In the context of cell cycle inhibition, anti-proliferation, and the dysregulation observed in certain cancer pathologies, the protein p21 assumes a pivotal role. p21 links DNA damage responses to cellular processes such as apoptosis, senescence, and cell cycle arrest, primarily functioning as a regulator of the cell cycle. However, accumulating empirical evidence suggests that p21 is both directly and indirectly linked to a number of different metabolic processes. Intriguingly, recent investigations indicate that p21 significantly contributes to the pathogenesis of diabetes. In this review, we present a comprehensive evaluation of the scientific literature regarding the involvement of p21 in metabolic processes, diabetes etiology, pancreatic function, glucose homeostasis, and insulin resistance. Furthermore, we provide an encapsulated overview of therapies that target p21 to alleviate metabolic disorders. A deeper understanding of the complex interrelationship between p21 and diabetes holds promise for informing current and future therapeutic strategies to address this rapidly escalating health crisis.

In vivo function of CDK5 and Abl enzyme substrate 2 (Cables2), belonging to the Cables protein family, is unknown. Here, we found that targeted disruption of the entireCables2locus (Cables2d) caused growth retardation and enhanced apoptosis at the gastrulation stage and then induced embryonic lethality in mice. Comparative transcriptome analysis revealed disruption ofCables2, 50% down-regulation ofRps21abutting on theCables2locus, and up-regulation of p53-target genes inCables2dgastrulas. We further revealed the lethality phenotype inRps21-deleted mice and unexpectedly, the exon 1-deletedCables2mice survived. Interestingly, chimeric mice derived fromCables2dESCs carrying exogenousCables2and tetraploid wild-type embryo overcame gastrulation. These results suggest that the diminished expression ofRps21and the completed lack ofCables2expression are intricately involved in the embryonic lethality via the p53 pathway. This study sheds light on the importance ofCables2locus in mouse embryonic development.

Two members of the CDK5 and ABL enzyme substrate (CABLES) family, CABLES1 and CABLES2, share a highly homologous C-terminus. They interact and associate with cyclin-dependent kinase 3 (CDK3), CDK5, and c-ABL. CABLES1 mediates tumor suppression, regulates cell proliferation, and prevents protein degradation. Although Cables2 is ubiquitously expressed in adult mouse tissues at RNA level, the role of CABLES2 in vivo remains unknown. Here, we generated bicistronic Cables2 knock-in reporter mice that expressed CABLES2 tagged with 3×FLAG and 2A-mediated fluorescent reporter tdTomato. Cables2-3×FLAG-2A-tdTomato (Cables2Tom) mice confirmed the expression of Cables2 in various mouse tissues. Interestingly, high intensity of tdTomato fluorescence was observed in the brain, testis and ovary, especially in the corpus luteum. Furthermore, immunoprecipitation analysis using the brain and testis in Cables2Tom/Tom revealed interaction of CABLES2 with CDK5. Collectively, our new Cables2 knock-in reporter model will enable the comprehensive analysis of in vivo CABLES2 function.

This study investigated the potential allergenicity of sporopollenin exine capsule preparations (SpECs) derived from plant pollen or spores as allergenicity could limit their use as a therapeutic oral drug delivery system. As allergenicity may differ depending on the method of preparation, raw spores from Lycopodium clavatum, together with 6 L. clavatum SpEC preparations were evaluated in vitro by adenosine triphosphate (ATP) bioassay for cell viability. Subsequently, in vivo evaluations were performed in 6–8 week male Balb/C mice gavaged daily with raw L. clavatum spores, a negative control (PBS), or one of SpEC-3, 4 or 5 preparations for five consecutive days; gastrointestinal tissues were collected 6 hours following the final gavage. In vitro cytotoxicity studies showed that, compared to the cell control, L. clavatum spores and SpEC-2 and SpEC-4 preparations showed significantly decreased cell viability, while no significant differences in cell viability were found for SpEC-1, 3, 5 or 6 preparations, all of which were extracted more intensively than SpEC-2 or SpEC-4 preparations. In vivo safety studies showed no increase in CD68-positive macrophage cell infiltration in any region of the gastrointestinal tract (stomach, duodenum, jejunum, ileum or colon), liver or kidneys. No exines were found in any tissue. We concluded that, whilst differing SpEC manufacturing processes may have residual in vitro cytotoxicity, this did not translate to an acute in vivo oral gastrointestinal immune response, suggesting their safety as a vehicle for gastrointestinal pharmaceutical delivery.