RHOA G17V induces T follicular helper cell specification and involves angioimmunoblastic T-cell lymphoma via upregulating the expression of PON2 through an NF-κB-dependent mechanism.

Angioimmunoblastic T-cell lymphoma (AITL) is a malignant hematologic tumor arising from T follicular helper (Tfh) cells. High-throughput genomic sequencing studies have shown that AITL is characterized by a novel highly recurring somatic mutation in RHOA, encoding p.Gly17Val (RHOA G17V). However, the specific role of RHOA G17V in AITL remains unknown. Here, we demonstrated that expression of Rhoa G17V in CD4+ T cells increased cell proliferation and induces Tfh cell specification associated with Pon2 upregulation through an NF-κB-dependent mechanism. Further, loss of Pon2 attenuated oncogenic function induced by genetic lesions in Rhoa. In addition, an abnormality of RHOA G17V mutation and PON2 expression is also detected in patients with AITL. Our findings suggest that PON2 associated with RHOA G17V mutation might control the direction of the molecular agents-based AITL and provide a new therapeutic target in AITL.

Nerve Growth Factor Improves the Outcome of Type 2 Diabetes-Induced Hypotestosteronemia and Erectile Dysfunction.

Hypotestosterone and erectile dysfunction (ED) occur frequently in males with type 2 diabetes. It is still clinically challenging to manage diabetes-induced ED. Here, we conducted a 2-arm randomized clinical study and in vitro cell line experiments to investigate the effects of nerve growth factor (NGF) on serum testosterone and ED in diabetic males with sensorimotor polyneuropathy and to identify its underlying mechanisms. The analyses of serum total testosterone (TT) and free testosterone (FT), and 5-item version of the International Index of Erectile Function (IIEF-5) score at baseline and after treatment show increases in TT (3.90 nmol/L, 95% confidence interval [CI]: 3.13-4.66 nmol/L vs 1.21 nmol/L [95% CI: 0.57-1.85 nmol/L]), FT (3.79 pg/mL [95% CI: 3.05-4.54 pg/mL] vs 1.27 pg/mL [95% CI: 0.85-1.70 pg/mL]), and IIEF-5 score (1.84 [95% CI: 1.21-2.47] vs 0.24 [95% CI: -0.24 to 0.73]) in the NGF treatment compared controls ( P < .005). In mouse Leydig cells, NGF significantly ameliorated the hyperglycemia-induced downregulation of steroidogenic acute regulatory protein and cytochrome P450 11A1 ( P < .05). Thus, NGF treatment effectively improves type 2 diabetes-induced hypotestosterone and ED outcome through a mechanism that includes upregulation of key enzymes in testosterone biosynthesis.