No abstract

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remain unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.

Rapid clearance and proteolysis limit delivery and efficacy of protein therapeutics. Loading into biodegradable polymer nanocarriers (PNC) might protect proteins, extending therapeutic duration, but loading can be complicated by protein unfolding and inactivation. We encapsulated active enzymes into methoxy-poly(ethylene glycol- block-lactic acid) (mPEG-PLA) PNC with a freeze-thaw double emulsion ( J. Controlled Release 2005, 102 (2), 427-439). On the basis of concepts of amphiphile self-assembly, we hypothesized that the copolymer block ratio that controls spontaneous curvature would influence PNC morphology and loading. We examined PNC yield, shape, stability, loading, activity, and protease resistance of the antioxidant enzyme, catalase. PNC transitioned from spherical to filamentous shapes with increasing hydrophobic polymer fraction, consistent with trends for self-assembly of lower MW amphiphiles. Importantly, one diblock copolymer formed filamentous particles loaded with significant levels of protease-resistant enzyme, demonstrating for the first time encapsulation of an active therapeutic enzyme into filamentous carriers. PNC morphology also greatly influenced its degradation, offering a new means of controlled delivery.

Relebactam is a novel class A and C β-lactamase inhibitor that is being developed in combination with imipenem-cilastatin for the treatment of serious infections with Gram-negative bacteria. Here we report on two phase 1 randomized, double-blind, placebo-controlled pharmacokinetics, safety, and tolerability studies of relebactam administered with or without imipenem-cilastatin to healthy participants: (i) a single-dose (25 to 1,150 mg) and multiple-dose (50 to 625 mg every 6 h [q6h] for 7 to 14 days) escalation study with men and (ii) a single-dose (125 mg) study with women and elderly individuals.

Obesity has escalated into a pandemic over the past few decades. In turn, research efforts have sought to elucidate the molecular mechanisms underlying the regulation of energy balance. A host of endogenous mediators regulate appetite and metabolism, and thereby control both short- and long-term energy balance. These mediators, which include gut, pancreatic and adipose neuropeptides, have been targeted in the development of anti-obesity pharmacotherapy, with the goal of amplifying anorexigenic and lipolytic signaling or blocking orexigenic and lipogenic signaling. This article presents the efficacy and safety of these anti-obesity drugs.

Chimaerins are a family of GTPase activating proteins (GAPs) for the small G-protein Rac that have gained recent attention due to their important roles in development, cancer, neuritogenesis, and T-cell function. Like protein kinase C isozymes, chimaerins possess a C1 domain capable of binding phorbol esters and the lipid second messenger diacylglycerol (DAG) in vitro. Here we identified an autoinhibitory mechanism in ␣2-chimaerin that restricts access of phorbol esters and DAG, thereby limiting its activation. Although phorbol 12-myristate 13-acetate (PMA) caused limited translocation of wild-type ␣2-chimaerin to the plasma membrane, deletion of either N-or C-terminal regions greatly sensitize ␣2-chimaerin for intracellular redistribution and activation. Based on modeling analysis that revealed an occlusion of the ligand binding site in the ␣2-chimaerin C1 domain, we identified key amino acids that stabilize the inactive conformation. Mutation of these sites renders ␣2-chimaerin hypersensitive to C1 ligands, as reflected by its enhanced ability to translocate in response to PMA and to inhibit Rac activity and cell migration. Notably, in contrast to PMA, epidermal growth factor promotes full translocation of ␣2-chimaerin in a phospholipase C-dependent manner, but not of a C1 domain mutant with reduced affinity for DAG (P216A-␣2-chimaerin). Therefore, DAG generation and binding to the C1 domain are required but not sufficient for epidermal growth factor-induced ␣2-chimaerin membrane association. Our studies suggest a role for DAG in anchoring rather than activation of ␣2-chimaerin. Like other DAG/phorbol ester receptors, including protein kinase C isozymes, ␣2-chimaerin is subject to autoinhibition by intramolecular contacts, suggesting a highly regulated mechanism for the activation of this Rac-GAP.Signaling via the small GTPase Rac has been implicated in a wide range of cell processes such as cytoskeleton reorganization, migration, gene expression, and cell cycle progression. Rac is a molecular switch that cycles between GTP-loaded "on" and GDP-loaded "off" states. Tight mechanisms exist to fine-tune Rac responses by controlling the cycling between Rac active and inactive states. In the off state, cytosolic GDP-bound Rac is associated with Rho family-specific guanine nucleotide dissociation inhibitors (RhoGDIs) (1). In response to an activating signal, such as the stimulation of tyrosine kinase or G proteincoupled receptors, Rac translocates to the plasma membrane where guanine nucleotide exchange factors promote the exchange of GDP for GTP, rendering Rac active. On the other hand, termination of Rac signal is mediated by GTPase activating proteins (GAPs), 3 which interact with GTP-bound Rac and accelerate GTP hydrolysis, leading to Rac inactivation (2, 3). Although the mechanisms by which Rac-guanine nucleotide exchange factor promote Rac activation have been extensively studied, much less is known about the mechanistic basis of Rac inactivation by Rac-GAPs.The chimaerin family of Rac-GAPs (␣1-, ␣2-, ␤1-, and ...

The increase in obesity in the Unites States and around the world in the last decade is overwhelming. The number of overweight adults in the world surpassed 1 billion in 2008. Health hazards associated with obesity are serious and include heart disease, sleep apnea, diabetes, and cancer. Although lifestyle modifications are the most straightforward way to control weight, a large portion of the population may not be able to rely on this modality alone. Thus, the development of anti-obesity therapeutics represents a major unmet medical need. Historically, anti-obesity pharmacotherapies have been unsafe and minimally efficacious. A better understanding of the biology of appetite and metabolism provides an opportunity to develop drugs that may offer safer and more effective alternatives for weight management. This review discusses drugs that are currently on the market and in development as anti-obesity therapeutics based on their target and mechanism of action. It should serve as a roadmap to establish expectations for the near future for anti-obesity drug development.

Atogepant is a potent, selective, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once‐daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double‐blind, placebo‐controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty‐four participants aged 23–55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well‐tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half‐life of ~ 11 hours, and no evidence of accumulation after once‐daily dosing. Overall, atogepant at a high oral dose is safe and well‐tolerated in healthy participants with no clinically meaningful elevations in ALT.