Cpt-Cgmp Is A New Ligand Of Epithelial Sodium Channels

Epithelial sodium channels (ENaC) are localized at the apical membrane of the epithelium, and are responsible for salt and fluid reabsorption. Renal ENaC takes up salt, thereby controlling salt content in serum. Loss-of-function ENaC mutations lead to low blood pressure due to salt-wasting, while gain-of-function mutations cause impaired sodium excretion and subsequent hypertension as well as hypokalemia. ENaC activity is regulated by intracellular and extracellular signals, including hormones, neurotransmitters, protein kinases, and small compounds. Cyclic nucleotides are broadly involved in stimulating protein kinase A and protein kinase G signaling pathways, and, surprisingly, also appear to have a role in regulating ENaC. Increasing evidence suggests that the cGMP analog, CPT-cGMP, activates αβγ-ENaC activity reversibly through an extracellular pathway in a dose-dependent manner. Furthermore, the parachlorophenylthio moiety and ribose 2’-hydroxy group of CPT-cGMP are essential for facilitating the opening of ENaC channels by this compound. Serving as an extracellular ligand, CPT-cGMP eliminates sodium self-inhibition, which is a novel mechanism for stimulating salt reabsorption in parallel to the traditional NO/cGMP/PKG signal pathway. In conclusion, ENaC may be a druggable target for CPT-cGMP, leading to treatments for kidney malfunctions in salt reabsorption

N′-(4-Hydr­oxy-3-methoxy­benzyl­idene)-4-methoxy­benzohydrazide monohydrate

In the title compound, C16H16N2O4·H2O, the dihedral angle between the two aromatic rings is 19.6 (2)°. In the crystal structure, mol­ecules are linked into a three-dimensional network by inter­molecular N—H⋯O, O—H⋯N and O—H⋯O hydrogen bonds

Drug resistance and new therapies in colorectal cancer

Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors

N′-(5-Bromo-2-hydr­oxy-3-methoxy­benzyl­idene)-4-hydr­oxy-3-methoxy­benzohydrazide dihydrate

In the title compound, C16H15BrN2O5·2H2O, the dihedral angle between the two aromatic rings is 2.9 (2)° and an intra­molecular O—H⋯N hydrogen bond is observed. One of the water mol­ecule is disordered over two positions, with occupancies of 0.83 (3) and 0.17 (3). In the crystal structure, mol­ecules are linked into a three-dimensional network by inter­molecular O—H⋯O, O—H⋯(O,O), O—H⋯N and N—H⋯O hydrogen bonds. π–π inter­actions involving Br-substituted benzene rings, with a centroid–centroid distance of 3.552 (3) Å are also observed

5-(Methoxy­carbon­yl)thio­phene-2-carboxylic acid

In the title compound, C7H6O4S, a monoester derivative of 2,5-thio­phene­dicarboxylic acid, the carboxylic acid and the carboxylic acid ester groups are approximately coplanar with thio­phene ring, making a dihedral angle of 3.1 (4) and 3.6 (4)°, respectively. In the crystal structure, mol­ecules are connected by classical inter­molecular O—H⋯O hydrogen bonds, forming centrosymmetric dimers

N,N′-Bis(pyridin-3-yl)terephthalamide–terephthalic acid (1/1)

In the title compound, C18H14N4O2·C8H6O4, both types of mol­ecule lie on inversion centers. In the N,N′-bis­(pyridin-3-yl)terephthalamide mol­ecule, the pyridine ring forms a dihedral angle of 11.33 (9)° with the central benzene ring. In the crystal, N—H⋯O and O—H⋯N hydrogen bonds connect the components into a three-dimensional network

Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial

Drug resistance due to overexpression of membrane transporters in cancer cells and the existence of cancer stem cells (CSCs) is a major hurdle to effective and safe cancer chemotherapy. Nanoparticles have been explored to overcome cancer drug resistance. However, drug slowly released from nanoparticles can still be efficiently pumped out of drug-resistant cells. Here, a hybrid nanoparticle of phospholipid and polymers is developed to achieve cold-triggered burst release of encapsulated drug. With ice cooling to below ∼12 °C for both burst drug release and reduced membrane transporter activity, binding of the drug with its target in drug-resistant cells is evident, while it is minimal in the cells kept at 37 °C. Moreover, targeted drug delivery with the cold-responsive nanoparticles in combination with ice cooling not only can effectively kill drug-resistant ovarian cancer cells and their CSCs in vitro but also destroy both subcutaneous and orthotopic ovarian tumors in vivo with no evident systemic toxicity