Kisspeptin-10

This study investigated the effects of Kisspeptin-10 (Kp-10) on HIV-1 Tat-induced blood-brain barrier (BBB) permeability and oxidative stress using both in vivo and in vitro models. In vivo, one hour after intraperitoneal administration of 50 nmol/kg (DSS)*6-Kp-10, mice were intravenously injected with HIV-1 Tat (100 μg/kg). Markers of oxidative stress, inflammatory cytokines, and BBB integrity were then evaluated. In vitro, bEnd.3 cells were treated with HIV-1 Tat and Kp-10, and endothelial permeability, Claudin-5 expression, and RhoA/ROCK signaling were assessed. HIV-1 Tat increased oxidative stress in the cortical tissue of mice, as evidenced by elevated malondialdehyde (MDA) and reduced levels of catalase (CAT) activity, glutathione peroxidase (GSH-Px) activity, and total antioxidant capacity (T-AOC). These effects were attenuated by Kp-10 administration. Additionally, Kp-10 suppressed the expression of pro-inflammatory cytokines, including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α), in response to HIV-1 Tat. Notably, Kp-10 mitigated HIV-1 Tat-induced BBB dysfunction by upregulating Claudin-5 expression in the cortical tissue of mice. In vitro, bEnd.3 cells were treated with HIV-1 Tat in the presence of Kp-10 at various concentrations. Our results demonstrated that Kp-10 prevented HIV-1 Tat-induced increases in trans-endothelial permeability and reductions in transepithelial electrical resistance (TEER) by upregulating Claudin-5 expression. Furthermore, Kp-10 inhibited the activation of the RhoA/Rho-associated protein kinase (RhoA/ROCK) signaling pathway in bEnd.3 cells. Overexpression of the RhoA-GTP Q63L mutant abolished the protective effects of Kp-10, suggesting that these effects are mediated through the RhoA/ROCK axis. These findings suggest that Kp-10 might be a potential therapeutic agent for HIV-associated neurocognitive disorders (HAND).

Gestational diabetes mellitus (GDM) is a common pregnancy complication that leads to insulin resistance (IR) and adversely affects both maternal and fetal health. Kisspeptin‐10 (Kp‐10), a peptide acting via G Protein‐Coupled Receptor 54 (Gpr54), has shown potential in modulating insulin secretion, but its role in GDM remains unclear. This study explores Kp‐10's therapeutic effects on GDM by targeting IR in placental tissues. We used GDM rat models (induced by a high‐fat diet and streptozotocin) and high‐glucose‐treated HTR8/SVneo trophoblast cells to investigate Kp‐10's effects on glucose metabolism, insulin signaling, and the cAMP/PKA pathway. Our results show that Gpr54 expression was significantly downregulated in the placental tissues of GDM rats, which was associated with impaired glucose uptake and IR. Kp‐10 treatment improved fasting blood glucose (FBG) levels, insulin sensitivity, and fetal outcomes, including increased fetal weight and decreased fetal blood glucose. Moreover, Kp‐10 restored the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway and enhanced glucose uptake by upregulating Glut‐4, Insr, and Irs1 expression in both placental tissues and HTR8/SVneo cells. The effects of Kp‐10 were reversed by the cAMP inhibitor SQ22536, confirming the involvement of the cAMP/PKA pathway in its anti‐IR effects. Our findings suggest that Kp‐10 has the potential as a therapeutic agent for alleviating IR in GDM and improving maternal–fetal outcomes.