PTEN inhibitor bisperoxovanadium protects against noise-induced hearing loss.

Studies have shown that phosphatase and tensin homolog deleted on chromosome ten (PTEN) participates in the regulation of cochlear hair cell survival. Bisperoxovanadium protects against neurodegeneration by inhibiting PTEN expression. However, whether bisperoxovanadium can protect against noise-induced hearing loss and the underlying mechanism remains unclear. In this study, we established a mouse model of noise-induced hearing loss by exposure to 105 dB sound for 2 hours. We found that PTEN expression was increased in the organ of Corti, including outer hair cells, inner hair cells, and lateral wall tissues. Intraperitoneal administration of bisperoxovanadium decreased the auditory threshold and the loss of cochlear hair cells and inner hair cell ribbons. In addition, noise exposure decreased p-PI3K and p-Akt levels. Bisperoxovanadium preconditioning or PTEN knockdown upregulated the activity of PI3K-Akt. Bisperoxovanadium also prevented H2O2-induced hair cell death by reducing mitochondrial reactive oxygen species generation in cochlear explants. These findings suggest that bisperoxovanadium reduces noise-induced hearing injury and reduces cochlear hair cell loss.

[Corrigendum] miR­29b overexpression induces cochlear hair cell apoptosis through the regulation of SIRT1/PGC­1α signaling: Implications for age­related hearing loss.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that the bar charts shown in Fig. 4A and B, which were intending to have shown the RT­qPCR and western blot analyses of SIRT1 and PGC­1α in HEI­OC1 cells, respectively, under different experimental conditions were apparently identical. Similarly, in Fig. 5, the histograms shown in Fig. 5C and D, which were intending to have shown the RT­qPCR and western blot analyses, respectively, of SIRT1 and PGC­1α in HEI­OC1 cells subjected to different treatments were also apparently identical. The authors have re­examined their data, and realize that the data properly belonging to the protein expression levels had been wrongly used to show the mRNA levels, and therefore Figs. 4A and 5C were presented incorrectly in these figures. The revised versions of Figs. 4 and 5, containing the correct data for the RT­qPCR experiments in Figs. 4A and 5C, are shown on the next page. These errors did not affect the major conclusions reported in the paper. All the authors have agreed to this corrigendum, and thank the Editor of International Journal of Molecular Medicine for allowing them the opportunity to publish this. The authors regret these errors went unnoticed during the compilation of the figures in question, and apologize to the readership for any confusion that this may have caused. [the original article was published in International Journal of Molecular Medicine 38: 1387­1394, 20186 DOI: 10.3892/ijmm.2016.2735].

Brain Functional and Structural Changes in Alzheimer's Disease With Sleep Disorders: A Systematic Review.

Introduction: Sleep disorders (SLD) are supposed to be associated with increased risk and development of Alzheimer's disease (AD), and patients with AD are more likely to show SLD. However, neurobiological performance of patients with both AD and SLD in previous studies is inconsistent, and identifying specific patterns of the brain functional network and structural characteristics in this kind of comorbidity is warranted for understanding how AD and SLD symptoms interact with each other as well as finding effective clinical intervention. Thus, the aims of this systematic review were to summarize the relevant findings and their limitations and provide future research directions. Methods: A systematic search on brain functional and structural changes in patients with both AD and SLD was conducted from PubMed, Web of Science, and EMBASE databases. Results: Nine original articles published between 2009 and 2021 were included with a total of 328 patients with comorbid AD and SLD, 367 patients with only AD, and 294 healthy controls. One single-photon emission computed tomography study and one multislice spiral computed tomography perfusion imaging study investigated changes of cerebral blood flow; four structural magnetic resonance imaging (MRI) studies investigated brain structural changes, two of them used whole brain analysis, and another two used regions of interest; two resting-state functional MRI studies investigated brain functional changes, and one 2-deoxy-2-(18F)fluoro-d-glucose positron emission tomography (18F-FDG-PET) investigated 18F-FDG-PET uptake in patients with comorbid AD and SLD. Findings were inconsistent, ranging from default mode network to sensorimotor cortex, hippocampus, brain stem, and pineal gland, which may be due to different imaging techniques, measurements of sleep disorder and subtypes of AD and SLD. Conclusions: Our review provides a systematic summary and promising implication of specific neuroimaging dysfunction underlying co-occurrence of AD and SLD. However, limited and inconsistent findings still restrict its neurobiological explanation. Further studies should use unified standards and comprehensive brain indices to investigate the pathophysiological basis of interaction between AD and SLD symptoms in the development of the disease spectrums.

Atrial Natriuretic Peptide Promotes Neurite Outgrowth and Survival of Cochlear Spiral Ganglion Neurons in vitro Through NPR-A/cGMP/PKG Signaling.

Sensorineural hearing loss (SNHL) is a dominant public health issue affecting millions of people around the globe, which is correlated with the irreversible deterioration of the hair cells and spiral ganglion neurons (SGNs) within the cochlea. Strategies using bioactive molecules that regulate neurite regeneration and neuronal survival to reestablish connections between auditory epithelium or implanted electrodes and SGN neurites would become attractive therapeutic candidates for SNHL. As an intracellular second messenger, cyclic guanosine-3',5'-monophosphate (cGMP) can be synthesized through activation of particulate guanylate cyclase-coupled natriuretic peptide receptors (NPRs) by natriuretic peptides, which in turn modulates multiple aspects of neuronal functions including neuronal development and neuronal survival. As a cardiac-derived hormone, atrial natriuretic peptide (ANP), and its specific receptors (NPR-A and NPR-C) are broadly expressed in the nervous system where they might be involved in the maintenance of diverse neural functions. Despite former literatures and our reports indicating the existence of ANP and its receptors within the inner ear, particularly in the spiral ganglion, their potential regulatory mechanisms underlying functional properties of auditory neurons are still incompletely understood. Our recently published investigation revealed that ANP could promote the neurite outgrowth of SGNs by activating NPR-A/cGMP/PKG cascade in a dose-dependent manner. In the present research, the influence of ANP and its receptor-mediated downstream signaling pathways on neurite outgrowth, neurite attraction, and neuronal survival of SGNs in vitro was evaluated by employing cultures of organotypic explant and dissociated neuron from postnatal rats. Our data indicated that ANP could support and attract neurite outgrowth of SGNs and possess a high capacity to improve neuronal survival of SGNs against glutamate-induced excitotoxicity by triggering the NPR-A/cGMP/PKG pathway. The neuroregenerative and neuroprotective effects of ANP/NPRA/cGMP/PKG-dependent signaling on SGNs would represent an attractive therapeutic candidate for hearing impairment.

Unusual presentation of a first branchial arch fistula with maxillofacial infection: a case report.

BACKGROUND: First branchial cleft anomaly (FBCA) is a rare congenital defect that arises due to incomplete closure of the ventral portion of the first and second branchial arches. There are variable complex clinical manifestations for patients with FBCA, which are prone to misdiagnosis and inadequate treatment. FBCAs usually involve the facial nerve with a consequent increased risk of facial nerve damage. Here, we present an unusual case of FBCA presenting with two preauricular pits in association with an abnormal maxillofacial cyst. CASE PRESENTATION: A 10-month-old girl presented to our department due to recurrent maxillofacial infections accompanied by swelling or abscess of the left cheek and purulent discharge from the preauricular pit for 4 months. A 3D-computed tomography (CT) fistulogram and magnetic resonance imaging (MRI) revealed two conjunctive tract lesions: one tract arose from the skin surface anteroinferior to the external auditory canal (EAC), through the deep lobe of the left parotid, and anteriorly extended to the left masseter; the other extended from the superficial lobe of the left parotid to the intertragic notch. After the maxillofacial infection was controlled by intravenous antibiotic administration, surgery was performed. Intraoperative tools, such as facial nerve monitors, microscopes, and methylene blue dyes, were used to facilitate the complete dissection and protection of the facial nerve. On follow-up over one year, the patient recovered well without facial palsy or recurrence. CONCLUSION: FBCA with maxillofacial cysts is rare and prone to misdiagnosis. Physicians should pay attention to this anatomic variant of FBCA with the fistula track located deep inside the facial nerve and projected medially to the masseter.

Nrg1/ErbB2 regulates differentiation and apoptosis of neural stem cells in the cochlear nucleus through PI3K/Akt pathway.

Sensorineural hearing loss (SNHL) is a common causes of disability. Neural stem cells (NSCs) from the cochlear nuclei have been considered to be a potential direction for the treatment of SNHL. Neuregulin 1 (NRG1)/ErbB2 signaling displays an essential role in nervous system development. In this study, we aimed to explore the roles of NRG1/ErbB2 in differentiation and apoptosis of cochlear nuclei NSCs. The data showed that the expression of NGR1 and ErbB2 in cochlear nuclei NSCs isolated from rats were increased with the age of rats. NRG1 treatment reduced the nestin-positive cells number, increased the MAP2-positive and GFAP-positive cells number, decreased the expression of cleaved-caspase-3, and increased the activation of PI3K/AKT. ErbB2 knockdown by lentiviral-mediated ErbB2 shRNA infection reversed the effect of NRG1 on cochlear nuclei NSCs. LY294002 administration further enhanced the effect of ErbB2 silencing on the expression of nestin, MAP2, GFAP and cleaved-caspase-3. Taken together, NRG1/ErbB2 regulates differentiation and apoptosis of cochlear nucleus NSCs through PI3K/Akt pathway.

Atrial Natriuretic Peptide Improves Neurite Outgrowth from Spiral Ganglion Neurons In Vitro through a cGMP-Dependent Manner.

The spiral ganglion neurons (SGNs) are the primary afferent neurons in the spiral ganglion (SG), while their degeneration or loss would cause sensorineural hearing loss. As a cardiac-derived hormone, atrial natriuretic peptide (ANP) plays a critical role in cardiovascular homeostasis through binding to its functional receptors (NPR-A and NPR-C). ANP and its receptors are widely expressed in the mammalian nervous system where they could be implicated in the regulation of multiple neural functions. Although previous studies have provided direct evidence for the presence of ANP and its functional receptors in the inner ear, their presence within the cochlear SG and their regulatory roles during auditory neurotransmission and development remain largely unknown. Based on our previous findings, we investigated the expression patterns of ANP and its receptors in the cochlear SG and dissociated SGNs and determined the influence of ANP on neurite outgrowth in vitro by using organotypic SG explants and dissociated SGN cultures from postnatal rats. We have demonstrated that ANP and its receptors are expressed in neurons within the cochlear SG of postnatal rat, while ANP may promote neurite outgrowth of SGNs via the NPR-A/cGMP/PKG pathway in a dose-dependent manner. These results indicate that ANP would play a role in normal neuritogenesis of SGN during cochlear development and represents a potential therapeutic candidate to enhance regeneration and regrowth of SGN neurites.

Inhibition of DHCR24 increases the cisplatin-induced damage to cochlear hair cells in vitro.

Hearing loss is a common sensory disorder that affects more than 360 million people worldwide, and is primarily caused by the loss of hair cells (HCs). Ototoxic drugs, viral infections, genetic predisposition, aging or noise all damage HCs. 3ß-hydroxysteroid-Δ24 reductase (DHCR24), one enzyme in the cholesterol biosynthetic pathway, is involved in inflammation, oxidative stress and neuroprotection. However, researchers have not determined whether DHCR24 is present in the cochlea and the mechanism by which it exerts its regulatory effect on HC loss. In the present study, we analyzed DHCR24 expression in the postnatal day 1 (P1) rat cochlea and found that DHCR24 was localized in HCs of the organ of Corti. Next, exposure to cisplatin caused HC loss in cochlear organotypic cultures. Then, we inhibited DHCR24 expression with U18666A and observed significantly increased cisplatin-induced damage of cochlear HCs. These findings were consistent with the observed increase in DHCR24 expression in response to cisplatin treatment, and U18666A significantly decreased DHCR24 expression. Finally, DHCR24 inhibition increased the levels of reactive oxygen species and cleaved caspase-3 after cisplatin-induced injury. Collectively, DHCR24 may play a significant role in regulating auditory function and potentially represents a new therapeutic target for the treatment of cisplatin-induced ototoxicity.

Outer hair cells isolation from postnatal Sprague-Dawley rats.

Outer hair cells (OHCs) damage is a general phenomenon in clinical disorders such as noise-induced hearing loss and drug-induced hearing loss. In order to elucidate the mechanism underlying these disorders, OHCs - its diseased region needs to be deeply investigated. However, OHCs array on the basilar membrane which contains massive cells with different types. Therefore, to isolate OHCs from this huge population is significant for revealing its pathological and molecular changes during disease processing. In the present study, we tried to isolate OHCs from the commonly used animal model -Sprague-Dawley (SD) rats. By separating outer hair cells from SD rats with different day ages, we found that 9 days after birth was a suitable time for the separation of the OHCs. At this time, the number of OHCs isolated from rats was large, and the cell morphology was typical of cylindrical shape. OHCs isolated using this method are histologically suitable and quantitatively adequate for molecular biological and electrophysiological analyses.

[Recurrent low frequency sensorineural deafness].

Low frequency sensorineural deafness is a common subtype of idiopathic sudden deafness. Certain patients suffered recurrent attacks without vertigo, much alike Meniere's disease. Few of them developed into definite Meniere's disease during long-term follow-up in many clinical studies. Although the pathophysiology of recurrent low frequency deafness is yet unknown, the desease is considered associated with early state of endolymphatic hydrops or migraine. Otologists shall be aware of its clinical course and careful explanation is necessary at time of initial informed consent.

Decreased expression of TERT correlated with postnatal cochlear development and proliferation reduction of cochlear progenitor cells.

Cochlear progenitor cells are considered as one of the best candidates for hair cell regeneration, thus, the regulation of cochlear progenitor cell proliferation has become a focus in this field. Several genes expressed in the inner ear during postnatal development have been demonstrated to be involved in maintaining the proliferative potential of progenitor cells, but the mechanism for regulating the proliferation and differentiation of cochlear progenitor cells remains poorly understood. Telomerase reverse transcriptase (TERT) has rate limiting telomerase activity and the overexpression of TERT has been shown to promote cell proliferation in series of cell lines. The aim of the present study was to evaluate the expression of TERT in the postnatal development of the cochlea and progenitor cells. The results demonstrated that TERT was expressed in the basilar membranes during the first postnatal week. In vitro, TERT expression in progenitor cells reached a maximum at day 4 after culture and decreased as the culture time prolonged or the cell passage number increased. These results led us to hypothesize that TERT may be involved in the development of the cochlea and in maintaining the proliferation ability of progenitor cells.

Sirt3 confers protection against acrolein-induced oxidative stress in cochlear nucleus neurons.

Acrolein is a ubiquitous dietary and environmental pollutant, which can also be generated endogenously during cellular stress. However, the molecular mechanisms underlying acrolein-induced neurotoxicity, especially in ototoxicity conditions, have not been fully determined. In this study, we investigated the mechanisms on acrolein-induced toxicity in primary cultured cochlear nucleus neurons with focus on Sirt3, a mitochondrial deacetylase. We found that acrolein treatment induced neuronal injury and programmed cell death (PCD) in a dose dependent manner in cochlear nucleus neurons, which was accompanied by increased intracellular reactive oxygen species (ROS) generation and lipid peroxidation. Acrolein exposure also significantly reduced the mitochondrial membrane potential (MMP) levels, promoted cytochrome c release and decreased mitochondrial ATP production. In addition, increased ER tracker fluorescence and activation of ER stress factors were observed after acrolein treatment, and the ER stress inhibitors were shown to attenuate acrolein-induced toxicity in cochlear nucleus neurons. The results of western blot and RT-PCR showed that acrolein markedly decreased the expression of Sirt3 at both mRNA and protein levels, and reduced the activity of downstream mitochondrial enzymes. Furthermore, overexpression of Sirt3 by lentivirus transfection partially prevented acrolein-induced neuronal injury in cochlear nucleus neurons. These results demonstrated that acrolein induces mitochondrial dysfunction and ER stress in cochlear nucleus neurons, and Sirt3 acts as an endogenous protective factor in acrolein-induced ototoxicity.

miR-29b overexpression induces cochlear hair cell apoptosis through the regulation of SIRT1/PGC-1α signaling: Implications for age-related hearing loss.

It has been reported that the degeneration of cochlear hair cells is the typical cause of presbycusis (or age-related hearing loss). However, the molecular mechanisms that mediate cochlear hair cell apoptosis are not yet fully understood and there is no effective treatment for this disorder. MicroRNAs (miRNAs or miRs) have been increasingly shown to be associated with age-related diseases and are emerging as promising therapeutic targets. In this study, we investigated whether miR-29b is involved in the degeneration of cochlear hair cells. To examine our hypothesis, nuclear staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) were used to quantify the hair cell counts. RT-qPCR and western blot analysis were used to examine miR-29b/sirtuin 1 (SIRT1)/proliferator-activated receptor-gamma coactivator 1α (PGC­1α) signaling in cochlear hair cells. We found that there was a significant degeneration of cochlear hair cells and a higher expression of miR-29b in aged C57BL/6 mice compared with young mice. There was also an age-related decrease in the expression of SIRT1 and PGC­1α. In the inner ear cell line, HEI-OC1, miR-29b overexpression (by transfection with miR-29b mimic) inhibited SIRT1 and PGC­1α expression, leading to an increase in mitochondrial dysfunction and apoptosis. Moreover, the inhibition of miR-29b (by transfection with miR-29b inhibitor) increased SIRT1 and PGC­1α expression, while it decreased apoptosis. Taken together, our findings support a link between age-related cochlear hair cell apoptosis and miR-29b/SIRT1/PGC­1α signaling, which may present an attractive pharmacological target for the development of novel drugs for the treatment of age-related hearing loss.

Exposure to acoustic stimuli promotes the development and differentiation of neural stem cells from the cochlear nuclei through the clusterin pathway.

Stem cell therapy has attracted widespread attention for a number of diseases. Recently, neural stem cells (NSCs) from the cochlear nuclei have been identified, indicating a potential direction for the treatment of sensorineural hearing loss. Acoustic stimuli play an important role in the development of the auditory system. In this study, we aimed to determine whether acoustic stimuli induce NSC development and differentiation through the upregulation of clusterin (CLU) in NSCs isolated from the cochlear nuclei. To further clarify the underlying mechanisms involved in the development and differentiation of NSCs exposed to acoustic stimuli, we successfully constructed animal models in which was CLU silenced by an intraperitoneal injection of shRNA targeting CLI. As expected, the NSCs from rats treated with LV-CLU shRNA exhibited a lower proliferation ratio when exposed to an augmented acoustic environment (AAE). Furthermore, the inhibition of cell apoptosis induced by exposure to AAE was abrogated after silencing the expression of the CLU gene. During the differentiation of acoustic stimuli-exposed stem cells into neurons, the number of astrocytes was significantly reduced, as evidenced by the expression of the cell markers, microtubule associated protein­2 (MAP-2) and glial fibrillary acidic protein (GFAP), which was markedly inhibited when the CLU gene was silenced. Our results indicate that acoustic stimuli may induce the development and differentiation of NSCs from the cochlear nucleus mainly through the CLU pathway. Our study suggests that CLU may be a novel target for the treatment of sensorineural hearing loss.

Favorable proliferation and differentiation capabilities of neural precursor cells derived from rat cochlear nucleus.

NSCs/NPCs could be used for Sensorineural hearing loss treatment, because of the extensive capacity for self-renewal and pluripotency. In order to isolate and identify neural precursor cells (NPCs), we established a strategy to isolate and cultivate NPCs. Immunohistochemistry, immunofluorescence, Western blotting, and electron microscopy were used to characterize the cells and compare their differentiation patterns with those of olfactory bulb and olfactory epithelium NPCs. Furthermore, NPCs from the cochlear nucleus were sustained good cell viability and cloning efficiency after cryopreservation and thawing. Finally, high capacity to differentiate into astrocytes, oligodendrocytes, and neurons of NPCs was found. In conclusion, NPCs isolated from the cochlear nucleus can proliferate and differentiate into functional neurons, which offers a potential strategy for sensorineural hearing loss treatment. In addition, the storage method developed here will benefit further exploration of NPCs.

Publications about hearing in otorhinolaryngology journals from chinese authors: a 11-year survey of the literature.

Hearing loss is a leading cause of disability in China. However, the research status in the field of hearing among Chinese individuals in the three major regions of China: Mainland (ML), Hong Kong (HK) and Taiwan (TW), are unknown. The output of hearing articles published in international otorhinolaryngology journals from these three regions were compared in this study. Articles published in 31 international otorhinolaryngology journals related to hearing originating from the ML, TW and HK from 2000 to 2011 were retrieved from the PubMed database search. The number of total articles, clinical trials, randomized controlled trials, case reports, and articles published in the top 5 international otorhinolaryngology journals were assessed in terms of quantity and quality comparisons. The total number of articles from the three regions increased significantly from 2000 to 2011. There were 379 articles from ML (143), TW (180) and HK (56) in the past 10 years. The number of articles published per year from the ML has exceeded those from TW in 2009 and HK in 2003. TW had the most articles (46) published in the top 5 international otorhinolaryngology journals among the three regions. The total number of articles from the three major regions of China increased significantly from 2000 to 2011. The numbers of articles published per year from the ML have exceeded those from TW and HK. However, the quality of articles from TW is better than that from ML.

Determining leak locations during transnasal endoscopic repair of cerebrospinal fluid rhinorrhea.

OBJECTIVE: For transnasal endoscopic repair procedures to be successful, it is critical to identify leak locations during surgery. We aim to evaluate different methods to more accurately detect leak locations during the endoscopic repair of cerebrospinal fluid rhinorrhea. MATERIALS AND METHODS: We performed a retrospective chart review of 39 cases undergoing endoscopic repair of cerebrospinal fluid rhinorrhea. The leak locations were determined using preoperative nasal endoscopy, radioisotope scanning, the intraoperative image-guided system, and intraspinal normal saline injection. RESULTS: The cerebrospinal fluid leak location was in the sphenoidal sinus in 9 cases, the ethmoid sinus in 17 cases, and in the frontal sinus in 1 case. The leak locations could not be determined in the remaining 12 cases using this method alone. For these 12 cases, after the ethmoid sinus was opened and the lateral wall of sphenoidal sinus was exposed with the aid of the intraoperative image-guided system, outflow of cerebrospinal fluid was present on the lateral wall of sphenoidal sinus (in 1 case) and on the ethmoid roof (in 3 cases). Furthermore, using intraspinal saline injection (20-30 ml), leak locations were detected in the sphenoidal sinus (2 cases) and in ethmoid sinus (6 cases) of the remaining cases. CONCLUSION: For cerebrospinal fluid rhinorrhea patients whose leak locations are difficult to determine, surgeons can increase their operative success rates by performing radioisotope scanning and intraspinal saline injections and by using image-guided surgical systems. These safe and effective methods can be used to successfully detect leak locations during transnasal endoscopic repair of cerebrospinal fluid leaks.

The biophysical origin of traveling-wave dispersion in the cochlea.

Sound processing begins at the peripheral auditory system, where it undergoes a highly complex transformation and spatial separation of the frequency components inside the cochlea. This sensory signal processing constitutes a neurophysiological basis for psychoacoustics. Wave propagation in the cochlea, as shown by measurements of basilar membrane velocity and auditory nerve responses to sound, has demonstrated significant frequency modulation (dispersion), in addition to tonotopic gain and active amplification. The physiological and physical basis for this dispersion remains elusive. In this article, a simple analytical model is presented, along with experimental validation using physiological measurements from guinea pigs, to identify the origin of traveling-wave dispersion in the cochlea. We show that dispersion throughout the cochlea is fundamentally due to the coupled fluid-structure interaction between the basilar membrane and the scala fluids. It is further influenced by the variation in physical and geometrical properties of the basilar membrane, the sensitivity or gain of the hearing organ, and the relative dominance of the compression mode at about one-third octave beyond the best frequency.

[Inhibitory effect of 1,25(OH)2D3 on proliferation of human laryngeal carcinoma cells and potential mechanisms].

BACKGROUND AND OBJECTIVE: 1Alpha,25-dihydroxy vitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, has antiproliferative activity against various tumor cells. This study was to explore the inhibitory effect of 1,25(OH)2D3 on human laryngeal carcinoma Hep-2 cells and potential mechanisms. METHODS: Hep-2 cells were treated by 1,25(OH)2D3 (0, 1, 10 and 100 nmol/L) for 24, 48, 72 and 96 h, respectively. Cell proliferation was measured by MTT assay. Cell apoptosis was measured by flow cytometry (FCM). The expression and phosphorylation of ERK, p38MAPK, and JNK proteins were detected by Western blot. RESULTS: 1,25(OH)2D3 significantly inhibited Hep-2 cell proliferation and induced cell apoptosis. 1,25(OH)2D3 increased p38MPAK phosphorylation but not ERK and JNK phosphorylation. The 1,25(OH)2D3-induced apoptosis of Hep-2 cells was partly blocked by p38 inhibitor SB2035080. CONCLUSION: 1,25(OH)2 D3 could induce apoptosis of Hep-2 cells and p38MAPK plays an important role in this process.