Cochlear implantation in patients with Streptococcus suis meningitis: clinical characteristics and postoperative evaluation.

BACKGROUND: Hearing loss is a common sequala of Streptococcus suis (S. suis) meningitis, but few have addressed cochlear implantation (CI) candidates with S. suis meningitis. OBJECTIVES: To assess the clinical characteristics and CI postoperative outcomes in S. suis meningitis patients. MATERIAL AND METHODS: Eight S. suis meningitis patients underwent CI at Sun Yat-sen Memorial Hospital between 2020 and 2023. Control groups included (1) non-Suis meningitis patients (n = 12) and (2) non-meningitis patients (n = 35). Electrode impedances and neural response telemetry (NRT) thresholds were recorded at one month after surgery. The auditory performance-II (CAP) and speech intelligibility rating (SIR) were recorded at the last visit. RESULTS: CAP scores of S. suis meningitis patients were significantly lower than those of non-Suis meningitis and non-meningitis patients (p = .019; p<.001). And NRT thresholds of S. suis meningitis patients were higher than those of non-Suis meningitis and non-meningitis patients (p = .006; p = .027). CONCLUSIONS AND SIGNIFICANCE: It is recommended for S. suis meningitis CI candidates to undergo CI promptly after controlling infection, preferably within four to six weeks. CI users with S. suis meningitis tend to exhibit suboptimal hearing rehabilitation outcomes, possibly associated with the more severe damage on spiral ganglion cells after S. suis meningitis.

The potassium channels: Neurobiology and pharmacology of tinnitus.

Tinnitus is a widespread public health issue that imposes a significant social burden. The occurrence and maintenance of tinnitus have been shown to be associated with abnormal neuronal activity in the auditory pathway. Based on this view, neurobiological and pharmacological developments in tinnitus focus on ion channels and synaptic neurotransmitter receptors in neurons in the auditory pathway. With major breakthroughs in the pathophysiology and research methodology of tinnitus in recent years, the role of the largest family of ion channels, potassium ion channels, in modulating the excitability of neurons involved in tinnitus has been increasingly demonstrated. More and more potassium channels involved in the neural mechanism of tinnitus have been discovered, and corresponding drugs have been developed. In this article, we review animal (mouse, rat, hamster, and guinea-pig), human, and genetic studies on the different potassium channels involved in tinnitus, analyze the limitations of current clinical research on potassium channels, and propose future prospects. The aim of this review is to promote the understanding of the role of potassium ion channels in tinnitus and to advance the development of drugs targeting potassium ion channels for tinnitus.

Autologous Fat Injection for the Treatment of Patulous Eustachian Tube.

BACKGROUND: Patulous eustachian tube is a disorder that leads to disturbing symptoms such as autophony, respiratory noise, and aural fullness. There has not been an established treatment found for this disorder. This study aims to assess the efficacy of autologous fat injection for a novel treatment of patients with patulous eustachian tube. METHODS: Twenty-eight patients with refractory patulous eustachian tube were recruited for the study. Endoscopic autologous fat injection was performed submucosally into the anterior and posterior portion of the pharyngeal orifice of the eustachian tube. The outcomes were quantitatively assessed by comparing the difference between pre- and postoperative scores with the visual analog scale on 4 criteria: aural fullness, respiratory noise, tinnitus, and autophony. RESULTS: Autologous fat injection was performed successfully in all patients without major complications. According to the combined visual analog scale scores, after the treatments, 20 patients showed significant improvement and 6 showed moderate improvement. The overall success rate of the treatment was 92.9%. CONCLUSION: Autologous fat injection is an effective and safe procedure for the treatment of patulous eustachian tube.

Cognitive reserve disorder in age-related hearing loss: cognitive cortical compensatory to auditory perceptual processing.

The aim of this study is to ascertain the mechanisms of cognitive reserve disorder in age-related hearing loss (ARHL), to study the correlation between ARHL and cognitive decline via EEG, and to reverse the adverse remodeling of auditory-cognitive connectivity with hearing aids (HAs). In this study, 32 participants were enrolled, including 12 with ARHLs, 9 with HAs, and 11 healthy controls (HCs), to undergo EEG, Pure Tone Average (PTA), Montreal Cognitive Assessment (MoCA), and other general cognitive tests. There were the lowest MoCA in the ARHL group (P = 0.001), especially in language and abstraction. In the ARHL group, power spectral density of the gamma in right middle temporal gyrus was significantly higher than HC and HA groups, while functional connectivity between superior frontal gyrus and cingulate gyrus was weaker than HC group (P = 0.036) and HA group (P = 0.021). In the HA group, superior temporal gyrus and cuneus had higher connectivity than in the HC group (P = 0.036). In the ARHL group, DeltaTM_DTA (P = 0.042) and CTB (P = 0.011) were more frequent than in the HC group, while there was less DeltaTM_CTA (P = 0.029). PTA was found to be associated with MoCA (r = -0.580) and language (r = -0.572), DeltaTM_CTB had a likewise correlation with MoCA (r = 0.483) and language (r = 0.493), while DeltaTM_DTA was related to abstraction (r = -0.458). Cognitive cortexes compensate for worse auditory perceptual processing in ARHL, which relates to cognitive decline. The impaired functional connectivity between auditory and cognitive cortexes can be remodeled by HAs. DeltaTM may serve as a biomarker for early cognitive decline and decreased auditory speech perception in ARHL.

Analysis of Clinical Efficacy and Influencing Factors of Nerve Growth Factor (NGF) Treatment for Sudden Sensorineural Hearing Loss.

Objective: This study aims to examine the clinical efficacy and prognostic factors associated with nerve growth factor (NGF) treatment for sudden sensorineural hearing loss (SSHL). Materials and methods: A retrospective analysis was conducted on the clinical data of 101 patients with moderate or more severe SSHL who underwent secondary treatment at Sun Yat-sen Memorial Hospital of Sun Yat-sen University between January 2019 and July 2020. Prior to treatment, all patients were assessed using Pure Tone Audiometry (PTA), auditory brainstem response, otoacoustic emission, temporal bone computed tomography, or inner ear magnetic resonance imaging. Fifty-seven patients received conventional systemic treatment and served as the control group, while 44 patients received NGF in conjunction with conventional systemic treatment, forming the experimental group. PTA results were compared between the two groups before treatment and at 1 week, 2 weeks, and 1 month post-treatment. Additionally, the impact of age, sex, affected side, hypertension, and other factors on patient prognosis was analyzed. Results: Both groups demonstrated significant PTA improvements following treatment, with a statistically significant difference (P < .05). The hearing recovery effective rate in the control group was 42.1%, while that of the experimental group reached 70.5%, with a statistically significant difference between the groups (P < .05). Most patients experienced notable hearing improvements 1 week after treatment, with some patients still showing progress 2 weeks post-treatment. Multifactor analysis revealed that hypertension and onset days were associated with treatment outcomes. Conclusion: Secondary treatment remains clinically significant for patients with SSHL who have not achieved a satisfactory response or show no clear improvement following initial treatment. The presence of hypertension and delayed treatment are negative factors related to treatment efficacy.

Apoptotic vesicles resist oxidative damage in noise-induced hearing loss through activation of FOXO3a-SOD2 pathway.

BACKGROUND: Mesenchymal stem cell (MSC) transplantation is a promising therapeutic approach for noise-induced hearing loss (NIHL). As the indispensable role of apoptosis in MSC transplantation was raised, the benefits of MSC-derived apoptotic vesicles (apoVs) in several disease models have been proved. However, whether apoVs benefit in NIHL have not been studied yet. METHODS: Female CBA/J mice and HEI-OC1 cells were used in this study. Flow cytometry, nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were used to characterize apoVs. Proteomic analysis was used to identify function proteins in apoVs. Immunofluorescence was used to reveal distribution pattern. Auditory brainstem response (ABR) test was used to measure the effect of apoVs treatment. DCFH-DA staining and MitoSOX staining were used to indicate oxidative damage. Western-blot and qRT-PCR were used to study the signaling pathways. RESULTS: We found that apoVs can be endocytosed by hair cells through systemic administration. Importantly, apoVs administration effectively attenuated NIHL and reduced hair cell loss by resisting oxidative damage in vivo. Further, apoVs application activated forkhead box o3 (FOXO3a)-mitochondrial superoxide dismutase 2(SOD2) pathway, which may relate to signal transduction and activators of transcription 3 (STAT3) in apoVs. CONCLUSIONS: These findings uncovered the role of apoVs in preventing NIHL and resisting oxidative damage, indicating that apoVs is a promising way for inner ear delivery and a prospective cell-free therapy for NIHL.

Epstein-Barr Virus Envelope Glycoprotein gp110 Inhibits IKKi-Mediated Activation of NF-κB and Promotes the Degradation of ß-Catenin.

Epstein-Barr virus (EBV) infects host cells and establishes a latent infection that requires evasion of host innate immunity. A variety of EBV-encoded proteins that manipulate the innate immune system have been reported, but whether other EBV proteins participate in this process is unclear. EBV-encoded envelope glycoprotein gp110 is a late protein involved in virus entry into target cells and enhancement of infectivity. Here, we reported that gp110 inhibits RIG-I-like receptor pathway-mediated promoter activity of interferon-ß (IFN-ß) as well as the transcription of downstream antiviral genes to promote viral proliferation. Mechanistically, gp110 interacts with the inhibitor of NF-κB kinase (IKKi) and restrains its K63-linked polyubiquitination, leading to attenuation of IKKi-mediated activation of NF-κB and repression of the phosphorylation and nuclear translocation of p65. Additionally, gp110 interacts with an important regulator of the Wnt signaling pathway, ß-catenin, and induces its K48-linked polyubiquitination degradation via the proteasome system, resulting in the suppression of ß-catenin-mediated IFN-ß production. Taken together, these results suggest that gp110 is a negative regulator of antiviral immunity, revealing a novel mechanism of EBV immune evasion during lytic infection. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects almost all human beings, and the persistence of EBV in the host is largely due to immune escape mediated by its encoded products. Thus, elucidation of EBV's immune escape mechanisms will provide a new direction for the design of novel antiviral strategies and vaccine development. Here, we report that EBV-encoded gp110 serves as a novel viral immune evasion factor, which inhibits RIG-I-like receptor pathway-mediated interferon-ß (IFN-ß) production. Furthermore, we found that gp110 targeted two key proteins, inhibitor of NF-κB kinase (IKKi) and ß-catenin, which mediate antiviral activity and the production of IFN-ß. gp110 inhibited K63-linked polyubiquitination of IKKi and induced ß-catenin degradation via the proteasome, resulting in decreased IFN-ß production. In summary, our data provide new insights into the EBV-mediated immune evasion surveillance strategy.

miR-34a/DRP-1-mediated mitophagy participated in cisplatin-induced ototoxicity via increasing oxidative stress.

PURPOSE: Cisplatin is a widely used and effective chemotherapeutic agent for most solid malignant tumors. However, cisplatin-induced ototoxicity is a common adverse effect that limits the therapeutic efficacy of tumors in the clinic. To date, the specific mechanism of ototoxicity has not been fully elucidated, and the management of cisplatin-induced ototoxicity is also an urgent challenge. Recently, some authors believed that miR34a and mitophagy played a role in age-related and drug-induced hearing loss. Our study aimed to explore the involvement of miR-34a/DRP-1-mediated mitophagy in cisplatin-induced ototoxicity. METHODS: In this study, C57BL/6 mice and HEI-OC1 cells were treated with cisplatin. MiR-34a and DRP-1 levels were analyzed by qRT‒PCR and western blotting, and mitochondrial function was assessed via oxidative stress, JC-1 and ATP content. Subsequently, we detected DRP-1 levels and observed mitochondrial function by modulating miR-34a expression in HEI-OC1 cells to determine the effect of miR-34a on DRP-1-mediated mitophagy. RESULTS: MiR-34a expression increased and DRP-1 levels decreased in C57BL/6 mice and HEI-OC1 cells treated with cisplatin, and mitochondrial dysfunction was involved in this process. Furthermore, the miR-34a mimic decreased DRP-1 expression, enhanced cisplatin-induced ototoxicity and aggravated mitochondrial dysfunction. We further verified that the miR-34a inhibitor increased DRP-1 expression, partially protected against cisplatin-induced ototoxicity and improved mitochondrial function. CONCLUSION: MiR-34a/DRP-1-mediated mitophagy was related to cisplatin-induced ototoxicity and might be a novel target for investigating the treatment and protection of cisplatin-induced ototoxicity.

Epstein-Barr virus envelope glycoprotein 110 inhibits NF-κB activation by interacting with NF-κB subunit p65.

Epstein-Barr virus (EBV) is a member of the lymphotropic virus family and is highly correlated with some human malignant tumors. It has been reported that envelope glycoprotein 110 (gp110) plays an essential role in viral fusion, DNA replication, and nucleocapsid assembly of EBV. However, it has not been established whether gp110 is involved in regulating the host's innate immunity. In this study, we found that gp110 inhibits tumor necrosis factor α-mediated NF- κB promoter activity and the downstream production of NF- κB-regulated cytokines under physiological conditions. Using dual-luciferase reporter assays, we showed that gp110 might impede the NF-κB promoter activation downstream of NF-κB transactivational subunit p65. Subsequently, we used coimmunoprecipitation assays to demonstrate that gp110 interacts with p65 during EBV lytic infection, and that the C-terminal cytoplasmic region of gp110 is the key interaction domain with p65. Furthermore, we determined that gp110 can bind to the N-terminal Rel homologous and C-terminal domains of p65. Alternatively, gp110 might not disturb the association of p65 with nontransactivational subunit p50, but we showed it restrains activational phosphorylation (at Ser536) and nuclear translocation of p65, which we also found to be executed by the C-terminal cytoplasmic region of gp110. Altogether, these data suggest that the surface protein gp110 may be a vital component for EBV to antagonize the host's innate immune response, which is also helpful for revealing the infectivity and pathogenesis of EBV.

A retrospective study of audiological outcomes after endoscopic tympanoplasty and tympanomastoidectomy in patients with cholesteatoma.

OBJECTIVES: To investigated whether endoscopic tympanoplasty and tympanomastoidectomy could present satisfying audiological outcomes for cholesteatoma patients. METHODS: This was a retrospective study of 83 patients with cholesteatoma who underwent endoscopic tympanoplasty and tympanomastoidectomy between 2019 and 2021. The preoperative and postoperative audiological evaluations were performed. The evaluation methods included air conduction (AC), bone conduction (BC), and air-bone gap (ABG) procedures. RESULTS: Eighty-three patients were included in the study, all of whom underwent endoscopic tympanoplasty and tympanomastoidectomy. Forty-seven patients presented postoperative ABG≤20 dB (59.49%). The frequencies tested included low-frequency (LF), middle-frequency (MF), high-frequency (HF), and pure-tone average (PTA). All three audiological parameters significantly decreased after surgery (P < 0.05) at every frequency, except for BC-LF (P > 0.05). There were also significant differences between the preoperative and postoperative proportions of degree of hearing (P < 0.05). Additionally, shifts in AC, BC, and ABG were linearly related to preoperative AC, BC, and ABG. Lastly, postoperative ABG-PTA presented differently depending on preoperative stapes superstructure conditions (present: 15.81 ± 11.23 dB, absent: 22.94 ± 12.20 dB, P = 0.009). CONCLUSIONS: Our study of endoscopic tympanoplasty and tympanomastoidectomy presented complete audiological outcomes for cholesteatoma patients. It had a positive surgery success rate and improved AC, BC, and ABG at every frequency except BC-LF. Additionally, AC-LF and AC-MF improved to a greater degree than AC-HF due to these procedures. Moreover, the linear regression analyses demonstrated that preoperative ABG-PTA was the most efficient audiological indicator for surgery. Likewise, the preoperative condition of the stapes superstructure was proved to be the most efficient anatomical indicator for hearing outcomes.

Regulating Charge Carrier Recombination in the Interconnecting Layer to Boost the Efficiency and Stability of Monolithic Perovskite/Organic Tandem Solar Cells.

The charge carriers of single-junction solar cells can be fluently extracted and then collected by electrodes, leading to weak charge carrier accumulation and low energy loss (Eloss ). However, in tandem solar cells (TSCs), it is a considerable challenge to obtain a balance between the densities of the holes and electrons extracted from the two respective subcells to facilitate an efficient recombination in the interconnecting layer (ICL). Herein, a charge-carrier-dynamic management strategy for inorganic perovskite/organic TSCs is proposed, centered on the simultaneous regulation of the defect states of CsPbI1.9 Br1.1 perovskite in the front subcell and hole transport ability from the perovskite to ICL. The target hole density on the perovskite surface and the hole loss before reaching the ICL are significantly improved. As a result, the hole/electron density offset in the ICL can be effectively narrowed, leading to a balanced charge carrier recombination, which reduces the Eloss in TSCs. The resulting inorganic perovskite/organic 0.062-cm2 TSC exhibits a remarkable power conversion efficiency (PCE) of 23.17% with an ultrahigh open-circuit voltage (Voc ) of 2.15 V, and the PCE of the 1.004-cm2 device (21.69%) exhibited a weak size-dependence. This charge-carrier-dynamic management strategy can also effectively enhance the operational and ultraviolet-light stabilities of the TSCs.

Efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) for Tinnitus: A Retrospective Study.

OBJECTIVE: Current studies still find insufficient evidence to support the routine use of repetitive transcranial magnetic stimulation (rTMS) in tinnitus. This study aimed to assess response of tinnitus to treatment with rTMS and identify factors influencing the overall response. METHODS: Between January 2016 and May 2017, 199 tinnitus patients were identified from a retrospective review of the electronic patient record at the Sun Yat-sen Memorial Hospital. All patients received rTMS treatment. Their clinicodemographic profile and outcomes, including the tinnitus handicap inventory (THI) and visual analog scale (VAS) scores, were extracted for analysis. RESULTS: Regarding the THI results, 62.3% of all patients responded to rTMS. The analysis of the VAS score revealed an overall response rate of 66.3%. Both percentages were close to the patient's subjective assessment result, of 63.8%. Patients with tinnitus of less than 1-week duration had the highest response rate to rTMS in terms of either THI/VAS scores or the patient's subjective assessment of symptoms. Tinnitus duration was recognized as a factor influencing the overall response to the treatment. CONCLUSIONS: Repetitive transcranial magnetic stimulation treatment is effective for patients with tinnitus, but its efficacy is affected by tinnitus duration. Tinnitus patients are advised to attend for rTMS as soon as possible since therapy was more effective in those with a shorter duration of disease of less than 1 week.

Organic-semiconductor-assisted dielectric screening effect for stable and efficient perovskite solar cells.

Perovskite solar cells (pero-SCs) performance is essentially limited by severe non-radiative losses and ion migration. Although numerous strategies have been proposed, challenges remain in the basic understanding of their origins. Here, we report a dielectric-screening-enhancement effect for perovskite defects by using organic semiconductors with finely tuned molecular structures from the atoms level. Our method produced various perovskite films with high dielectric constant values, reduced charge capture regions, suppressed ion migration, and it provides an efficient charge transport pathway for suppressing non-radiative recombination beyond the passivation effect. The resulting pero-SCs showed a promising power conversion efficiency (PCE) of 23.35% with a high open-circuit voltage (1.22 V); and the 1-cm2 pero-SCs maintained an excellent PCE (21.93%), showing feasibility for scalable fabrication. The robust operational and thermal stabilities revealed that this method paved a new way to understand the degradation mechanism of pero-SCs, promoting the efficiency, stability and scaled fabrication of the pero-SCs.

A comparative study of changes in audiological characteristics when using endoscopic and microscopic stapes surgery in patients with otosclerosis.

Background: Endoscopic stapes surgery (ESS) is widely used to treat patients with otosclerosis, and accumulating evidence demonstrates that endoscopic stapedotomy is feasible and has similar, and often even better, audiological outcomes compared with microscopic stapedotomy. There is a lack of studies on comparisons of ESS and the audiological outcomes of ESS and microscopic stapes surgery (MSS). Therefore, in the present study, we investigated these to figure out if ESS could be a reasonable alternative treatment for otosclerosis patients. Methods: This was a cohort study of 65 patients with otosclerosis who underwent ESS (n=30) or MSS (n=35) between 2017 and 2021, whose diagnoses were mainly based on a history of progressive conductive or mixed deafness over 25 dB in the range of 0.25-4 kHz. Preoperative and postoperative audiological evaluation, including air-conduction (AC), bone-conduction (BC) and air-bone gap (ABG), was carried out using pure-tone audiometry and performed within 4 weeks before surgery and from 1-14 months after surgery. Results: Thirty ESS and 35 MSS patients were included. There were no significant differences in preoperative and postoperative pure-tone average AC (AC-PTA), BC-PTA, and ABG-PTA between the 2 groups. Postoperative ABG ≤10 dB was found in 8 ESS patients (60%) and 15 MSS patients (43%) (P=0.168). AC and ABG changes in the low-frequency (LF) and mid-frequency (MF) ranges were greater than those in the high-frequency (HF) range for both groups (P<0.05). Although auditory changes between the 2 groups were similar, MSS appeared to have a better BC-PTA compared with ESS (P=0.049). Shifts in ABG and BC were linearly related to preoperative ABG and BC in both groups, and shifts in AC were linearly related to preoperative AC in the ESS group (P<0.05). Conclusions: ESS had a similar audiological outcome compared with MSS, and LF and MF hearing improved to a greater degree than HF hearing in both groups in our study. Based on the linear regression analysis in our study, preoperative ABG-PTA was proved to be the most efficient surgical indicator for both types of stapes surgery for patients with otosclerosis.

Audiological characteristics and effect of endoscopic surgery for simple congenital malformation of ossicular chain.

OBJECTIVE: To analyze the audiological characteristics and surgical results in patients undergoing surgery for simple congenital ossicular chain malformation, and the effect of endoscopic surgery. METHODS: A retrospective review was performed on 86 patients who underwent surgery for the congenital malformation of the ossicular chain. Clinical characteristics and audiometric data were analyzed. Fifty-eight patients had detailed postoperative data, and the preoperative and postoperative audiometric results were compared. The subjects were further divided into endoscopic and microscopic groups, and their surgical effects were examined. RESULTS: The preoperative audiometry results in the low-frequency group were worse than those in the high-frequency group (P < 0.05). A postoperative air-bone gap closure to 20 dB or less was achieved in 73.33% of the 60 ears of patients postoperatively. The postoperative air conduction and air-bone gap were significantly better than the preoperative ones (P < 0.05), and the improvement effect was the best in class III patients (P < 0.05). Postoperative hearing had no significant differences between the endoscopic and microscopic groups. However, endoscopic surgery also was more advantageous in terms of operating time (P < 0.05). CONCLUSIONS: Preoperative pure tone audiometric results showed moderate or moderate-severe hearing loss, especially in the low-frequency area. The reconstruction of the auditory ossicle chain can achieve satisfactory results, especially in class III patients. Endoscopic and microscopic surgery in the treatment of simple congenital ossicular chain malformations can effectively improve postoperative hearing.

Regulation of ACSL4-Catalyzed Lipid Peroxidation Process Resists Cisplatin Ototoxicity.

Cisplatin-induced ototoxicity is one of the common side effects during its treatment and there are no effective measures to prevent it. Our study aimed to investigate the effect of ACSL4-catalyzed lipid peroxidation on cisplatin-induced hearing loss and its possible protective mechanisms. We used a variety of cisplatin ototoxicity models, including HEI-OC1 cell line, cochlear explants, and ET4 GFP+ zebrafish. After measuring the experimental concentrations of cisplatin by CCK8 assay and immunofluorescence, respectively, we examined the levels of lipid peroxidation by MDA content, 4-HNE content, and C11-BODIPY (581/591) probe. Then, we used two ferroptosis inhibitors, FER-1, and Vit-E to protect hair cells. We found that cisplatin significantly increased the levels of lipid peroxidation and that this process can be resisted by the ferroptosis inhibitors. Afterwards, we performed metabolomic assays on the cisplatin-treated hair cells. The metabolite levels were significantly altered in the experimental group compared to the control group, and the highest degree of change was observed in the glutathione metabolic pathway and the arachidonic acid metabolic pathway. Therefore, we screened the key enzymes on the arachidonic acid metabolic pathway in the hair cells after cisplatin treatment and found that ACSL4 had the greatest regulatory value. Further, we reduced the level of lipid peroxide in hair cells by specifically inhibiting the expression of ACSL4, which protected hair cells from cisplatin damage at source. In conclusion, the lipid peroxidation process regulated by ACSL4 may be an important factor contributing to the sensitivity of hair cells to cisplatin. Inhibition of ACSL4 expression may be an effective preventive measure against cisplatin ototoxicity.

Asymmetric total synthesis of (+)-(2R,4'R,8'R)-α-tocopherol enabled by enzymatic desymmetrization.

A new and highly stereoselective synthesis of chiral diol (S)-14, the common synthetic intermediate to (+)-(2R,4'R,8'R)-α-tocopherol (1), was accomplished in seven steps with 13.8% overall yield. This developed route featured a lipase-catalyzed desymmetric hydrolysis of prochiral diester 39a, which was prepared through a challenging Heck coupling, to chiral quaternary carbon-containing monoester (R)-37a of the correct configuration in 81% yield and 96.7% ee, to the best of our knowledge, leading to the most efficient enzymatic desymmetric synthesis of the chiral chroman skeleton of vitamin E members reported to date. Coupled with the modified preparation of the phytol-derived side chain, the chemoenzymatic total synthesis of 1 was completed in 15 longest linear steps with 3.1% overall yield.

Nitric oxide protects against cochlear hair cell damage and noise-induced hearing loss through glucose metabolic reprogramming.

Nitric oxide (NO) is critically involved in the regulation of a wide variety of physiological and pathophysiological processes. However, the role of NO in the pathogenesis of noise-induced hearing loss (NIHL) is complex and remains controversial. Here we reported that treatment of CBA/J mice with l-arginine, a physiological precursor of NO, significantly reduced noise-induced reactive oxygen species accumulation in outer hair cells (OHCs), attenuated noise-induced loss of OHCs and NIHL consequently. Conversely, pharmacological inhibition of endothelial nitric oxide synthase exacerbated noise-induced loss of OHCs and aggravated NIHL. In HEI-OC1 cells, NO also showed substantial protection against H2O2-induced oxidative stress and cytotoxicity. Mechanistically, NO increased S-nitrosylation of pyruvate kinase M2 (PKM2) and inhibited its activity, which thus diverted glucose metabolic flux from glycolysis into the pentose phosphate pathway to increase production of reducing equivalents (NADPH and GSH) and eventually prevented H2O2-induced oxidative damage. These findings open new avenues for protection of cochlear hair cells from oxidative stress and prevention of NIHL through NO modulation of PKM2 and glucose metabolism reprogramming.

Development and validation of a novel ferroptosis-related gene signature for predicting prognosis and immune microenvironment in head and neck squamous cell carcinoma.

Ferroptosis plays an important role across variable cancer types. However, few studies have focused on the prognostic patterns of ferroptosis-related genes in HNSCC. Cohorts with mRNA expression profiles, as well as corresponding clinical data of HNSCC patients from published studies, were collected and consolidated from public databases. We performed random survival forest analysis, Kaplan-Meier (KM) analysis of best combinations, and Cox regression analysis on 231 ferroptosis-related genes to construct a gene signature in the discovery cohort (TCGA), and later validated it in the validation cohort (GEO). The 7-gene signature was constructed to stratify patients into two groups according to their level of risk. Poorer overall survival (OS) was detected in the high risk (HRisk) group than in the low risk (LRisk) group in both the TCGA cohort (P < 0.0001, HR = 1.71, 95%CI:1.41-2.07) and the GEO cohort (P < 0.001, HR = 1.68, 95%CI:1.32-2.13). The risk score was identified as an independent predictive factor of OS in multivariate Cox regression analyses (HR > 1, P < 0.0001) in both cohorts. The signature's predictive capacity was proven by the time-dependent receiver operating characteristic (ROC) curve analysis and nomogram analysis. Functional enrichment analysis revealed that immunosuppressive pathways such as matrix extracellular space, and (transforming growth factor-ß)TGF-ß were enriched. The HRisk group was strongly associated with upregulation of both cancer-related pathways and stromal scores, while higher proportions of anti-tumor immune cells and immune signatures were enriched in the LRisk group. In conclusion, the signature based on 7 ferroptosis-related genes could be applicable for predicting the prognosis of HNSCC, indicating that ferroptosis may be a potential therapeutic target for HNSCC.

Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity.

Cisplatin, the most widely used platinum-based anticancer drug, often causes progressive and irreversible sensorineural hearing loss in cancer patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reducing hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect on hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.