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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 -
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 -
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 -
Proceedings of the National Academy of... Aug 2021In this study, we use molecular genetic approaches to clarify the role of the Hedgehog (Hh) pathway in regulating the blood-brain/spinal cord barrier (BBB) in the adult...
In this study, we use molecular genetic approaches to clarify the role of the Hedgehog (Hh) pathway in regulating the blood-brain/spinal cord barrier (BBB) in the adult mouse central nervous system (CNS). Our work confirms and extends prior studies to demonstrate that astrocytes are the predominant cell type in the adult CNS that transduce Hh signaling, revealed by the expression of , a target gene of the canonical pathway that is activated in cells receiving Hh, and other key pathway transduction components. Gli1+ (Hh-responsive) astrocytes are distributed in specific regions of the CNS parenchyma, including layers 4/5/6 of the neocortex, hypothalamus, thalamus, and spinal cord, among others. Notably, although BBB properties in endothelial cells are normally regulated by both paracellular and transcellular mechanisms, conditional inactivation of Hh signaling in astrocytes results in transient, region-specific BBB defects that affect transcytosis but not paracellular diffusion. These findings stand in contrast to prior studies that implicated astrocytes as a source of Sonic hedgehog that limited extravasation via both mechanisms [J. I. Alvarez et al., 334, 1727-1731 (2011)]. Furthermore, using three distinct Cre driver lines as well as pharmacological approaches to inactivate Hh-pathway transduction globally in CNS astrocytes, we find that these specific BBB defects are only detected in the rostral hypothalamus and spinal cord but not the cortex or other regions where Gli1+ astrocytes are found. Together, our data show that Gli1+ Hh-responsive astrocytes have regionally distinct molecular and functional properties and that the pathway is required to maintain BBB properties in specific regions of the adult mammalian CNS.
Topics: Animals; Astrocytes; Blood-Brain Barrier; Brain; Gene Expression Regulation; Gliosis; Hedgehog Proteins; Mice; Mice, Transgenic; Selective Estrogen Receptor Modulators; Smoothened Receptor; Spinal Cord; Tamoxifen; Veratrum Alkaloids
PubMed: 34417306
DOI: 10.1073/pnas.2017779118 -
Pharmaceutical Biology Dec 2021Eriodictyol (EDT) is a flavonoid with strong anti-inflammatory, anti-apoptotic, and antioxidant properties.
CONTEXT
Eriodictyol (EDT) is a flavonoid with strong anti-inflammatory, anti-apoptotic, and antioxidant properties.
OBJECTIVE
To investigate the protective effect and mechanism of EDT in ulcerative colitis (UC).
MATERIALS AND METHODS
UC model was induced by 3% dextran sulphate sodium (DSS) solution for 7 days, meanwhile, EDT and Smoothened (Smo) inhibitor cyclopamine (Cyc) were intraperitoneally injected. In the first experiment, C57BL/6 mice divided into blank control, DSS, DSS + EDT (20 or 40 mg/kg) groups. In second experiment, added Cyc (5 mg/kg) and EDT + Cyc groups. All mice were sacrificed on day 8. Disease activity index (DAI), colon length and colon histology as well as MDA levels, SOD, and GSH-Px activities were measured. The expression of Sonic hedgehog (Shh), Patched, Smo, glioblastoma-1, zonula occludens-1 (ZO-1), occludin, cleaved caspase 3, Bax and Bcl-2 in colon was detected using RT-PCR and Western blotting.
RESULTS
After EDT treatment, compared with the DSS group, DAI (2.33 ± 0.516 vs. 3.67 ± 0.516), colon shortening (5.27 ± 0.476 vs. 4.53 ± 0.528 cm) and histological score (6.67 ± 1.211 vs. 12 ± 1.265) was significantly decreased. EDT also reduced inflammation, oxidative stress and apoptosis in colon. Additionally, EDT increased the expression of the tight junction proteins ZO-1 (35%) and occludin (66.3%). Mechanistically, EDT upregulated the Shh signalling pathway. However, Cyc-mediated inhibition of the Shh pathway partially abolished the effects of EDT.
DISCUSSION AND CONCLUSIONS
These results indicate EDT attenuates DSS-induced colitis by activating the Shh pathway. Further clinical trials are needed to demonstrate its efficacy on UC.
Topics: Animals; Colitis, Ulcerative; Colon; Cytokines; Dextran Sulfate; Flavanones; Hedgehog Proteins; Inflammation; Male; Mice; Mice, Inbred C57BL; Models, Animal; Oxidative Stress; Signal Transduction; Veratrum Alkaloids
PubMed: 34348563
DOI: 10.1080/13880209.2021.1948066 -
Nature Communications Jun 2021The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD) subtypes and Smoothened (SMO), remains one of the most enigmatic GPCR...
The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD) subtypes and Smoothened (SMO), remains one of the most enigmatic GPCR families. While SMO relies on cholesterol binding to the 7TM core of the receptor to activate downstream signaling, underlying details of receptor activation remain obscure for FZDs. Here, we aimed to investigate the activation mechanisms of class F receptors utilizing a computational biology approach and mutational analysis of receptor function in combination with ligand binding and downstream signaling assays in living cells. Our results indicate that FZDs differ substantially from SMO in receptor activation-associated conformational changes. SMO manifests a preference for a straight TM6 in both ligand binding and functional readouts. Similar to the majority of GPCRs, FZDs present with a kinked TM6 upon activation owing to the presence of residue P. Functional comparison of FZD and FZD PF mutants in different assay formats monitoring ligand binding, G protein activation, DVL2 recruitment and TOPflash activity, however, underlines further the functional diversity among FZDs and not only between FZDs and SMO.
Topics: Binding Sites; Bioluminescence Resonance Energy Transfer Techniques; Boron Compounds; Cryoelectron Microscopy; Cyclic AMP-Dependent Protein Kinases; Frizzled Receptors; Humans; Molecular Dynamics Simulation; Mutation; Phosphoproteins; Protein Conformation; Smoothened Receptor; Veratrum Alkaloids
PubMed: 34168128
DOI: 10.1038/s41467-021-24004-z