Chemical Inhibitors of the Calcium Entry Channel TRPV6

ABSTRACT: Purpose: Calcium entry channels in the plasma membrane are thought to play a major role in maintaining cellular Ca2+ levels, crucial for growth and survival of normal and cancer cells. The calcium-selective channel TRPV6 is expressed in prostate, breast, and other cancer cells. Its expression coincides with cancer progression, suggesting that it drives cancer cell growth. However, no specific inhibitors for TRPV6 have been identified thus far. Methods: To develop specific TRPV6 inhibitors, we synthesized molecules based on the lead compound TH-1177, reported to inhibit calcium entry channels in prostate cancer cells in vitro and in vivo. Results: We found that one of our compounds (#03) selectively inhibited TRPV6 over five times better than TRPV5, whereas TH-1177 and the other synthesized compounds preferentially inhibited TRPV5. The IC50 value for growth inhibition by blocking endogenous Ca2+ entry channels in the LNCaP human prostate cancer cell line was 0.44 ± 0.07μM compared to TH-1177 (50 ± 0.4μM). Conclusions: These results suggest that compound #03 is a relatively selective and potent inhibitor for TRPV6 and that it is an interesting lead compound for the treatment of prostate cancer and other cancers of epithelial origi

Free-bound excitation and predissociation of ytterbium dimers near the ¹S₀-¹P₁ atomic transition

A continuous excitation band of a free-bound photoassociation transition of ytterbium atoms is observed as a red wing of the ¹S₀-¹P₁ atomic line at 399 nm for a hot thermal vapor. The excitation to the 0u⁺ molecular state is observed by monitoring fluorescence from the ³P₁ state atoms, which allows us to detect the production of Yb₂ molecules with high sensitivity. The photoassociation is characterized in comparison with transitions to atomic Rydberg states. The time profile of the fluorescence signal suggests that the 0u⁺ molecular state predissociates with states correlating to the ¹S₀+³D₂ atomic states

Comparison of Impressions of COVID-19 Vaccination and Influenza Vaccination in Japan by Analyzing Social Media Using Text Mining

The aim of this study was to compare impressions of COVID-19 vaccination and influenza vaccination in Japan by analyzing social media (Twitter®) using a text-mining method. We obtained 10,000 tweets using the keywords “corona vaccine” and “influenza vaccine” on 15 December 2022 and 19 February 2023. We then counted the number of times the words were used and listed frequency of these words by a text-mining method called KH Coder. We also investigated concepts in the data using groups of words that often appeared together or groups of documents that contained the same words using multi-dimensional scaling (MDS). “Death” in relation to corona vaccine and “severe disease” for influenza vaccine were frequently used on 15 December 2022. The number of times the word “death” was used decreased, “after effect” was newly recognized for corona vaccine, and “severe disease” was not used in relation to influenza vaccine. Through this comprehensive analysis of social media data, we observed distinct variations in public perceptions of corona vaccination and influenza vaccination in Japan. These findings provide valuable insights for public health authorities and policymakers to better understand public sentiment and tailor their communication strategies accordingly

Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation

The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a 45Ca2+ uptake assay (7.11 ± 1.93 versus 3.61 ± 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuri