Rodent models in sensorineural hearing loss research: A comprehensive review.

Sensorineural hearing loss (SNHL) constitutes a major global health challenge, affecting millions of individuals and substantially impairing social integration and quality of life. The complexity of the auditory system and the multifaceted nature of SNHL necessitate advanced methodologies to understand its etiology, progression, and potential therapeutic interventions. This review provides a comprehensive overview of the current animal models used in SNHL research, focusing on their selection based on specific characteristics and their contributions to elucidating pathophysiological mechanisms and evaluating novel treatment strategies. It discusses the most commonly used rodent models in hearing research, including mice, rats, guinea pigs, Mongolian gerbils, and chinchillas. Through a comparative analysis, this review underscores the importance of selecting models that align with specific research objectives in SNHL studies, discussing the advantages and limitations of each model. By advocating for a multidisciplinary approach that leverages the strengths of various animal models with technological advancements, this review aims to facilitate significant advancements in the prevention, diagnosis, and treatment of sensorineural hearing loss.

Ototoxicity-Alleviating and Cytoprotective Allomelanin Nanomedicine for Efficient Sensorineural Hearing Loss Treatment.

Sensorineural hearing loss (SNHL) represents a significant clinical challenge, predominantly attributed to oxidative stress-related mechanisms. In this work, we report an innovative antioxidant strategy for mitigating SNHL, utilizing synthetically engineered allomelanin nanoparticles (AMNPs). Empirical evidence elucidates AMNPs' profound capability in free radical neutralization, substantiated by a significant decrement in reactive oxygen species (ROS) levels within HEI-OC1 auditory cells exposure to cisplatin or hydrogen peroxide (H2O2). Comparative analyses reveal that AMNPs afford protection against cisplatin-induced and noise-induced auditory impairments, mirroring the effect of dexamethasone (DEX), a standard pharmacological treatment for acute SNHL. AMNPs exhibit notable cytoprotective properties for auditory hair cells (HCs), effectively preventing ototoxicity from cisplatin or H2O2 exposure, as confirmed by both in vitro assays and cultured organ of Corti studies. Further in vivo research corroborates AMNPs' ability to reverse auditory brainstem response (ABR) threshold shifts resulting from acoustic injury, concurrently reducing HCs loss, ribbon synapse depletion, and spiral ganglion neuron degeneration. The therapeutic benefits of AMNPs are attributed to mitigating oxidative stress and inflammation within the cochlea, with transcriptome analysis indicating downregulated gene expression related to these processes post-AMNPs treatment. The pronounced antioxidative and anti-inflammatory effects of AMNPs position them as a promising alternative to DEX for SNHL treatment.

A dual-pathway pyroptosis inducer based on Au-Cu2-xSe@ZIF-8 enhances tumor immunotherapy by disrupting the zinc ion homeostasis.

The regulation of intracellular ionic homeostasis to trigger antigen-specific immune responses has attracted extensive interest in tumor therapy. In this study, we developed a dual-pathway nanoreactor, Au-Cu2-xSe@ZIF-8@P18 NPs (ACS-Z-P NPs), which targets danger-associated molecular patterns (DAMPs) and releases Zn2+ and reactive oxygen species (ROS) within the tumor microenvironment (TME). Zn2+ released from the metal-organic frameworks (MOFs) was deposited in the cytoplasm, leading to aberrant transcription levels of intracellular zinc-regulated proteins and DNA damage, thereby inducing pyroptosis and immunogenic cell death (ICD) dependent on caspase1/gasdermin D (GSDMD) pathway. Furthermore, upon laser irradiation, ACS-Z-P NPs could break through the limitations of inherent defects of immunosuppression in TME, enhance ROS generation through a Fenton-like reaction cascade, which subsequently triggered the activation of inflammatory vesicles and the release of damage-associated molecular patterns (DAMPs). This cascade effect led to the amplification of pyroptosis and immunogenic cell death (ICD), thereby remodeling the immunosuppressed TME. Consequently, this process improved dendritic cell (DC) antigen presentation and augmented anti-tumor T-cell responses, effectively initiating antigen-specific immune responses and further enhancing pyroptosis and ICD. This study explores the therapeutic properties of these mechanisms in detail. STATEMENT OF SIGNIFICANCE: The synthesized Au-Cu2-xSe@ZIF-8@P18 nanoparticles (ACS-Z-Ps) can effectively enhance the body's immune response by regulating zinc ion levels within cells. This regulation leads to abnormal levels of zinc-regulated protein transcription and DNA damage, which induces cellular pyroptosis. As a result, antigen presentation to dendritic cells (DCs) is improved, and anti-tumor T-cell responses are enhanced. The ACS-Z-P NPs overcome the limitations of ROS deficiency and immunosuppression in the tumor microenvironment by using H2O2 in the tumor microenvironment through a Fenton-like reaction. This leads to an increased production of ROS and O2, remodeling of the immunosuppressed tumor microenvironment, and enhanced induction of cell pyroptosis and immunogenic cell death. ACS-Z-P NPs targeted B16 cells using the photosensitizer P18 in combination with PDT treatment. This approach significantly inhibited the proliferation of B16 cells and effectively inhibited tumor growth.

Solid-state electron-mediated z-scheme heterostructured semiconductor nanomaterials induce dual programmed cell death for melanoma therapy.

The programmed cell death (PCD) pathway removes functionally insignificant, infection-prone, or potentially tumorigenic cells, underscoring its important role in maintaining the stability of the internal environment and warding off cancer and a host of other diseases. PCD includes various forms, such as apoptosis, copper death, iron death, and cellular pyroptosis. However, emerging solid-state electron-mediated Z-scheme heterostructured semiconductor nanomaterials with high electron-hole (e-h+) separation as a new method for inducing PCD have not been well studied. We synthesize the Bi2S3-Bi2O3-Au-PEG nanorods (BB-A-P NRs) Z-scheme heterostructured semiconductor has a higher redox capacity and biocompatibility. Firstly, the BB-A-P NRs are excited by near-infrared (NIR) light, which mimics the action of catalase by supplying oxygen (O2) and converting it to a single-linear state of oxygen (1O2) via e-h+ transfer. Secondly, they react with hydrogen peroxide (H2O2) and water (H2O) in tumor to produce hydroxyl radicals (•OH), inducing apoptosis. Intriguingly, the Caspase-1/Gasdermin D (GSDMD)-dependent conventional pyroptosis pathway induced cellular pyroptosis activated by apoptosis and reactive oxygen species (ROS) which causes the intense release of damage associated molecular patterns (DAMPs), leading to the inflammatory death of tumor cells. This, in turn, activates the immunological environment to achieve immunogenic cell death (ICD). BB-A-P enables computed tomography imaging, which allows for visualization of the treatment. BB-A-P activated dual PCD can be viewed as an effective mode of cell death that coordinates the intracellular environment, and the various pathways are interrelated and mutually reinforcing which shows promising therapeutic effects and provides a new strategy for eliminating anoxic tumors.

Emergence of Debye Scaling in the Density of States of Liquids under Nanoconfinement.

In the realm of nanoscience, the dynamic behaviors of liquids at scales beyond the conventional structural relaxation time, τ, unfold a fascinating blend of solid-like characteristics, including the propagation of collective shear waves and the emergence of elasticity. However, in classical bulk liquids, where τ is typically of the order of 1 ps or less, this solid-like behavior remains elusive in the low-frequency region of the density of states (DOS). Here, we provide evidence for the emergent solid-like nature of liquids at short distances through inelastic neutron scattering measurements of the low-frequency DOS in liquid water and glycerol confined within graphene oxide membranes. In particular, upon increasing the strength of confinement, we observe a transition from a liquid-like DOS (linear in the frequency ω) to a solid-like behavior (Debye law, ∼ω2) in the range of 1-4 meV. Molecular dynamics simulations confirm these findings and reveal additional solid-like features, including propagating collective shear waves and a reduction in the self-diffusion constant. Finally, we show that the onset of solid-like dynamics is pushed toward low frequency along with the slowing-down of the relaxation processes upon confinement. This nanoconfinement-induced transition, aligning with k-gap theory, underscores the potential of leveraging liquid nanoconfinement in advancing nanoscale science and technology, building more connections between fluid dynamics and materials engineering.

Strong interlayer magnetic exchange coupling in La3Ni2O7-δ revealed by inelastic neutron scattering.

After several decades of studies of high-temperature superconductivity, there is no compelling theory for the mechanism yet; however, the spin fluctuations have been widely believed to play a crucial role in forming the superconducting Cooper pairs. The recent discovery of high-temperature superconductivity near 80 K in the bilayer nickelate La3Ni2O7 under pressure provides a new platform to elucidate the origins of high-temperature superconductivity. We perform elastic and inelastic neutron scattering studies on a polycrystalline sample of La3Ni2O7-δ at ambient pressure. No magnetic order can be identified down to 10 K. The absence of long-range magnetic order in neutron diffraction measurements may be ascribed to the smallness of the magnetic moment. However, we observe a weak flat spin-fluctuation signal in the inelastic scattering spectra at ∼ 45 meV. The observed spin excitations could be interpreted as a result of strong interlayer and weak intralayer magnetic couplings for stripe-type antiferromagnetic orders. Our results provide crucial information on the spin dynamics and are thus important for understanding the superconductivity in La3Ni2O7.

On the temperature dependence of the density of states of liquids at low energies.

We report neutron-scattering measurements of the density of states (DOS) of water and liquid Fomblin in a wide range of temperatures. In the liquid phase, we confirm the presence of a universal low-energy linear scaling of the experimental DOS as a function of the frequency, g ( ω ) = a ( T ) ω , which persists at all temperatures. The low-frequency scaling of the DOS exhibits a sharp jump at the melting point of water, below which the standard Debye's law, g ( ω ) ∝ ω 2 , is recovered. On the contrary, in Fomblin, we observe a continuous transition between the two exponents reflecting its glassy dynamics, which is confirmed by structure measurements. More importantly, in both systems, we find that the slope a(T) grows with temperature following an exponential Arrhenius-like form, a ( T ) ∝ exp ( - ⟨ E ⟩ / T ) . We confirm this experimental trend using molecular dynamics simulations and show that the prediction of instantaneous normal mode (INM) theory for a(T) is in qualitative agreement with the experimental data.

A noble metal-enhanced Au@CuO heterostructure with multienzyme-mimicking activities for colorimetric detection of tannic acid.

Nanozymes, serving as synthetic alternatives to natural enzymes, offer several benefits including cost-effectiveness, enzyme-like catalytic abilities, enhanced stability, adjustable catalytic activity, easy recyclability, mild reaction conditions, and environmental friendliness. Nonetheless, the ongoing quest to develop nanozymes with enhanced activity and to delve into the catalytic mechanism remains a challenge. In our research, we effectively developed Au@CuO nanocomposites (Au@CuO Nc), replicating the functions of four enzymes found in nature: peroxidase (POD), catalase (CAT), glutathione peroxidase (GPx), and oxidase (OXD). The catalytic efficiency of Au@CuO Nc for TMB oxidation (oxTMB) was approximately 4.8 times greater than that of plain Cu2O cubes, attributed to the synergistic catalytic impact between the Au element and Cu2O within Au@CuO Nc. Mechanistic studies revealed that the novel Au@CuO Nc nanozyme greatly enhances the decomposition of H2O2 to reactive oxygen species (ROS) intermediates (˙OH, ˙O2- and 1O2), resulting in increased POD-like activity of the single-component Cu2O cubes. When an antioxidant like TA was added to the chromogenic system, it converted oxTMB into a colorless form of TMB, enabling further evaluation of TA. Hence, a colorimetric sensor was developed for the rapid and precise quantitative measurement of TA, demonstrating strong linearity between 0.3 and 2.4 µM and featuring a low detection threshold of 0.25 µM. Moreover, this sensor was effectively utilized for the assessment of TA in actual tea samples. This work innovatively proposes a simplified and reliable strategy for the advanced design of highly effective Cu-based nanozymes, enhancing enzyme-like reactions for simultaneous, on-site colorimetric probing of antioxidants.

Sonosynthetic Cyanobacteria Oxygenation for Self-Enhanced Tumor-Specific Treatment.

Photosynthesis, essential for life on earth, sustains diverse processes by providing nutrition in plants and microorganisms. Especially, photosynthesis is increasingly applied in disease treatments, but its efficacy is substantially limited by the well-known low penetration depth of external light. Here, ultrasound-mediated photosynthesis is reported for enhanced sonodynamic tumor therapy using organic sonoafterglow (ultrasound-induced afterglow) nanoparticles combined with cyanobacteria, demonstrating the proof-of-concept sonosynthesis (sonoafterglow-induced photosynthesis) in cancer therapy. Chlorin e6, a typical small-molecule chlorine, is formulated into nanoparticles to stimulate cyanobacteria for sonosynthesis, which serves three roles, i.e., overcoming the tissue-penetration limitations of external light sources, reducing hypoxia, and acting as a sonosensitizer for in vivo tumor suppression. Furthermore, sonosynthetic oxygenation suppresses the expression of hypoxia-inducible factor 1α, leading to reduced stability of downstream SLC7A11 mRNA, which results in glutathione depletion and inactivation of glutathione peroxidase 4, thereby inducing ferroptosis of cancer cells. This study not only broadens the scope of microbial nanomedicine but also offers a distinct direction for sonosynthesis.

Genetic Engineering Bacillus thuringiensis Enable Melanin Biosynthesis for Anti-Tumor and Anti-Inflammation.

Collaboration between cancer treatment and inflammation management has emerged as an integral facet of comprehensive cancer care. Nevertheless, the development of interventions concurrently targeting both inflammation and cancer has encountered significant challenges stemming from various external factors. Herein, a bioactive agent synthesized by genetically engineering melanin-producing Bacillus thuringiensis (B. thuringiensis) bacteria, simultaneously achieves eco-friendly photothermal agent and efficient reactive oxygen/nitrogen species (RONS) scavenger benefits, perfectly tackling present toughies from inflammation to cancer therapies. The biologically derived melanin exhibits exceptional photothermal-conversion performance, facilitating potent photonic hyperthermia that effectively eradicates tumor cells and tissues, thereby impeding tumor growth. Additionally, the RONS-scavenging properties of melanin produced by B. thuringiensis bacteria contribute to inflammation reduction, augmenting the efficacy of photothermal tumor repression. This study presents a representative paradigm of genetic engineering in B. thuringiensis bacteria to produce functional agents tailored for diverse biomedical applications, encompassing inflammation and cancer therapy.

Mfsd2a regulates the blood-labyrinth-barrier formation and function through tight junctions and transcytosis.

The Blood-Labyrinth Barrier (BLB) is pivotal for the maintenance of lymphatic homeostasis within the inner ear, yet the intricacies of its development and function are inadequately understood. The present investigation delves into the contribution of the Mfsd2a molecule, integral to the structural and functional integrity of the Blood-Brain Barrier (BBB), to the ontogeny and sustenance of the BLB. Our empirical findings delineate that the maturation of the BLB in murine models is not realized until approximately two weeks post-birth, with preceding stages characterized by notable permeability. Transcriptomic analysis elucidates a marked augmentation in Mfsd2a expression within the lateral wall of the cochlea in specimens exhibiting an intact BLB. Moreover, both in vitro and in vivo assays substantiate that a diminution in Mfsd2a expression detrimentally impacts BLB permeability and structural integrity, principally via the attenuation of tight junction protein expression and the enhancement of endothelial cell transcytosis. These insights underscore the indispensable role of Mfsd2a in ensuring BLB integrity and propose it as a viable target for therapeutic interventions aimed at the amelioration of hearing loss.

Evaluating the quality of home care in community health service centres: A machine learning approach.

AIMS: The aim of the study is to develop a model using a machine learning approach that can effectively identify the quality of home care in communities. DESIGN: A cross-sectional design. METHODS: In this study, we evaluated the quality of home care in 170 community health service centres between October 2022 and February 2023. The Home Care Service Quality Questionnaire was used to collect information on home care structure, process and outcome quality. Then, an intelligent and comprehensive evaluation model was developed using a convolutional neural network, and its performance was compared with random forest and logistic regression models through various performance indicators. RESULTS: The convolutional neural network model was built upon seven variables, which encompassed the qualification of home nursing staff, developing and practicing emergency plan to cope with different emergency rescues in home environment, being equipped with medication and supplies for first aid according to specific situations, assessing nutrition condition of home patients, allocation of the number of home nursing staff, cases of new pressure ulcers and patient satisfaction rate. Remarkably, the convolutional neural network model demonstrated superior performance, outperforming both the random forest and regression models. CONCLUSION: The successful development and application of the convolutional neural network model highlight its ability to leverage data from community health service centres for rapid and accurate grading of home care quality. This research points the way to home care quality improvement. IMPACT: The model proposed in this study, coupled with the aforementioned factors, is expected to enhance the accuracy and efficiency of a comprehensive evaluation of home care quality. It will also help managers to take purposeful measures to improve the quality of home care. REPORTING METHOD: The reporting of this study (Observational, cross-sectional study) conforms to the STROBE statement. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The application of this model has the potential to contribute to the advancement of high-quality home care, particularly in lower-middle-income communities.

Anti-angiogenesis agents plus chemoradiotherapy for locally advanced nasopharyngeal cancer: a systematic review and meta-analysis.

PURPOSE: To evaluate literature evidences about the efficacy and safety of anti-angiogenesis agents plus chemoradiotherapy versus chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma. METHODS: The relevant literature was systematically searched from the date of establishment to April 2023 in PubMed, Embase, Web of Science, The Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biological Medicine, Wanfang and VIP database. Search terms included: Nasopharyngeal Neoplasms, Angiogenesis inhibitors, Endostar, Anlotinib, Apatinib, Bevacizumab, Sunitinib, Pazopanib, Chemoradiotherapy. The literature was strictly screened according to the inclusion and exclusion criteria, and 8 eligible studies were finally included in our meta-analysis (4 randomized controlled trials and 4 retrospective studies). RESULTS: A total of 642 patients were included, with 316 in the anti-angiogenesis agents plus chemoradiotherapy group and 326 in the chemoradiotherapy group. The results of our meta-analysis showed that compared with chemoradiotherapy group, the complete response rate (RR = 1.35, 95% CI 1.05-1.74, P = 0.02), objective response rate (RR = 1.26, 95% CI 1.12-1.43, P = 0.0002) in the anti-angiogenesis agents plus chemoradiotherapy group were significantly improved. In terms of safety, there was a higher incidence of cardiac arrhythmia (RR = 3.63, 95% CI 1.16-11.37, P = 0.03) and hypertension (RR = 1.85, 95% CI 1.04-3.27, P = 0.004) in the anti-angiogenesis agents plus chemoradiotherapy group, while no statistically significant differences were reported in other adverse reactions (all P > 0.05). CONCLUSION: Compared with chemoradiotherapy, anti-angiogenesis agents plus chemoradiotherapy could bring more benefits in terms of short-term efficacy, particularly by notably improving both complete response rate and objective response rate, and overall adverse reactions were acceptable. Anti-angiogenesis agents plus chemoradiotherapy may provide a promising direction for the treatment of locally advanced nasopharyngeal carcinoma. SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2023-8-0076/ , registration number INPLASY202380076.

Gelatin-Encapsulated Tetrahedral DNA Nanostructure Enhances Cellular Internalization for Treating Noise-Induced Hearing Loss.

Nanoparticle-based drug delivery strategies have emerged as a crucial avenue for comprehensive sensorineural hearing loss treatment. Nevertheless, developing therapy vectors crossing both biological and cellular barriers has encountered significant challenges deriving from various external factors. Herein, the rational integration of gelatin nanoparticles (GNPs) with tetrahedral DNA nanostructures (TDNs) to engineer a distinct drug-delivery nanosystem (designed as TDN@GNP) efficiently enhances the biological permeability and cellular internalization, further resolving the dilemma of noise-induced hearing loss via loading epigallocatechin gallate (EGCG) with anti-lipid peroxidation property. Rationally engineering of TDN@GNP demonstrates dramatic alterations in the physicochemical key parameters of TDNs that are pivotal in cell-particle interactions and promote cellular uptake through multiple endocytic pathways. Furthermore, the EGCG-loaded nanosystem (TDN-EGCG@GNP) facilitates efficient inner ear drug delivery by superior permeability through the biological barrier (round window membrane), maintaining high drug concentration within the inner ear. The TDN-EGCG@GNP actively overcomes the cell membrane, exhibiting hearing protection from noise insults via reduced lipid peroxidation in outer hair cells and spiral ganglion neurons. This work exemplifies how integrating diverse vector functionalities can overcome biological and cellular barriers in the inner ear, offering promising applications for inner ear disorders.

Taming heat with tiny pressure.

Heat is almost everywhere. Unlike electricity, which can be easily manipulated, the current ability to control heat is still highly limited owing to spontaneous thermal dissipation imposed by the second law of thermodynamics. Optical illumination and pressure have been used to switch endothermic/exothermic responses of materials via phase transitions; however, these strategies are less cost-effective and unscalable. Here, we spectroscopically demonstrate the glassy crystal state of 2-amino-2-methyl-1,3-propanediol (AMP) to realize an affordable, easily manageable approach for thermal energy recycling. The supercooled state of AMP is so sensitive to pressure that even several megapascals can induce crystallization to the ordered crystal, resulting in a substantial temperature increase of 48 K within 20 s. Furthermore, we demonstrate a proof-of-concept device capable of programable heating with an extremely high work-to-heat conversion efficiency of ∼383. Such delicate and efficient tuning of heat may remarkably facilitate rational utilization of waste heat.

Identification of natural xanthine oxidase inhibitors: Virtual screening, anti-xanthine oxidase activity, and interaction mechanism.

Xanthine oxidase (XO) is a crucial target for hyperuricemia treatment(s). Naturally occurred XO inhibitors with minimal toxicity and high efficacy have attracted researchers' attention. With the goal of quickly identifying natural XO inhibitors, an integrated computational screening strategy was constructed by molecular docking and calculating the free energy of binding. Twenty-seven hits were achieved from a database containing 19,377 natural molecules. This includes fourteen known XO inhibitors and four firstly-reported inhibitors (isolicoflavonol, 5,7-dihydroxycoumarin, parvifolol D and clauszoline M, IC50 < 40 µM). Iolicoflavonol (hit 8, IC50 = 8.45 ± 0.68 µM) and 5,7-dihydroxycoumarin (hit 25, IC50 = 10.91 ± 0.71 µM) displayed the great potency as mixed-type inhibitors. Docking study and molecular dynamics simulation revealed that both hits could interact with XO's primarily active site residues ARG880, MOS1328, and ASN768 of XO. Fluorescence spectroscopy studies showed that hit 8 bound to the active cavity region of XO, causing changes in XO's conformation and hydrophobicity. Hits 8 and 25 exhibit favorable Absorption, Distribution, Metabolism, and Excretion (ADME) properties. Additionally, no cytotoxicity against human liver cells was observed at their median inhibition concentrations against XO. Therefore, the present study offers isolicoflavonol and 5,7-dihydroxycoumarin with the potential to be disease-modifying agents for hyperuricemia.

Data mining-guided alleviation of hyperuricemia by Paeonia veitchii Lynch through inhibition of xanthine oxidase and regulation of renal urate transporters.

BACKGROUND: Hyperuricemia (HUA) is a metabolic disease characterized by a high level of uric acid (UA). The extensive historical application of traditional Chinese medicine (TCM) offers a range of herbs and prescriptions used for the treatment of HUA-related disorders. However, the core herbs in the prescriptions and their mechanisms have not been sufficiently explained. PURPOSE: Our current investigation aimed to estimate the anti-HUA effect and mechanisms of Paeonia veitchii Lynch, an herb with high use frequency identified from data mining of TCM prescriptions. METHODS: Prescriptions for HUA/gout treatment were statistically analyzed through a data mining approach to determine the common nature and use frequency of their composition herbs. The chemical constituents of Paeonia veitchii extract (PVE) were analyzed by UPLC-QTOF-MS/MS, while its UA-lowering effect was further evaluated in adenosine-induced liver cells and potassium oxonate (PO) and hypoxanthine (HX)-induced HUA mice. RESULTS: A total of 225 prescriptions involving 246 herbs were sorted out. The properties, flavors and meridians of the appearing herbs were mainly cold, bitter and liver, respectively, while their efficacy was primarily concentrated on clearing heat and dispelling wind. Further usage frequency analysis yielded the top 20 most commonly used herbs, in which PVE presented significant inhibitory activity (IC50 = 131.33 µg/ml) against xanthine oxidase (XOD), and its constituents showed strong binding with XOD in a molecular docking study and further were experimentally validated through XOD enzymatic inhibition and surface plasmon resonance (SPR). PVE (50 to 200 µg/ml) dose-dependently decreased UA levels by inhibiting XOD expression and activity in BRL 3A liver cells. In HUA mice, oral administration of PVE exhibited a significant UA-lowering effect, which was attributed to the reduction of UA production by inhibiting XOD activity and expression, as well as the enhancement of UA excretion by regulating renal urate transporters (URAT1, GLUT9, OAT1 and ABCG2). Noticeably, all doses of PVE treatment did not cause any liver injury, and displayed a renal protective effect. CONCLUSIONS: Our results first comprehensively clarified the therapeutic effect and mechanisms of PVE against HUA through suppressing UA production and promoting UA excretion with hepatic and renal protection, suggesting that PVE could be a promising UA-lowering candidate with a desirable safety profile for the treatment of HUA and prevention of gout.

Sound conditioning strategy promoting paracellular permeability of the blood-labyrinth-barrier benefits inner ear drug delivery.

The therapeutic effects of pharmaceuticals depend on their drug concentrations in the cochlea. Efficient drug delivery from the systemic circulation into the inner ear is limited by the blood-labyrinth-barrier (BLB). This study investigated a novel noninvasive sound conditioning (SC) strategy (90 dB SPL, 8-16 kHz, 2 h sound exposure) to temporally enhance BLB permeability in a controllable way, contributing to maximizing the penetration of pharmaceuticals from blood circulation into the cochlea. Trafficking of Fluorescein Isothiocyanate conjugated dextran and bovine serum albumin (FITC-dextran and FITC-BSA) demonstrated that paracellular leakage of BLB sustained for 6 h after SC, providing a controllable time window for systemic administration. Cochlear concentrations of dexamethasone (DEX) and dexamethasone phosphate (DEX-P), respectively transported by transcellular and paracellular pathways, showed a higher content of the latter one after SC, further confirming the key role of paracellular pathway in the SC-induced hyperpermeability. Results of high-throughput RNA-sequencing identified a series of tight junction (TJ)-associated genes after SC. The expressions of TJ (ZO-1) were reduced and irregular rearrangements of the junction were observed by transmission electron microscopy after SC. We further determined the inhibiting role of Rab13 in the recruitment of ZO-1 and later in the regulation of cellular permeability. Meanwhile, no significant change in the quantifications of endothelial caveolae vesicles after SC indicated that cellular transcytosis accounted little for the temporary hyperpermeability after SC. Based on these results, SC enhances the BLB permeability within 6 h and allows systemically applied drugs which tend to be transported by paracellular pathway to readily enter the inner ear, contributing to guiding the clinical medications on hearing loss.

Synergistic action of cavity and catalytic sites in etched Pd-Cu2O octahedra to augment the peroxidase-like activity of Cu2O nanoparticles for the colorimetric detection of isoniazid and ascorbic acid.

Despite the widespread use of nanozyme-based colorimetric assays in biosensing, challenges such as limited catalytic efficiency, inadequate sensitivity to analytes, and insufficient understanding of the structure-activity relationship still persist. Overcoming these hurdles by enhancing the inherent enzyme-like performance of nanozymes using the unique attributes of nanomaterials is still a significant obstacle. Here, we designed and constructed Pd-Cu2O nanocages (Pd-Cu2O NCs) by selectively etching the vertices of the copper octahedra to enhance the peroxidase-like (POD-like) activity of Cu2O nanoparticles. The improved catalytic activity of Pd-Cu2O NCs was attributed to their high specific surface area and abundant catalytic sites. Mechanistic studies revealed that reactive oxygen species (ROS) intermediates (•OH) were generated through the decomposition of H2O2, resulting in POD-like activity of the Pd-Cu2O NCs. The designed Pd-Cu2O NCs can oxidize 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2, producing a blue oxidation product (oxTMB). The oxidation reaction was inhibited and led to a significant bleaching of the blue color in the presence of reducing substances isoniazid (INH) and ascorbic acid (AA). Based on these principles, we developed a colorimetric sensing platform for the detection of INH and AA, exhibiting good sensitivity and stability. This work provided a straightforward approach to the structural engineering of nanomaterials and the enhancement of enzyme-mimicking properties.

Proximity hybridization induced bipedal DNA walker for label-free electrochemical detection of apolipoprotein A4 based on DNA meditated Ag nanoparticles growth.

Apolipoprotein A4 (Apo-A4) is considered as a prospective molecular biomarker for diagnosis of depression due to its neurosynaptic toxicity. Here, we propose a neighboring hybridization induced catalyzed hairpin assembly (CHA) driven bipedal DNA walker that mediates hybridization of Ag nanoparticles (Ag NPs) with DNA probes for highly sensitive electrochemical quantitative detection of Apo-A4. Driven by CHA, this bipedal DNA walker can spread all over the surface of the sensor, induce the HP1-HP2 double chain structure, make the surface of the sensor negatively charged, and adsorb a large number of Ag ions. After chemical reduction with hydroquinone, the Ag NPs formed provide signal tracers for electrochemical dissolution analysis of the target. The Ag NPs formed by chemical reduction of hydroquinone can provide signal traces for electrochemical stripping analysis of target thrombin. The linear range of this method is from 10 pg mL-1 to 1000 ng mL-1, and the detection limit is 5.1 pg mL-1. This enzyme-free and labeling detection method provides a new strategy for rapid clinical detection of Apo-A4 and accurate identification of depression.