Detecting potential mechanism of vitamin D in treating rheumatoid arthritis based on network pharmacology and molecular docking.

Aim: Vitamin D plays a vital role in Rheumatoid arthritis (RA). However, the mechanism of vitamin D and rheumatism is still unclear. Therefore, a strategy based on network pharmacology and molecular docking was used to explore the mechanism of vitamin D and RA. Methods: The targets of RA were obtained from the GeneCards database and Therapeutic Targets Database, and the targets of vitamin D were obtained from the Drugbank database and STITCH database. Next, overlapping genes were identified by Venny, and further Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking analyses were performed. Results: A total of 1,139 targets of RA and 201 targets of vitamin D were obtained. A total of 76 overlapping genes were identified by Venny. The enrichment analysis showed that cell proliferation, immune response, and apoptotic process were the critical biological processes of vitamin D in treating RA. Antifolate resistance, osteoclast differentiation, and the nuclear factor-kappa B (NF-κB) signalling pathway are fundamental mechanisms of vitamin D in treating RA. According to further molecular docking, ALB, TNF, CASP3, and TP53 may be important punctuation points or diagnostic markers for future RA treatment. Conclusion: By analysing overlapping genes of diseases and drugs, this study confirmed that ALB, TNF, CASP3, and TP53 may be essential markers or diagnostic markers for future RA treatment.

The bridge of the gut-joint axis: Gut microbial metabolites in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint destruction, synovitis, and pannus formation. Gut microbiota dysbiosis may exert direct pathogenic effects on gut homeostasis. It may trigger the host's innate immune system and activate the "gut-joint axis", which exacerbates the RA. However, although the importance of the gut microbiota in the development and progression of RA is widely recognized, the mechanisms regulating the interactions between the gut microbiota and the host immune system remain incompletely defined. In this review, we discuss the role of gut microbiota-derived biological mediators, such as short-chain fatty acids, bile acids, and tryptophan metabolites, in maintaining intestinal barrier integrity, immune balance and bone destruction in RA patients as the bridge of the gut-joint axis.

Channel Interaction During Infrared Light Stimulation in the Cochlea.

BACKGROUND AND OBJECTIVES: The number of perceptually independent channels to encode acoustic information is limited in contemporary cochlear implants (CIs) because of the current spread in the tissue. It has been suggested that neighboring electrodes have to be separated in humans by a distance of more than 2 mm to eliminate significant overlap of the electric current fields and subsequent interaction between the channels. It has also been argued that an increase in the number of independent channels could improve CI user performance in challenging listening environments, such as speech in noise, tonal languages, or music perception. Optical stimulation has been suggested as an alternative modality for neural stimulation because it is spatially selective. This study reports the results of experiments designed to quantify the interaction between neighboring optical sources in the cochlea during stimulation with infrared radiation. STUDY DESIGN/MATERIALS AND METHODS: In seven adult albino guinea pigs, a forward masking method was used to quantify the interaction between two neighboring optical sources during stimulation. Two optical fibers were placed through cochleostomies into the scala tympani of the basal cochlear turn. The radiation beams were directed towards different neuron populations along the spiral ganglion. Optically evoked compound action potentials were recorded for different radiant energies and distances between the optical fibers. The outcome measure was the radiant energy of a masker pulse delivered 3 milliseconds before a probe pulse to reduce the response evoked by the probe pulse by 3 dB. Results were compared for different distances between the fibers placed along the cochlea. RESULTS: The energy required to reduce the probe's response by 3 dB increased by 20.4 dB/mm and by 26.0 dB/octave. The inhibition was symmetrical for the masker placed basal to the probe (base-to-apex) and the masker placed apical to the probe (apex-to-base). CONCLUSION: The interaction between neighboring optical sources during infrared laser stimulation is less than the interaction between neighboring electrical contacts during electrical stimulation. Previously published data for electrical stimulation reported an average current spread in human and cat cochleae of 2.8 dB/mm. With the increased number of independent channels for optical stimulation, it is anticipated that speech and music performance will improve. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Infrared neural stimulation at different wavelengths and pulse shapes.

Neural stimulation with infrared radiation has been explored for brain tissue, peripheral nerves, and cranial nerves including the auditory nerve. Initial experiments were conducted at wavelengths between λ = 1850 and λ = 2140 nm and the radiant energy was delivered with square pulses. Water absorption of the infrared radiation at λ = 1860 nm is similar to absorption at wavelengths between λ = 1310 and λ = 1600 nm, which are in the radiation wavelength range used for the communication industry. Technology for those wavelengths has already been developed and miniaturized and is readily available. The possibility of the infrared light to evoke compound action potentials (CAP) in the cochlea at λ = 1,375, λ = 1,460, and λ = 1550 nm was explored and compared to that of λ = 1860 nm in guinea pigs. Furthermore, rise and fall times of the 100 µs long pulses were changed and four basic pulse shapes (square, triangular, ramp-up, and ramp-down) were explored in their ability to evoke a CAP. In animals with pure tone threshold averages (PTAs) above 70 dB SPL, the results show that the favorable wavelength is λ = 1460 nm to reach threshold for stimulation and λ = 1375 nm or λ = 1460 nm for obtaining maximum amplitude. The most favorable pulse shape is either ramp-up or triangular.

Enhancing photoluminescence of carbon quantum dots doped PVA films with randomly dispersed silica microspheres.

As a kind of excellent photoluminescent material, carbon quantum dots have been extensively studied in many fields, including biomedical applications and optoelectronic devices. They have been dispersed in polymer matrices to form luminescent films which can be used in LEDs, displays, sensors, etc. Owing to the total internal reflection at the flat polymer/air interfaces, a significant portion of the emitted light are trapped and dissipated. In this paper, we fabricate free standing flexible PVA films with photoluminescent carbon quantum dots embedded in them. We disperse silica microspheres at the film surfaces to couple out the total internal reflection. The effects of sphere densities and diameters on the enhancement of photoluminescence are experimentally investigated with a homemade microscope. The enhancement of fluorescence intensity is as high as 1.83 when the film is fully covered by spheres of 0.86 [Formula: see text]m diameter. It is worth noting that the light extraction originates from rather the scattering of individual spheres than the diffraction of ordered arrays. The mechanism of scattering is confirmed by numerical simulations. The simulated results show that the evanescent wave at the flat PVA/air interface can be effectively scattered out of the film.

Systemic application of honokiol prevents cisplatin ototoxicity without compromising its antitumor effect.

Cisplatin is a potent drug used in about 40% of cancer treatment but also leads to severe deafness in 60-80% of the cases. Although the mechanism is known to be related to the accumulation of reactive oxygen species (ROS), no drug or FDA approved treatment is currently available to prevent cisplatin ototoxicity. With this study, we show for the first time that honokiol (HNK), a pleiotropic poly-phenol prevents cisplatin-induced hearing loss. HNK also improves the wellbeing of the mice during the treatment, determined by the increase in the number of surviving animals. In a transgenic tumor mouse model, HNK does not hinder cisplatin's antitumor effect. The mechanism is related to the activation of sirtuin 3, a deacetylase in mitochondria essential for ROS detoxification. We expect a paradigm shift in cisplatin chemotherapy based on the current study and future clinical trials, where honokiol is applied to reduce side effects including hearing loss.

Multichannel optrodes for photonic stimulation.

An emerging method in the field of neural stimulation is the use of photons to activate neurons. The possible advantage of optical stimulation over electrical is attributable to its spatially selective activation of small neuron populations, which is promising in generating superior spatial resolution in neural interfaces. Two principal methods are explored for cochlear prostheses: direct stimulation of nerves with infrared light and optogenetics. This paper discusses basic requirements for developing a light delivery system (LDS) for the cochlea and provides examples for building such devices. The proposed device relies on small optical sources, which are assembled in an array to be inserted into the cochlea. The mechanical properties, the biocompatibility, and the efficacy of optrodes have been tested in animal models. The force required to insert optrodes into a model of the human scala tympani was comparable to insertion forces obtained for contemporary cochlear implant electrodes. Side-emitting diodes are powerful enough to evoke auditory responses in guinea pigs. Chronic implantation of the LDS did not elevate auditory brainstem responses over 26 weeks.

Auditory Neural Activity in Congenitally Deaf Mice Induced by Infrared Neural Stimulation.

To determine whether responses during infrared neural stimulation (INS) result from the direct interaction with spiral ganglion neurons (SGNs), we tested three genetically modified deaf mouse models: Atoh1-cre; Atoh1 f/f (Atoh1 conditional knockout, CKO), Atoh1-cre; Atoh1 f/kiNeurog1 (Neurog1 knockin, KI), and the Vglut3 knockout (Vglut3 -/-) mice. All animals were exposed to tone bursts and clicks up to 107 dB (re 20 µPa) and to INS, delivered with a 200 µm optical fiber. The wavelength (λ) was 1860 nm, the radiant energy (Q) 0-800 µJ/pulse, and the pulse width (PW) 100-500 µs. No auditory responses to acoustic stimuli could be evoked in any of these animals. INS could not evoke auditory brainstem responses in Atoh1 CKO mice but could in Neurog1 KI and Vglut3 -/- mice. X-ray micro-computed tomography of the cochleae showed that responses correlated with the presence of SGNs and hair cells. Results in Neurog1 KI mice do not support a mechanical stimulation through the vibration of the basilar membrane, but cannot rule out the direct activation of the inner hair cells. Results in Vglut3 -/- mice, which have no synaptic transmission between inner hair cells and SGNs, suggested that hair cells are not required.

Pressure in the Cochlea During Infrared Irradiation.

OBJECTIVE: The purpose of the study is to demonstrate laser-evoked pressure waves in small confined volumes such as the cochlea. METHODS: Custom-fabricated pressure probes were used to determine the pressure in front of the optical fiber in a small dish and patch pipettes to measure temperature changes. Pressure probes were inserted into scala tympani (ST) or vestibuli during laser stimulation. With a sensitive microphone the pressure was measured in the outer ear canal. RESULTS: Heating was spatially confined. The heat relaxation time was 35 ms. During laser stimulation in the cochlea at 17 µJ/pulse, the pressure in the outer ear canal (EC) was 43.5 dB (re 20 µPa). The corresponding intracochlear pressure was calculated to be about 78.5 dB (re 20 µPa) using the middle ear reverse transfer function of -35 dB. At 164 µJ/pulse, the pressure in the EC was on average 63 dB (re 20 µPa) and the intracochlear pressure was estimated to be 98 dB (re 20 µPa), which is similar to the value obtained with the pressure probe, 100 dB (re 20 µPa). Side-emitting optical fibers were used to steer the beam path. The pressure values were independent of the orientation of the beam path. Evoked compound action potentials of the auditory nerve were maximum when spiral ganglion neurons were in the beam path. CONCLUSION: Pressure waves are generated during infrared laser stimulation. The intracochlear pressure was independent from the orientation of the beam path. SIGNIFICANCE: Neural responses required the spiral ganglion neurons to be directly irradiated.

Distorting temporal fine structure by phase shifting and its effects on speech intelligibility and neural phase locking.

Envelope (E) and temporal fine structure (TFS) are important features of acoustic signals and their corresponding perceptual function has been investigated with various listening tasks. To further understand the underlying neural processing of TFS, experiments in humans and animals were conducted to demonstrate the effects of modifying the TFS in natural speech sentences on both speech recognition and neural coding. The TFS of natural speech sentences was modified by distorting the phase and maintaining the magnitude. Speech intelligibility was then tested for normal-hearing listeners using the intact and reconstructed sentences presented in quiet and against background noise. Sentences with modified TFS were then used to evoke neural activity in auditory neurons of the inferior colliculus in guinea pigs. Our study demonstrated that speech intelligibility in humans relied on the periodic cues of speech TFS in both quiet and noisy listening conditions. Furthermore, recordings of neural activity from the guinea pig inferior colliculus have shown that individual auditory neurons exhibit phase locking patterns to the periodic cues of speech TFS that disappear when reconstructed sounds do not show periodic patterns anymore. Thus, the periodic cues of TFS are essential for speech intelligibility and are encoded in auditory neurons by phase locking.

Identifying the Origin of Effects of Contralateral Noise on Transient Evoked Otoacoustic Emissions in Unanesthetized Mice.

Descending neural pathways in the mammalian auditory system are known to modulate the function of the peripheral auditory system. These pathways include the medial olivocochlear (MOC) efferent innervation to outer hair cells (OHCs) and the acoustic reflex pathways mediating middle ear muscle (MEM) contractions. Based on measurements in humans (Marks and Siegel, companion paper), we applied a sensitive method to attempt to differentiate MEM and MOC reflexes using contralateral acoustic stimulation in mice under different levels of anesthesia. Separation of these effects is based on the knowledge that OHC-generated transient evoked otoacoustic emissions (TEOAE) are delayed relative to the stimulus, and that the MOC reflex affects the emission through its innervation of OHC. In contrast, the MEM-mediated changes in middle ear reflectance alter both the stimulus (with a short delay) and the emission. Using this approach, time averages to transient stimuli were evaluated to determine if thresholds for a contralateral effect on the delayed emission, indicating potential MOC activation, could be observed in the absence of a change in the stimulus pressure. This outcome was not observed in the majority of cases. There were also no statistically significant differences between MEM and putative MOC thresholds, and variability was high for both thresholds regardless of anesthesia level. Since the two reflex pathways could not be differentiated on the basis of activation thresholds, it was concluded that the MEM reflex dominates changes in TEOAEs induced by contralateral noise. This result complicates the identification of purely MOC-induced changes on OAEs in mice unless the MEM reflex is inactivated surgically or pharmacologically.