scholarly journals Traditional use of Cissampelos pareira L. for hormone disorder and fever provides molecular links of ESR1 modulation to viral inhibition

2021 ◽  
Author(s):  
Madiha Haider ◽  
Dhwani Dholakia ◽  
Aleksha Panwar ◽  
Parth Garg ◽  
Vivek Anand ◽  
...  
Keyword(s):  
Protein Translation ◽  
Infection Model ◽  
The Novel ◽  
Viral Inhibition ◽  
Mcf7 Cells ◽  
Traditional Use ◽  
Biological Targets ◽  
Herbal Formulation ◽  
Estrogen Response ◽  
Connectivity Score

AbstractIn traditional systems, a single herbal formulation is often used in the treatment of diverse diseases, including some that are newly emergent and prevalent today. We provide here a multi-omics framework to probe the molecular basis of a multicomponent example herb, Cissampelos pareira L. (Cipa) used in the treatment of hormonal disorders and fever in Ayurveda. Cipa treated MCF7 cells exhibit downregulation of signatures of estrogen response. 38 constituent molecules in Cipa potentially bind (∆G< -7.5) with ERα at the same site as estrogen. Cipa transcriptome signatures in the connectivity map exhibit positive scores with protein translation inhibitors and knockdown signatures of genes linked to the antiviral response. This includes the knockdown signature of RPL7, a coactivator of ESRI with a connectivity score > 99.92. This axis was found to be upregulated in the COVID-19 patient transcriptome. The antiviral activity through ESR1 modulation was validated in the DENV-2 infection model. We further observed 98% inhibition of SARs-COV-2 replication in infected Vero cell cultures with the whole extract. A few of its prominent pure constituents e.g pareirarine, cissamine, magnoflorine exhibited 40-80% inhibition. This study provides a novel framework for querying the molecular links of multicomponent Ayurveda formulations and explains their use in the treatment of disparate diseases. The novel biological targets identified here can become potential that could be applicable to more than one viral infection, such as the use of Cipa in dengue and COVID-19.

scholarly journals Transcriptome analysis and connectivity mapping of Cissampelos pareira L. provides molecular links of ESR1 modulation to viral inhibition

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Madiha Haider ◽  
Dhwani Dholakia ◽  
Aleksha Panwar ◽  
Parth Garg ◽  
Atish Gheware ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mcf7 Cell ◽  
Estrogen Receptor Α ◽  
Viral Inhibition ◽  
Mcf7 Cells ◽  
Docking Analysis ◽  
Female Hormone ◽  
Herbal Formulation ◽  
Estrogen Response ◽  
Estrogen Receptor 1

AbstractBioactive fractions obtained from medicinal plants which have been used for the treatment of multiple diseases could exert their effects by targeting common pathways. Prior knowledge of their usage could allow us to identify novel molecular links. In this study, we explored the molecular basis of action of one such herbal formulation Cissampelos pareira L. (Cipa), used for the treatment of female hormone disorders and fever. Transcriptomic studies on MCF7 cell lines treated with Cipa extract carried out using Affymetrix arrays revealed a downregulation of signatures of estrogen response potentially modulated through estrogen receptor α (ERα). Molecular docking analysis identified 38 Cipa constituents that potentially bind (ΔG <  − 7.5) with ERα at the same site as estrogen. The expression signatures in the connectivity map (https://clue.io/;) revealed high positive scores with translation inhibitors such as emetine (score: 99.61) and knockdown signatures of genes linked to the antiviral response such as ribosomal protein RPL7 (score: 99.92), which is a reported ERα coactivator. Further, gene knockdown experiments revealed that Cipa exhibits antiviral activity in dengue infected MCF7 cells potentially modulated through estrogen receptor 1. This approach reveals a novel pathway involving the ESR1-RPL7 axis which could be a potential target in dengue viral infection.

scholarly journals “One, Two, Many = One too many?” Conceptualizations of mother tongue

2021 ◽  
Vol 11 (2) ◽  
pp. 135-157
Author(s):  
Anne Golden ◽  
Toril Opsahl ◽  
Ingebjørg Tonne
Keyword(s):  
Discourse Analysis ◽  
Critical Discourse Analysis ◽  
Conceptual Metaphor ◽  
Mother Tongue ◽  
Point Of View ◽  
Critical Discourse ◽  
The Novel ◽  
Conceptual Metaphor Theory ◽  
Traditional Use ◽  
Metaphor Theory

In this article, we analyze the use of the term ‘morsmål’ (‘mother tongue’) in official Norwegian documents and in media texts to identify if and how its conceptualization has changed in the era of increasing globalization. Our point of view is explorative. When examining our data, we highlight the importance of reflecting openly about the instability of powerful concepts. We highlight two partly conflicting conceptualizations that we name the ‘traditional use’ and the ‘novel use’, respectively. Building on critical discourse analysis and conceptual metaphor theory we explore how the conceptualizations reveal certain aspects of ideologies and the potential management of multilingualism in society. A broader understanding of how conceptualizations of mother tongue(s) are played out in the Norwegian context may contribute to the dialogue about multilingualism as it is understood and recognized across diverse contexts.

scholarly journals The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation

2020 ◽  
Vol 48 (7) ◽  
pp. 3816-3831 ◽  
Author(s):  
Tao Liu ◽  
Qinglv Wei ◽  
Jing Jin ◽  
Qingya Luo ◽  
Yi Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Protein Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Rna Modification ◽  
Dependent Manner ◽  
The Novel ◽  
A Subunit

Abstract N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

scholarly journals Contribution of the Major Secreted Yops of Yersinia enterocolitica O:8 to Pathogenicity in the Mouse Infection Model

2004 ◽  
Vol 72 (9) ◽  
pp. 5227-5234 ◽  
Author(s):  
Konrad Trülzsch ◽  
Thorsten Sporleder ◽  
Emeka I. Igwe ◽  
Holger Rüssmann ◽  
Jürgen Heesemann
Keyword(s):  
Small Intestine ◽  
Systemic Infection ◽  
Effector Proteins ◽  
Infection Model ◽  
Virulence Plasmid ◽  
The Novel ◽  
Serotype O ◽  
Mouse Infection Model ◽  
Mouse Tissues ◽  
First Time

ABSTRACT Pathogenic yersiniae (Yersinia pestis, Y. pseudotuberculosis, and Y. enterocolitica) harbor a 70-kb virulence plasmid (pYV) that encodes a type III secretion system and a set of at least six effector proteins (YopH, YopO, YopP, YopE, YopM, and YopT) that are injected into the host cell cytoplasm. Yops (Yersinia outer proteins) disturb the dynamics of the cytoskeleton, inhibit phagocytosis by macrophages, and downregulate the production of proinflammatory cytokines, which makes it possible for yersiniae to multiply extracellularly in lymphoid tissue. Y. enterocolitica serotype O:8 belongs to the highly mouse-pathogenic group of yersiniae in contrast to Y. enterocolitica serotype O:9. However, there has been no systematic study of the contribution of Yops to the pathogenicity of Y. enterocolitica O:8 in mice. We generated a set of yop gene deletion mutants of Y. enterocolitica O:8 by using the novel Red cloning procedure. We subsequently analyzed the contribution of yopH, -O, -P, -E, -M, -T, and -Q deletions to pathogenicity after oral and intravenous infection of mice. Here we showed for the first time that a ΔyopT deletion mutant colonizes mouse tissues to a greater extent than the parental strain. The ΔyopO, ΔyopP, and ΔyopE mutants were only slightly attenuated after oral infection since they were still able to colonize the spleen and liver and cause systemic infection. The ΔyopO mutant was lethal for mice, whereas ΔyopP and ΔyopE mutants were successfully eliminated from the spleen and liver 2 weeks after infection. In contrast the ΔyopH, ΔyopM, and ΔyopQ mutants were highly attenuated and not able to colonize the spleen and liver on any of the days tested. The ΔyopH, ΔyopO, ΔyopP, ΔyopE, ΔyopM, and ΔyopQ mutants had only modest defects in the colonization of the small intestine and Peyer's patches. The ΔyopE mutant was eliminated from the small intestine 3 weeks after infection, whereas the ΔyopH, ΔyopP, ΔyopM, and ΔyopQ mutants continued to colonize the small intestine at this time.

scholarly journals Sea Buckthorn Leaves and the Novel Food Evaluation

2017 ◽  
Vol 71 (3) ◽  
pp. 111-114
Author(s):  
Sanna Kauppinen
Keyword(s):  
European Union ◽  
Significant Degree ◽  
Sea Buckthorn ◽  
Human Consumption ◽  
The Novel ◽  
The European Union ◽  
Traditional Use ◽  
Food Ingredients ◽  
Novel Food ◽  
History Of

AbstractNovel food means any food that was not used for human consumption to a significant degree within the European Union before 1997. The novel food regulation (EC) 258/97 concerns also foods and food ingredients consisting of or isolated from plants, except the food having a history of safe food use within the European Union before 1997. According to the knowledge thus far, sea buckthorn (Hippophaë rhamnoides L.) leaves have not been used to a significant degree as food, food supplement, or spice in European Union before 1997. The new regulation on novel foods (EU) No. 2015/2283 (Anonymous, 2015) comes into force in the beginning of 2018. After that also history of safe use in a third country is accepted as information of its traditional use. This means continued use for at least 25 years in the customary diet of a significant number of people. Novel food application has to include the description of the product, production process, characteristics and composition, proposed uses and use levels, anticipated intake, history of its use, absorption, distribution, metabolism, excretion, nutritional and toxicological information and allergenicity. Sea buckthorn leaves have been under active research lately and a lot of information is already available, but safety assessment required for novel food evaluation may still be needed.

scholarly journals In VivoEfficacy of a Human-Simulated Regimen of Ceftaroline Combined with NXL104 against Extended-Spectrum-β-Lactamase (ESBL)-Producing and Non-ESBL-Producing Enterobacteriaceae

2011 ◽  
Vol 55 (7) ◽  
pp. 3220-3225 ◽  
Author(s):  
Dora E. Wiskirchen ◽  
Jared L. Crandon ◽  
Guilherme H. Furtado ◽  
Gregory Williams ◽  
David P. Nicolau
Keyword(s):  
Immune Status ◽  
Free Drug ◽  
Infection Model ◽  
The Novel ◽  
Immunocompetent Host ◽  
Content Type ◽  
Extended Spectrum ◽  
Drug Concentrations ◽  
Immunocompetent Mice

ABSTRACTCeftaroline exhibitsin vitroactivity against extended-spectrum β-lactamase (ESBL)-, AmpC-, and KPC-producingEnterobacteriaceaewhen combined with the novel β-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 againstEnterobacteriaceaein a murine thigh infection model.IMPORTANCETwelveEnterobacteriaceaeisolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log10CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 μg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤1 μg/ml and could be useful in combating the growing threat of resistantEnterobacteriaceae.

scholarly journals Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel for the prevention of heartworm disease in cats

Parasite ◽  
2021 ◽  
Vol 28 ◽  
pp. 30
Author(s):  
Christine Baker ◽  
John McCall ◽  
Abdelmoneim Mansour ◽  
Scott McCall ◽  
Tayna Shaffer ◽  
...  
Keyword(s):  
Adverse Reactions ◽  
Experimental Studies ◽  
Controlled Study ◽  
Infection Model ◽  
The Novel ◽  
Geometric Means ◽  
Treatment Groups ◽  
Heartworm Disease ◽  
Third Stage ◽  
Label Dose

NexGard® Combo is a novel topical endectoparasiticide formulation for cats combining the insecticide/acaricide esafoxolaner, the nematodicide eprinomectin and the cestodicide praziquantel. The efficacy of this novel formulation for the prevention of heartworm disease in cats was tested in two experimental studies using an induced infection model and a randomized, blinded, placebo-controlled study design, and two USA isolates of Dirofilaria immitis. In each study, 20 naïve cats were each inoculated sub-cutaneously with 100 third-stage larvae of D. immitis 30 days before treatment. Following randomization to two treatment groups of ten cats, each cat was treated topically once, either with the minimum recommended dose of the novel formulation, or with an identical volume of placebo. Five months after treatment (6 months after infections), the cats were humanely euthanized for parasite recovery and count. Efficacy was calculated by comparison of the numbers of adult D. immitis recovered in the control and in the novel formulation groups. In the control groups of each study, D. immitis were recovered in seven and nine cats (respective worm counts ranges 1–7 and 1–16, respective geometric means 1.6 and 5.1). In both studies, none of the treated cats harbored any D. immitis at necropsy and the calculated efficacy of the novel formulation was 100%. There were no adverse reactions related to treatment with the novel formulation. The results of these two studies demonstrate that a topical NexGard® Combo application at the minimum label dose is well-tolerated and efficacious in preventing heartworm disease in cats.

scholarly journals A Histone Methyltransferase Is Required for Maximal Response to Female Sex Hormones

2004 ◽  
Vol 24 (16) ◽  
pp. 7032-7042 ◽  
Author(s):  
Tobias Carling ◽  
Keun-Cheol Kim ◽  
Xiao-Hong Yang ◽  
Jian Gu ◽  
Xiao-Kun Zhang ◽  
...  
Keyword(s):  
Sex Hormones ◽  
Target Genes ◽  
Histone Methyltransferase ◽  
Maximal Response ◽  
Mcf7 Cells ◽  
Female Sex ◽  
Female Sex Hormones ◽  
Estrogen Response ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase

ABSTRACT RIZ1 is an estrogen receptor (ER) coactivator but is also a histone lysine methyltransferase that methylates lysine 9 of histone H3, an activity known to repress transcription. We show here that target organs of mice deficient in RIZ1 exhibit decreased response to female sex hormones. RIZ1 interacted with SRC1 and p300, suggesting that the coactivator function of RIZ1 may be mediated by its interaction with other transcriptional coactivators. In the presence of estrogen, RIZ1 binding to estrogen target genes became less direct and followed the binding of ER to DNA and RIZ1 methyltransferase activity on H3-Lys 9 was inhibited, indicating derepression may play a role in estrogen induction of gene transcription. Reducing RIZ1 level correlated with decreased induction of pS2 gene by estrogen in MCF7 cells. The data suggest that a histone methyltransferase is required for optimal estrogen response in female reproductive tissues and that estrogen-bound ER may turn a transcriptional repressor into a coactivator.

scholarly journals Pharmacokinetic Determinants of Virological Response to Raltegravir in theIn VitroPharmacodynamic Hollow-Fiber Infection Model System

2015 ◽  
Vol 59 (7) ◽  
pp. 3771-3777 ◽  
Author(s):  
Ashley N. Brown ◽  
Jonathan R. Adams ◽  
Dodge L. Baluya ◽  
George L. Drusano
Keyword(s):  
Hollow Fiber ◽  
Viral Suppression ◽  
Daily Administration ◽  
Interindividual Variation ◽  
Infection Model ◽  
Viral Inhibition ◽  
Daily Exposure ◽  
Viral Spread

ABSTRACTDaily administration (q24h) of raltegravir has been shown to be as efficacious as twice-daily administration (q12h) in the hollow-fiber infection model (HFIM) system. However, q24h regimens were not noninferior to q12h dosing in a clinical trial. We hypothesized that between-patient variability in raltegravir pharmacokinetics (PK) was responsible for the discordance in conclusions between thein vitroandin vivostudies. Hollow-fiber cartridges were inoculated with HIV-infected H9 cells and uninfected CEM-SS cells. Four cartridges received the total daily exposure (800 mg) q24h and four received half the daily exposure (400 mg) q12h. PK profiles with half-lives of 8, 4, 3, and 2 h were simulated for each dosing interval. Cell-to-cell viral spread was assessed by flow cytometry. Viral inhibition was similar between q24h and q12h dosing at the 8- and 4-h half-lives. The q24h dosing was not as efficacious as the q12h dosing when faster half-lives were simulated; a lack of viral suppression was observed at days 3 and 4 for the 2- and 3-h half-lives, respectively. The discrepancy in conclusions between thein vitroHFIM system studies and clinical trials is likely due to the large interindividual variation in raltegravir PK.

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