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Article ; Online: Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

Hajjo, Rima / Sabbah, Dima A / Bardaweel, Sanaa K / Zhong, Haizhen A

2024 Volume 34, Issue 1-2, Page(s) 51–69

Abstract: Introduction: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer ... ...

Abstract	Introduction: Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions. Area covered: This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation. Expert opinion: To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.
MeSH term(s)	Humans ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins p21(ras) ; Patents as Topic ; Signal Transduction ; ErbB Receptors ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ErbB Receptors (EC 2.7.10.1) ; Protein Kinase Inhibitors ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2024-03-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1186201-4
ISSN	1744-7674 ; 0962-2594 ; 1354-3776
ISSN (online)	1744-7674
ISSN	0962-2594 ; 1354-3776
DOI	10.1080/13543776.2024.2327307
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Article ; Online: Targeting the PI3K/AKT signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023).

Sabbah, Dima A / Hajjo, Rima / Bardaweel, Sanaa K / Zhong, Haizhen A

Expert opinion on therapeutic patents

2024 Volume 34, Issue 3, Page(s) 141–158

Abstract: Introduction: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest ... ...

Abstract	Introduction: Recent years have witnessed great achievements in drug design and development targeting the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT) signaling pathway, a pathway central to cell growth and proliferation. The nearest neighbor protein-protein interaction networks for PI3K and AKT show the interplays between these target proteins which can be harnessed for drug discovery. In this review, we discuss the drug design and clinical development of inhibitors of PI3K/AKT in the past three years. We review in detail the structures, selectivity, efficacy, and combination therapy of 35 inhibitors targeting these proteins, classified based on the target proteins. Approaches to overcoming drug resistance and to minimizing toxicities are discussed. Future research directions for developing combinational therapy and PROTACs of PI3K and AKT inhibitors are also discussed. Area covered: This review covers clinical trial reports and patent literature on inhibitors of PI3K and AKT published between 2020 and 2023. Expert opinion: To address drug resistance and drug toxicity of inhibitors of PI3K and AKT, it is highly desirable to design and develop subtype-selective PI3K inhibitors or subtype-selective AKT1 inhibitors to minimize toxicity or to develop allosteric drugs that can form covalent bonds. The development of PROTACs of PI3Kα or AKT helps to reduce off-target toxicities.
MeSH term(s)	Humans ; Drug Design ; Signal Transduction/drug effects ; Antineoplastic Agents/pharmacology ; Phosphoinositide-3 Kinase Inhibitors/pharmacology ; Animals ; Neoplasms/drug therapy ; Neoplasms/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Patents as Topic ; Drug Development ; Protein Kinase Inhibitors/pharmacology ; Drug Resistance, Neoplasm ; Phosphatidylinositol 3-Kinases/metabolism ; Cell Proliferation/drug effects ; Molecular Targeted Therapy
Chemical Substances	Antineoplastic Agents ; Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Protein Kinase Inhibitors ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
Language	English
Publishing date	2024-04-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1186201-4
ISSN	1744-7674 ; 0962-2594 ; 1354-3776
ISSN (online)	1744-7674
ISSN	0962-2594 ; 1354-3776
DOI	10.1080/13543776.2024.2338100
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Article ; Online: A Critical Assessment of COVID-19 Genomic Vaccines.

Sabbah, Dima A / Hajjo, Rima / Sunoqrot, Suhair

Current topics in medicinal chemistry

2023 Volume 23, Issue 27, Page(s) 2552–2589

Abstract: Vaccines are instrumental tools to fight against novel and re-emerging pathogens and curb pandemics. Vaccination has been an integral part of the multifaceted public health response to the COVID-19 pandemic. Diverse vaccine platforms have been designed ... ...

Abstract	Vaccines are instrumental tools to fight against novel and re-emerging pathogens and curb pandemics. Vaccination has been an integral part of the multifaceted public health response to the COVID-19 pandemic. Diverse vaccine platforms have been designed and are currently at different stages of development. Some vaccines are still in early biological testing, while others have been launched after being approved by regulatory agencies worldwide. Genomic vaccines that deliver parts of the viral DNA or RNA to host cells have gained popularity recently due to their high efficiency and fast manufacture. Furthermore, recent clinical studies encouraged the use of different vaccine platforms within the primary vaccination course to enhance the efficacy of vaccination. Herein, we discuss COVID-19 genomic vaccines, which deliver viral genetic material to host cells through diverse biotechnology platforms, including viral vector vaccines, messenger RNA nucleic acid vaccines, and DNA nucleic acid vaccines. We compare and contrast vaccine characteristics, composition, and pros and cons among different genomic vaccine platforms as well as non-genomic vaccines. This review summarizes all current knowledge about COVID-19 genomic vaccines, which could be highly valuable to researchers interested in public health and vaccine development.
MeSH term(s)	Humans ; COVID-19 Vaccines ; Pandemics/prevention & control ; COVID-19/prevention & control ; Genomics ; Viral Vaccines ; Nucleic Acid-Based Vaccines ; mRNA Vaccines ; Vaccines
Chemical Substances	COVID-19 Vaccines ; Viral Vaccines ; Nucleic Acid-Based Vaccines ; mRNA Vaccines ; Vaccines
Language	English
Publishing date	2023-08-24
Publishing country	United Arab Emirates
Document type	Review ; Journal Article
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/1568026623666230825094341
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Article ; Online: Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein.

Abu Khalaf, Reema / Lafi, Ala'a / Hajjo, Rima / Al-Sha'er, Mahmoud A

Current computer-aided drug design

2024

Abstract: Background: Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) ...

Abstract	Background: Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL. Objective: This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis. Results: Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 μM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness. Conclusion: It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.
Language	English
Publishing date	2024-02-27
Publishing country	United Arab Emirates
Document type	Journal Article
ISSN	1875-6697
ISSN (online)	1875-6697
DOI	10.2174/0115734099292078240218095540
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Unlocking the Potential of the Human Microbiome for Identifying Disease Diagnostic Biomarkers.

Hajjo, Rima / Sabbah, Dima A / Al Bawab, Abdel Qader

Diagnostics (Basel, Switzerland)

2022 Volume 12, Issue 7

Abstract: The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a ... ...

Abstract	The human microbiome encodes more than three million genes, outnumbering human genes by more than 100 times, while microbial cells in the human microbiota outnumber human cells by 10 times. Thus, the human microbiota and related microbiome constitute a vast source for identifying disease biomarkers and therapeutic drug targets. Herein, we review the evidence backing the exploitation of the human microbiome for identifying diagnostic biomarkers for human disease. We describe the importance of the human microbiome in health and disease and detail the use of the human microbiome and microbiota metabolites as potential diagnostic biomarkers for multiple diseases, including cancer, as well as inflammatory, neurological, and metabolic diseases. Thus, the human microbiota has enormous potential to pave the road for a new era in biomarker research for diagnostic and therapeutic purposes. The scientific community needs to collaborate to overcome current challenges in microbiome research concerning the lack of standardization of research methods and the lack of understanding of causal relationships between microbiota and human disease.
Language	English
Publishing date	2022-07-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics12071742
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Article: Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects.

Hajjo, Rima / Sabbah, Dima A / Tropsha, Alexander

Pathogens (Basel, Switzerland)

2022 Volume 11, Issue 7

Abstract: COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. ... ...

Abstract	COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.
Language	English
Publishing date	2022-06-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens11070743
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Article: Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects

Hajjo, Rima / Sabbah, Dima A. / Tropsha, Alexander

Pathogens. 2022 June 29, v. 11, no. 7

2022

Abstract	COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.
Keywords	COVID-19 infection ; Severe acute respiratory syndrome coronavirus 2 ; calcium ; cytokines ; homeostasis ; immune response ; interferons ; transcription (genetics) ; vaccination ; vaccines
Language	English
Dates of publication	2022-0629
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2695572-6
ISSN	2076-0817
ISSN	2076-0817
DOI	10.3390/pathogens11070743
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A Systems Biology Workflow for Drug and Vaccine Repurposing: Identifying Small-Molecule BCG Mimics to Reduce or Prevent COVID-19 Mortality.

Hajjo, Rima / Tropsha, Alexander

Pharmaceutical research

2020 Volume 37, Issue 11, Page(s) 212

Abstract: Purpose: Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops 'herd immunity', or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to ... ...

Abstract	Purpose: Coronavirus disease 2019 (COVID-19) is expected to continue to cause worldwide fatalities until the World population develops 'herd immunity', or until a vaccine is developed and used as a prevention. Meanwhile, there is an urgent need to identify alternative means of antiviral defense. Bacillus Calmette-Guérin (BCG) vaccine that has been recognized for its off-target beneficial effects on the immune system can be exploited to boast immunity and protect from emerging novel viruses. Methods: We developed and employed a systems biology workflow capable of identifying small-molecule antiviral drugs and vaccines that can boast immunity and affect a wide variety of viral disease pathways to protect from the fatal consequences of emerging viruses. Results: Our analysis demonstrates that BCG vaccine affects the production and maturation of naïve T cells resulting in enhanced, long-lasting trained innate immune responses that can provide protection against novel viruses. We have identified small-molecule BCG mimics, including antiviral drugs such as raltegravir and lopinavir as high confidence hits. Strikingly, our top hits emetine and lopinavir were independently validated by recent experimental findings that these compounds inhibit the growth of SARS-CoV-2 in vitro. Conclusions: Our results provide systems biology support for using BCG and small-molecule BCG mimics as putative vaccine and drug candidates against emergent viruses including SARS-CoV-2.
MeSH term(s)	BCG Vaccine/administration & dosage ; BCG Vaccine/immunology ; Betacoronavirus/immunology ; Biomimetic Materials/administration & dosage ; COVID-19 ; COVID-19 Vaccines ; Coronavirus Infections/drug therapy ; Coronavirus Infections/immunology ; Coronavirus Infections/mortality ; Coronavirus Infections/prevention & control ; Drug Repositioning/methods ; Humans ; Immunity, Innate ; Pandemics/prevention & control ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/immunology ; Pneumonia, Viral/mortality ; Pneumonia, Viral/prevention & control ; SARS-CoV-2 ; Small Molecule Libraries/administration & dosage ; Systems Biology/methods ; Viral Vaccines/administration & dosage ; Viral Vaccines/immunology ; Workflow ; COVID-19 Drug Treatment
Chemical Substances	BCG Vaccine ; COVID-19 Vaccines ; Small Molecule Libraries ; Viral Vaccines
Keywords	covid19
Language	English
Publishing date	2020-10-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	843063-9
ISSN	1573-904X ; 0724-8741 ; 0739-0742
ISSN (online)	1573-904X
ISSN	0724-8741 ; 0739-0742
DOI	10.1007/s11095-020-02930-9
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Article ; Online: Analyzing the Systems Biology Effects of COVID-19 mRNA Vaccines to Assess Their Safety and Putative Side Effects

Rima Hajjo / Dima A. Sabbah / Alexander Tropsha

Pathogens, Vol 11, Iss 743, p

2022 Volume 743

Abstract	COVID-19 vaccines have been instrumental tools in reducing the impact of SARS-CoV-2 infections around the world by preventing 80% to 90% of hospitalizations and deaths from reinfection, in addition to preventing 40% to 65% of symptomatic illnesses. However, the simultaneous large-scale vaccination of the global population will indubitably unveil heterogeneity in immune responses as well as in the propensity to developing post-vaccine adverse events, especially in vulnerable individuals. Herein, we applied a systems biology workflow, integrating vaccine transcriptional signatures with chemogenomics, to study the pharmacological effects of mRNA vaccines. First, we derived transcriptional signatures and predicted their biological effects using pathway enrichment and network approaches. Second, we queried the Connectivity Map (CMap) to prioritize adverse events hypotheses. Finally, we accepted higher-confidence hypotheses that have been predicted by independent approaches. Our results reveal that the mRNA-based BNT162b2 vaccine affects immune response pathways related to interferon and cytokine signaling, which should lead to vaccine success, but may also result in some adverse events. Our results emphasize the effects of BNT162b2 on calcium homeostasis, which could be contributing to some frequently encountered adverse events related to mRNA vaccines. Notably, cardiac side effects were signaled in the CMap query results. In summary, our approach has identified mechanisms underlying both the expected protective effects of vaccination as well as possible post-vaccine adverse effects. Our study illustrates the power of systems biology approaches in improving our understanding of the comprehensive biological response to vaccination against COVID-19.
Keywords	COVID-19 ; mRNA vaccine ; informatics workflow ; SARS-CoV-2 ; systems biology ; vaccine adverse events ; Medicine ; R
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identifying a causal link between prolactin signaling pathways and COVID-19 vaccine-induced menstrual changes.

Hajjo, Rima / Momani, Ensaf / Sabbah, Dima A / Baker, Nancy / Tropsha, Alexander

NPJ vaccines

2023 Volume 8, Issue 1, Page(s) 129

Abstract: COVID-19 vaccines have been instrumental tools in the fight against SARS-CoV-2 helping to reduce disease severity and mortality. At the same time, just like any other therapeutic, COVID-19 vaccines were associated with adverse events. Women have reported ...

Abstract	COVID-19 vaccines have been instrumental tools in the fight against SARS-CoV-2 helping to reduce disease severity and mortality. At the same time, just like any other therapeutic, COVID-19 vaccines were associated with adverse events. Women have reported menstrual cycle irregularity after receiving COVID-19 vaccines, and this led to renewed fears concerning COVID-19 vaccines and their effects on fertility. Herein we devised an informatics workflow to explore the causal drivers of menstrual cycle irregularity in response to vaccination with mRNA COVID-19 vaccine BNT162b2. Our methods relied on gene expression analysis in response to vaccination, followed by network biology analysis to derive testable hypotheses regarding the causal links between BNT162b2 and menstrual cycle irregularity. Five high-confidence transcription factors were identified as causal drivers of BNT162b2-induced menstrual irregularity, namely: IRF1, STAT1, RelA (p65 NF-kB subunit), STAT2 and IRF3. Furthermore, some biomarkers of menstrual irregularity, including TNF, IL6R, IL6ST, LIF, BIRC3, FGF2, ARHGDIB, RPS3, RHOU, MIF, were identified as topological genes and predicted as causal drivers of menstrual irregularity. Our network-based mechanism reconstruction results indicated that BNT162b2 exerted biological effects similar to those resulting from prolactin signaling. However, these effects were short-lived and didn't raise concerns about long-term infertility issues. This approach can be applied to interrogate the functional links between drugs/vaccines and other side effects.
Language	English
Publishing date	2023-09-01
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-023-00719-6
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