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Advances in Cell Biology and Drug Discovery
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Advances in Cell Biology and Drug Discovery

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Cell Biology and Tissue Engineering".

Deadline for manuscript submissions: closed (28 June 2024) | Viewed by 12447

Special Issue Editor

Dr. Muhammad Rafehi

E-Mail Website
Guest Editor
Institute of Clinical Pharmacology, University Medical Centre Göttingen, Göttingen, Germany
Interests: pharmacology; medicinal chemistry; personalised medicine; drug development; drug transporters

Special Issue Information

Dear Colleagues,

The drug discovery process is the basis for developing new medications. It involves the synthesis of compound libraries and their assessment for activity at a biological target, often in high-throughput in vitro assays, to identify hit compounds. These are subsequently optimised with regard to their pharmacodynamics (e.g., potency, selectivity for the respective target) and pharmacokinetics (e.g., oral bioavailability, elimination) before being further assessed for potential toxicity.

Cell biology plays a substantial role in drug discovery, as the above-described functional and toxicity studies usually involve cell-based assays. Moreover, research in this field is essential in order to understand pathophysiological mechanisms and to identify drug targets.

This Special Issue, “Advances in Cell Biology and Drug Discovery”, collects recent high-quality original research data and review reports that complement and advance current knowledge with respect to biological targets and the discovery of drug candidates. Manuscripts that address these topics in any of the multiple facets and from all disciplines are welcome, including molecular pharmacology (e.g., functional assays, assay development, pharmacokinetics), toxicology (e.g., in vivo studies), medicinal chemistry (e.g., hit identification, hit-to-lead optimisation), molecular biology (e.g., target identification and characterisation), computational chemistry (e.g., molecular modelling, virtual screenings), bioinformatics (e.g., machine learning, big data, data analysis), structural biology (e.g., X-ray, cryogenic electron microscopy), pharmacogenetics (e.g., genetic variant studies, expression analysis), pharmacogenomics (e.g., genome-wide association studies, epigenetics), and other preferentially multidisciplinary research areas. This will support the development of new drug therapies and improve clinical outcome for patients.

Dr. Muhammad Rafehi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • target identification
  • target characterisation
  • hit identification
  • lead optimisation
  • molecular pharmacology
  • medicinal chemistry
  • molecular biology
  • computational chemistry
  • bioinformatics
  • toxicology
  • structural biology
  • pharmacogenetics
  • pharmacogenomics

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Published Papers (6 papers)

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Research

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15 pages, 2957 KiB  
Article
PAI1 Regulates Cell Morphology and Migration Markers in Trastuzumab-Resistant HER2-Positive Breast Cancer Cells
by Asiye Busra Boz Er and Idris Er
Life 2024, 14(8), 1040; https://doi.org/10.3390/life14081040 - 20 Aug 2024
Viewed by 1011
Abstract
HER2-positive breast cancer is a significant cause of mortality. Overcoming trastuzumab resistance requires a deeper understanding of its molecular mechanisms to develop effective therapies. This study investigates the role of plasminogen activator inhibitor-1 (PAI1) in migration and drug resistance in trastuzumab-resistant HER2-positive breast [...] Read more.
HER2-positive breast cancer is a significant cause of mortality. Overcoming trastuzumab resistance requires a deeper understanding of its molecular mechanisms to develop effective therapies. This study investigates the role of plasminogen activator inhibitor-1 (PAI1) in migration and drug resistance in trastuzumab-resistant HER2-positive breast cancer. Trastuzumab resistance poses a significant challenge in clinical management due to its association with aggressive disease behaviour and limited treatment options. This study focuses on PAI1, a key player in the TGF-β signalling pathway, which is implicated in cancer progression and metastasis. Trastuzumab-resistant cell lines (SKBR3 and HCC1954) demonstrated markedly elevated PAI1 expression levels, up to 40-fold compared to parental lines. This elevation was accompanied by increased expression of migration markers such as Col4a1, Fibronectin, ICAM1, Timp2, and Vimentin. Through overexpression and silencing experiments, we observed that modulating PAI1 levels significantly impacts cell morphology, transitioning cells from an epithelial to mesenchymal phenotype. Importantly, combining trastuzumab with aleplasinin, a PAI1 inhibitor, synergistically reduced PAI1 expression in both parental and resistant cell lines. This suggests a potential therapeutic strategy to overcome trastuzumab resistance. These findings emphasise PAI1 as a critical mediator of migration and therapeutic response in HER2-positive breast cancer, offering insights into novel treatment approaches targeting PAI1 to improve clinical outcomes in drug resistance. Full article
(This article belongs to the Special Issue Advances in Cell Biology and Drug Discovery)
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11 pages, 621 KiB  
Article
Epidemiology and Risk Factors for Nosocomial Infections in Left Ventricular Assist Device Recipients
by Simone Mornese Pinna, Silvia Corcione, Elena Cavallone, Nour Shbaklo, Davide Vita, Ilaria De Benedetto, Giorgia Montrucchio, Daniela Pasero, Anna Chiara Trompeo, Andrea Costamagna, Luca Brazzi, Mauro Rinaldi, Massimo Boffini and Francesco Giuseppe De Rosa
Life 2024, 14(2), 270; https://doi.org/10.3390/life14020270 - 17 Feb 2024
Cited by 1 | Viewed by 1486
Abstract
Left ventricular assist devices (LVADs) have been increasingly used as a valid option to improve the prognosis and reduce the symptoms of end-stage heart failure. However, long-term complications, mostly infections and coagulation disorders, are frequent. We described the epidemiology and risk factors for [...] Read more.
Left ventricular assist devices (LVADs) have been increasingly used as a valid option to improve the prognosis and reduce the symptoms of end-stage heart failure. However, long-term complications, mostly infections and coagulation disorders, are frequent. We described the epidemiology and risk factors for nosocomial infections (NIs) in a cohort of adult patients who underwent continuous-flow LVAD implant between January 2010 and December 2017 in Turin, Italy. Secondary outcomes were the prevalence of multidrug-resistant (MDR) bacteria and mortality. Results: Overall, 64 LVADs were implanted. A total of 32 (50%) patients experienced at least one episode of NI, with a total of 46 infectious events. VAD-related infections occurred in 22 patients (68.8%). Non VAD-related NIs occurred in 12 patients (37.5%), mainly low respiratory tract infections. Length of intensive care unit admission was a risk factor for NI (OR 1.224, 95%CI; 1.049, 1.429). Gram-negative bacilli were responsible for 58.8% of VAD-related infections and 79.5% of non-VAD related infections. In sixteen patients (50%), at least one episode of infection was related to an MDR strain. INTERMACS class and length of MV were independent risk factors for NIs by MDR strains (respectively, OR 2.12, 95%CI: 1.08, 6.80; p = 0.02 and OR 1.46, 95%CI: 1.07, 5.52, p = 0.047). In-hospital mortality was 6.3%. No differences in mortality were observed between infected and non-infected patients (p = 0.61) even when caused by MDR strains (p = 0.143). Conclusion: the rate of nosocomial infections in LVAD patients is associated with the length of ICU admission, and the etiology of nosocomial infection after LVAD implant is mainly due to GNB, including a high rate of MDR strains, especially KPC-KP and MDR PA. Full article
(This article belongs to the Special Issue Advances in Cell Biology and Drug Discovery)
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19 pages, 5598 KiB  
Article
Characterization, Bioactivity, and Biodistribution of 35 kDa Hyaluronan Fragment
by Munkh-Amgalan Gantumur, Xiaoxiao Jia, Jessica H. Hui, Christy Barber, Li Wan, Lars R. Furenlid, Diego R. Martin, Mizhou Hui and Zhonglin Liu
Life 2024, 14(1), 97; https://doi.org/10.3390/life14010097 - 8 Jan 2024
Cited by 2 | Viewed by 1660
Abstract
It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 [...] Read more.
It has been reported that hyaluronic acid (HA) with a 35 kDa molecular weight (HA35) acts biologically to protect tissue from injury, but its biological properties are not yet fully characterized. This study aimed to evaluate the cellular effects and biodistribution of HA35 compared to HA with a 1600 kDa molecular weight (HA1600). We assessed the effects of HA35 and HA1600 on cell migration, NO and ROS generation, and gene expression in cultured macrophages, microglia, and lymphocytes. HA35 was separately radiolabeled with 99mTc and 125I and administered to C57BL/6J mice for in vivo biodistribution imaging. In vitro studies indicated that HA35 and HA1600 similarly enhanced cell migration through HA receptor binding mechanisms, reduced the generation of NO and ROS, and upregulated gene expression profiles related to cell signaling pathways in immune cells. HA35 showed a more pronounced effect in regulating a broader range of genes in macrophages and microglia than HA1600. Upon intradermal or intravenous administration, radiolabeled HA35 rapidly accumulated in the liver, spleen, and lymph nodes. In conclusion, HA35 not only exhibits effects on cellular bioactivity comparable to those of HA1600 but also exerts biological effects on a broader range of immune cell gene expression. The findings herein offer valuable insights for further research into the therapeutic potential of HA35 in inflammation-mediated tissue injury. Full article
(This article belongs to the Special Issue Advances in Cell Biology and Drug Discovery)
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16 pages, 2648 KiB  
Article
Tacrolimus Maintains the Balance of Neutrophil Extracellular Traps by Inducing DNA Methylation of Neutrophils to Reduce Immune Rejection
by Liang Xu and Ming Cai
Life 2023, 13(12), 2253; https://doi.org/10.3390/life13122253 - 25 Nov 2023
Cited by 1 | Viewed by 1558
Abstract
Immune rejection is a significant concern in organ transplantation, as it can lead to damage to and failure of the transplanted organ. To prevent or treat immune rejection, transplant recipients are commonly administered immunosuppressive drugs. Tacrolimus (FK506) is a widely used immunosuppressive drug [...] Read more.
Immune rejection is a significant concern in organ transplantation, as it can lead to damage to and failure of the transplanted organ. To prevent or treat immune rejection, transplant recipients are commonly administered immunosuppressive drugs. Tacrolimus (FK506) is a widely used immunosuppressive drug in organ transplantation. The excessive formation of neutrophil extracellular traps (NETs) can contribute to inflammation and tissue damage. Although NETs play an antimicrobial role, their overproduction can be harmful. To investigate the mechanism by which FK506 suppresses immune rejection, we utilized HL-60 cells, which were differentiated into neutrophils using DMSO and induced to form NETs with phorbol myristate acetate (PMA), a very efficient and frequently used drug for inducing NET formation. By comparing pre- and post-treatment with FK506, we examined whether FK506 affects the formation of NETs. Various experimental techniques were employed, including confocal imaging for visualizing cell NETs, qPCR and Western blotting for gene and protein expression analyses, ELISAs for protein content detection, and LC-MS/MS for methylation detection. In our study, we discovered that FK506 can enhance DNA methylation, which likely contributes to the reduction in NETs. Genes and proteins related to methylation, namely, DNMT3B and TET3, exhibited significant correlations with methylation. Consistent changes in both genes and proteins suggest that DNMT3B and TET3 are key factors that are influenced by FK506, resulting in enhanced DNA methylation and the potential inhibition of PMA-induced NET production. In summary, we have identified a novel mechanism by which FK506 inhibits NET production through the enhancement of DNA methylation. This finding highlights a new aspect of FK506′s immunosuppressive effect. Our results provide valuable insights for clinical research, immunosuppression, and organ preservation strategies. Full article
(This article belongs to the Special Issue Advances in Cell Biology and Drug Discovery)
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12 pages, 2994 KiB  
Article
Stimulation of Angiotensin II Type 2 Receptor Modulates Pro-Inflammatory Response in Microglia and Macrophages: Therapeutic Implications for the Treatment of Stroke
by Abdulkarim Alshammari, Yohan Han, Timothy W. Jones, Bindu Pillai, Duo Zhang, Adviye Ergul, Payaningal R. Somanath and Susan C. Fagan
Life 2023, 13(6), 1274; https://doi.org/10.3390/life13061274 - 29 May 2023
Cited by 1 | Viewed by 1908
Abstract
Background: Sustained microglial activation contributes to the development of post-stroke cognitive impairment (PSCI). Compound 21 (C21), an angiotensin II type 2 receptor agonist, has shown some neurovascular protection after stroke. This study aimed to investigate the direct anti-inflammatory effects of C21 on macrophages, [...] Read more.
Background: Sustained microglial activation contributes to the development of post-stroke cognitive impairment (PSCI). Compound 21 (C21), an angiotensin II type 2 receptor agonist, has shown some neurovascular protection after stroke. This study aimed to investigate the direct anti-inflammatory effects of C21 on macrophages, as well as brain innate immune cells. Methods: Murine microglial cell line (C8-B4) and RAW 264.7 macrophages were exposed to lipopolysaccharide (LPS) and co-treated with C21. Pro-inflammatory mediators were assessed via RT-qPCR and ELISA. Cellular reactive oxygen species (ROS) were evaluated via CellROXGreen staining, and nitrate production was assessed using Griess assay. Results: C21 suppressed LPS-induced inflammation and ROS generation in both cells. In microglia, C21 blunted LPS-induced mRNA expression of IL-1β, IL-12b, COX-1, iNOS, and IL-6. A similar pattern was observed in macrophages, where C21 suppressed LPS-induced IL-1β, TNF-α, and CXCL1 expression. These anti-inflammatory effects in microglia and macrophages were associated with increased neuroprotective gene expression, including GDNF and BDNF, in a dose-dependent manner. Conclusions: Our findings suggest a protective effect of C21 against the inflammatory response, in both macrophages and microglia, via suppression of the release of pro-inflammatory cytokines/chemokines and the generation of ROS while stimulating the production of neurotrophic factors. Full article
(This article belongs to the Special Issue Advances in Cell Biology and Drug Discovery)
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Review

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22 pages, 1397 KiB  
Review
Cell Immortality: In Vitro Effective Techniques to Achieve and Investigate Its Applications and Challenges
by Mahla Chalak, Mahdi Hesaraki, Seyedeh Nasim Mirbahari, Meghdad Yeganeh, Shaghayegh Abdi, Sarah Rajabi and Farhid Hemmatzadeh
Life 2024, 14(3), 417; https://doi.org/10.3390/life14030417 - 21 Mar 2024
Cited by 4 | Viewed by 4018
Abstract
Cells are very important to researchers due to their use in various biological studies in in vitro and in vivo settings. This importance stems from the short lifespan of most cells under laboratory conditions, which can pose significant challenges, such as the difficulties [...] Read more.
Cells are very important to researchers due to their use in various biological studies in in vitro and in vivo settings. This importance stems from the short lifespan of most cells under laboratory conditions, which can pose significant challenges, such as the difficulties associated with extraction from the source tissue, ethical concerns about separating cells from human or animal models, limited cell passage ability, and variation in results due to differences in the source of the obtained cells, among other issues. In general, cells in laboratory conditions can divide into a limited number, known as the Hayflick limit, due to telomere erosion at the end of each cellular cycle. Given this problem, researchers require cell lines that do not enter the senescence phase after a limited number of divisions. This can allow for more stable studies over time, prevent the laborious work associated with cell separation and repeated cultivation, and save time and money in research projects. The aim of this review is to summarize the function and effect of immortalization techniques, various methods, their advantages and disadvantages, and ultimately the application of immortalization and cell line production in various research fields. Full article
(This article belongs to the Special Issue Advances in Cell Biology and Drug Discovery)
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