Excessive processing and acetylation of OPA1 aggravate age-related hearing loss via the dysregulation of mitochondrial dynamics.

The pathogenesis of age-related hearing loss (ARHL) remains unclear. OPA1 is the sole fusion protein currently known to be situated in the inner mitochondrial membrane, which is pivotal for maintaining normal mitochondrial function. While it has already been demonstrated that mutations in OPA1 may lead to hereditary deafness, its involvement in the occurrence and development of ARHL has not been previously explored. In our study, we constructed D-gal-induced senescent HEI-OC1 cells and the cochlea of C57BL/6J mice with a mutated SUMOylation site of SIRT3 using CRISPR/Cas9 technology. We found enhanced L-OPA1 processing mediated by activated OMA1, and increased OPA1 acetylation resulting from reductions in SIRT3 levels in senescent HEI-OC1 cells. Consequently, the fusion function of OPA1 was inhibited, leading to mitochondrial fission and pyroptosis in hair cells, ultimately exacerbating the aging process of hair cells. Our results suggest that the dysregulation of mitochondrial dynamics in cochlear hair cells in aged mice can be ameliorated by activating the SIRT3/OPA1 signaling. This has the potential to alleviate the senescence of cochlear hair cells and reduce hearing loss in mice. Our study highlights the significant roles played by the quantities of long and short chains and the acetylation activity of OPA1 in the occurrence and development of ARHL. This finding offers new perspectives and potential targets for the prevention and treatment of ARHL.

Enhancing prognostic accuracy in head and neck squamous cell carcinoma chemotherapy via a lipid metabolism-related clustered polygenic model.

OBJECTIVE: Systemic chemotherapy is the first-line therapeutic option for head and neck squamous cell carcinoma (HNSCC), but it often fails. This study aimed to develop an effective prognostic model for evaluating the therapeutic effects of systemic chemotherapy. METHODS: This study utilized CRISPR/cas9 whole gene loss-of-function library screening and data from The Cancer Genome Atlas (TCGA) HNSCC patients who have undergone systemic therapy to examine differentially expressed genes (DEGs). A lipid metabolism-related clustered polygenic model called the lipid metabolism related score (LMRS) model was established based on the identified functionally enriched DEGs. The prediction efficiency of the model for survival outcome, chemotherapy, and immunotherapy response was evaluated using HNSCC datasets, the GEO database and clinical samples. RESULTS: Screening results from the study demonstrated that genes those were differentially expressed were highly associated with lipid metabolism-related pathways, and patients receiving systemic therapy had significantly different prognoses based on lipid metabolism gene characteristics. The LMRS model, consisting of eight lipid metabolism-related genes, outperformed each lipid metabolism gene-based model in predicting outcome and drug response. Further validation of the LMRS model in HNSCCs confirmed its prognostic value. CONCLUSION: In conclusion, the LMRS polygenic prognostic model is helpful to assess outcome and drug response for HNSCCs and could assist in the timely selection of the appropriate treatment for HNSCC patients. This study provides important insights for improving systemic chemotherapy and enhancing patient outcomes.

Spatio-temporal pattern of c-Jun N-terminal kinase isoforms in the cochleae of C57BL/6J mice with presbycusis.

The c-Jun N-terminal kinase (JNK) pathway is a vital component of the mitogen-activated protein kinase cascade, which regulates cell death and survival. The present study aimed to explore the Spatio-temporal changes in all JNK isoforms in the cochleae of C57/BL6J mice with age-related hearing loss. Changes in the three isoforms of JNKs in the cochleae of an animal model with presbycusis and the senescent HEI-OC1 cell line were tested by immunohistochemistry staining and western blotting. Our results demonstrated that all three JNK isoforms are distributed in the cochleae, and the expression patterns of JNK1, JNK2, and JNK3 differed in hair cells, spiral ganglion neurons, and stria vascularis, with great significance in the cochleae of adult C57BL/6J mice. The levels of JNK1, JNK2, and JNK3 showed various spatio-temporal changes in the aging mice. In a senescent hair cell model, changes in JNK1, JNK2, and JNK3 expression levels were similar to those observed in the cochleae. Our study is the first to show that JNK3 is highly expressed in the hair cells of C57BL/6J mice and further increases in conjunction with age-related hearing loss, suggesting that it may play a more critical role than previously believed in hair cell loss and spiral ganglion degeneration.

Impact of cholesterol homeostasis within cochlear cells on auditory development and hearing loss.

Cholesterol is the most abundant sterol molecule in mammalian cells, which not only constitutes the cell membrane but also plays essential roles in the synthesis of important hormones, synapse formation, and cell signal transduction. The effect of hypercholesterolemia on hearing has been studied extensively, and multiple studies have demonstrated that hypercholesterolemia is a risk factor for hearing loss. However, the impact of cholesterol homeostasis within auditory cells on peripheral auditory development and maintenance has not been evaluated in detail. Mutations in certain cholesterol metabolism-related genes, such as NPC1, SERAC1, DHCR7, and OSBPL2, as well as derivatives of cholesterol metabolism-related ototoxic drugs, such as ß-cyclodextrin, can lead to disruptions of cholesterol homeostasis within auditory cells, resulting in hearing loss. This article aims to review the impact of cholesterol homeostasis within auditory cells on the peripheral auditory function from the following two perspectives: (1) changes in cholesterol homeostasis regulatory genes in various hearing loss models; (2) mechanisms underlying the effects of some drugs that have a therapeutic effect on hearing loss via regulating cholesterol homeostasis. This article aims to summarize and analyze the impact of disruption of cellular cholesterol homeostasis within auditory cells on hearing, in order to provide evidence regarding the underlying mechanisms.

Perspectives of lipid metabolism reprogramming in head and neck squamous cell carcinoma: An overview.

Recent studies showed that lipid metabolism reprogramming contributes to tumorigenicity and malignancy by interfering energy production, membrane formation, and signal transduction in cancers. HNSCCs are highly reliant on aerobic glycolysis and glutamine metabolism. However, the mechanisms underlying lipid metabolism reprogramming in HNSCCs remains obscure. The present review summarizes and discusses the "vital" cellular signaling roles of the lipid metabolism reprogramming in HNSCCs. We also address the differences between HNSCCs regions caused by anatomical heterogeneity. We enumerate these recent findings into our current understanding of lipid metabolism reprogramming in HNSCCs and introduce the new and exciting therapeutic implications of targeting the lipid metabolism.

The influence of metabolic syndrome on age-related hearing loss from the perspective of mitochondrial dysfunction.

With the increase in life expectancy in the global population, aging societies have emerged in many countries, including China. As a common sensory defect in the elderly population, the prevalence of age-related hearing loss and its influence on society are increasing yearly. Metabolic syndrome is currently one of the main health problems in the world. Many studies have demonstrated that metabolic syndrome and its components are correlated with a variety of age-related diseases of the peripheral sensory system, including age-related hearing loss. Both age-related hearing loss and metabolic syndrome are high-prevalence chronic diseases, and many people suffer from both at the same time. In recent years, more and more studies have found that mitochondrial dysfunction occurs in both metabolic syndrome and age-related hearing loss. Therefore, to better understand the impact of metabolic syndrome on age-related hearing loss from the perspective of mitochondrial dysfunction, we reviewed the literature related to the relationship between age-related hearing loss and metabolic syndrome and their components to discern the possible role of mitochondria in both conditions.

Tlr2/4 Double Knockout Attenuates the Degeneration of Primary Auditory Neurons: Potential Mechanisms From Transcriptomic Perspectives.

The transcriptomic landscape of mice with primary auditory neurons degeneration (PAND) indicates key pathways in its pathogenesis, including complement cascades, immune responses, tumor necrosis factor (TNF) signaling pathway, and cytokine-cytokine receptor interaction. Toll-like receptors (TLRs) are important immune and inflammatory molecules that have been shown to disrupt the disease network of PAND. In a PAND model involving administration of kanamycin combined with furosemide to destroy cochlear hair cells, Tlr 2/4 double knockout (DKO) mice had auditory preservation advantages, which were mainly manifested at 4-16 kHz. DKO mice and wild type (WT) mice had completely damaged cochlear hair cells on the 30th day, but the density of spiral ganglion neurons (SGN) in the Rosenthal canal was significantly higher in the DKO group than in the WT group. The results of immunohistochemistry for p38 and p65 showed that the attenuation of SGN degeneration in DKO mice may not be mediated by canonical Tlr signaling pathways. The SGN transcriptome of DKO and WT mice indicated that there was an inverted gene set enrichment relationship between their different transcriptomes and the SGN degeneration transcriptome, which is consistent with the morphology results. Core module analysis suggested that DKO mice may modulate SGN degeneration by activating two clusters, and the involved molecules include EGF, STAT3, CALB2, LOX, SNAP25, CAV2, SDC4, MYL1, NCS1, PVALB, TPM4, and TMOD4.

Efficient One-Step Biocatalytic Multienzyme Cascade Strategy for Direct Conversion of Phytosterol to C-17-Hydroxylated Steroids.

Steroidal 17-carbonyl reduction is crucial to the production of natural bioactive steroid medicines, and boldenone (BD) is one of the important C-17-hydroxylated steroids. Although efforts have been made to produce BD through biotransformation, the challenges of the complex transformation process, high substrate costs, and low catalytic efficiencies have yet to be mastered. Phytosterol (PS) is the most widely accepted substrate for the production of steroid medicines due to its similar foundational structure and ubiquitous sources. 17ß-Hydroxysteroid dehydrogenase (17ßHSD) and its native electron donor play significant roles in the 17ß-carbonyl reduction reaction of steroids. In this study, we bridged 17ßHSD with a cofactor regeneration strategy in Mycobacterium neoaurum to establish a one-step biocatalytic carbonyl reduction strategy for the efficient biosynthesis of BD from PS for the first time. After investigating different intracellular electron transfer strategies, we rationally designed the engineered strain with the coexpression of 17ßhsd and the glucose-6-phosphate dehydrogenase (G6PDH) gene in M. neoaurum. With the establishment of an intracellular cofactor regeneration strategy, the ratio of [NADPH]/[NADP+] was maintained at a relatively high level, the yield of BD increased from 17% (in MNR M3M-ayr1S.c) to 78% (in MNR M3M-ayr1&g6p with glucose supplementation), and the productivity was increased by 6.5-fold. Furthermore, under optimal glucose supplementation conditions, the yield of BD reached 82%, which is the highest yield reported for transformation from PS in one step. This study demonstrated an excellent strategy for the production of many other valuable carbonyl reduction steroidal products from natural inexpensive raw materials. IMPORTANCE Steroid C-17-carbonyl reduction is one of the important transformations for the production of valuable steroidal medicines or intermediates for the further synthesis of steroidal medicines, but it remains a challenge through either chemical or biological synthesis. Phytosterol can be obtained from low-cost residues of waste natural materials, and it is preferred as the economical and applicable substrate for steroid medicine production by Mycobacterium. This study explored a green and efficient one-step biocatalytic carbonyl reduction strategy for the direct conversion of phytosterol to C-17-hydroxylated steroids by bridging 17ß-hydroxysteroid dehydrogenase with a cofactor regeneration strategy in Mycobacterium neoaurum. This work has practical value for the production of many valuable hydroxylated steroids from natural inexpensive raw materials.

[Perinatal antibiotics exposure causes increase in serum 5-hydroxytryptamine level as well as changes in behavior and gastrointestinal motility in the male offspring in mice].

The current study was aimed to investigate the potential effects of perinatal exposure to therapeutic dose of penicillin and cefixime on the cognitive behaviors, gastrointestinal (GI) motility and serum 5-hydroxytryptamine (5-HT) level in the offspring. Pregnant rats were continuously treated with cefixime or penicillin in the period between 1 week before and 1 week after labor. Behavior tests, including social preference, self-grooming and elevated plus maze tests, and intestinal motility tests were carried out on the offspring at age of 4 to 10 weeks. Serum 5-HT levels were detected with ELISA, and potassium/sodium hyperpolarization activated cyclic nucleotide-gated channel 2 (HCN2) and tryptophan hydroxylase 1 (TPH1) expression levels in colon epithelium of offspring were detected by Western blot and RT-qPCR. The results showed that, compared with the naive group, cefixime increased social behavior in the female offspring, but did not affect the male offspring. Compared with the naive group, cefixime significantly decreased colonic and intestinal transits, and increased cecum net weight and standardized cecum net weight in the male offspring, but did not affect the female offspring. The serum 5-HT levels in the male offspring, rather than the female offspring, in cefixime and penicillin groups were significantly increased compared with that in the naive group. The protein expression level of HCN2 in colon epithelium of the offspring in cefixime group was significantly down-regulated, and the TPH1 expression level was not significantly changed, compared with that in the naive group. These results suggest that perinatal antibiotics exposure may affect neural development and GI functions of the offspring, and the mechanism may involve peripheral 5-HT and gender-dependent factor.

Antibiotic supplement in feed can perturb the intestinal microbial composition and function in Pacific white shrimp.

The intestinal microbiota plays crucial roles in host health. The Pacific white shrimp is one of the most profitable aquaculture species in the world. Antibiotic supplement in feed is an optional practice to treat shrimp bacterial diseases. However, little is known about antibiotic effects on intestinal microbiota in pacific white shrimp. Here, shrimps were given feed supplemented with ciprofloxacin (Cip) (40 and 80 mg kg-1) and sulfonamide (Sul) (200 and 400 mg kg-1) to investigate the microbial community by targeting the V4 region of 16S rRNA genes. Within 4 days after feeding with normal feed and with antibiotics, antibiotic concentrations of Cip and Sul groups in the intestine dropped sharply. Significantly, increased abundance of antibiotic resistance genes (ARGs) of ciprofloxacin (qnrB, qnrD, and qnrS) and sulfonamide (sul1, sul2, and sul3) was observed in Cip and Sul groups (P < 0.05). A total of 3191 operational taxonomic units (OTUs) were obtained and 41 phyla were identified from 63 samples in shrimp intestine. The numbers of OTUs and Shannon index decreased rapidly at day 1 (the first day after feeding with antibiotics) and increased at day 3 (the third day after feeding with antibiotics). The relative abundance of dominant phyla and genera in Cip and Sul groups were significantly different from that in the control group (Ctrl). Furthermore, functional potentials that were related to amino acid metabolism, carbohydrate metabolism, and cellular processes and signaling varied significantly in Cip and Sul groups. These results point to an antibiotic-induced shift in shrimp intestinal microbiota, which highlights the importance of considering the microbiota in shrimp health management.