Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases

 GSK-3β activity has been strictly related to neuroinflammation and neurodegeneration. Alzheimer’s disease is the most studied neurodegenerative disease, but GSK-3β seems to be involved in almost all neurodegenerative diseases including Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington’s disease and the autoimmune disease multiple sclerosis.
 The aim of this review is to help researchers both working on this research topic or not to have a comprehensive overview on GSK-3β in the context of neuroinflammation and neurodegeneration.
 Literature has been searched using PubMed and SciFinder databases by inserting specific keywords. A total of more than 500 articles have been discussed.
 First of all, the structure and regulation of the kinase were briefly discussed and then, specific GSK-3β implications in neuroinflammation and neurodegenerative diseases were illustrated also with the help of figures, to conclude with a comprehensive overview on the most important GSK-3β and multitarget inhibitors.
For all discussed compounds, the structure and IC50 values at the target kinase have been reported.
GSK-3β is involved in several signaling pathways both in neurons as well as in glial cells and immune cells.
The fine regulation and interconnection of all these pathways are at the base of the rationale use of GSK-3β inhibitors in neuroinflammation and neurodegeneration.
In fact, some compounds are now under clinical trials. Despite this, pharmacodynamic and ADME/Tox profiles of the compounds were often not fully characterized and this is deleterious in such a complex system.

In silico discovery of novel inhibitors from Northern African natural products database against main protease (Mpro) of SARS-CoV-2.

  1. The recent outbreak of COVID-19 (Coronavirus Disease 2019), caused by a novel SARS-CoV-2 virus, has led to public health emergencies worldwide where time is as important as equipment to save lives.
  2. Antimalarial drugs such as hydroxychloroquine and chloroquine derivatives are used in emergencies but they are not suitable for patients with high blood pressure, diabetes and heart problems.
  3. Since there are no approved drugs for this disease, science is challenged to find vaccines and new drugs. Therefore, as part of our Silico drug design strategy, we identified drug-like compounds that inhibit replication of the main protease (Mpro) of SARS-CoV-2 based on receptor-based virtual database screening, molecular docking, molecular dynamics, and drug-similarity profiling from the NANPDB natural products database available at North African.
  4. The two resulting hit compounds named 5- Chloro-Omega-hydroxy-1-O-methylemodin and cystodion E showed the highest binding energy with Mpro of SARS-CoV-2 and strong inhibitory activity compared with the previously published N3 inhibitor.
  5. The complexes of these two compounds were validated by molecular dynamics analysis (RMSD, RMSF, Rg, total number of hydrogen bonds and secondary structure fractions of the protein in the complex) as the best method to evaluate the biological stability of the system.
  6. Therefore, these molecules deserve more attention in drug development compared to COVID-19. HighlightsA large database of natural compounds was screened against nCoV-2’s Mpro.Molecular docking and Molecular dynamics were used as powerful methods.
  7. Two compounds were found are very attractive to inhibit Mpro of nCoV-2.ADME-Tox profiling is evaluated the active compounds are not cancerogenic.Communicated by Ramaswamy H. Sarma.

Functional and molecular characterization of PD1 + tumor-infiltrating lymphocytes from lung cancer patients.

  • Antibody-mediated cancer immunotherapy targets inhibitory surface molecules, such as PD1, PD-L1, and CTLA-4, aiming to re-invigorate dysfunctional T cells.
  • We purified and characterized tumor-infiltrating lymphocytes (TILs) and their patient-matched non-tumor counterparts from treatment-naïve NSCLC patient biopsies to evaluate the effect of PD1 expression on the functional and molecular profiles of tumor-resident T cells.
  • We show that PD1+ CD8+ TILs have elevated expression of the transcriptional regulator ID3 and that the cytotoxic potential of CD8 T cells can be improved by knocking down ID3, defining it as a potential regulator of T cell effector function. PD1+ CD4+ memory TILs display transcriptional patterns consistent with both helper and regulator function, but can robustly facilitate B cell activation and expansion.
  • Furthermore, we show that expanding ex vivo-prepared TILs in vitro broadly preserves their functionality with respect to tumor cell killing, B cell help, and TCR repertoire.
  • Although purified PD1+ CD8+ TILs generally maintain an exhausted phenotype upon expansion in vitro, transcriptional analysis reveals a downregulation of markers of T-cell dysfunction, including the co-inhibitory molecules PD1 and CTLA-4 and transcription factors ID3, <em>TOX</em> and <em>TOX</em>2, while genes involved in cell cycle and DNA repair are upregulated.
  • We find reduced expression of WNT signaling components to be a hallmark of PD1+ CD8+ exhausted T cells in vivo and in vitro and demonstrate that restoring WNT signaling, by pharmacological blockade of GSK3β, can improve effector function.
  • These data unveil novel targets for tumor immunotherapy and have promising implications for the development of a personalized TIL-based cell therapy for lung cancer.

Dynamics of circulating immune cells during chemoradiotherapy in patients with non-small cell lung cancer support earlier administration of anti-PD-1/PD-L1 therapy.

Chemoradiotherapy (CRT) followed by consolidation immune checkpoint inhibitors (ICIs) significantly improves survival in unresectable locally advanced non-small cell lung cancer (LA-NSCLC).
However, the optimal sequence for CRT and ICIs has not yet been established. We investigated the dynamics of peripheral blood immune cells during CRT to determine the best sequence for treatment.
Peripheral blood samples were prospectively collected pre-treatment, weekly during CRT for 6 weeks, and 1 month post-treatment in 24 patients with LA-NSCLC who received definitive CRT.
Immune cell analysis was performed by flow cytometry.
Ex vivo PD-1 blockade assays were performed by IFN-γ intracellular cytokine staining.
Lymphopenia was prominently observed during CRT and mostly recovered 1 month post-CRT. Robust proliferation of CD8+ T cells was induced, peaking in the last week during CRT and decreasing post-CRT.
The robust proliferation of CD8+ T cells led to an increase in the frequency of CD28CD57+ replicative senescent and terminally differentiated cells post-CRT.
Tumor-reactive CD8+ T cells increased during CRT and peaked in the last week. One month post-CRT, the frequency of tumor-reactive CD8+ T cells decreased and TOXhiTCF1lo terminally exhausted CD8+ T cells significantly increased. Anti-PD-1-induced functional restoration of PD-1+CD8+ T cells was maximized in the last week of CRT and significantly decreased post-CRT.

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The findings suggest that earlier administration of PD-1 blockade may be associated with superior efficacy compared to delayed administration after completion of CRT. These findings provide an immunological rationale for optimal timing of combining ICIs with CRT in clinical trials.

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