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Pharmaceutics
Special Issues
Serpins: Therapeutic Targets for Various Diseases
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Serpins: Therapeutic Targets for Various Diseases

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 20 September 2024 | Viewed by 5760

Special Issue Editor

Prof. Dr. Crispin R. Dass

E-Mail Website
Guest Editor
School of Pharmacy, Curtin Medical School, GPO Box U1987, Perth 6845, Australia
Interests: nanomedicine; cancer; diabetes; drug delivery; cell biology; bone
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The purpose of this Special Issue is to highlight the historical developmental work, as well as more recent work, that has been performed concerning serine protease inhibitors (serpins) in various disease states. This Special Issue will cover the mechanisms behind serpin functions in a normal body and how these are perturbed in particular disease states. Special attention will be given to specific serpins that researchers are working on, by way of original research papers or comprehensive review papers. Given that this is a somewhat niche area of study, this Special Issue may have the flow-on effect of linking researchers who are working on serpins, perhaps finding concerted and better ways to target these critical proteins in various diseases. The Guest Editor is happy to receive brief EoIs from authors to gauge whether their papers will fit the remit of this Special Issue, but this is not necessary if you would like to submit your full paper directly for evaluation.

Prof. Dr. Crispin R. Dass
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. Pharmaceutics 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 2900 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

  • serpins
  • serine protease inhibitors
  • disease
  • cancer
  • diabetes
  • cardiovascular disease
  • inflammatory disease
  • therapy
  • drug development
  • oxidative stress

Published Papers (4 papers)

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Research

13 pages, 2217 KiB  
Article
The Impact of Pigment-Epithelium-Derived Factor on MCF-7 Cell Metabolism in the Context of Glycaemic Condition
by Raziyeh Abooshahab, Kourosh Hooshmand, Hani-Al Salami and Crispin R. Dass
Pharmaceutics 2023, 15(8), 2140; https://doi.org/10.3390/pharmaceutics15082140 - 14 Aug 2023
Cited by 2 | Viewed by 979
Abstract
Studies have demonstrated that pigment-epithelium-derived factor (PEDF) is a robust inhibitor of tumour growth and development, implying that this may serve as a promising target for therapeutic intervention. However, the precise impact of PEDF on cancerous cell metabolic pathways remains uncertain despite ongoing [...] Read more.
Studies have demonstrated that pigment-epithelium-derived factor (PEDF) is a robust inhibitor of tumour growth and development, implying that this may serve as a promising target for therapeutic intervention. However, the precise impact of PEDF on cancerous cell metabolic pathways remains uncertain despite ongoing research. In this light, this study aimed to employ a metabolomics approach for understanding the metabolic reprogramming events in breast cancer across different glycaemic loads and their response to PEDF. Gas chromatography-quadrupole mass spectrometry (GC/Q-MS) analysis revealed metabolic alterations in ER+ human cell line MCF-7 cells treated with PEDF under varying glycaemic conditions. The identification of significantly altered metabolites was accomplished through MetaboAnalyst (v.5.0) and R packages, which enabled both multivariate and univariate analyses. Out of the 48 metabolites identified, 14 were chosen based on their significant alterations in MCF-7 cells under different glycaemic conditions and PEDF treatment (p < 0.05, VIP > 0.8). Dysregulation in pathways associated with amino acid metabolism, intermediates of the TCA cycle, nucleotide metabolism, and lipid metabolism were detected, and they exhibited different responses to PEDF. Our results suggest that PEDF has a diverse influence on the metabolism of MCF-7 cells in both normo- and hyperglycaemic environments, thereby warranting studies using patient samples to correlate our findings with clinical response in the future. Full article
(This article belongs to the Special Issue Serpins: Therapeutic Targets for Various Diseases)
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15 pages, 2822 KiB  
Article
Pigment Epithelium-Derived Factor: Inhibition of Phosphorylation of Insulin Receptor (IR)/IR Substrate (IRS), Osteogeneration from Adipocytes, and Increased Levels Due to Doxorubicin Exposure
by Isobel C. Jones, Revathy Carnagarin, Jo Armstrong, Daphne P. L. Lin, Mia Baxter-Holland, Mina Elahy and Crispin R. Dass
Pharmaceutics 2023, 15(7), 1960; https://doi.org/10.3390/pharmaceutics15071960 - 15 Jul 2023
Cited by 3 | Viewed by 1295
Abstract
Objectives: Pigment epithelium-derived factor (PEDF) has been recently linked to insulin resistance and is capable of differentiating myocytes to bone. We examined in more detail the intricate signalling of the insulin pathway influenced by PEDF in skeletal myocytes. We tested whether this serpin [...] Read more.
Objectives: Pigment epithelium-derived factor (PEDF) has been recently linked to insulin resistance and is capable of differentiating myocytes to bone. We examined in more detail the intricate signalling of the insulin pathway influenced by PEDF in skeletal myocytes. We tested whether this serpin is also capable of generating de novo bone from adipocytes in vitro and in vivo, and how the anticancer drug doxorubicin links with PEDF and cellular metabolism. Methods and key findings: We demonstrate that PEDF can inhibit phosphorylation of insulin receptor (IR) and insulin receptor substrate (IRS) in skeletal myocytes. PEDF constitutively activates p42/44 MAPK/Erk, but paradoxically does not affect mitogenic signalling. PEDF did not perturb either mitochondrial activity or proliferation in cells representing mesenchymal stem cells, cardiomyocytes, and skeletal myocytes and adipocytes. PEDF induced transdifferentiation of adipocytes to osteoblasts, promoting bone formation in cultured adipocytes in vitro and gelfoam fatpad implants in vivo. Bone formation in white adipose tissue (WAT) was better than in brown adipose tissue (BAT). The frontline anticancer drug doxorubicin increased levels of PEDF in a human breast cancer cell line, mirroring the in vivo finding where cardiac muscle tissue was stained increasingly for PEDF as the dose of doxorubicin increased in mice. PEDF also increased levels of reactive oxygen species (ROS) and glutathione (GSH) in the breast cancer cell line. Conclusions: PEDF may be used to regenerate bone from adipose tissue in cases of trauma such as fractures or bone cancers. The increased presence of PEDF in doxorubicin-treated tumour cells need further exploration, and could be useful therapeutically in future. The safety of PEDF administration in vivo was further demonstrated in this study. Full article
(This article belongs to the Special Issue Serpins: Therapeutic Targets for Various Diseases)
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23 pages, 3850 KiB  
Article
Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema
by Galina Florova, Christian J. De Vera, Rebekah L. Emerine, René A. Girard, Ali O. Azghani, Krishna Sarva, Jincy Jacob, Danna E. Morris, Mignote Chamiso, Steven Idell and Andrey A. Komissarov
Pharmaceutics 2023, 15(5), 1498; https://doi.org/10.3390/pharmaceutics15051498 - 14 May 2023
Cited by 1 | Viewed by 1317
Abstract
The incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A Streptococcus pneumoniae-induced rabbit [...] Read more.
The incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A Streptococcus pneumoniae-induced rabbit model of chronic empyema recapitulates the progression, loculation, fibrotic repair, and pleural thickening of human disease. Treatment with single chain (sc) urokinase (scuPA) or tissue type (sctPA) plasminogen activators in doses 1.0–4.0 mg/kg were only partially effective in this model. Docking Site Peptide (DSP; 8.0 mg/kg), which decreased the dose of sctPA for successful fibrinolytic therapy in acute empyema model did not improve efficacy in combination with 2.0 mg/kg scuPA or sctPA. However, a two-fold increase in either sctPA or DSP (4.0 and 8.0 mg/kg or 2.0 and 16.0 mg/kg sctPA and DSP, respectively) resulted in 100% effective outcome. Thus, DSP-based Plasminogen Activator Inhibitor 1-Targeted Fibrinolytic Therapy (PAI-1-TFT) of chronic infectious pleural injury in rabbits increases the efficacy of alteplase rendering ineffective doses of sctPA effective. PAI-1-TFT represents a novel, well-tolerated treatment of empyema that is amenable to clinical introduction. The chronic empyema model recapitulates increased resistance of advanced human empyema to fibrinolytic therapy, thus allowing for studies of muti-injection treatments. Full article
(This article belongs to the Special Issue Serpins: Therapeutic Targets for Various Diseases)
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13 pages, 2280 KiB  
Article
Metabolomics Profiling Reveals the Role of PEDF in Triple-Negative Breast Cancer Cell MDA-MB-231 under Glycaemic Loading
by Raziyeh Abooshahab, Kourosh Hooshmand, Giuseppe Luna, Hani Al-Salami and Crispin R. Dass
Pharmaceutics 2023, 15(2), 543; https://doi.org/10.3390/pharmaceutics15020543 - 06 Feb 2023
Cited by 5 | Viewed by 1607
Abstract
Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that belongs to the serine protease inhibitor (serpin) family. An increase in PEDF activity has been shown to be a potent inhibitor of tumour progression and proliferation, suggesting a possible therapeutic target. There is still [...] Read more.
Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein that belongs to the serine protease inhibitor (serpin) family. An increase in PEDF activity has been shown to be a potent inhibitor of tumour progression and proliferation, suggesting a possible therapeutic target. There is still a great deal to learn about how PEDF controls metabolic pathways in breast cancer and its metastatic form. Given this, the primary purpose of this study was to use a metabolomics approach to gain a better understanding of the mechanisms driving the reprogramming of metabolic events involved in breast cancer pertaining to PEDF under various glycaemic loads. We employed gas chromatography–quadrupole mass spectrometry (GC-Q-MS) to investigate metabolic changes in the triple-negative breast cancer (TNBC) cell line MDA-MB-231 treated with PEDF under glycaemic loading. Multivariate and univariate analyses were carried out as indicative tools via MetaboAnalyst (V.5.0) and R packages to identify the significantly altered metabolites in the MDA-MB-231 cell line after PEDF exposure under glycaemic loading. A total of 61 metabolites were found, of which nine were selected to be distinctively expressed in MDA-MB-231 cells under glycaemic conditions and exhibited differential responses to PEDF (p < 0.05, VIP > 1). Abnormalities in amino acid metabolism pathways were observed. In particular, glutamic acid, glutamine, and phenylalanine showed different levels of expression across different treatment groups. The lactate and glucose-6-phosphate production significantly increased in high-glucose vs. normal conditions while it decreased when the cells were exposed to PEDF, confirming the positive influence on the Warburg effect. The TCA cycle intermediates, including malate and citric acid, showed different patterns of expression. This is an important finding in understanding the link of PEDF with metabolic perturbation in TNBC cells in response to glycaemic conditions. Our findings suggest that PEDF significantly influenced the Warburg effect (as evidenced by the significantly lower levels of lactate), one of the well-known metabolic reprogramming pathways in cancer cells that may be responsive to metabolic-targeted therapeutic strategies. Moreover, our results demonstrated that GC-MS-based metabolomics is an effective tool for identifying metabolic changes in breast cancer cells after glycaemic stress or in response to PEDF treatment. Full article
(This article belongs to the Special Issue Serpins: Therapeutic Targets for Various Diseases)
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