scholarly journals Logical and experimental modeling of cytokine and eicosanoid signaling in psoriatic keratinocytes

2021 ◽  
Author(s):  
Eirini Tsirvouli ◽  
Felicity Ashcroft ◽  
Berit Johansen ◽  
Martin Kuiper
Keyword(s):  
Computational Model ◽  
Drug Targets ◽  
Systems Approach ◽  
Knowledge Network ◽  
Action Model ◽  
Th17 Cytokines ◽  
Eicosanoid Release ◽  
Th1 Cytokines ◽  
Novel Drug

Psoriasis is characterized by chronic inflammation, perpetuated by a Th17-dependent signaling loop between the immune system and keratinocytes that could involve phospholipase A2 (PLA2)-dependent eicosanoid release. A prior knowledge network supported by experimental observations was used to encode the regulatory network of psoriatic keratinocytes in a computational model for studying the mode of action of a cytosolic (c) PLA2α inhibitor. A combination of evidence derived from the computational model and experimental data suggests that Th17 cytokines stimulate pro-inflammatory cytokine expression in psoriatic keratinocytes via activation of cPLA2α-PGE2-EP4 signaling, which could be suppressed using the anti-psoriatic calcipotriol. cPLA2α inhibition and calcipotriol showed overlapping and distinct modes of action. Model analyses revealed the immunomodulatory role of Th1 cytokines, the modulation of the physiological states of keratinocytes by Th17 cytokines, and how Th1 and Th17 cells together promote the development of psoriasis. Model simulations additionally suggest novel drug targets, including EP4 and PRKACA, for treatment that may restore a normal phenotype. Our work illustrates how the study of complex diseases can benefit from an integrated systems approach.

scholarly journals Sirtuin 1 and Sirtuin 3 in Granulosa Cell Tumors

2021 ◽  
Vol 22 (4) ◽  
pp. 2047
Author(s):  
Nina Schmid ◽  
Kim-Gwendolyn Dietrich ◽  
Ignasi Forne ◽  
Alexander Burges ◽  
Magdalena Szymanska ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Drug Targets ◽  
Growth Regulation ◽  
Sirtuin 1 ◽  
Ki 67 ◽  
Granulosa Cell Tumors ◽  
Novel Drug

Sirtuins (SIRTs) are NAD+-dependent deacetylases that regulate proliferation and cell death. In the human ovary, granulosa cells express sirtuin 1 (SIRT1), which has also been detected in human tumors derived from granulosa cells, i.e., granulosa cell tumors (GCTs), and in KGN cells. KGN cells are an established cellular model for the majority of GCTs and were used to explore the role of SIRT1. The SIRT1 activator SRT2104 increased cell proliferation. By contrast, the inhibitor EX527 reduced cell numbers, without inducing apoptosis. These results were supported by the outcome of siRNA-mediated silencing studies. A tissue microarray containing 92 GCTs revealed nuclear and/or cytoplasmic SIRT1 staining in the majority of the samples, and also, SIRT2-7 were detected in most samples. The expression of SIRT1–7 was not correlated with the survival of the patients; however, SIRT3 and SIRT7 expression was significantly correlated with the proliferation marker Ki-67, implying roles in tumor cell proliferation. SIRT3 was identified by a proteomic analysis as the most abundant SIRT in KGN. The results of the siRNA-silencing experiments indicate involvement of SIRT3 in proliferation. Thus, several SIRTs are expressed by GCTs, and SIRT1 and SIRT3 are involved in the growth regulation of KGN. If transferable to GCTs, these SIRTs may represent novel drug targets.

scholarly journals Mutation ofRv2887, amarR-Like Gene, Confers Mycobacterium tuberculosis Resistance to an Imidazopyridine-Based Agent

2015 ◽  
Vol 59 (11) ◽  
pp. 6873-6881 ◽  
Author(s):  
Kathryn Winglee ◽  
Shichun Lun ◽  
Marco Pieroni ◽  
Alan Kozikowski ◽  
William Bishai
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Efflux Pump ◽  
Transcriptional Regulator ◽  
Cross Resistance ◽  
Loss Of Function ◽  
Strong Activity ◽  
Content Type ◽  
Novel Drug

ABSTRACTDrug resistance is a major problem inMycobacterium tuberculosiscontrol, and it is critical to identify novel drug targets and new antimycobacterial compounds. We have previously identified an imidazo[1,2-a]pyridine-4-carbonitrile-based agent, MP-III-71, with strong activity againstM. tuberculosis. In this study, we evaluated mechanisms of resistance to MP-III-71. We derived three independentM. tuberculosismutants resistant to MP-III-71 and conducted whole-genome sequencing of these mutants. Loss-of-function mutations inRv2887were common to all three MP-III-71-resistant mutants, and we confirmed the role ofRv2887as a gene required for MP-III-71 susceptibility using complementation. The Rv2887 protein was previously unannotated, but domain and homology analyses suggested it to be a transcriptional regulator in the MarR (multiple antibiotic resistance repressor) family, a group of proteins first identified inEscherichia colito negatively regulate efflux pumps and other mechanisms of multidrug resistance. We found that two efflux pump inhibitors, verapamil and chlorpromazine, potentiate the action of MP-III-71 and that mutation ofRv2887abrogates their activity. We also used transcriptome sequencing (RNA-seq) to identify genes which are differentially expressed in the presence and absence of a functional Rv2887 protein. We found that genes involved in benzoquinone and menaquinone biosynthesis were repressed by functional Rv2887. Thus, inactivating mutations ofRv2887, encoding a putative MarR-like transcriptional regulator, confer resistance to MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs. The mechanism of resistance ofM. tuberculosisRv2887mutants may involve efflux pump upregulation and also drug methylation.

Potential Role of Endonuclease Inhibition and Other Targets in the Treatment of Influenza

2020 ◽  
Vol 21 (2) ◽  
pp. 202-211
Author(s):  
Doreen Szollosi ◽  
Ashley Bill
Keyword(s):  
Rna Polymerase ◽  
Drug Targets ◽  
Rna Virus ◽  
Neuraminidase Inhibitor ◽  
Viral Fusion ◽  
Dependent Endonuclease ◽  
Resistant Strains ◽  
Polymerase Basic 1 ◽  
Novel Drug

Background: Influenza is a single-stranded RNA virus that is highly contagious and infects millions of people in the U.S. annually. Due to complications, approximately 959,000 people were hospitalized and another 79,400 people died during the 2017-2018 flu season. While the best methods of prevention continue to be vaccination and hygiene, antiviral treatments may help reduce symptoms for those who are infected. Until recently, the only antiviral drugs in use have been the neuraminidase inhibitors: oseltamivir, zanamivir, and peramivir. Objective: We reviewed novel drug targets that can be used in the treatment of influenza, particularly in the case of neuraminidase inhibitor-resistant strains that may emerge. Results: More recently, a drug with a new mechanism of action has been approved. Baloxavir marboxil inhibits the influenza cap-dependent endonuclease that is needed for the virus to initiate replication within the host cell. This endonuclease target is within the polymerase acid (PA) subunit of RNA polymerase. Since the RNA-dependent RNA polymerase consists of two other subunits, polymerase basic 1 and 2, RNA polymerase has several targets that prevent viral replication. Other targets still under investigation include viral kinases, endocytosis, and viral fusion. Conclusion: Due to the possibility of viral mutations and resistance, it is important to have antivirals with different mechanisms available, especially in the case of a new pandemic strain. Several novel antivirals are within various stages of development and may represent new classes of treatments that can reduce symptoms and complications in those patients who may be at higher risk.

scholarly journals ‘FAS’t inhibition of malaria

2004 ◽  
Vol 383 (3) ◽  
pp. 401-412 ◽  
Author(s):  
Avadhesha SUROLIA ◽  
T. N. C. RAMYA ◽  
V. RAMYA ◽  
Namita SUROLIA
Keyword(s):  
Fatty Acid ◽  
Drug Targets ◽  
Fatty Acid Biosynthesis ◽  
Present Review ◽  
Acid Biosynthesis ◽  
The Status ◽  
Novel Drug ◽  
Emergence Of Resistance ◽  
Specific Pathway

Malaria, a tropical disease caused by Plasmodium sp., has been haunting mankind for ages. Unsuccessful attempts to develop a vaccine, the emergence of resistance against the existing drugs and the increasing mortality rate all call for immediate strategies to treat it. Intense attempts are underway to develop potent analogues of the current antimalarials, as well as a search for novel drug targets in the parasite. The indispensability of apicoplast (plastid) to the survival of the parasite has attracted a lot of attention in the recent past. The present review describes the origin and the essentiality of this relict organelle to the parasite. We also show that among the apicoplast specific pathways, the fatty acid biosynthesis system is an attractive target, because its inhibition decimates the parasite swiftly unlike the ‘delayed death’ phenotype exhibited by the inhibition of the other apicoplast processes. As the enzymes of the fatty acid biosynthesis system are present as discrete entities, unlike those of the host, they are amenable to inhibition without impairing the operation of the host-specific pathway. The present review describes the role of these enzymes, the status of their molecular characterization and the current advancements in the area of developing inhibitors against each of the enzymes of the pathway.

scholarly journals A Novel FtsZ-Like Protein Is Involved in Replication of the Anthrax Toxin-Encoding pXO1 Plasmid in Bacillus anthracis

2006 ◽  
Vol 188 (8) ◽  
pp. 2829-2835 ◽  
Author(s):  
Eowyn Tinsley ◽  
Saleem A. Khan
Keyword(s):  
Bacillus Anthracis ◽  
Drug Targets ◽  
Mutational Analysis ◽  
Anthrax Toxin ◽  
Replication Proteins ◽  
Reading Frame ◽  
Virulence Plasmids ◽  
Novel Drug ◽  
Novel Drug Targets

ABSTRACTPlasmid pXO1 encodes the tripartite anthrax toxin, which is the major virulence factor ofBacillus anthracis. In spite of the important role of pXO1 in anthrax pathogenesis, very little is known about its replication and maintenance inB. anthracis. We cloned a 5-kb region of the pXO1 plasmid into anEscherichia colivector and showed that this plasmid can replicate when introduced intoB. anthracis. Mutational analysis showed that open reading frame 45 (repX) of pXO1 was required for the replication of the miniplasmid inB. anthracis. Interestingly,repXshowed limited homology to bacterial FtsZ proteins that are involved in cell division. A mutation in the predicted GTP binding domain of RepX abolished its replication activity. Genes almost identical torepXare contained on several megaplasmids in members of theBacillus cereusgroup, including aB. cereusstrain that causes an anthrax-like disease. Our results identify a novel group of FtsZ-related initiator proteins that are required for the replication of virulence plasmids inB. anthracisand possibly in related organisms. Such replication proteins may provide novel drug targets for the elimination of plasmids encoding the anthrax toxin and other virulence factors.

scholarly journals Piper longum: A review of its phytochemicals and their network pharmacological evaluation

2017 ◽  
Author(s):  
Neha Choudhary ◽  
Vikram Singh
Keyword(s):  
Drug Targets ◽  
Network Pharmacology ◽  
High Confidence ◽  
Protein Targets ◽  
Piper Longum ◽  
Protein Target ◽  
The Common ◽  
Novel Drug ◽  
Novel Drug Targets

AbstractPiper longum L. (P. longum, also called as long pepper) is one of the common culinary herb and has been extensively used as an important constituent of various indigenous medicines, specifically in traditional Indian medicinal system known as Ayurveda. Towards obtaining a global regulatory framework of P. longum’s constituents, in this work we first reviewed phytochemicals present in this herb and then studied their pharmacological and medicinal features using network pharmacology approach. We developed high-confidence level tripartite networks consisting of phytochemicals – protein targets – disease association and explain the role of its phytochemicals to various chronic diseases. 7 drug-like phytochemicals in this herb were found as the potential regulators of 5 FDA approved drug targets; and 28 novel drug targets were also reported. 105 phytochemicals were linked with immunomodulatory potency by pathway level mapping in human metabolic network. A sub-network of human PPI regulated by its phytochemicals was derived and various modules in this sub-network were successfully associated with specific diseases.Graphical abstractAbbreviationsP. longumPiper longum L.PCPhytochemicalPTProtein targetBPBiological pathwaysDADisease asscociationPCtNumber of protein targets corresponding to a particular phytochemicalTtTotal number of protein targets of P. longumADMETAbsorption, Distribution, Metabolism, Excretion and Toxicity.

scholarly journals Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-A

2019 ◽  
Author(s):  
Jillienne C. Touchette ◽  
Janna K. Moen ◽  
Jenna M. Robinson ◽  
Anna M. Lee
Keyword(s):  
Alcohol Consumption ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Drug Targets ◽  
The United States ◽  
Nicotinic Acetylcholine ◽  
Knock Out ◽  
Nicotine Consumption ◽  
Novel Drug

AbstractThe prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating the neurocircuitries in this region in mediating the effects of sazetidine-A. Furthermore, sazetidine-A-induced reduction in alcohol consumption was mediated by non-α4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both α4 knock-out and wild-type mice. Finally, we found that in mice pre-treated with sazetidine-A, alcohol induced Fos transcript within Th-expressing but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A acts on non-α4 nAChRs to enhance the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-α4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs.

Receptor Mediated Uptake of Pepsin: Significance in Otolaryngology

2008 ◽  
Vol 18 (3) ◽  
pp. 134-142
Author(s):  
Nikki Johnston
Keyword(s):  
Drug Targets ◽  
Proton Pump Inhibitor Therapy ◽  
Positive Symptom ◽  
Persistent Symptoms ◽  
Laryngeal Injury ◽  
Intraluminal Impedance ◽  
Gastric Contents ◽  
Novel Drug ◽  
Novel Drug Targets

Abstract Reflux of gastric contents into the laryngopharynx contributes to voice disorders, otolaryngological inflammatory disorders, and perhaps even neoplastic diseases of the laryngopharynx. Treatment is currently focuses on increasing the pH of the refluxate because it was thought that the refluxate would not cause injury/symptoms at higher pH. However, many patients with reflux-attributed laryngeal injury/disease have persistent symptoms despite aggressive acid supression therapy. Recent studies using combined multi-channel intraluminal impedance with pH montioring have shown a positive symptom association with non- and weakly-acidic reflux and an association between non-/weakly acidic reflux and refractory symptoms on proton pump inhibitor therapy. Thus, the role of acid alone in the development of reflux related laryngeal pathology has to be questioned and studies examining the effects of the other components of the refluxate are clearly needed. Our data, described herein, supports a role for pepsin in reflux-attributed laryngeal injury/disease independent of the pH of the refluxate and highlights potential novel drug targets.

Understanding Mass Spectrometry-based Global Mycobacterial Lipidomics

2020 ◽  
Vol 20 (8) ◽  
pp. 607-623
Author(s):  
Zeeshan Fatima ◽  
Shiv Nandan ◽  
Saif Hameed
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Infectious Agent ◽  
Dry Weight ◽  
Diagnostic Methods ◽  
Detection Methods ◽  
Novel Drug ◽  
Significant Attention ◽  
Novel Drug Targets

: Tuberculosis (TB) is the foremost cause of mortality from single infectious agent Mycobacterium tuberculosis (MTB). Current therapeutic regimes suffer from several problems, including side effects, costs and emergence of multidrug resistance (MDR). Moreover, conventional diagnostic methods are either too slow, or lack accurate and robust biomarkers. Under such circumstances, identification of rapid metabolite based biomarkers as novel drug targets could be a potential approach to circumvent MDR. In the era of “OMIC” sciences, lipidomics has gained significant attention to unravel the complexity of lipid-loaded Mycobacterium species. Lipidomics is a subbranch of metabolomics with extreme atomic diversity between the metabolites. There is no single principle on which the metabolite diversity can be defined, unlike other biomolecules viz. nucleic acid, proteins or carbohydrates. MTB encodes 10% of the genome for lipid metabolism and lipids account for 60% of its dry weight. Mycobacterium harbor a wide spectra of lipid repertoire ranging from highly apolar to highly polar lipids, adding complexity to their identification and analysis. Compared to targeted approaches, untargeted or global lipidomics of MTB is still more challenging. This review describes recent advances in lipidomics technology with regard to chromatography, detection methods and assessment on the existing mass spectrometry-based lipidomics tools to study the untargeted or global MTB lipidomics. It also identifies the limitations associated with present technologies as well as explores solutions to practical challenges concurrent with the establishment of MTB lipidome. Together we endorse that the emerging tools of lipidomics have provided a broader vision to comprehend the role of lipid molecules in MTB pathogenesis and the need for further improvements.

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