Greerray9896

The oral bioavailability of hydrophilic and macromolecular drugs is generally poor owing to their poor membrane permeability. For example, peptide and protein drugs are poorly absorbed because of their low stability and poor membrane permeability in the gastrointestinal tract. Consequently, these drugs can be clinically administered only via injection. However, such frequent administration of injections subjects the patients to considerable pain, along with increasing the possibility of serious side effects. Several approaches have been examined to overcome the delivery problems associated with the poorly absorbed drugs. These include (1) use of additives such as absorption enhancers and protease inhibitors, (2) modification of the chemical structure of drugs to produce prodrugs and analogs, (3) application of dosage forms to entrap these poorly absorbed drugs, and (4) development of novel and alternative administration methods (apart from oral and parenteral administration). We examined these approaches and demonstrated their effectiveness in improving intestinal and transmucosal absorption of several poorly absorbed drugs. These approaches may provide useful and basic information to improve the intestinal and transmucosal absorption of poorly absorbed drugs including peptide and protein drugs. G protein-coupled receptors (GPCRs) are targeted by about a third of clinically used drugs. Many GPCRs couple to more than one type of heterotrimeric G proteins, become phosphorylated by any of several different GRKs, and then bind one or more types of arrestin. Thus, classical therapeutically active drugs simultaneously initiate several branches of signaling, some of which are beneficial, whereas others result in unwanted on-target side effects. The development of novel compounds to selectively channel the signaling into the desired direction has the potential to become a breakthrough in health care. However, there are natural and technological hurdles that must be overcome. The fact that most GPCRs are subject to homologous desensitization, where the active receptor couples to G proteins, is phosphorylated by GRKs, and then binds arrestins, suggest that in most cases the GPCR conformations that facilitate their interactions with these three classes of binding partners significantly overlap. Thus, while partner-specific conformations might exist, they are likely low-probability states. GPCRs are inherently flexible, which suggests that complete bias is highly unlikely to be feasible in the conformational ensemble induced by any ligand, there would be some conformations facilitating receptor coupling to unwanted partners. Things are further complicated by the fact that virtually every cell expresses numerous G proteins, several GRK subtypes, and two non-visual arrestins with distinct signaling capabilities. Finally, novel screening methods for measuring ligand bias must be devised, as the existing methods are not specific for one particular branch of signaling. Apical Sodium-dependent Bile Acid Transporter (ASBT) actively reabsorbs bile acids (BAs) from the gut lumen. This process is a critical step in the enterohepatic circulation (EHC) of BAs and plays important roles in the homeostasis of BAs in the body. Therefore, ASBT is considered a favorite target for intervention to regulate the levels of BAs, cholesterol, lipid and glucose etc. In addition, ASBT is also a popular delivery target for developing prodrugs, due to its intestinal localization, high expression and high uptake capacity. In the past ten years, ASBT has been the focus by both academia and pharmaceutical industry as research targets not only for BA-related diseases but also for prodrug delivery. Numerous studies have been published and many candidate ASBT inhibitors are being developed. Here we review and summarize the current states of ASBT research with a focus on the therapeutic applications of ASBT as a target for therapy as well as a delivery target for prodrugs. The current and future challenges in ASBT research and outlook of drug developments are discussed. Protein folding in the endoplasmic reticulum is an oxidative process that relies on protein disulfide isomerase (PDI) and endoplasmic reticulum oxidase 1 (ERO1). Over 30% of proteins require the chaperone PDI to promote disulfide bond formation. PDI oxidizes cysteines in nascent polypeptides to form disulfide bonds and can also reduce and isomerize disulfide bonds. ERO1 recycles reduced PDI family member PDIA1 using a FAD cofactor to transfer electrons to oxygen. ERO1 dysfunction critically affects several diseases states. Both ERO1 and PDIA1 are overexpressed in cancers and implicated in diabetes and neurodegenerative diseases. Cancer-associated ERO1 promotes cell migration and invasion. Furthermore, the ERO1-PDIA1 interaction is critical for epithelial-to-mesenchymal transition. Co-expression analysis of ERO1A gene expression in cancer patients demonstrated that ERO1A is significantly upregulated in lung adenocarcinoma (LUAD), glioblastoma and low-grade glioma (GBMLGG), pancreatic ductal adenocarcinoma (PAAD), and kidney renal papillary cell carcinoma (KIRP) cancers. Tauroursodeoxycholic ERO1Α knockdown gene signature correlates with knockdown of cancer signaling proteins including IGF1R, supporting the search for novel, selective ERO1 inhibitors for the treatment of cancer. In this review, we explore the functions of ERO1 and PDI to support inhibition of this interaction in cancer and other diseases. Prostate Cancer (PCa) is the second leading cause of cancer-related death in men. Adenocarcinoma of the prostate is primarily composed of Androgen Receptor-positive (AR+) luminal cells that require AR transcriptional activity for survival and proliferation. As a consequence, androgen deprivation and anti-androgens are used to treat PCa patients whose disease progresses following attempted surgical or radiation interventions. Unfortunately, patients with advanced PCa can develop incurable castration-resistant PCa (CRPCa) due to mutated, variant, or overexpressed AR. Conversely, low or no AR accumulation or activity can also underlie castration resistance. Whether CRPCa is due to aberrant AR activity or AR independence, NF-κB signaling is also implicated in the initiation and maintenance of CRPCa and, thus, the NF-κB pathway may be a promising alternative therapeutic target. In this review, we present evidence that NF-κB signaling promotes CRPCa initiation and progression, describe the dichotomic role of NF-κB in the regulation of AR expression and activity and outline studies that explore NF-κB inhibitors as PCa therapies.