Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death

Uppala, Jagadeesh Kumar; Gani, Amina R.; Konakanchi, Ramaiah

doi:10.1038/s41598-017-03940-1

Cited by 75 publications

(70 citation statements)

References 59 publications

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“…At the molecular level, 1‐week in vivo TUDCA treatment caused a slight increase in the expression of some genes related to protein folding and modification in progerin‐expressing medial aortas. Importantly, TUDCA diminished the mRNA levels of pro‐apoptotic Ddit3 , consistent with the known cytoprotective properties of this compound (Xie et al , ; Rivard et al , ; Gavin et al , ; Uppala et al , ). Overall, these results suggest that TUDCA simulates the pro‐survival UPR and attenuates the pro‐apoptotic UPR; however, the exact molecular mechanism of action of TUDCA in progerin‐expressing cells remains to be explored in further details.…”

Section: Discussionsupporting

confidence: 74%

Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells

et al. 2019

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Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin‐driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E‐deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC‐specific progerin expression. This stress pathway was also activated in HGPS patient‐derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC‐specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging‐dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A.

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Section: Discussionsupporting

confidence: 74%

Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells

et al. 2019

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“…However, aspartame had no effect on caspase activity while all concentrations of rebaudioside A, as well as 10 and 20 mM of sucralose, led to a decrease in caspase 3/7 activity ( Figure 4A). TUDCA treatment at a dose that has previously been shown to improve ER stress (27,28) had no effect on sucralose-or ACEK-induced changes in caspase 3/7 activity ( Figure 4A). The positive control, staurosporine (50 nM), showed significantly enhanced caspase activity ( Figure 4B).…”

Section: Sucralose Is Cytotoxic and Acek Induces Caspase3/7 Activity mentioning

confidence: 86%

Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth

2019

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With the prevalence of obesity, non-nutritive sweeteners (NNS) have been widely used as sugar substitutes as they deliver a sweet taste without excessive caloric load. However, it is increasingly recognized that NNS are not inert compounds and may cause long-term metabolic perturbations. Endoplasmic reticulum (ER) stress has emerged as a critical link in the development of obesity and type 2 diabetes. In this study, we investigated the effects of NNS found in common diet beverages (i.e., sucralose, aspartame, acesulfame potassium) and a natural sweetener (i.e., rebaudioside A) on ER stress in the hypothalamic cell line mHypoE-N43/5 in vivo and on axonal outgrowth ex vivo. Sucralose, aspartame, and acesulfame potassium caused elevated ER stress gene expression in mHypoE-N43/5 cells, with sucralose and acesulfame potassium having the most potent effect. Moreover, acesulfame potassium treatment reduced axon outgrowth from arcuate nucleus explants and this effect was attenuated with the ER stress-relieving drug tauroursodeoxycholic acid. Furthermore, sucralose induced cytotoxicity and acesulfame potassium increases caspase3/7 activity at high concentrations in mHypoE-N43/5 cells. In contrast, rebaudioside A only had moderate effects on hypothalamic ER stress and no adverse effects on axon outgrowth, cytotoxicity, or caspase3/7 activity. Together, our data reveal that commonly consumed NNS cause cellular stress in hypothalamic cells disrupting axon outgrowth and that these biological alterations are not seen with rebaudioside A. These data provide biological plausibility for some NNS to adversely impact metabolic health and identifies rebaudioside A as a sweetener with lower detrimental biological impact on hypothalamic cells.

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“…Of which, 14 mutants responded by at least 30% increase in the enzymatic activity, and four mutants showed an increased formation of CBS tetramers, without an increase in the CBS activity [80]. For instance, PBA and TUDCA are FDA approved chemical chaperones used for urea cycle disorders and biliary cirrhosis treatment, respectively [81]. Furthermore, studies showed that PBA attenuates the endoplasmic reticulum (ER) stress and acts as an ammonia scavenger in urea cycle disorders [82].…”

Section: Current and Potential Treatment Approachesmentioning

confidence: 99%

The Spectrum of Mutations of Homocystinuria in the MENA Region

Al-Sadeq

Nasrallah

2020

Genes

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Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both homocysteine and methionine levels in the blood and urine. Consequently, this build-up could lead to several complications such as nearsightedness, dislocated eye lenses, a variety of psychiatric and behavioral disorders, as well as vascular system complications. The prevalence of homocystinuria is around 1/200,000 births worldwide. However, its prevalence in the Gulf region, notably Qatar, is exceptionally high and reached 1:1800. To date, more than 191 pathogenic CBS mutations have been documented. The majority of these mutations were identified in Caucasians of European ancestry, whereas only a few mutations from African-Americans or Asians were reported. Approximately 87% of all CBS mutations are missense and do not target the CBS catalytic site, but rather result in unstable misfolded proteins lacking the normal biological function, designating them for degradation. The early detection of homocystinuria along with low protein and methionine-restricted diet is the best treatment approach for all types of homocystinuria patients. Yet, less than 50% of affected individuals show a significant reduction in plasma homocysteine levels after treatment. Patients who fail to lower the elevated homocysteine levels, through high protein-restricted diet or by B6 and folic acid supplements, are at higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to examine the mutations spectrum of the CBS gene, the disease management, as well as the current and potential treatment approaches with a greater emphasis on studies reported in the Middle East and North Africa (MENA) region.

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Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death

Cited by 75 publications

References 59 publications

Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells

Progerin accelerates atherosclerosis by inducing endoplasmic reticulum stress in vascular smooth muscle cells

Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth

The Spectrum of Mutations of Homocystinuria in the MENA Region

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