Despite the importance of extracellular phosphate in many essential biological processes, the mechanisms of phosphate transport across the epithelium of different intestinal segments remain unclear. We have used an in vitro method to investigate phosphate transport at the brush border membrane (BBM) of intact intestinal segments and an in vivo method to study transepithelial phosphate absorption. We have used micromolar phosphate concentrations known to favor NaPi‐IIb‐mediated transport, and millimolar concentrations that are representative of the levels we have measured in luminal contents, to compare the extent of Na+‐dependent and Na+‐independent phosphate transport along the rat duodenum, jejunum, ileum, and proximal and distal colon. Our findings confirm that overall the jejunum is the main site of phosphate absorption; however, at millimolar concentrations, absorption shows ~30% Na+‐dependency, suggesting that transport is unlikely to be mediated exclusively by the Na+‐dependent NaPi‐IIb co‐transporter. In the ileum, studies in vitro confirmed that relatively low levels of phosphate transport occur at the BBM of this segment, although significant Na+‐dependent transport was detected using millimolar levels of phosphate in vivo. Since NaPi‐IIb protein is not detectable at the rat ileal BBM, our data suggest the presence of an as yet unidentified Na+‐dependent uptake pathway in this intestinal segment in vivo. In addition, we have confirmed that the colon has a significant capacity for phosphate absorption. Overall, this study highlights the complexities of intestinal phosphate absorption that can be revealed using different phosphate concentrations and experimental techniques.

Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. .

RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) that form a complex involved in a variety of cellular processes, including chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression is correlated with tumor growth and poor prognosis in several cancer types. CB-6644, an allosteric small-molecule inhibitor of the ATPase activity of the RUVBL1/2 complex, interacts specifically with RUVBL1/2 in cancer cells, leading to cell death. Importantly, drug-acquired-resistant cell clones have amino acid mutations in either RUVBL1 or RUVBL2, suggesting that cell killing is an on-target consequence of RUVBL1/2 engagement. In xenograft models of acute myeloid leukemia and multiple myeloma, CB-6644 significantly reduced tumor growth without obvious toxicity. This work demonstrates the therapeutic potential of targeting RUVBLs in the treatment of cancer and establishes a chemical entity for probing the many facets of RUVBL biology.

Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group. Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion; however, relatively little is known about the mechanisms of intestinal phosphate transport. Our current understanding is that the intestinal type II sodium phosphate cotransporter, NaPi-IIb, plays a significant role in absorption. It may also be involved in the sensing of dietary phosphate composition and the release of hormonal factors that modulate renal phosphate reabsorption to achieve phosphate balance. Interestingly, studies using NaPi-IIb knockout mice with adenine-induced CKD show only partial attenuation of hyperphosphatemia, suggesting that an additional sodium-independent pathway is involved in phosphate absorption. The aim of this review is to discuss our current knowledge of the processes and role of the intestine in phosphate homeostasis and to provide evidence that this organ could be targeted for the treatment of hypophosphatemia and hyperphosphatemia.

What is the central question of this study? Does a previously hypothesized signalling mechanism, believed to detect postprandial increases in intestinal phosphate and that can stimulate the kidneys to rapidly excrete phosphate, operate under physiological conditions? What is the main finding and its importance? Contrary to earlier reports, rapid signalling between the small intestine and kidney mediated by a gut-derived phosphaturic factor in response to a physiological intestinal phosphate load is not supported by the present findings; moreover, hyperphosphataemia and increased parathyroid hormone concentrations are likely to be the underlying factors responsible for the phosphaturia following a supraphysiological intestinal phosphate load. To date, the role of the small intestine in the regulation of postprandial phosphate homeostasis has remained unclear and controversial. Previous studies have proposed the presence of a gut-derived phosphaturic factor that acts independently of changes in plasma phosphate concentration or parathyroid hormone (PTH) concentration; however, these early studies used duodenal luminal phosphate concentrations in the molar range, and therefore, the physiological relevance of this is uncertain. In the present study, we used both in vivo and in vitro approaches to investigate the presence of this putative 'intestinal phosphatonin'. Instillation of 1.3 m phosphate into the duodenum rapidly induced phosphaturia, but in contrast to previous reports, this was associated with significant hyperphosphataemia and elevated PTH concentration; however, there was not the expected decrease in abundance of the renal sodium-phosphate cotransporter NaPi-IIa. Instillation of a physiological (10 mm) phosphate load had no effect on plasma phosphate concentration, PTH concentration or phosphate excretion. Moreover, phosphate uptake by opossum kidney cells was unaffected after incubation with serosal fluid collected from intestinal segments perfused with different concentrations of phosphate. Taken together, these findings do not support the concept of a gut-derived phosphaturic factor that can mediate rapid signalling between the gut and kidney, leading to increased urinary phosphate excretion, as part of normal phosphate homeostasis.