scholarly journals Similarities and Differences of Hsp70, hsc70, Grp78 and Mortalin as Cancer Biomarkers and Drug Targets

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2996
Author(s):  
Rajani Rai ◽  
Amy L. Kennedy ◽  
Zitha Redempta Isingizwe ◽  
Pouya Javadian ◽  
Doris Mangiaracina Benbrook
Keyword(s):  
Drug Targets ◽  
Treatment Strategies ◽  
Cellular Effects ◽  
Hsp70 Family ◽  
Literature Reviews ◽  
Cancer Cell Survival ◽  
Client Proteins ◽  
Similarities And Differences ◽  
Patient Prognosis ◽  
Hsp70 Inhibitors

Background: Upregulation of Heath Shock Protein 70 (HSP70) chaperones supports cancer cell survival. Their high homology causes a challenge to differentiate them in experimental or prevention and treatment strategies. The objective of this investigation was to determine similarities and differences of Hsp70, hsc70, Grp78 and Mortalin members of the HSP70 family encoded by HSPA1, HSPA8, HSPA5 and HSPA9 genes, respectively. Methods: Literature reviews were conducted using HSPA1, HSPA5, HSPA8 and HSPA9 gene or protein names or synonyms combined with biological or cancer-relevant terms. Ingenuity Pathway Analysis was used to identify and compare profiles of proteins that directly bind individual chaperones and their associated pathways. TCGA data was probed to identify associations of hsc70 with cancer patient survival. ClinicalTrials.gov was used to identify HSP70 family studies. Results: The chaperones have similar protein folding functions. Their different cellular effects are determined by co-chaperones and client proteins combined with their intra- and extra-cellular localizations. Their upregulation is associated with worse patient prognosis in multiple cancers and can stimulate tumor immune responses or drug resistance. Their inhibition selectively kills cancer over healthy cells. Conclusions: Differences in Hsp70, hsc70, Grp78 and mortalin provide opportunities to calibrate HSP70 inhibitors for individual cancers and combination therapies.

The Role of Purinergic Signaling in Trichomonas vaginalis Infection

2020 ◽  
Vol 20 ◽  
Author(s):  
Micheli Ferla ◽  
Tiana Tasca
Keyword(s):  
Drug Targets ◽  
Trichomonas Vaginalis ◽  
Hiv Transmission ◽  
Cell Damage ◽  
Purinergic Signaling ◽  
Host Cells ◽  
Purine Nucleotides ◽  
Cellular Effects ◽  
Adverse Pregnancy ◽  
Purine Salvage Pathways

: Trichomoniasis, one of the most common non-viral sexually transmitted infections worldwide, is caused by the parasite Trichomonas vaginalis. The pathogen colonizes the human urogenital tract and the infection is associated with complications such as adverse pregnancy outcomes, cervical cancer, and an increase in HIV transmission. The mecha-nisms of pathogenicity are multifactorial, and controlling immune responses is essential for infection maintenance. Extra-cellular purine nucleotides are released by cells in physiological and pathological conditions, and they are hydrolyzed by enzymes called ecto-nucleotidases. The cellular effects of nucleotides and nucleosides occur via binding to purinoceptors, or throughthe uptake by nucleoside transporters. Altogether, enzymes, receptors and transporters constitute the purinergic signaling, a cellular network that regulates several effects in practically all systems including mammals, helminths, proto-zoa, bacteria, and fungi. In this context, this review updates the data on purinergic signaling involved in T. vaginalis biol-ogy and interaction with host cells, focusing on the characterization of ecto-nucleotidases and on purine salvage pathways. The implications of the final products, the nucleosides adenosine and guanosine, for human neutrophil response and vagi-nal epithelial cell damage reveal the purinergic signaling as a potential new mechanism for alternative drug targets.

scholarly journals Roles of tumor-associated macrophages in tumor progression: implications on therapeutic strategies

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Shangli Zhu ◽  
Ming Yi ◽  
Yuze Wu ◽  
Bing Dong ◽  
Kongming Wu
Keyword(s):  
Tumor Progression ◽  
Tumor Development ◽  
Treatment Strategies ◽  
Therapeutic Strategies ◽  
Tumor Associated Macrophages ◽  
Promising Target ◽  
Multiple Processes ◽  
Enhance Tumor Cell ◽  
Patient Prognosis ◽  
Anti Tumor Activity

AbstractMacrophages are heterogeneous cells that present as different functional phenotypes due to their plasticity. They can be classified into two categories, namely M1- and M2-like macrophages, which are involved in processes as diverse as anti-tumor activity and immunosuppressive tumor promotion. Tumor-associated macrophages (TAMs) are defined as being of an M2-type and are considered as the active component in tumor microenvironment. TAMs are involved in multiple processes of tumor progression through the expression of cytokines, chemokines, growth factors, protein hydrolases and more, which lead to enhance tumor cell proliferation, angiogenesis, and immunosuppression, which in turn supports invasion and metastasis. It is assumed that the abundance of TAMs in major solid tumors is correlated to a negative patient prognosis. Because of the currently available data of the TAMs’ role in tumor development, these cells have emerged as a promising target for novel cancer treatment strategies. In this paper, we will briefly describe the origins and types of TAMs and will try to comprehensively show how TAMs contribute to tumorigenesis and disease progression. Finally, we will present the main TAM-based therapeutic strategies currently available.

scholarly journals Functional Stratification of Cancer Drugs through Integrated Network Similarity

2022 ◽  
Author(s):  
Nurcan Tuncbag ◽  
Seyma Unsal Beyge
Keyword(s):  
Cell Lines ◽  
Drug Targets ◽  
Hdac Inhibitors ◽  
Treatment Strategies ◽  
Network Models ◽  
Drug Combinations ◽  
Multiple Cancer ◽  
Integrated Network ◽  
Drug Molecules ◽  
The Difference

Abstract Heterogeneity across tumors is the main obstacle in developing treatment strategies. Drug molecules not only perturb their immediate protein targets but also modulate multiple signaling pathways. In this study, we explored the networks modulated by several drug molecules across multiple cancer cell lines by integrating the drug targets with transcriptomic and phosphoproteomic data. As a result, we obtained 236 reconstructed networks covering five cell lines and 70 drugs. A rigorous topological and pathway analysis showed that chemically and functionally different drugs may modulate overlapping networks. Additionally, we revealed a set of tumor-specific hidden pathways with the help of drug network models that are not detectable from the initial data. The difference in the target selectivity of the drugs leads to disjoint networks despite sharing the exact mechanism of action, e.g., HDAC inhibitors. We also used the reconstructed network models to study potential drug combinations based on the topological separation, found literature evidence for a set of drug pairs. Overall, the network-level exploration of the drug perturbations may potentially help optimize treatment strategies and suggest new drug combinations.

scholarly journals Effects of Xuefu Zhuyu Decoction on Cell Migration and Ocular Tumor Invasion in Drosophila

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Sitong Wang ◽  
Fanwu Wu ◽  
Bin Ye ◽  
Shiping Zhang ◽  
Xingjun Wang ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Invasion ◽  
Drug Targets ◽  
Tumor Metastasis ◽  
Blood Stasis ◽  
Treatment Strategies ◽  
Blood Stasis Syndrome ◽  
Positive Role ◽  
Xuefu Zhuyu Decoction

Xuefu Zhuyu Decoction (XFZYD), a Traditional Chinese Medicine (TCM) decoction mainly for treating blood stasis syndrome, has been widely investigated and applied in clinic and in laboratory. XFZYD contains 11 herbs and has been identified to promoting blood circulation to remove blood stasis for cardiovascular disease. Meanwhile, blood stasis is directly related to malignant tumor according to TCM basic theory. However, the effects of XFZYD on tumor metastasis and the underlying mechanisms are still largely unknown. Here, we employed well-established Drosophila cell migration and tumor invasion models to explore whether XFZYD has the anticancer activity on tumor metastasis in vivo. Our work has demonstrated that XFZYD could suppress cell migration and tumor invasion at the moderate concentrations. In addition, XFZYD altered the expression of MMP1, β-integrin, and E-cadherin to impede cell migration. Moreover, XFZYD inhibited ocular tumor invasion presumably by reducing the activity of Notch signaling. Together, these evidences reveal a positive role of XFZYD in suppressing cell migration and tumor metastasis, providing the potential drug targets and key clues for cancer clinical treatment strategies.

scholarly journals How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency

2019 ◽  
Vol 20 (9) ◽  
pp. 2179
Author(s):  
Tim Breitenbach ◽  
Kristina Lorenz ◽  
Thomas Dandekar
Keyword(s):  
Drug Targets ◽  
Muscle Growth ◽  
Treatment Strategies ◽  
Mathematical Optimization ◽  
Activity Level ◽  
Cardiac Insufficiency ◽  
Pharmacological Intervention ◽  
Beneficial Effects ◽  
Optimal Drug ◽  
Automatic Search

Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK Thr 188 phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.

scholarly journals The Yeast Hsp70 Cochaperone Ydj1 Regulates Functional Distinction of Ssa Hsp70s in the Hsp90 Chaperoning Pathway

Genetics ◽  
2020 ◽  
Vol 215 (3) ◽  
pp. 683-698 ◽  
Author(s):  
Deepika Gaur ◽  
Prashant Singh ◽  
Jyoti Guleria ◽  
Arpit Gupta ◽  
Satinderdeep Kaur ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Heat Shock ◽  
Hormone Receptors ◽  
Growth Defects ◽  
Link Type ◽  
Hsp70 Family ◽  
Final Maturation ◽  
Client Proteins ◽  
Hsp 90

Heat-shock protein (Hsp) 90 assists in the folding of diverse sets of client proteins including kinases and growth hormone receptors. Hsp70 plays a major role in many Hsp90 functions by interacting and modulating conformation of its substrates before being transferred to Hsp90s for final maturation. Each eukaryote contains multiple members of the Hsp70 family. However, the role of different Hsp70 isoforms in Hsp90 chaperoning actions remains unknown. Using v-Src as an Hsp90 substrate, we examined the role of each of the four yeast cytosolic Ssa Hsp70s in regulating Hsp90 functions. We show that the strain expressing stress-inducible Ssa3 or Ssa4, and the not constitutively expressed Ssa1 or Ssa2, as the sole Ssa Hsp70 isoform reduces v-Src-mediated growth defects. The study shows that although different Hsp70 isoforms interact similarly with Hsp90s, v-Src maturation is less efficient in strains expressing Ssa4 as the sole Hsp70. We further show that the functional distinction between Ssa2 and Ssa4 is regulated by its C-terminal domain. Further studies reveal that Ydj1, which is known to assist substrate transfer to Hsp70s, interacts relatively weakly with Ssa4 compared with Ssa2, which could be the basis for poor maturation of the Hsp90 client in cells expressing stress-inducible Ssa4 as the sole Ssa Hsp70. The study thus reveals a novel role of Ydj1 in determining the functional distinction among Hsp70 isoforms with respect to the Hsp90 chaperoning action.

scholarly journals Tissue-Resident Memory T Cells in the Liver—Unique Characteristics of Local Specialists

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2457
Author(s):  
Lea M. Bartsch ◽  
Marcos P. S. Damasio ◽  
Sonu Subudhi ◽  
Hannah K. Drescher
Keyword(s):  
T Cells ◽  
Liver Diseases ◽  
Drug Targets ◽  
Memory T Cells ◽  
Secondary Infection ◽  
Treatment Strategies ◽  
Alcoholic Fatty Liver ◽  
Cytokine Milieu ◽  
Novel Treatment Strategies ◽  
Resident Memory T Cells

T cells play an important role to build up an effective immune response and are essential in the eradication of pathogens. To establish a long-lasting protection even after a re-challenge with the same pathogen, some T cells differentiate into memory T cells. Recently, a certain subpopulation of memory T cells at different tissue-sites of infection was detected—tissue-resident memory T cells (TRM cells). These cells can patrol in the tissue in order to encounter their cognate antigen to establish an effective protection against secondary infection. The liver as an immunogenic organ is exposed to a variety of pathogens entering the liver through the systemic blood circulation or via the portal vein from the gut. It could be shown that intrahepatic TRM cells can reside within the liver tissue for several years. Interestingly, hepatic TRM cell differentiation requires a distinct cytokine milieu. In addition, TRM cells express specific surface markers and transcription factors, which allow their identification delimited from their circulating counterparts. It could be demonstrated that liver TRM cells play a particular role in many liver diseases such as hepatitis B and C infection, non-alcoholic fatty liver disease and even play a role in the development of hepatocellular carcinoma and in building long-lasting immune responses after vaccination. A better understanding of intrahepatic TRM cells is critical to understand the pathophysiology of many liver diseases and to identify new potential drug targets for the development of novel treatment strategies.

scholarly journals Hsp70 molecular chaperones: multifunctional allosteric holding and unfolding machines

2019 ◽  
Vol 476 (11) ◽  
pp. 1653-1677 ◽  
Author(s):  
Eugenia M. Clerico ◽  
Wenli Meng ◽  
Alexandra Pozhidaeva ◽  
Karishma Bhasne ◽  
Constantine Petridis ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Protein Homeostasis ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
The Past ◽  
Hsp70 Family ◽  
Nucleotide Exchange Factors ◽  
Client Proteins ◽  
Structural Insights ◽  
Insight Into

AbstractThe Hsp70 family of chaperones works with its co-chaperones, the nucleotide exchange factors and J-domain proteins, to facilitate a multitude of cellular functions. Central players in protein homeostasis, these jacks-of-many-trades are utilized in a variety of ways because of their ability to bind with selective promiscuity to regions of their client proteins that are exposed when the client is unfolded, either fully or partially, or visits a conformational state that exposes the binding region in a regulated manner. The key to Hsp70 functions is that their substrate binding is transient and allosterically cycles in a nucleotide-dependent fashion between high- and low-affinity states. In the past few years, structural insights into the molecular mechanism of this allosterically regulated binding have emerged and provided deep insight into the deceptively simple Hsp70 molecular machine that is so widely harnessed by nature for diverse cellular functions. In this review, these structural insights are discussed to give a picture of the current understanding of how Hsp70 chaperones work.

Brain circuitry of compulsivity and impulsivity

CNS Spectrums ◽  
2013 ◽  
Vol 19 (1) ◽  
pp. 21-27 ◽  
Author(s):  
Jon E. Grant ◽  
Suck Won Kim
Keyword(s):  
Continuous Spectrum ◽  
Treatment Strategies ◽  
Complex Disorders ◽  
Additional Investigation ◽  
Prevention And Treatment ◽  
Brain Circuitry ◽  
Similarities And Differences

Impulsivity and compulsivity have been considered opposite poles of a continuous spectrum, but their relationship appears to be more complex. Disorders characterized by impulsivity often have features of compulsivity and vice versa. The overlaps of the constructs of compulsivity and impulsivity warrant additional investigation, not only to identify the similarities and differences, but also to examine the implications for prevention and treatment strategies of both compulsive and impulsive behaviors.

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