Research Spotlight

Alsahhar, J. S. and R. S. Rahimi (2019). “Updates on the pathophysiology and therapeutic targets for hepatic encephalopathy.” Curr Opin Gastroenterol 35(3): 145-154.

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PURPOSE OF REVIEW: Hepatic encephalopathy is one of the most debilitating clinical manifestations of cirrhosis and associated with increased morbidity and mortality. Treatment modalities available include the nonabsorbable disaccharides (lactulose) and the nonabsorbable antibiotics (rifaximin). RECENT FINDINGS: Newer therapeutic targets under evaluation include ammonia scavengers (ornithine phenylacetate) and modulation of gut microbiota (fecal microbiota transplantation). SUMMARY: This review will focus on the pathophysiology of hepatic encephalopathy along with an update on therapeutic targets under investigation.

Zanoli, L., P. Lentini, M. Briet, P. Castellino, A. A. House, G. M. London, L. Malatino, P. A. McCullough, D. P. Mikhailidis and P. Boutouyrie (2019). “Arterial Stiffness in the Heart Disease of CKD.” J Am Soc Nephrol Apr 30. [Epub ahead of print].

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CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

Walters, D. C., E. Arning, T. Bottiglieri, E. E. W. Jansen, G. S. Salomons, M. N. Brown, M. A. Schmidt, G. R. Ainslie, J. B. Roullet and K. M. Gibson (2019). “Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues.” Neurochem Int 125: 151-162.

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The anticonvulsant vigabatrin (VGB; Sabril(R)) irreversibly inhibits GABA transaminase to increase neural GABA, yet its mechanism of retinal toxicity remains unclear. VGB is suggested to alter several amino acids, including homocarnosine, beta-alanine, ornithine, glycine, taurine, and 2-aminoadipic acid (AADA), the latter a homologue of glutamic acid. Here, we evaluate the effect of VGB on amino acid concentrations in mice, employing a continuous VGB infusion (subcutaneously implanted osmotic minipumps), dose-escalation paradigm (35-140mg/kg/d, 12 days), and amino acid quantitation in eye, visual and prefrontal cortex, total brain, liver and plasma. We hypothesized that continuous VGB dosing would reveal numerous hitherto undescribed amino acid disturbances. Consistent amino acid elevations across tissues included GABA, beta-alanine, carnosine, ornithine and AADA, as well as neuroactive aspartic and glutamic acids, serine and glycine. Maximal increase of AADA in eye occurred at 35mg/kg/d (41+/-2nmol/g (n=21, vehicle) to 60+/-8.5 (n=8)), and at 70mg/kg/d for brain (97+/-6 (n=21) to 145+/-6 (n=6)), visual cortex (128+/-6 to 215+/-19) and prefrontal cortex (124+/-11 to 200+/-13; mean+/-SEM; p<0.05), the first demonstration of tissue AADA accumulation with VGB in mammal. VGB effects on basic amino acids, including guanidino-species, suggested the capacity of VGB to alter urea cycle function and nitrogen disposal. The known toxicity of AADA in retinal glial cells highlights new avenues for assessing VGB retinal toxicity and other off-target effects.

Tian, W., Z. Ye, S. Wang, M. A. Schulz, J. Van Coillie, L. Sun, Y. H. Chen, Y. Narimatsu, L. Hansen, C. Kristensen, U. Mandel, E. P. Bennett, S. Jabbarzadeh-Tabrizi, R. Schiffmann, J. S. Shen, S. Y. Vakhrushev, H. Clausen and Z. Yang (2019). “The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells.” Nat Commun 10(1): 1785.

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Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of alpha-galactosidase A in a Fabry disease mouse model, and find that an alpha2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.

Tan, M., A. Mamun, H. Kitzman and L. Dodgen (2019). “Longitudinal Changes in Allostatic Load during a Randomized Church-based, Lifestyle Intervention in African American Women.” Ethn Dis 29(2): 297-308.

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Introduction: African American (AA) women have disproportionately higher risk of cardiovascular disease than White women, which may be explained by the uniquely higher allostatic load (AL) found in AA women. No studies have tested the effect of lifestyle interventions on AL in AA women. Our objectives were to assess the change in allostatic load following a lifestyle intervention and explore the roles of lifestyle behaviors and socioeconomic factors on allostatic load change. Methods: Participants were non-diabetic (mean age and SD: 48.8+/-11.2 y) AA women (n=221) enrolled in a church-based, cluster randomized trial testing a standard diabetes prevention program (DPP) and a faith-enhanced DPP with 4-months of follow-up. We assessed the relationships of changes in diet, physical activity, neighborhood disadvantage, individual socioeconomic factors, and other lifestyle variables to changes in AL at 4-months using a multilevel multinomial logistic regression model. Results: Average AL decreased (-.13+/-.99, P=.02) from baseline to 4-months. After adjusting for other variables, a high school education or less (OR:.1, CI:.02-.49) and alcohol use (OR: .31, CI: .09-.99) contributed to increased AL. Living in a disadvantaged neighborhood was responsible for increased AL, though it was not statistically significant. There were no statistically significant associations between AL and other health behavior changes. Conclusions: Lower education levels may dampen the benefits of lifestyle interventions in reducing AL. Although a significant reduction in AL was found after participation in a lifestyle intervention, more research is needed to determine how lifestyle behaviors and socioeconomic factors influence AL in AA women.