scholarly journals Thapsigargin—From Traditional Medicine to Anticancer Drug

2020 ◽  
Vol 22 (1) ◽  
pp. 4
Author(s):  
Agata Jaskulska ◽  
Anna Ewa Janecka ◽  
Katarzyna Gach-Janczak
Keyword(s):  
Biological Activity ◽  
Lung Diseases ◽  
Molecular Mechanisms ◽  
Antineoplastic Agent ◽  
Folk Medicine ◽  
Cellular Viability ◽  
High Toxicity ◽  
Normal Cells ◽  
Mediterranean Plants ◽  
Serca Pump

A sesquiterpene lactone, thapsigargin, is a phytochemical found in the roots and fruits of Mediterranean plants from Thapsia L. species that have been used for centuries in folk medicine to treat rheumatic pain, lung diseases, and female infertility. More recently thapsigargin was found to be a potent cytotoxin that induces apoptosis by inhibiting the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump, which is necessary for cellular viability. This biological activity encouraged studies on the use of thapsigargin as a novel antineoplastic agent, which were, however, hampered due to high toxicity of this compound to normal cells. In this review, we summarized the recent knowledge on the biological activity and molecular mechanisms of thapsigargin action and advances in the synthesis of less-toxic thapsigargin derivatives that are being developed as novel anticancer drugs.

The Mechanisms Behind the Biological Activity of Flavonoids

2019 ◽  
Vol 26 (39) ◽  
pp. 6976-6990 ◽  
Author(s):  
Ana María González-Paramás ◽  
Begoña Ayuda-Durán ◽  
Sofía Martínez ◽  
Susana González-Manzano ◽  
Celestino Santos-Buelga
Keyword(s):  
Gene Expression ◽  
Biological Activity ◽  
Phenolic Compounds ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Radical Scavenging ◽  
Model Organism ◽  
Stress Theory ◽  
Radical Scavenging Properties

: Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidants in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed.

Urotensin II: Molecular Mechanisms of Biological Activity

2018 ◽  
Vol 19 (9) ◽  
pp. 924-934 ◽  
Author(s):  
Andrey A. Svistunov ◽  
Vadim V. Tarasov ◽  
Svetlana A. Shakhmardanova ◽  
Susanna S. Sologova ◽  
Ekaterina T. Bagaturiya ◽  
...  
Keyword(s):  
Biological Activity ◽  
Molecular Mechanisms ◽  
Urotensin Ii

scholarly journals Transcriptome Reveals Roles of Lignin-Modifying Enzymes and Abscisic Acid in the Symbiosis of Mycena and Gastrodia elata

2021 ◽  
Vol 22 (12) ◽  
pp. 6557
Author(s):  
Li-Ying Ren ◽  
Heng Zhao ◽  
Xiao-Ling Liu ◽  
Tong-Kai Zong ◽  
Min Qiao ◽  
...  
Keyword(s):  
Biological Activity ◽  
Abscisic Acid ◽  
Lignin Degradation ◽  
Molecular Mechanisms ◽  
Receptor Protein ◽  
Gastrodia Elata ◽  
Upregulated Genes ◽  
Aba Biosynthesis ◽  
Seed Coats

Gastrodia elata is a well-known medicinal and heterotrophic orchid. Its germination, limited by the impermeability of seed coat lignin and inhibition by abscisic acid (ABA), is triggered by symbiosis with fungi such as Mycena spp. However, the molecular mechanisms of lignin degradation by Mycena and ABA biosynthesis and signaling in G. elata remain unclear. In order to gain insights into these two processes, this study analyzed the transcriptomes of these organisms during their dynamic symbiosis. Among the 25 lignin-modifying enzyme genes in Mycena, two ligninolytic class II peroxidases and two laccases were significantly upregulated, most likely enabling Mycena hyphae to break through the lignin seed coats of G. elata. Genes related to reduced virulence and loss of pathogenicity in Mycena accounted for more than half of annotated genes, presumably contributing to symbiosis. After coculture, upregulated genes outnumbered downregulated genes in G. elata seeds, suggesting slightly increased biological activity, while Mycena hyphae had fewer upregulated than downregulated genes, indicating decreased biological activity. ABA biosynthesis in G. elata was reduced by the downregulated expression of 9-cis-epoxycarotenoid dioxygenase (NCED-2), and ABA signaling was blocked by the downregulated expression of a receptor protein (PYL12-like). This is the first report to describe the role of NCED-2 and PYL12-like in breaking G. elata seed dormancy by reducing the synthesis and blocking the signaling of the germination inhibitor ABA. This study provides a theoretical basis for screening germination fungi to identify effective symbionts and for reducing ABA inhibition of G. elata seed germination.

When things go wrong: Exploring possible mechanisms driving the progressive fibrosis phenotype in interstitial lung diseases

2021 ◽  
pp. 2004507
Author(s):  
Moisés Selman ◽  
Annie Pardo
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Diseases ◽  
Molecular Mechanisms ◽  
Lung Parenchyma ◽  
Interstitial Lung Diseases ◽  
Unknown Etiology ◽  
Clinical Behavior ◽  
The Past ◽  
Appropriate Treatment ◽  
Different Types

Interstitial lung diseases (ILD) comprise a large and heterogeneous group of disorders of known and unknown etiology characterised by diffuse damage of the lung parenchyma. In the past years, it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis known as pulmonary fibrosing ILD (PF-ILD). This is a phenotype behaving similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILD with a similar clinical behavior. This phenotype may occur in diseases displaying distinct etiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering in the progressive fibrosing phase. The crucial questions are (1) why a subset of patients develops a progressive and irreversible fibrotic phenotype even with appropriate treatment, and (2) what the pathogenic mechanisms driving progression possibly are. We here provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, aging, epigenetics, the structural fibrotic distortion, the aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct profibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutical strategies.

scholarly journals Trpm5 channels encode bistability of spinal motoneurons and ensure motor control of hindlimbs in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rémi Bos ◽  
Benoît Drouillas ◽  
Mouloud Bouhadfane ◽  
Emilie Pecchi ◽  
Virginie Trouplin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Endoplasmic Reticulum ◽  
Molecular Mechanisms ◽  
Central Pattern Generators ◽  
Cellular Level ◽  
Spinal Motoneurons ◽  
Plateau Potential ◽  
Serca Pump ◽  
Pattern Generators ◽  
Postural Tone

AbstractBistable motoneurons of the spinal cord exhibit warmth-activated plateau potential driven by Na+ and triggered by a brief excitation. The thermoregulating molecular mechanisms of bistability and their role in motor functions remain unknown. Here, we identify thermosensitive Na+-permeable Trpm5 channels as the main molecular players for bistability in mouse motoneurons. Pharmacological, genetic or computational inhibition of Trpm5 occlude bistable-related properties (slow afterdepolarization, windup, plateau potentials) and reduce spinal locomotor outputs while central pattern generators for locomotion operate normally. At cellular level, Trpm5 is activated by a ryanodine-mediated Ca2+ release and turned off by Ca2+ reuptake through the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump. Mice in which Trpm5 is genetically silenced in most lumbar motoneurons develop hindlimb paresis and show difficulties in executing high-demanding locomotor tasks. Overall, by encoding bistability in motoneurons, Trpm5 appears indispensable for producing a postural tone in hindlimbs and amplifying the locomotor output.

scholarly journals Impaired Translesion Synthesis in Xeroderma Pigmentosum Variant Extracts

1999 ◽  
Vol 19 (3) ◽  
pp. 2206-2211 ◽  
Author(s):  
Agnes M. Cordonnier ◽  
Alan R. Lehmann ◽  
Robert P. P. Fuchs
Keyword(s):  
Xeroderma Pigmentosum ◽  
Replication Fork ◽  
Molecular Mechanisms ◽  
Translesion Synthesis ◽  
Distinct Pattern ◽  
Skin Fibroblasts ◽  
Primer Extension ◽  
Normal Cells ◽  
Replication Fork Progression ◽  
Dna Strands

ABSTRACT Xeroderma pigmentosum variant (XPV) cells are characterized by a cellular defect in the ability to synthesize intact daughter DNA strands on damaged templates. Molecular mechanisms that facilitate replication fork progression on damaged DNA in normal cells are not well defined. In this study, we used single-stranded plasmid molecules containing a single N-2-acetylaminofluorene (AAF) adduct to analyze translesion synthesis (TLS) catalyzed by extracts of either normal or XPV primary skin fibroblasts. In one of the substrates, the single AAF adduct was located at the 3′ end of a run of three guanines that was previously shown to induce deletion of one G by a slippage mechanism. Primer extension reactions performed by normal cellular extracts from four different individuals produced the same distinct pattern of TLS, with over 80% of the products resulting from the elongation of a slipped intermediate and the remaining 20% resulting from a nonslipped intermediate. In contrast, with cellular extracts from five different XPV patients, the TLS reaction was strongly reduced, yielding only low amounts of TLS via the nonslipped intermediate. With our second substrate, in which the AAF adduct was located at the first G in the run, thus preventing slippage from occurring, we confirmed that normal extracts were able to perform TLS 10-fold more efficiently than XPV extracts. These data demonstrate unequivocally that the defect in XPV cells resides in translesion synthesis independently of the slippage process.

scholarly journals Dissecting Adaptation Mechanisms to Contrasting Solar Irradiance in the Mediterranean Shrub Cistus incanus

2019 ◽  
Vol 20 (14) ◽  
pp. 3599 ◽  
Author(s):  
Federico Sebastiani ◽  
Sara Torre ◽  
Antonella Gori ◽  
Cecilia Brunetti ◽  
Mauro Centritto ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Limited Attention ◽  
Severe Drought ◽  
Shade Avoidance ◽  
Environmental Pressures ◽  
Adaptive Mechanisms ◽  
Mediterranean Plants ◽  
Psii Photochemistry ◽  
The Stability

Molecular mechanisms that are the base of the strategies adopted by Mediterranean plants to cope with the challenges imposed by limited or excessive solar radiation during the summer season have received limited attention. In our study, conducted on C. incanus plants growing in the shade or in full sunlight, we performed measurements of relevant physiological traits, such as leaf water potential, gas exchange and PSII photochemistry, RNA-Seq with de-novo assembly, and the analysis of differentially expressed genes. We also identified and quantified photosynthetic pigments, abscisic acid, and flavonoids. Here, we show major mechanisms regulating light perception and signaling which, in turn, sustain the shade avoidance syndrome displayed by the ‘sun loving’ C. incanus. We offer clear evidence of the detrimental effects of excessive light on both the assembly and the stability of PSII, and the activation of a suite of both repair and effective antioxidant mechanisms in sun-adapted leaves. For instance, our study supports the view of major antioxidant functions of zeaxanthin in sunny plants concomitantly challenged by severe drought stress. Finally, our study confirms the multiple functions served by flavonoids, both flavonols and flavanols, in the adaptive mechanisms of plants to the environmental pressures associated to Mediterranean climate.

Cancer and Signaling Pathway Deregulation

2011 ◽  
pp. 369-379
Author(s):  
Yingchun Liu
Keyword(s):  
Cancer Patients ◽  
Tumor Cells ◽  
Malignant Tumor ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Normal Cells ◽  
Genetic Aberrations ◽  
Cancer Subtypes ◽  
Pathway Deregulation

Cancer is a complex disease that is associated with a variety of genetic aberrations. The diagnosis and treatment of cancer have been difficult because of poor understanding of cancer and lack of effective cancer therapies. Many studies have investigated cancer from different perspectives. It remains unclear what molecular mechanisms have triggered and sustained the transition of normal cells to malignant tumor cells in cancer patients. This chapter gives an introduction to the genetic aberrations associated with cancer and a brief view of the topics key to decode cancer, from identifying clinically relevant cancer subtypes to uncovering the pathways deregulated in particular subtypes of cancer.

scholarly journals Insight into the Presence of Stilbenes in Medicinal Plants Traditionally Used in Croatian Folk Medicine

2016 ◽  
Vol 11 (6) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Ivana Generalić Mekinić ◽  
Danijela Skroza ◽  
Ivica Ljubenkov ◽  
Višnja Katalinić
Keyword(s):  
Biological Activity ◽  
Medicinal Plants ◽  
Biological Activities ◽  
Folk Medicine ◽  
Free Form ◽  
Naturally Occurring ◽  
Derivatives Of ◽  
Insight Into ◽  
Phenolic Extracts

Over the last years, great interest has arisen concerning plant stilbenes, especially resveratrol, which has a whole spectrum of positive biological activities. In this study, we investigated the presence of resveratrol monomers (trans- and cis- form) and naturally occurring derivatives of fraas-resveratrol (piceid, astringin and isorhapontin) in phenolic extracts of twenty medicinal plants traditionally used in Croatian folk medicine. The investigated compounds were present in the samples, in free form or as glucosides, and the highest share was found in immortelle, common yarrow and Lamiaceae plants. The obtained results indicate that biological activity of selected medicinal plants can be related to the presence of this valuable group of phytochemicals.

scholarly journals The Molecular Mechanisms Underlying the Regulation of the Biological Activity of Corticotropin-Releasing Hormone Receptors: Implications for Physiology and Pathophysiology

2006 ◽  
Vol 27 (3) ◽  
pp. 260-286 ◽  
Author(s):  
Edward W. Hillhouse ◽  
Dimitris K. Grammatopoulos
Keyword(s):  
Biological Activity ◽  
Molecular Mechanisms ◽  
Hormone Receptors ◽  
Wide Spectrum ◽  
Critical Role ◽  
Tissue Specific ◽  
Functional Flexibility ◽  
Biological Responses ◽  
The Central Nervous System ◽  
The Impact

The CRH receptor (CRH-R) is a member of the secretin family of G protein-coupled receptors. Wide expression of CRH-Rs in the central nervous system and periphery ensures that their cognate agonists, the family of CRH-like peptides, are capable of exerting a wide spectrum of actions that underpin their critical role in integrating the stress response and coordinating the activity of fundamental physiological functions, such as the regulation of the cardiovascular system, energy balance, and homeostasis. Two types of mammal CRH-R exist, CRH-R1 and CRH-R2, each with unique splicing patterns and remarkably distinct pharmacological properties, but similar signaling properties, probably reflecting their distinct and sometimes contrasting biological functions. The regulation of CRH-R expression and activity is not fully elucidated, and we only now begin to fully understand the impact on mammalian pathophysiology. The focus of this review is the current and evolving understanding of the molecular mechanisms controlling CRH-R biological activity and functional flexibility. This shows notable tissue-specific characteristics, highlighted by their ability to couple to distinct G proteins and activate tissue-specific signaling cascades. The type of activating agonist, receptor, and target cell appears to play a major role in determining the overall signaling and biological responses in health and disease.

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