Transport of the Photodynamic Therapy Agent 5-Aminolevulinic Acid by Distinct H ϩ -Coupled Nutrient Carriers Coexpressed in the Small Intestine

ABSTRACT 5-Aminolevulinic acid (ALA) is a prodrug used in photodynamic therapy, fluorescent diagnosis, and fluorescent-guided resection because it leads to accumulation of the photosensitizer protoporphyrin IX (PpIX) in tumor tissues. ALA has good oral bioavailability, but high oral doses are required to obtain selective PpIX accumulation in colonic tumors because accumulation is also observed in normal gut mucosa. Structural similarities between ALA and GABA led us to test the hypothesis that the H ϩ -coupled amino acid transporter PAT1 (SLC36A1) will contribute to luminal ALA uptake. Radiolabel uptake and electrophysiological measurements identified PAT1-mediated H ϩ -coupled ALA symport after heterologous expression in Xenopus oocytes. The selectivity of the nontransported inhibitors 5-hydroxytryptophan and 4-aminomethylbenzoic acid for, respectively, PAT1 and the H ϩ -coupled di/tripeptide transporter PepT1 (SLC15A1) were examined. 5-Hydroxytryptophan selectively inhibited PAT1-mediated amino acid uptake across the brush-border membrane of the human intestinal (Caco-2) epithelium whereas 4-aminomethylbenzoic acid selectively inhibited PepT1-mediated dipeptide uptake. The inhibitory effects of 5-hydroxytryptophan and 4-aminomethylbenzoic acid were additive, demonstrating that both PAT1 and PepT1 contribute to intestinal transport of ALA. This is the first demonstration of overlap in substrate specificity between these distinct transporters for amino acids and dipeptides. PAT1 and PepT1 expression was monitored by reverse transcriptase-polymerase chain reaction using paired samples of normal and cancer tissue from human colon. mRNA for both transporters was detected. PepT1 mRNA was increased 2.3-fold in cancer tissues. Thus, increased PepT1 expression in colonic cancer could contribute to the increased PpIX accumulation observed. Selective inhibition of PAT1 could enhance PpIX loading in tumor tissue relative to that in normal tissue

The Concise Guide to PHARMACOLOGY 2023/24:Transporters

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16182. Transporters are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.</p

NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches

Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies

Early Release Science of the exoplanet WASP-39b with JWST NIRCam

Measuring the metallicity and carbon-to-oxygen (C/O) ratio in exoplanet atmospheres is a fundamental step towards constraining the dominant chemical processes at work and, if in equilibrium, revealing planet formation histories. Transmission spectroscopy provides the necessary means by constraining the abundances of oxygen- and carbon-bearing species; however, this requires broad wavelength coverage, moderate spectral resolution, and high precision that, together, are not achievable with previous observatories. Now that JWST has commenced science operations, we are able to observe exoplanets at previously uncharted wavelengths and spectral resolutions. Here we report time-series observations of the transiting exoplanet WASP-39b using JWST's Near InfraRed Camera (NIRCam). The long-wavelength spectroscopic and short-wavelength photometric light curves span 2.0 - 4.0 $\mu$m, exhibit minimal systematics, and reveal well-defined molecular absorption features in the planet's spectrum. Specifically, we detect gaseous H$_2$O in the atmosphere and place an upper limit on the abundance of CH$_4$. The otherwise prominent CO$_2$ feature at 2.8 $\mu$m is largely masked by H$_2$O. The best-fit chemical equilibrium models favour an atmospheric metallicity of 1-100$\times$ solar (i.e., an enrichment of elements heavier than helium relative to the Sun) and a sub-stellar carbon-to-oxygen (C/O) ratio. The inferred high metallicity and low C/O ratio may indicate significant accretion of solid materials during planet formation or disequilibrium processes in the upper atmosphere.Comment: 35 pages, 13 figures, 3 tables, Nature, accepte

WASP-193b: An extremely low-density super-Neptune

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WASP-193b: An extremely low-density super-Neptune

Gas giants transiting bright nearby stars are stepping stones for our understanding of planetary system formation and evolution mechanisms. This paper presents a particularly interesting new specimen of this kind of exoplanet discovered by the WASP-South transit survey, WASP-193b. This planet completes an orbit around its Vmag = 12.2 F9 main-sequence host star every 6.25 d. Our analyses found that WASP-193b has a mass of Mp = 0.139 +/- 0.029 M_Jup and a radius of Rp = 1.464 +/- 0.058 R_ Jup, translating into an extremely low density of rhop = 0.059 +\- 0.014 g/cm^3. The planet was confirmed photometrically by the 0.6-m TRAPPIST-South, the 1.0-m SPECULOOS-South telescopes, and the TESS mission, and spectroscopically by the ESO-3.6-m/HARPS and Euler-1.2-m/CORALIE spectrographs. The combination of its large transit depth (dF~1.4 %), its extremely-low density, its high-equilibrium temperature (Teq = 1254 +/- 31 K), and the infrared brightness of its host star (magnitude Kmag=10.7) makes WASP-193b an exquisite target for characterization by transmission spectroscopy (transmission spectroscopy metric: TSM ~ 600). One single JWST transit observation would yield detailed insights into its atmospheric properties and planetary mass, within ~0.1 dex and ~1% (vs ~20% currently with radial velocity data) respectively

An extended low-density atmosphere around the Jupiter-sized planet WASP-193 b

Gas giants transiting bright nearby stars provide crucial insights into planetary system formation and evolution mechanisms. Most of these planets show certain average characteristics, serving as benchmarks for our understanding of planetary systems. However, outliers like the planet we present in this study, WASP-193 b, offer unique opportunities to explore unconventional formation and evolution processes. This planet completes an orbit around its V-band-magnitude 12.2 F9 main-sequence host star every 6.25 days. Our analyses found that WASP-193 b has a mass of 0.139 +/- 0.029 M-J and a radius of 1.464 +/- 0.058 R-J, translating into an extremely low density of 0.059 +/- 0.014g cm(-3), at least one order of magnitude less than standard gas giants like Jupiter. Typical gas giants such as Jupiter have densities that range between 0.2 g cm(-3) and 2 g cm(-3). The combination of its large transit depth (1.4%), extremely low density, high-equilibrium temperature (1,254 +/- 31 K) and the infrared brightness of its host star (K-band magnitude 10.7) makes WASP-193 b an exquisite target for characterization by transmission spectroscopy (transmission spectroscopy metric similar to 600). One single JWST transit observation would yield detailed insights into its atmospheric properties and planetary mass, providing a unique window to explore the mechanisms behind its exceptionally low density and shed light on giant planets' diverse nature