Scientia Pharmaceutica

Radiotherapy (RT) is a standard treatment for cervical cancer, but its efficacy is often limited by tumor hypoxia and low radiosensitivity. Radiosensitizers that enhance RT without dose escalation are therefore of clinical interest. Alpha-mangostin (AM), a xanthone from Garcinia mangostana, exhibits anticancer and ROS-inducing properties. This study evaluated whether AM enhances radiosensitivity in vitro. Cytotoxicity (0–35 µM) was assessed by the MTT assay, and radiation sensitivity (0–6 Gy) was assessed by clonogenic survival. γ-H2AX immunofluorescence, cell cycle distribution, apoptosis induction, and clonogenic survival assessments were used to investigate the radiosensitization effect. AM showed dose-dependent cytotoxicity in HeLa cells at an inhibitory concentration 20 (IC20) of 13.67 µM while sparing fibroblasts. The radiation lethal dose 20 (LD20) was 1.4 Gy. However, combination treatment used AM at 12 µM (IC14) combined with 2 Gy (LD30) irradiation to avoid 50% cell death. AM enhanced G2/M arrest by 21.10% (p < 0.01) versus controls. In combination treatment, AM significantly increased γ-H2AX-positive cells to 48.2% (p < 0.0001), elevated apoptosis to 39.48% (p < 0.0001), and decreased clonogenic survival to 28% (p < 0.0001) compared with control. A combination index of about 0.9 indicated synergism. Therefore, AM effectively radiosensitized HeLa cells via increased DNA double-strand breaks and G2/M arrest.

The γδ T cells belong to a subgroup of T cells known as non-conventional T cells due to their limited T cell receptor (TCR) repertoire and ability to recognize non-peptide antigens. They play a crucial role in combating infections and tumors. Vγ9Vδ2 T cells are typically activated by molecules containing diphosphate groups, collectively known as phosphoantigens (pAgs), through a non-canonical mechanism which involves the intracellular domain of butyrofilin (BTN)3A1 protein. However, no FDA-approved drugs have yet been shown to activate them, and the underlying cellular mechanisms remain unknown. In this study, we combined high-throughput virtual screening of an FDA-approved drug database with in vitro cellular assays to identify potential γδ T cells activators. Our findings demonstrate that Nitazoxanide (NTZ) and Tinidazole induce moderate elicited a statistically significant increase in interferon (IFN)-γ production of Vγ9Vδ2 T cells by their probably interaction with the pAg binding site of BTN3A1. Additionally, NTZ induces expression of CD107a, but only at the highest concentrations tested and promotes the upregulation of HLA-DR in total PBMCs and CD14⁺ monocytes. Blocking BTN3A with a specific antibody led to a marked reduction in all NTZ-induced activations. This work identifies NTZ as a previously unrecognized activator of γδ T cells, highlighting its immunomodulatory potential beyond its known clinical uses. These findings broaden our understanding of γδ T cells pharmacology and suggest new opportunities for drug repurposing and the design of novel chemical scaffolds. Further mechanistic studies will be essential to fully define how NTZ engages the BTN3A–γδ T cells axis.

As a metabolism-controlling peptide, insulin affects activity of almost all tissues in human organisms, including the ones located in the central nervous system. By modifying glucose uptake and processing, as well as inducing anabolic effects, insulin alters functions of various nerve centers. Data from numerous clinical trials prove that such actions can have positive influence on cognitive processes or might be utilized as measures to control appetite, mood, and blood flow, or to prevent unfavorable mental states associated with diminished ability to maintain homeostasis. The intranasal route of administration provides an efficient and targeted delivery method, allowing insulin to be applied directly to different brain regions via the nasal mucosa. Such an approach can also reduce the risk of potential adverse effects associated with this medication, including drops in plasma glucose levels. This review gathers clinical studies’ findings on intranasal insulin’s neuromodulatory properties and its efficacy as additional treatment measure in several neuropsychiatric disease entities.