Cisplatin ototoxicity mechanism and antagonistic intervention strategy: a scope review.

Cisplatin is a first-line chemotherapeutic agent in the treatment of malignant tumors with remarkable clinical effects and low cost. However, the ototoxicity and neurotoxicity of cisplatin greatly limit its clinical application. This article reviews the possible pathways and molecular mechanisms of cisplatin trafficking from peripheral blood into the inner ear, the toxic response of cisplatin to inner ear cells, as well as the cascade reactions leading to cell death. Moreover, this article highlights the latest research progress in cisplatin resistance mechanism and cisplatin ototoxicity. Two effective protective mechanisms, anti-apoptosis and mitophagy activation, and their interaction in the inner ear are discussed. Additionally, the current clinical preventive measures and novel therapeutic agents for cisplatin ototoxicity are described. Finally, this article also forecasts the prospect of possible drug targets for mitigating cisplatin-induced ototoxicity. These include the use of antioxidants, inhibitors of transporter proteins, inhibitors of cellular pathways, combination drug delivery methods, and other mechanisms that have shown promise in preclinical studies. Further research is needed to evaluate the efficacy and safety of these approaches.

Retrospective analysis of clinical features and prognosis of nasopharyngeal carcinoma in children and adolescents.

Objectives: To investigate the clinical characteristics and prognosis of nasopharyngeal carcinoma (NPC) in children and adolescents in different age groups. Materials and methods: The clinical data of 51 patients with NPC aged ≤ 18 years who were treated in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2012 to May 2017 were retrospectively analyzed. The patients were divided into children group (≤12 years old) and adolescent group (12-18 years old) with 12 years old as the boundary. The clinical characteristics, diagnosis, treatment, and prognosis of the children and adolescent groups were compared. Results: The symptoms of the first diagnosis in the children group were mainly nasal congestion (P = 0.043) and ear symptoms (P = 0.008). The diagnosis rate of nasopharyngeal biopsy in the children group was lower (P = 0.001), while the rate of diagnosis of cervical mass biopsy was significantly higher than that in the adolescent group (P = 0.009). The proportion of keratinizing squamous cell carcinoma of the children group was higher than that of the adolescent group (P = 0.006). There was no significant difference in TNM stage and risk stratification between the two groups, but the number of cases in the III-IVa children group who received induction chemotherapy + concurrent chemoradiotherapy was less than that in the adolescent group (P = 0.013). The proportion of radiotherapy in the upper and lower cervical lymph node drainage areas was lower than that in the adolescent group (P = 0.001). The percentage of recurrence and metastasis in the children group was higher than that in the adolescent group (P = 0.026). Conclusion: The diagnosis in the children group depended on endoscopic biopsy and neck mass biopsy, and the proportion of keratinizing squamous cell carcinoma was higher. The number of cases of induction chemotherapy and concurrent chemoradiotherapy in the children group was less than that in the adolescent group, and the proportion of radiotherapy in the upper and lower cervical lymph node drainage areas was lower than that in the adolescent group. Clinically, it is necessary to improve the understanding of the clinical characteristics of children with NPC and take appropriate treatment strategies.

NAD+ attenuates bilirubin-induced augmentation of voltage-gated calcium currents in neurons of the ventral cochlear nucleus.

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous molecule with wide-ranging roles in several cell processes, such as regulation of calcium homeostasis and protection against cell injuries. However, the roles of NAD+ in neuroprotection is poorly understood. The main neurons in ventral cochlear nucleus (VCN) are highly susceptible to bilirubin-associated excitotoxicity. We investigated the effects of NAD+ on VCN neurons by whole cell patch-clamp recordings. We found that NAD+ effectively reverses and inhibits bilirubin-mediated enhancement of voltage-gated calcium (VGCC) currents in VCN neurons. Moreover, NAD+ itself did not affect VGCC currents. These results collectively suggest that NAD+ may be neuroprotective by attenuating Ca2+ influx to suppress bilirubin-induced intracellular Ca2+ overloads. Our research provides a basis for evaluation of NAD+ as a promising therapeutic target for bilirubin encephalopathy and excitotoxicity associated with other neurological disorders.

Overexpression of XIAP inhibits cisplatin-induced hair cell loss.

Cisplatin is a platinum-containing drug with ototoxicity commonly used clinically and has significant efficacy against a variety of solid tumors. One of the most important mechanisms of ototoxicity is that cisplatin induces apoptosis of hair cells. According to relevant literature, X-linked inhibitor of apoptosis protein (XIAP, anti-apoptotic protein) could inhibit the apoptotic pathway. We hypothesized that this protein might protect cochlear hair cells from cisplatin-induced injury. To figure it out, we treated cochlea of normal mice with various concentrations of cisplatin to observe the response and morphology of hair cells and determine a reasonable concentration. Next, Western Blot and quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) experiments were conducted to make an investigation about the expression of XIAP protein and mRNA. In addition, we constructed and identified XIAP overexpressing mice. Finally, we treated cochlear tissues of normal and overexpressing mice with cisplatin to investigate the cyto-protection of XIAP on hair cells, respectively. It was found that 50 µmol/L cisplatin resulted in significant loss and disorganization of hair cells, while simultaneously downregulating the protein and mRNA of XIAP. In XIAP overexpressing mice, the loss and disorganization of hair cells were significantly lessened. These results showed that XIAP can lessen cisplatin-induced hair cell loss and play a role in otoprotection.

XIAP inhibits gentamicin-induced hair cell damage and ototoxicity through the caspase-3/9 pathway.

Gentamicin (GM), an aminoglycoside antibiotic, is one commonly used clinical drugs with ototoxic side effects. One of the most principal mechanisms of its ototoxicity is that GM can activate caspase-mediated cell death pathways in the cochlea. Since the anti-apoptotic protein known as X-linked Inhibitor of Apoptosis Protein (XIAP) has been reported to directly bind to activated caspase protein and inhibit their activities, we hypothesized that it might protect cochlea hair cells from GM ototoxicity. To evaluate this hypothesis, postnatal day 2-3 (P2-3) transgenic (TG) mice, in which XIAP gene is over-expressed under a pure C57BL/6J genetic background was constructed. We first extracted the cochlea tissue of normal mice and treated them with different concentrations of GM, and the number of hair cells were observed to determine the concentration of GM used in subsequent experiments. Next, we used Western Blot experiment to examine the effect of GM on XIAP protein expression in normal mouse cochlea, and then Western Blot and RT-PCR experiments were used to identify the transgenic mice. Finally, immunofluorescence assays were used to detect the effect of GM on the expression of caspase protein and verify the protective effect of XIAP. We found that GM at a concentration of 0.5 mM significantly affected the function of cochlea hair cells, up-regulating the expression of cleaved-caspase-3 and cleaved-caspase-9 protein but down-regulating XIAP protein. In the cochlea tissues of TG mice, this effect of GM was suppressed, and the destruction of hair cells was significantly reduced, and the cleaved-caspase-3 and cleaved-caspase-9 proteins were significantly suppressed. These results suggested that XIAP reduces GM-induced ototoxicity and caspase-3/9 pathway is associated with this process.

Cytochrome P450 1A2 Is Incapable of Oxidizing Bilirubin Under Physiological Conditions.

Background: Bilirubin (BR) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) through glucuronidation in the liver. Some studies have shown that several subtypes of cytochrome P450 (CYP) enzymes, including CYP1A2, are upregulated by inducers and proposed to be alternative BR degradation enzymes. However, no information is available on the BR degradation ability of CYP in normal rats without manipulation by CYP inducers. Methods: Quantitative real-time polymerase chain reaction (QRT-PCR), western blot, immunofluorescence, and confocal microscopy were used to find expression of CYP1A2 in the brain and the liver. BR metabolites in microsomal fractions during development were examined by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (LC-MS/MS). Results: In the present study, we observed that CYP1A2 mRNA levels increased at postnatal days (P)14 and P30 with respect to the level at P7 both in liver and brain, this increment was especially pronounced in the brain at P14. The expression of CYP1A2 in the brainstem (BS) was higher than that in the cerebellum (CLL) and cortex (COR). Meanwhile, the CYP1A2 protein level was significantly higher in the COR than in the brainstem and CLL at P14. The levels of BR and its metabolites (m/z values 301, 315, 333 and biliverdin) were statistically unaltered by incubation with liver and brain microsomal fractions. Conclusion: Our results indicated that the region-specific expression of CYP1A2 increased during development, but CYP family enzymes were physiologically incapable of metabolizing BR. The ability of CYPs to oxidize BR may be triggered by CYP inducers.

Accelerated Development of the First-Order Central Auditory Neurons With Spontaneous Activity.

In developing sensory systems, elaborate morphological connectivity between peripheral cells and first-order central neurons emerges via genetic programming before the onset of sensory activities. However, how the first-order central neurons acquire the capacity to interface with peripheral cells remains elusive. By making patch-clamp recordings from mouse brainstem slices, we found that a subset of neurons in the cochlear nuclei, the first central station to receive peripheral acoustic impulses, exhibits spontaneous firings (SFs) as early as at birth, and the fraction of such neurons increases during the prehearing period. SFs are reduced but not eliminated by a cocktail of blockers for excitatory and inhibitory synaptic inputs, implicating the involvement of intrinsic pacemaker channels. Furthermore, we demonstrate that these intrinsic firings (IFs) are largely driven by hyperpolarization- and cyclic nucleotide-gated channel (HCN) mediated currents (Ih), as evidenced by their attenuation in the presence of HCN blockers or in neurons from HCN1 knockout mice. Interestingly, genetic deletion of HCN1 cannot be fully compensated by other pacemaker conductances and precludes age-dependent up regulation in the fraction of spontaneous active neurons and their firing rate. Surprisingly, neurons with SFs show accelerated development in excitability, spike waveform and firing pattern as well as synaptic pruning towards mature phenotypes compared to those without SFs. Our results imply that SFs of the first-order central neurons may reciprocally promote their wiring and firing with peripheral inputs, potentially enabling the correlated activity and crosstalk between the developing brain and external environment.