PRKAB1

Cognitive impairment is anotable complication of type 2 diabetes (T2DM), accompanied by reduced brain-derived neurotrophic factor (BDNF) in the brain and blood. Anti-diabetic drugs reduce hyperglycemia, yet their effect on cognitive improvement is unknown. We aimed to investigate the effect of anti-diabetic drugs regulating BDNF in T2DM through computational and case-control study design. We obtained T2DMproteins viatext-mining to construct a T2DMprotein network. From the T2DMnetwork, the metformin and glimepiride interactomes and their crucial shortest-path-stimulating BDNF were identified. Using qRTPCR, the genes encoding the shortest-path proteins were assessed in four groups (untreated-T2DM, metformin-treated, glimepiride-treated, and healthy controls). Finally, ELISA was used to assess serum BDNF levels to validate drug efficacy. As a result of this investigation, aT2DMnetwork was constructed with 3683 text-mined proteins. Then, the T2DMnetwork was explored to generate a metformin and glimepiride interactome that establishes the critical shortest-path for BDNF stimulation. Metformin stimulates BDNF via APP binding to the PRKAB1 receptor. Whereas, glimepiride increases BDNF by binding to KCNJ11 via AP2M1 and ESR1 proteins. Both drug shortest-path encoding genes differed significantly between the groups. Unlike metformin, BDNF gene and protein expression rise significantly with glimepiride. Overall, glimepiride can effectively increase BDNF, which could benefit T2DM patients with cognitive deterioration.

Enzalutamide, docetaxel, and cabazitaxel treatment resistance is a major problem in metastatic castration resistant prostate cancer (mCRPC), but the underlying genetic determinants are poorly understood. To identify genes that modulate treatment response to these drugs, we performed three genome-wide CRISPR/Cas9 knockout screens in the mCRPC cell line C4. The screens identified seven candidates for enzalutamide (BCL2L13, CEP135, E2F4, IP6K2, KDM6A, SMS, and XPO4), four candidates for docetaxel (DRG1, LMO7, NCOA2, and ZNF268), and nine candidates for cabazitaxel (ARHGAP11B, DRG1, FKBP5, FRYL, PRKAB1, RP2, SMPD2, TCEA2, and ZNF585B). We generated single-gene C4 knockout clones/populations for all genes and could validate effect on treatment response for five genes (IP6K2, XPO4, DRG1, PRKAB1, and RP2). Altered enzalutamide response upon IP6K2 and XPO4 knockout was associated with deregulation of AR, mTORC1, and E2F signaling, and deregulated p53 signaling (IP6K2 only) in C4 mCRPC cells. Our study highlights the necessity of performing individual validation of candidate hits from genome-wide CRISPR screens. Further studies are needed to assess the generalizability and translational potential of these findings.

Circadian rhythms have an established role in regulating physiological processes, such as inflammation, immunity, and metabolism. Ozone, a common environmental pollutant with strong oxidative potential, is implicated in lung inflammation/injury in asthmatics. However, whether O₃ exposure affects the expression of circadian clock genes in the lungs is not known. In this study, changes in the expression of core clock genes are analyzed in the lungs of adult female and male mice exposed to filtered air (FA) or O₃ using qRT-PCR. The findings are confirmed using an existing RNA-sequencing dataset from repeated FA- and O₃ -exposed mouse lungs and validated by qRT-PCR. Acute O₃ exposure significantly alters the expression of clock genes in the lungs of females (Per1, Cry1, and Rora) and males (Per1). RNA-seq data revealing sex-based differences in clock gene expression in the airway of males (decreased Nr1d1/Rev-erbα) and females (increased Skp1), parenchyma of females and males (decreased Nr1d1 and Fbxl3 and increased Bhlhe40 and Skp1), and alveolar macrophages of males (decreased Arntl/Bmal1, Per1, Per2, Prkab1, and Prkab2) and females (increased Cry2, Per1, Per2, Csnk1d, Csnk1e, Prkab2, and Fbxl3). These findings suggest that lung inflammation caused by O₃ exposure affects clock genes which may regulate key signaling pathways.