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Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P2. They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linkedwith susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.

Phosphatidylinositol (PI)-related signaling plays a pivotal role in many cellular aspects, including survival, cell proliferation, differentiation, DNA damage, and trafficking. PI is the core of a network of proteins represented by kinases, phosphatases, and lipases which are able to add, remove or hydrolyze PI, leading to different phosphoinositide products. Among the seven known phosphoinositides, phosphatidylinositol 5 phosphate (PI5P) was the last to be discovered. PI5P presence in cells is very low compared to other PIs. However, much evidence collected throughout the years has described the role of this mono-phosphoinositide in cell cycles, stress response, T-cell activation, and chromatin remodeling. Interestingly, PI5P has been found in different cellular compartments, including the nucleus. Here, we will review the nuclear role of PI5P, describing how it is synthesized and regulated, and how changes in the levels of this rare phosphoinositide can lead to different nuclear outputs.

Osteoporosis pascamenopaus merupakan salah satu masalah kesihatan utama yang melanda kaum wanita berumur. Ia disebabkan oleh beberapa faktor termasuk tekanan oksidatif, yang dipercayai dapat dikawal melalui pengambilan antioksidan daripada sumber makanan. Minyak kelapa dara (VCO) merupakan salah satu hasil semula jadi yang kaya dengan antioksidan dan telah dibuktikan mampu memelihara tulang yang mengalami osteoporosis. Kajian ini dijalankan untuk mendapatkan kefahaman yang lebih mendalam tentang aktiviti minyak kelapa dara terhadap osteoporosis pada peringkat molekular. Tiga puluh dua ekor tikus betina Sprague-Dawley dibahagikan kepada empat kumpulan, iaitu kumpulan pembedahan Sham, kawalan terovariektomi (Ovx+Ctrl), kumpulan terovariektomi dengan rawatan VCO (Ovx+VCO) dan kumpulan terovariektomi dengan rawatan estrogen (Ovx+E). Kesemua rawatan diberikan melalui oral selama sepuluh minggu. Sampel tulang femur tikus diambil untuk mengkaji perubahan pada ekspresi gen superoksida dismutase (SOD), glutation peroksidase (GPX), osteokalsin dan transkripsi faktor 2 berkaitan run (Runx2). Hasil kajian mendapati bahawa tikus yang menerima rawatan VCO mengalami peningkatan yang signifikan pada ekspresi gen SOD, GPX dan osteokalsin berbanding kumpulan kawalan terovariektomi, disamping ekspresi gen Runx2 yang turut menunjukkan pola peningkatan. Secara kesimpulannya, VCO membantu memelihara tulang pada tikus model osteoporosis melalui tindakannya meningkatkan ekspresi gen antioksidan serta gen yang menigkatkan aktiviti sel osteoblas.