Diet-Induced Obesity Exacerbates Auditory Degeneration via Hypoxia, Inflammation, and Apoptosis Signaling Pathways in CD/1 Mice

Abstract

The aim of this study was to investigate the mechanisms of diet-induced obesity on hearing degeneration in CD/1 mice. Sixty 4-week-old male CD/1 mice were randomly and equally divided into 2 groups. For 16 weeks, the diet-induced obesity (DIO) group was fed a high fat diet and the control group was fed a standard diet of 13.43 % kcal fat. The morphometry, biochemistry, auditory brainstem response thresholds, omental fat, and histopathology of the cochlea were compared between the beginning and end of the study (4 vs. 20 weeks old). The results show that the body weight, fasting plasma triglyceride concentrations, and omental fat weight were higher in the DIO group than in the control group at the end of experiment. The auditory brainstem response thresholds at high frequencies were significantly elevated in the DIO group compared to those of the control group. Histology studies showed that, compared to the control group, the DIO group had blood vessels with smaller diameters and thicker walls in the stria vascularis at the middle and basal turns of the cochlea. The cell densities in the spiral ganglion and spiral ligament at the basal turn of the cochlea were significantly lower in the DIO group. Immunohistochemical staining showed that hypoxia-induced factor 1 (HIF-1), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB), caspase 3, poly(ADP-ribose) polymerase-1, and apoptosis inducing factor were all significantly more dense in the spiral ganglion and spiral ligament at the basal turn of cochlea in the DIO group. Our results suggest that diet-induced obesity exacerbates hearing degeneration via increased hypoxia, inflammatory responses, and cell loss in the spiral ganglion and spiral ligament and is associated with the activation of both caspase-dependent and -independent apoptosis signaling pathways in CD/1 mice.

Clinical observations and risk factors for tinnitus in a Sicilian cohort

“…Specifically, of the 76 subjects with normal hearing, 58 corresponding to 76.31 % were controls (P \ 0.001). Table 2 reports the average hearing threshold levels for each frequency relative to tinnitus and control groups; it is clear that patients suffering from tinnitus presented higher hearing thresholds with respect to controls, particularly for the frequencies above 4 kHz (P \ 0.001); it confirmed that patients with tinnitus had a worse cochlear dysfunction than control group especially in the cochlear basal turn, where high frequencies are represented, as suggested in CD/1 mice by Riva et al and Hwang et al [24,32].…”

“…Audiometric threshold was considered as the pure tone average for the frequencies 0.5-1-2-4 kHz (PTA 0.5-4 kHz ) and divided in: normal hearing (\20 dB); light hearing loss (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) TEOAE measurements were evaluated in reproducibility (expressed as the correlation between two waveforms, namely for responses stored in buffers A and B, acquired alternately) and were done using defined criteria as response detection in 4/5 different frequency bands (1, 1.5, 2, 3, and 4 kHz); a minimum signal-to-noise ratio (SNRs) of 6 dB for each frequency band was chosen. The instrument used was the 'SENTIERO by Path Medical GmbH', that is based on the nonlinear cross-correlation method (ILO88) of TEOAE recording.…”

“…This leads to a total score ranging from 0 (indicating no tinnitus handicap) to 100 (indicating the worst patients' annoyance). Classically it grades five categories of tinnitus severity: slight (0-16); mild (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36); moderate (38-56); severe (58-76); catastrophic (78-100).…”

“…vascular disease, diabetes, hypertension, autoimmune disorders, and degenerative neural disorders) [12,22,23]. All these conditions could be responsible for a periodic hypoxia/re-oxygenation with a consequent oxidative stress, endothelial dysfunction, and activation of the inflammatory cascade [24]. These noxious stimuli can activate the sympathetic nervous system, depress parasympathetic activity, provoke oxidative stress and systemic inflammation, activate platelets, and impair vascular endothelial cochlear function.…”

Overexpression of 4EBP1, p70S6K, Akt1 or Akt2 differentially promotes Coxsackievirus B3-induced apoptosis in HeLa cells

“…Although a recent study has reported that there is a caspase-independent apoptosis signaling pathway, 28 as a classical pro-apoptotic family, caspase has a major role both in the intrinsic and extrinsic apoptosis pathways, of which caspase-3 contributes to the apoptosis execution, whereas caspase-9 participates in the apoptosis origination. In this study, we determined the caspase-9 activation by real-time fluorescence quantitative PCR and western blot analysis using cells containing the plasmid pcDNA3.1-myc-HisA(-)-4EBP1, pcDNA3.1-myc-HisA(-)-p70S6K, pcDNA3.1-myc-HisA(-)-Akt1, pcDNA3.1-myc-HisA(-)-Akt2 or the empty vector alone to further illustrate the role of PI3K/mTOR pathway in the viral-induced apoptosis.…”