scholarly journals Molecular Mechanisms to Target Cellular Senescence in Hepatocellular Carcinoma

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2540
Author(s):  
Constanze Mittermeier ◽  
Andreas Konopa ◽  
Susanne Muehlich
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Pharmacological Interventions ◽  
Therapeutic Concepts ◽  
Novel Drug ◽  
Serum Response ◽  
Novel Drug Targets

Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death and is the most common type of liver cancer. Due to the current paucity of drugs for HCC therapy there is a pressing need to develop new therapeutic concepts. In recent years, the role of Serum Response Factor (SRF) and its coactivators, Myocardin-Related Transcription Factors A and B (MRTF-A and -B), in HCC formation and progression has received considerable attention. Targeting MRTFs results in HCC growth arrest provoked by oncogene-induced senescence. The induction of senescence acts as a tumor-suppressive mechanism and therefore gains consideration for pharmacological interventions in cancer therapy. In this article, we describe the key features and the functional role of senescence in light of the development of novel drug targets for HCC therapy with a focus on MRTFs.

scholarly journals The Aging Vasculature: Glucose Tolerance, Hypoglycemia and the Role of the Serum Response Factor

2021 ◽  
Vol 8 (5) ◽  
pp. 58
Author(s):  
Hazel Aberdeen ◽  
Kaela Battles ◽  
Ariana Taylor ◽  
Jeranae Garner-Donald ◽  
Ana Davis-Wilson ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Response Factor ◽  
Homeostatic Control ◽  
Older Americans ◽  
The Subject ◽  
Serum Response

The fastest growing demographic in the U.S. at the present time is those aged 65 years and older. Accompanying advancing age are a myriad of physiological changes in which reserve capacity is diminished and homeostatic control attenuates. One facet of homeostatic control lost with advancing age is glucose tolerance. Nowhere is this more accentuated than in the high proportion of older Americans who are diabetic. Coupled with advancing age, diabetes predisposes affected subjects to the onset and progression of cardiovascular disease (CVD). In the treatment of type 2 diabetes, hypoglycemic episodes are a frequent clinical manifestation, which often result in more severe pathological outcomes compared to those observed in cases of insulin resistance, including premature appearance of biomarkers of senescence. Unfortunately, molecular mechanisms of hypoglycemia remain unclear and the subject of much debate. In this review, the molecular basis of the aging vasculature (endothelium) and how glycemic flux drives the appearance of cardiovascular lesions and injury are discussed. Further, we review the potential role of the serum response factor (SRF) in driving glycemic flux-related cellular signaling through its association with various proteins.

scholarly journals Multi-omics data integration reveals novel drug targets in hepatocellular carcinoma

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Christos Dimitrakopoulos ◽  
Sravanth Kumar Hindupur ◽  
Marco Colombi ◽  
Dritan Liko ◽  
Charlotte K. Y. Ng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Targets ◽  
Mtor Signaling ◽  
Omics Data ◽  
Genetic Changes ◽  
Genetic Aberrations ◽  
Functional Consequences ◽  
Novel Drug ◽  
Novel Drug Targets ◽  
Omics Data Integration

Abstract Background Genetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood. Results Here, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 ‘mediators’ that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC. Conclusions This study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.

scholarly journals Genetic Analysis of Azole Resistance by Transposon Mutagenesis in Saccharomyces cerevisiae

1999 ◽  
Vol 43 (11) ◽  
pp. 2731-2735 ◽  
Author(s):  
D. P. Kontoyiannis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Screening Tool ◽  
Transposon Mutagenesis ◽  
Antifungal Drugs ◽  
Azole Resistance ◽  
Recessive Mutations ◽  
Novel Drug ◽  
Novel Drug Targets

ABSTRACT The increasing resistance of Candida species to fluconazole is cause for concern. To determine the molecular mechanisms involved in resistance to fluconazole, I used a scheme of transposon mutagenesis in Saccharomyces cerevisiae, a genetically tractable yeast that is closely related to Candida albicans. This technique, which permits the generation and analysis of multiple random Tn3::LEU2::lacZfusions, can be used as a disruption mutagen (N. B. Burns et al., Genes Dev. 8:1087–1105, 1994). By using the Tn3::LEU2::lacZlibrary as a disruption mutagen, I found recessive mutations in genes that were previously found to be involved in azole resistance, e.g.,PDR5 and CPR1, and in genes previously found to be involved in azole sensitivity, e.g., ERG3. This approach also enabled me to identify recessive mutations in three genes not previously known to be involved in azole sensitivity. Two of the genes,ADA3 and SPT7, are general transcriptional regulators; the third, YMR034c, is a putative sterol transporter. Finally, by screening the Tn3::LEU2::lacZlibrary for lacZ fusions induced by a low concentration of fluconazole, I identified genes known to be induced by azoles as well as a variety of other genes not previously known to be induced by the drug. In conclusion, transposon mutagenesis is a promising screening tool for use in identifying novel drug targets and in uncovering the mechanisms involved in the response of S. cerevisiae to antifungal drugs.

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 Updates in the Systemic Treatment of Hepatocellular Carcinoma

2018 ◽  
Vol 14 (2) ◽  
pp. 76
Author(s):  
Emerson Y Chen ◽  
Charles D Lopez ◽  
Gina M Vaccaro ◽  
◽  
◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Targets ◽  
Systemic Treatment ◽  
Treatment Options ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Recent Phase ◽  
Novel Drug ◽  
Near Future ◽  
Novel Drug Targets

Oncology drug development has recently introduced new systemic treatment options for hepatocellular carcinoma (HCC). Here we consider the general approaches to diagnostic workup, staging, and overall management of HCC with emphasis on systemic treatment options based on recent phase III clinical trials. Novel drug targets involving immunotherapy may change how we treat HCC in the near future.

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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