The centromere is a chromosomal locus that is essential for the accurate segregation of chromosomes during cell division. Transcription of noncoding RNA (ncRNA) at the centromere plays a crucial role in centromere function. The zinc-finger transcriptional regulator ZFAT binds to a specific 8-bp DNA sequence at the centromere, named the ZFAT box, to control ncRNA transcription. However, the precise molecular mechanisms by which ZFAT localizes to the centromere remain elusive. Here we show that the centromeric protein CENP-B is required for the centromeric localization of ZFAT to regulate ncRNA transcription. The ectopic expression of CENP-B induces the accumulation of both endogenous and ectopically expressed ZFAT protein at the centromere in human cells, suggesting that the centromeric localization of ZFAT requires the presence of CENP-B. Coimmunoprecipitation analysis reveals that ZFAT interacts with the acidic domain of CENP-B, and depletion of endogenous CENP-B reduces the centromeric levels of ZFAT protein, further supporting that CENP-B is required for the centromeric localization of ZFAT. In addition, knockdown of CENP-B significantly decreased the expression levels of ncRNA at the centromere where ZFAT regulates the transcription, suggesting that CENP-B is involved in the ZFAT-regulated centromeric ncRNA transcription. Thus, we concluded that CENP-B contributes to the establishment of the centromeric localization of ZFAT to regulate ncRNA transcription.

Purpose of Review:The gut barrier serves as the primary interface between the environment and host in terms of surface area and complexity. Luminal chemosensing is a term used to describe how small molecules in the gut lumen interact with the host through surface receptors or via transport into the subepithelial space. In this review, we have summarized recent advances in the understanding of the luminal chemosensory system in the gastroduodenal epithelium consisting of enterocytes, enteroendocrine, and tuft cells, with particular emphasis on how chemosensing affects mucosal protective responses and the metabolic syndrome.Recent Findings: Recent single cell RNA sequencing provides detailed cell type-specific expression of chemosensory receptors and other bioactive molecules as well cell lineages; some are similar to lingual taste cells whereas some are gut specific. Gut luminal chemosensing is not only important for the local or remote regulation of gut function, but also contributes to the systemic regulation of metabolism, energy balance, and food intake. We will discuss the chemosensory mechanisms of the proximal intestine, in particular to gastric acid, with a focus on the cell types and receptors involved in chemosensing, with emphasis on the rare chemosensory cells termed tuft cells. We will also discuss the chemosensory functions of intestinal ectoenzymes and bacterial components (e.g., lipopolysaccharide (LPS)) as well as how they affect mucosal function through altering the gut-hormonal-neural axis.Summary: Recent updates in luminal chemosensing by different chemosensory cells have provided new possibilities for identifying novel molecular targets for the treatment of mucosal injury, metabolic disorders, and abnormal visceral sensation.

Background/Aim: Among compounds from natural products selectively suppressing the growth of cancer spheroids, which have mutant (mt) KRAS, NP910 was selected and its derivatives explored. Materials and Methods: The area of HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in three-dimensional floating (3DF) cultures treated with 18 NP910 derivatives. The 50% cell growth inhibition (GI50) was determined by long-term 3DF (LT3DF) culture and nude mice assay. Results: We selected NP882 (named STAR3) as the most effective inhibitor of growth of HKe3-mtKRAS spheroids with the least toxicity among NP910 derivatives. GI50s of STAR3 in LT3DF and nude mice assay were 6 μM and 30.75 mg/kg, respectively. However, growth suppression by STAR3 was observed in 50% of cell lines independent of KRAS mutation, suggesting that the target of STAR3 was not directly associated with KRAS mutation and KRAS-related signals. Conclusion: STAR3 is a low-toxicity compound that inhibits growth of certain tumour cells.KRAS is the most frequently mutated oncogene among human cancers (1), with high rates of activating missense mutations in pancreatic cancers (86 to 96%) (2), in colorectal cancers (CRC) (40 to 54%), and in non-small cell lung cancer (NSCLC) (15 to 20%) (3, 4). Once activated, mutated RAS remains "on" persistently, thereby enhancing downstream signalling and leading tumourigenesis. Recently, AMG510, which targets specifically KRAS G12C mutant, was developed and was found to be effective in clinical trials in some patients with NSCLC (5). However, the KRAS G12C mutation occur in about 13% of NSCLCs (6, 7), in 3 to 5% of CRCs, and in 1 to 2% of various other solid cancers (3, 5, 8-10). Therefore, the range of use of AMG510 is limited, and the KRAS mutation is still an "undruggable" target.Canonical anticancer agents, including alkylating drugs, platinum compounds, antimetabolites, topoisomerase inhibitors, and microtubule inhibitors, are highly toxic and cause serious side effects such as myelosuppression (11,12). Recently, molecularly targeted drugs are expected to be the new drugs with low toxicity (13); however, drug resistance is unavoidable (14). Therefore, new types of compounds are indispensable for cancer treatment.Recently, we screened genes that were up-regulated by mtKRAS in a three-dimensional (3D) matrigel culture and found that the phosphodiesterase 4B (PDE4B) levels were higher in clinical tumour samples from CRC patients in comparison to those from healthy control (15). We examined several PDE4 inhibitors, such as pan PDE4 inhibitor, resveratrol, and PDE4 selective inhibitor, apremilast (16, 17), revealing that these compounds are selective for cancer spheroids with mtKRAS, and exhibit high efficacy and low toxicity. Notably, resveratrol, which has similar PDE4inhibitory activity to that of rolipram ( 16), is present in various natural products, suggesting that some compounds from natural products will become low-toxicity anticancer agents.