scholarly journals Molecular Insight into Stereoselective ADME Characteristics of C20-24 Epimeric Epoxides of Protopanaxadiol by Docking Analysis

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 112 ◽  
Author(s):  
Wenna Guo ◽  
Zhiyong Li ◽  
Meng Yuan ◽  
Geng Chen ◽  
Qiao Li ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Binding Free Energy ◽  
3D Structure ◽  
Docking Analysis ◽  
Rational Development ◽  
Stereo Selectivity ◽  
Energy Dependent ◽  
Drug Pump ◽  
Insight Into

Chirality is a common phenomenon, and it is meaningful to explore interactions between stereoselective bio-macromolecules and chiral small molecules with preclinical and clinical significance. Protopanaxadiol-type ginsenosides are main effective ingredients in ginseng and are prone to biotransformation into a pair of ocotillol C20-24 epoxide epimers, namely, (20S,24S)-epoxy-dammarane-3,12,25-triol (24S-PDQ) and (20S,24R)-epoxy dammarane-3,12,25-triol (24R-PDQ) that display stereoselective fate in vivo. However, possible molecular mechanisms involved are still unclear. The present study aimed to investigate stereoselective ADME (absorption, distribution, metabolism and excretion) characteristics of PDQ epimers based on molecular docking analysis of their interaction with some vital proteins responsible for drug disposal. Homology modeling was performed to obtain 3D-structure of the human isoenzyme UGT1A8, while calculation of docking score and binding free energy and ligand–protein interaction pattern analysis were achieved by using the Schrödinger package. Stereoselective interaction was found for both UGT1A8 and CYP3A4, demonstrating that 24S-PDQ was more susceptible to glucuronidation, whereas 24R-PDQ was more prone to oxidation catalyzed by CYP3A4. However, both epimers displayed similarly strong interaction with P-gp, a protein with energy-dependent drug-pump function, suggesting an effect of the dammarane skeleton but not C-24 stereo-configuration. These findings provide an insight into stereo-selectivity of ginsenosides, as well as a support the rational development of ginseng products.

scholarly journals The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Saishu Yoshida ◽  
Katsuhiko Aoki ◽  
Ken Fujiwara ◽  
Takashi Nakakura ◽  
Akira Kawamura ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
The Novel ◽  
Mammalian Development ◽  
Hh Signaling ◽  
Functional Analyses ◽  
First Time ◽  
Insight Into

Mammalian Hedgehog (Hh) signaling plays key roles in embryogenesis and uniquely requires primary cilia. Functional analyses of several ciliogenesis-related genes led to the discovery of the developmental diseases known as ciliopathies. Hence, identification of mammalian factors that regulate ciliogenesis can provide insight into the molecular mechanisms of embryogenesis and ciliopathy. Here, we demonstrate that DYRK2 acts as a novel mammalian ciliogenesis-related protein kinase. Loss of Dyrk2 in mice causes suppression of Hh signaling and results in skeletal abnormalities during in vivo embryogenesis. Deletion of Dyrk2 induces abnormal ciliary morphology and trafficking of Hh pathway components. Mechanistically, transcriptome analyses demonstrate down-regulation of Aurka and other disassembly genes following Dyrk2 deletion. Taken together, the present study demonstrates for the first time that DYRK2 controls ciliogenesis and is necessary for Hh signaling during mammalian development.

scholarly journals OSCA/TMEM63 are an evolutionarily conserved family of mechanically activated ion channels

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Swetha E Murthy ◽  
Adrienne E Dubin ◽  
Tess Whitwam ◽  
Sebastian Jojoa-Cruz ◽  
Stuart M Cahalan ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Ion Channels ◽  
Ion Channel ◽  
Molecular Mechanisms ◽  
Deep Insight ◽  
Evolutionarily Conserved ◽  
Bona Fide ◽  
Physical Forces ◽  
Insight Into

Mechanically activated (MA) ion channels convert physical forces into electrical signals, and are essential for eukaryotic physiology. Despite their importance, few bona-fide MA channels have been described in plants and animals. Here, we show that various members of the OSCA and TMEM63 family of proteins from plants, flies, and mammals confer mechanosensitivity to naïve cells. We conclusively demonstrate that OSCA1.2, one of the Arabidopsis thaliana OSCA proteins, is an inherently mechanosensitive, pore-forming ion channel. Our results suggest that OSCA/TMEM63 proteins are the largest family of MA ion channels identified, and are conserved across eukaryotes. Our findings will enable studies to gain deep insight into molecular mechanisms of MA channel gating, and will facilitate a better understanding of mechanosensory processes in vivo across plants and animals.

scholarly journals Structures of collagen IV globular domains: insight into associated pathologies, folding and network assembly

IUCrJ ◽  
2018 ◽  
Vol 5 (6) ◽  
pp. 765-779 ◽  
Author(s):  
Patricia Casino ◽  
Roberto Gozalbo-Rovira ◽  
Jesús Rodríguez-Díaz ◽  
Sreedatta Banerjee ◽  
Ariel Boutaud ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Self Assembly ◽  
Molecular Mechanisms ◽  
Collagen Iv ◽  
Basement Membranes ◽  
Missense Mutations ◽  
The Core ◽  
Extracellular Structures ◽  
Insight Into

Basement membranes are extracellular structures of epithelia and endothelia that have collagen IV scaffolds of triple α-chain helical protomers that associate end-to-end, forming networks. The molecular mechanisms by which the noncollagenous C-terminal domains of α-chains direct the selection and assembly of the α1α2α1 and α3α4α5 hetero-oligomers found in vivo remain obscure. Autoantibodies against the noncollagenous domains of the α3α4α5 hexamer or mutations therein cause Goodpasture's or Alport's syndromes, respectively. To gain further insight into oligomer-assembly mechanisms as well as into Goodpasture's and Alport's syndromes, crystal structures of noncollagenous domains produced by recombinant methods were determined. The spontaneous formation of canonical homohexamers (dimers of trimers) of these domains of the α1, α3 and α5 chains was shown and the components of the Goodpasture's disease epitopes were viewed. Crystal structures of the α2 and α4 noncollagenous domains generated by recombinant methods were also determined. These domains spontaneously form homo-oligomers that deviate from the canonical architectures since they have a higher number of subunits (dimers of tetramers and of hexamers, respectively). Six flexible structural motifs largely explain the architectural variations. These findings provide insight into noncollagenous domain folding, while supporting the in vivo operation of extrinsic mechanisms for restricting the self-assembly of noncollagenous domains. Intriguingly, Alport's syndrome missense mutations concentrate within the core that nucleates the folding of the noncollagenous domain, suggesting that this syndrome, when owing to missense changes, is a folding disorder that is potentially amenable to pharmacochaperone therapy.

scholarly journals Structure and function of outer dynein arm intermediate and light chain complex

2016 ◽  
Vol 27 (7) ◽  
pp. 1051-1059 ◽  
Author(s):  
Toshiyuki Oda ◽  
Tatsuki Abe ◽  
Haruaki Yanagisawa ◽  
Masahide Kikkawa
Keyword(s):  
Molecular Mechanisms ◽  
Electron Tomography ◽  
3D Structure ◽  
Three Dimensional ◽  
Coiled Coil ◽  
Chain Complex ◽  
Flagellar Motility ◽  
Chemically Induced Dimerization ◽  
And Function

The outer dynein arm (ODA) is a molecular complex that drives the beating motion of cilia/flagella. Chlamydomonas ODA is composed of three heavy chains (HCs), two ICs, and 11 light chains (LCs). Although the three-dimensional (3D) structure of the whole ODA complex has been investigated, the 3D configurations of the ICs and LCs are largely unknown. Here we identified the 3D positions of the two ICs and three LCs using cryo–electron tomography and structural labeling. We found that these ICs and LCs were all localized at the root of the outer-inner dynein (OID) linker, designated the ODA-Beak complex. Of interest, the coiled-coil domain of IC2 extended from the ODA-Beak to the outer surface of ODA. Furthermore, we investigated the molecular mechanisms of how the OID linker transmits signals to the ODA-Beak, by manipulating the interaction within the OID linker using a chemically induced dimerization system. We showed that the cross-linking of the OID linker strongly suppresses flagellar motility in vivo. These results suggest that the ICs and LCs of the ODA form the ODA-Beak, which may be involved in mechanosignaling from the OID linker to the HCs.

scholarly journals Cellular sensing of micron-scale curvature: a frontier in understanding the microenvironment

Open Biology ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 190155 ◽  
Author(s):  
Richard K. Assoian ◽  
Nathan D. Bade ◽  
Caroline V. Cameron ◽  
Kathleen J. Stebe
Keyword(s):  
Molecular Mechanisms ◽  
Radius Of Curvature ◽  
Valuable Insight ◽  
Glass Plastic ◽  
Cell Behaviour ◽  
Flat Surfaces ◽  
Biological Studies ◽  
And Function ◽  
Insight Into

The vast majority of cell biological studies examine function and molecular mechanisms using cells on flat surfaces: glass, plastic and more recently elastomeric polymers. While these studies have provided a wealth of valuable insight, they fail to consider that most biologically occurring surfaces are curved, with a radius of curvature roughly corresponding to the length scale of cells themselves. Here, we review recent studies showing that cells detect and respond to these curvature cues by adjusting and re-orienting their cell bodies, actin fibres and nuclei as well as by changing their transcriptional programme. Modelling substratum curvature has the potential to provide fundamental new insight into cell behaviour and function in vivo .

scholarly journals Research progress in acute hypertensive renal injury by “in vivo cryotechnique”

2019 ◽  
Vol 7 (4) ◽  
pp. 132-136
Author(s):  
Da Sun ◽  
Jiaojiao Wang ◽  
Li Yao ◽  
Zilong Li ◽  
Shinichi Ohno
Keyword(s):  
Renal Injury ◽  
Molecular Mechanisms ◽  
Research Progress ◽  
In Vivo Cryotechnique ◽  
Acute Hypertension ◽  
Podocyte Injury ◽  
Systemic Signaling ◽  
New Research ◽  
Insight Into

Abstract Arterial hypertension has a large prevalence in the general population and as a major hypertensive target organ, the involvement of kidney is usually hard to avoid and gradually develops into chronic kidney disease (CKD). Acute hypertension is defined as a blood pressure greater than 180/120, also known as hypertensive emergency (HE). In acute severe hypertension, the pathophysiology damage to the kidney tends to worsen on the basis of chronic damage, and accounts for more significant mortality. However, the mechanisms of renal injury induced by acute hypertension remain unclear. This review summarizes the clinical and histopathological features of hypertensive renal injury by using “in vivo cyrotechnique” and focusses on the interplay of distinct systemic signaling pathways, which drive glomerular podocyte injury. A thorough understanding of the cellular and molecular mechanisms of kidney damage and repair in hypertension will provide significant insight into the development of new research methods and therapeutic strategies for global CKD progression.

scholarly journals Structural organization of the C1a-e-c supercomplex within the ciliary central apparatus

2019 ◽  
Vol 218 (12) ◽  
pp. 4236-4251 ◽  
Author(s):  
Gang Fu ◽  
Lei Zhao ◽  
Erin Dymek ◽  
Yuqing Hou ◽  
Kangkang Song ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Electron Tomography ◽  
3D Structure ◽  
Protein Composition ◽  
Ciliary Beating ◽  
Ciliary Motility ◽  
Cryo Electron Tomography ◽  
Central Apparatus ◽  
Subunit Organization ◽  
Insight Into

Nearly all motile cilia contain a central apparatus (CA) composed of two connected singlet microtubules with attached projections that play crucial roles in regulating ciliary motility. Defects in CA assembly usually result in motility-impaired or paralyzed cilia, which in humans causes disease. Despite their importance, the protein composition and functions of the CA projections are largely unknown. Here, we integrated biochemical and genetic approaches with cryo-electron tomography to compare the CA of wild-type Chlamydomonas with CA mutants. We identified a large (>2 MD) complex, the C1a-e-c supercomplex, that requires the PF16 protein for assembly and contains the CA components FAP76, FAP81, FAP92, and FAP216. We localized these subunits within the supercomplex using nanogold labeling and show that loss of any one of them results in impaired ciliary motility. These data provide insight into the subunit organization and 3D structure of the CA, which is a prerequisite for understanding the molecular mechanisms by which the CA regulates ciliary beating.

Sepsis induces the transcription of the glucocorticoid receptor in skeletal muscle cells

2003 ◽  
Vol 105 (3) ◽  
pp. 383-391 ◽  
Author(s):  
Xiaoyan SUN ◽  
Joshua M. V. MAMMEN ◽  
Xintian TIAN
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
L6 Myotubes ◽  
Breakdown Rates ◽  
Dependent Protein ◽  
Vitro Model ◽  
Energy Dependent ◽  
L6 Myocytes

Evidence from a recent study indicates that glucocorticoids (GCs) mediate skeletal muscle proteolysis during sepsis via the GC receptor (GR) pathway. Attempts to identify the mechanisms regulating GR gene expression in skeletal muscle during sepsis have been hampered by the lack of an appropriate in vitro model system that can mimic in vivo septic conditions. In the present study, we report that GR gene transcription in L6 myocytes in vitro is up-regulated by treatment with sera from septic rats in a manner similar to that measured in septic rats in vivo. Sera from septic rats were collected from animals in which sepsis was induced by caecal ligation and puncture and from control rats that were sham-operated. Finally, by treating L6 myotubes with the GR antagonist RU 38486, thereby preventing sepsis-induced GR transcription, we confirmed that the possible septic effect on the GR was due to increased GCs. L6 myocytes treated with sera from septic rats might therefore be useful as an experimental model for identifying the molecular mechanisms by which the GR regulates muscle cachexia during sepsis. Furthermore, RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates in incubated extensor digitorum longus muscles from septic and sham-operated rats, as measured by release of tyrosine and 3-methylhistidine respectively. Our results demonstrate for the first time that sepsis induces GR transcription in skeletal muscle, and supports the hypothesis that the GC-induced proteolysis under sepsis is partially a consequence of GR activation.

scholarly journals Rational design of adjuvants targeting the C-type lectin Mincle

2017 ◽  
Vol 114 (10) ◽  
pp. 2675-2680 ◽  
Author(s):  
Alexiane Decout ◽  
Sandro Silva-Gomes ◽  
Daniel Drocourt ◽  
Sophie Barbe ◽  
Isabelle André ◽  
...  
Keyword(s):  
Immune Responses ◽  
Rational Design ◽  
Biological Evaluation ◽  
Subunit Vaccines ◽  
Rational Development ◽  
Dynamics Simulations ◽  
Mycobacterial Cell Wall ◽  
Molecular Bases ◽  
Insight Into

The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cell-mediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6′-dimycolate (TDM), has opened avenues for the rational design of such molecules. Using a combination of chemical synthesis, biological evaluation, molecular dynamics simulations, and protein mutagenesis, we gained insight into the molecular bases of glycolipid recognition by Mincle. Unexpectedly, the fine structure of the fatty acids was found to play a key role in the binding of a glycolipid to the carbohydrate recognition domain of the lectin. Glucose and mannose esterified atO-6 by a synthetic α-ramified 32-carbon fatty acid showed agonist activity similar to that of TDM, despite their much simpler structure. Moreover, they were seen to stimulate proinflammatory cytokine production in primary human and murine cells in a Mincle-dependent fashion. Finally, they were found to induce strong Th1 and Th17 immune responses in vivo in immunization experiments in mice and conferred protection in a murine model ofMycobacterium tuberculosisinfection. Here we describe the rational development of new molecules with powerful adjuvant properties.

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