Phytogenic; Biological Products; Humans; Neoplasms; Veratrum
PubMed: 34641477
DOI: 10.3390/molecules26195934 -
International Journal of Molecular... Oct 2021Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies.
METHODS
We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search.
RESULTS
Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit.
CONCLUSION
Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies.
Topics: Antineoplastic Agents; Biphenyl Compounds; Clinical Trials as Topic; Dermatology; Hedgehog Proteins; Humans; Molecular Targeted Therapy; Prognosis; Pyridines; Signal Transduction; Skin Neoplasms; Treatment Outcome; Veratrum Alkaloids
PubMed: 34639065
DOI: 10.3390/ijms221910725 -
International Journal of Molecular... Sep 2021Parkinson's disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the...
Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson's Disease Models In Vivo and In Vitro.
Parkinson's disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Miq that has antioxidant and anti-neuroinflammatory effects. We used and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin-proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.
Topics: Animals; Animals, Genetically Modified; Apoptosis Regulatory Proteins; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cevanes; Dopamine; Dopaminergic Neurons; Nerve Degeneration; Parkinson Disease; Proteasome Endopeptidase Complex; Protein Serine-Threonine Kinases; Substantia Nigra; Ubiquitin; Ubiquitin-Protein Ligases; X-Linked Inhibitor of Apoptosis Protein; alpha-Synuclein
PubMed: 34638579
DOI: 10.3390/ijms221910240 -
Frontiers in Endocrinology 2021Osteoclasts (OCs) play an important role in osteoporosis, a disease that is mainly characterized by bone loss. In our research, we aimed to identify novel approach for...
Osteoclasts (OCs) play an important role in osteoporosis, a disease that is mainly characterized by bone loss. In our research, we aimed to identify novel approach for regulating osteoclastogenesis and thereby treating osteoporosis. Previous studies have set a precedent for screening traditional Chinese herbal extracts for effective inhibitors. Peiminine is an alkaloid extracted from the bulb of that reportedly has anticancer and anti-inflammatory effects. Thus, the potential inhibitory effect of peiminine on OC differentiation was investigated a series of experiments. According to the results, peiminine downregulated the levels of specific genes and proteins and consequently suppressed OC differentiation and function. Based on these findings, we further investigated the underlying molecular mechanisms and identified the NF-κB and ERK1/2 signaling pathways as potential targets of peiminine. , peiminine alleviated bone loss in an ovariectomized mouse model.
Topics: Animals; Cevanes; Extracellular Signal-Regulated MAP Kinases; Female; Femur; Mice; NF-kappa B; NFATC Transcription Factors; Osteoclasts; Osteogenesis; Ovariectomy; RANK Ligand; Signal Transduction
PubMed: 34630331
DOI: 10.3389/fendo.2021.736863 -
Neurological Research Apr 2022Ischemic stroke is a major cause of death in the global population, with a high disability and mortality rate. Lack of regenerative ability is considered to be the...
OBJECTIVE
Ischemic stroke is a major cause of death in the global population, with a high disability and mortality rate. Lack of regenerative ability is considered to be the fundamental cause. This study aims to determine the effect of Shh pathway, which mediates regenerative signaling in response to CNS injury, on myelin repair and Olig1 expression in focal ischemic lesions in the rat.
METHODS
A model of middle cerebral artery occlusion (MCAO) was established using the intraluminal suture method where the middle cerebral artery (MCA) was restricted for 120 min. Cyclopamine, a specific inhibitor of Shh, or saline was administered 12h after MCAO surgery and lasted for 7d. After MCA occlusion, male Sprague-Dawley rats were randomly allocated to cyclopamine- or saline-treated groups. A group of no-injection animals after MCAO were used as control. The Shh signaling pathway, myelinogenesis-related factor MBP and Olig1 were tested using immunohistochemistry and RT-PCR assay.
RESULTS
The levels of Shh and its component Gli1 were elevated from 1d up to 14d following ischemia, indicating that the Shh-Gli1 axis was broadly reactivated. Treatment with cyclopamine can partially block the Shh signaling pathway, prevent myelin repair, and decrease the Olig1 expression following ischemic stroke.
CONCLUSION
That blockade of Shh signaling concurrently with the creation of a lesion aggravated ischemic myelin damage, probably via its downstream effects on Olig1 transcription. Shh plays a contributory role during regeneration in the CNS, thereby providing promising new therapeutic strategies to assist in recovery from ischemic stroke.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Disease Models, Animal; Hedgehog Proteins; Infarction, Middle Cerebral Artery; Male; Nerve Regeneration; Nerve Tissue Proteins; Random Allocation; Rats; Rats, Sprague-Dawley; Signal Transduction; Veratrum Alkaloids; Zinc Finger Protein GLI1
PubMed: 34592910
DOI: 10.1080/01616412.2021.1981106 -
Journal of the American Chemical Society Oct 2021Chemical transformations that rapidly and efficiently construct a high level of molecular complexity in a single step are perhaps the most valuable in total synthesis....
Chemical transformations that rapidly and efficiently construct a high level of molecular complexity in a single step are perhaps the most valuable in total synthesis. Among such transformations is the transition metal catalyzed [2 + 2 + 2] cycloisomerization reaction, which forges three new C-C bonds and one or more rings in a single synthetic operation. We report here a strategy that leverages this transformation to open access to the family of alkaloids. The highly convergent approach described herein includes (i) the enantioselective synthesis of a diyne fragment containing the steroidal A/B rings, (ii) the asymmetric synthesis of a propargyl-substituted piperidinone (F ring) unit, (iii) the high-yielding union of the above fragments, and (iv) the intramolecular [2 + 2 + 2] cycloisomerization reaction of the resulting carbon framework to construct in a single step the remaining three rings (C/D/E) of the hexacyclic cevanine skeleton. Efficient late-stage maneuvers culminated in the first total synthesis of heilonine (), achieved in 21 steps starting from ethyl vinyl ketone.
Topics: Alkaloids
PubMed: 34585920
DOI: 10.1021/jacs.1c08756 -
PloS One 2021Sensory experience modulates proliferation, differentiation, and migration of oligodendrocyte progenitor cells (OPCs). In the mouse primary visual cortex (V1), visual...
Sensory experience modulates proliferation, differentiation, and migration of oligodendrocyte progenitor cells (OPCs). In the mouse primary visual cortex (V1), visual deprivation-dependent modulation of OPCs has not been demonstrated. Here, we demonstrate that undifferentiated OPCs developmentally peaked around postnatal day (P) 25, and binocular enucleation (BE) from the time of eye opening (P14-15) elevated symmetrically-divided undifferentiated OPCs in a reversible G0/G1 state even more at the bottom lamina of the cortex by reducing maturing oligodendrocyte (OL) lineage cells. Experiments using the sonic hedgehog (Shh) signaling inhibitor cyclopamine in vivo suggested that Shh signaling pathway was involved in the BE-induced undifferentiation process. The undifferentiated OPCs then differentiated within 5 days, independent of the experience, becoming mostly quiescent cells in control mice, while altering the mode of sister cell symmetry and forming quiescent as well as maturing cells in the enucleated mice. At P50, BE increased mature OLs via symmetric and asymmetric modes of cell segregation, resulting in more populated mature OLs at the bottom layer of the cortex. These data suggest that fourth postnatal week, corresponding to the early critical period of ocular dominance plasticity, is a developmentally sensitive period for OPC state changes. Overall, the visual loss promoted undifferentiation at the early period, but later increased the formation of mature OLs via a change in the mode of cell type symmetry at the bottom layer of mouse V1.
Topics: Animals; Cell Differentiation; Cell Division; Cell Lineage; Cell Proliferation; Eye; Hedgehog Proteins; Mice; Mice, Inbred C57BL; Models, Statistical; Neurogenesis; Oligodendrocyte Precursor Cells; Oligodendroglia; Signal Transduction; Stem Cells; Veratrum Alkaloids; Visual Cortex
PubMed: 34534256
DOI: 10.1371/journal.pone.0257395 -
Organic Letters Jan 2022Two distinctive alkaloids with 6/6/6/5/6/6 fused rings, in which a previously unidentified linkage of C-12/23 generates a rigid skeleton, resulting in a new subtype of...
Two distinctive alkaloids with 6/6/6/5/6/6 fused rings, in which a previously unidentified linkage of C-12/23 generates a rigid skeleton, resulting in a new subtype of steroidal alkaloid, were isolated from . Compounds and showed potent analgesic effects , superior to the well-known analgesic, pethidine (Dolantin), likely by inhibiting Ca2.2 voltage-gated calcium channels.
PubMed: 34477387
DOI: 10.1021/acs.orglett.1c02853