From the gut to the heart: L. plantarum and inulin administration as a novel approach to control cardiac apoptosis via 5-HT2B and TrkB receptors in diabetes

Introduction: Sepsis remains a significant cause of mortality in the intensive care unit till today. Recent research suggests nearly one in four deaths in people with heart failure is caused by sepsis. Overexpression of mammalian Pellino-1 (Peli1), a E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Therefore, in the present study, we explored the possibility to overcome sepsis mediated heart failure by overexpressing Peli1 (AMPEL1Tg/+) in a mouse model of severe sepsis. Methods: C57BL/6J (WT) and AMPEL1 Tg/+ mice were divided into Wild-type sham (WTS), Wild-type Cecal Ligation and Puncture (WTCLP), AMPEL1 Tg/+ sham (AMPEL1 Tg/+ S) and AMPEL1 Tg/+ CLP. Cardiac function (LVEF, FS) by two-dimensional echocardiography was assessed pre-procedure, at 6, and 24 hours post-surgery. Serum IL-6 and TNF-alpha (ELISA) at 6 hours and cardiac apoptosis (TUNEL assay) at 24 hours were measured. Results are expressed as mean ± SEM. Results: Analysis of echocardiographic parameters (EF, FS) preoperatively and among the sham groups were similar however there was significant preservation of post-procedure LVEF (%) in the AMPEL1 Tg/+ CLP at the 6 hour (AMPEL1 Tg/+ :52.7 ± 3.71 vs WT:40.7 ±2.46, p=0.013, n=10-11) and 24-hour time point (AMPEL1 Tg/+ :63.1 ± 1.63 vs WT:49.3 ± 4.41, p=0.002, n=9-11) compared to WT. Similar trend was observed in estimation of FS (%) at 6 hours (AMPEL1 Tg/+ :26.3 ± 2.22 vs WT:19.3 ±1.37, p=0.014, n=10-11) and 24 hours (AMPEL1 Tg/+ :32.4 ± 1.89 vs WT:24.4 ± 2.67, p=0.031, n=9-11). A marked decrease in serum IL-6 (AMPEL1 Tg/+ :259.7 ± 18.70 vs WT:483.2 ± 24.01, p<0.0001, n=6, pg/mL) and TNF-alpha (AMPEL1 Tg/+ :86.89 ± 14.36 vs WT:161.8 ± 20, p=0.012, n=6, pg/mL) was observed in the AMPEL1 Tg/+ CLP at 6 hours. The preserved cardiac function in CLP was further supported by a noticeable decrease in cardiac apoptosis (% TUNEL positive cells) at 24 hours in the AMPEL1 Tg/+ CLP group (4.7 ± 0.94 vs 11.7 ± 2.82, p=0.040, n=6,) compared to WTCLP. Conclusions: Thus, Peli1 overexpression is a novel approach that preserved cardiac function, reduced inflammatory markers, and apoptosis following severe sepsis in a murine genetic model.

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Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity

Biochemical Journal ◽

10.1042/bcj20190591 ◽

2019 ◽

Vol 476 (24) ◽

pp. 3705-3719 ◽

Cited By ~ 2

Author(s):

Avani Vyas ◽

Umamaheswar Duvvuri ◽

Kirill Kiselyov

Keyword(s):

Oxidative Stress ◽

Head And Neck ◽

Transcriptional Activation ◽

Platinum Resistance ◽

Mrna Levels ◽

Strong Positive Correlation ◽

Platinum Compounds ◽

Copper Chelation ◽

Novel Approach ◽

Cancer Models

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.

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Collecting Words: A Clinical Example of a Morphology-Focused Orthographic Intervention

Language Speech and Hearing Services in Schools ◽

10.1044/2020_lshss-19-00050 ◽

2020 ◽

Vol 51 (3) ◽

pp. 544-560 ◽

Cited By ~ 3

Author(s):

Kimberly A. Murphy ◽

Emily A. Diehm

Keyword(s):

Written Language ◽

Morphological Knowledge ◽

English Orthography ◽

Word Level ◽

Novel Approach ◽

Language Pathology ◽

The One ◽

Critical Intervention ◽

Reading And Spelling ◽

Reading And Spelling Difficulties

Purpose Morphological interventions promote gains in morphological knowledge and in other oral and written language skills (e.g., phonological awareness, vocabulary, reading, and spelling), yet we have a limited understanding of critical intervention features. In this clinical focus article, we describe a relatively novel approach to teaching morphology that considers its role as the key organizing principle of English orthography. We also present a clinical example of such an intervention delivered during a summer camp at a university speech and hearing clinic. Method Graduate speech-language pathology students provided a 6-week morphology-focused orthographic intervention to children in first through fourth grade ( n = 10) who demonstrated word-level reading and spelling difficulties. The intervention focused children's attention on morphological families, teaching how morphology is interrelated with phonology and etymology in English orthography. Results Comparing pre- and posttest scores, children demonstrated improvement in reading and/or spelling abilities, with the largest gains observed in spelling affixes within polymorphemic words. Children and their caregivers reacted positively to the intervention. Therefore, data from the camp offer preliminary support for teaching morphology within the context of written words, and the intervention appears to be a feasible approach for simultaneously increasing morphological knowledge, reading, and spelling. Conclusion Children with word-level reading and spelling difficulties may benefit from a morphology-focused orthographic intervention, such as the one described here. Research on the approach is warranted, and clinicians are encouraged to explore its possible effectiveness in their practice. Supplemental Material https://doi.org/10.23641/asha.12290687

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