Alzheimer's disease: The role of T lymphocytes in neuroinflammation and neurodegeneration.

Alzheimer's disease, the leading cause of progressive cognitive decline globally, has been reported to be enhanced by neuroinflammation. Brain-resident innate immune cells and adaptive immune cells work together to produce neuroinflammation. Studies over the past decade have established the neuroimmune axis present in Alzheimer's disease; the crosstalk between adaptive and innate immune cells within and outside the brain is crucial to the onset and progression of Alzheimer's disease. Although the role of the adaptive immune system in Alzheimer's disease is not fully understood, it has been hypothesized that the brain's immune homeostasis is significantly disrupted, which greatly contributes to neuroinflammation. Brain-infiltrating T cells possess proinflammatory phenotypes and activities that directly contribute to neuroinflammation. The pro-inflammatory activities of the adaptive immune system in Alzheimer's disease are characterized by the upregulation of effector T cell activities and the downregulation of regulatory T cell activities in the brain, blood, and cerebrospinal fluid. In this review, we discuss the major impact of T lymphocytes on the pathogenesis and progression of Alzheimer's disease. Understanding the role and mechanism of action of T cells in Alzheimer's disease would significantly contribute to the identification of novel biomarkers for diagnosing and monitoring the progression of the disease. This knowledge could also be crucial to the development of immunotherapies for Alzheimer's disease.

Identification of HER2 inhibitors from curcumin derivatives using combination of in silico screening and molecular dynamics simulation.

Breast cancer remains a major world health challenge in women. Some Breast cancers are human epidermal growth factor receptor 2 (HER2) positive. Since this protein promotes the growth of cancer cells, it remains a therapeutic target for novel drugs. This study uses in silico model to predict HER2 inhibitors from curcumin derivatives via QSAR, e-pharmacophore, ADMET as well as structure-based virtual screening using Schrodinger suite. The molecular dynamics simulation of lead compounds, reference ligand and co-crystalized ligand was performed using GROMACS. At the end, eight active curcumin derivatives were predicted as inhibitors of HER2 with high binding affinity and better interaction compared with the reference drug (Neratinib) but lower binding affinity compared with the co-crystalized ligand (TAK-285). After prediction of the bioactivity of the molecules using AutoQSAR, the hit compounds showed appreciable inhibitory pIC50 compared with the reference and co-crystalized ligands against HER2. The pharmacokinetics profile predicted the eight hit compounds as drug-like and drug candidates. The MD simulation predicted the stability of the two top-scored compounds (10763284 and 78321412) in complex with HER2 for the final 80 ns of the trajectory period after initial equilibration with higher H-bond interactions in the protein-reference drug complex compared to the hit compounds-HER2 complexes. This study revealed that curcumin derivatives especially (1E,6E)-1,8-bis(4-hydroxy-3-methoxyphenyl)octa-1,6-diene-3,5-dione and (1E,6E)-4-ethyl-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione were identified to demonstrate inhibitory activity against HER2 which is comparable to neratinib. Conclusively, the lead compounds require further in vitro and in vivo experimental validation for the discovery of new HER2 antagonists for breast cancer management.Communicated by Ramaswamy H. Sarma.

Protein-protein interaction and interference of carcinogenesis by supramolecular modifications.

Protein-protein interactions (PPIs) are essential in normal biological processes, but they can become disrupted or imbalanced in cancer. Various technological advancements have led to an increase in the number of PPI inhibitors, which target hubs in cancer cell's protein networks. However, it remains difficult to develop PPI inhibitors with desired potency and specificity. Supramolecular chemistry has only lately become recognized as a promising method to modify protein activities. In this review, we highlight recent advances in the use of supramolecular modification approaches in cancer therapy. We make special note of efforts to apply supramolecular modifications, such as molecular tweezers, to targeting the nuclear export signal (NES), which can be used to attenuate signaling processes in carcinogenesis. Finally, we discuss the strengths and weaknesses of using supramolecular approaches to targeting PPIs.

Regulation of effector and memory CD8 + T cell differentiation: a focus on orphan nuclear receptor NR4A family, transcription factor, and metabolism.

CD8 + T cells undergo rapid expansion followed by contraction and the development of memory cells after their receptors are activated. The development of immunological memory following acute infection is a complex phenomenon that involves several molecular, transcriptional, and metabolic mechanisms. As memory cells confer long-term protection and respond to secondary stimulation with strong effector function, understanding the mechanisms that influence their development is of great importance. Orphan nuclear receptors, NR4As, are immediate early genes that function as transcription factors and bind with the NBRE region of chromatin. Interestingly, the NBRE region of activated CD8 + T cells is highly accessible at the same time the expression of NR4As is induced. This suggests a potential role of NR4As in the early events post T cell activation that determines cell fate decisions. In this review, we will discuss the influence of NR4As on the differentiation of CD8 + T cells during the immune response to acute infection and the development of immunological memory. We will also discuss the signals, transcription factors, and metabolic mechanisms that control cell fate decisions. HIGHLIGHTS: Memory CD8 + T cells are an essential subset that mediates long-term protection after pathogen encounters. Some specific environmental cues, transcriptional factors, and metabolic pathways regulate the differentiation of CD8 + T cells and the development of memory cells. Orphan nuclear receptor NR4As are early genes that act as transcription factors and are highly expressed post-T cell receptor activation. NR4As influence the effector function and differentiation of CD8 + T cells and also control the development of immunological memory following acute infection.