The transcription factor Stat-1 is essential for Schwann cell differentiation, myelination and myelin sheath regeneration.

BACKGROUND: Myelin sheath is a crucial accessory to the functional nerve-fiber unit, its disruption or loss can lead to axonal degeneration and subsequent neurodegenerative diseases (NDs). Notwithstanding of substantial progress in possible molecular mechanisms underlying myelination, there is no therapeutics that prevent demyelination in NDs. Therefore, it is crucial to seek for potential intervention targets. Here, we focused on the transcriptional factor, signal transducer and activator of transcription 1 (Stat1), to explore its effects on myelination and its potential as a drug target. METHODS: By analyzing the transcriptome data obtained from Schwann cells (SCs) at different stages of myelination, it was found that Stat1 might be involved in myelination. To test this, we used the following experiments: (1) In vivo, the effect of Stat1 on remyelination was observed in an in vivo myelination mode with Stat1 knockdown in sciatic nerves or specific knockdown in SCs. (2) In vitro, the RNA interference combined with cell proliferation assay, scratch assay, SC aggregate sphere migration assay, and a SC differentiation model, were used to assess the effects of Stat1 on SC proliferation, migration and differentiation. Chromatin immunoprecipitation sequencing (ChIP-Seq), RNA-Seq, ChIP-qPCR and luciferase activity reporter assay were performed to investigate the possible mechanisms of Stat1 regulating myelination. RESULTS: Stat1 is important for myelination. Stat1 knockdown in nerve or in SCs reduces the axonal remyelination in the injured sciatic nerve of rats. Deletion of Stat1 in SCs blocks SC differentiation thereby inhibiting the myelination program. Stat1 interacts with the promoter of Rab11-family interacting protein 1 (Rab11fip1) to initiate SC differentiation. CONCLUSION: Our findings demonstrate that Stat1 regulates SC differentiation to control myelinogenic programs and repair, uncover a novel function of Stat1, providing a candidate molecule for clinical intervention in demyelinating diseases.

Schwann cell-derived CXCL2 contributes to cancer pain by modulating macrophage infiltration in a mouse breast cancer model.

Pain is one of the most severe complications affecting the quality of life of cancer patients. Although substantial progress has been made in the diagnosis and treatment of cancer, the neurobiological mechanism of cancer pain is still unclear. In the present study, we identified the critical role of CXC chemokine 2 (CXCL2), released by Schwann cells after being activated by cancer cells, in maintaining cancer-induced macrophage infiltration and the resulting mechanical hypersensitivity and persistent spontaneous nociception. In vitro, Schwann cells cocultured with breast cancer cells exhibited a significant increase in CXCL2 expression; in addition, conditioned medium from Schwann cells activated by breast cancer cells had a similar effect to recombinant CXCL2 in terms of inducing macrophage migration. Targeting CXCL2 signaling by both CXC chemokine receptor 2 (CXCR2) antagonist pharmacological blockade and anti-CXCL2 mAb immunological blockade robustly prevented conditioned medium-induced macrophage migration. In vivo, both application of recombinant CXCL2 and perineural breast cancer cell implantation resulted in mechanical hypersensitivity and persistent spontaneous nociception in mice, along with increased macrophage infiltration into the sciatic nerves. Similar to the in vitro results, inhibition of CXCL2/CXCR2 signaling or conditional knockdown of CXCL2 in sciatic nerve Schwann cells effectively attenuated breast cancer cell-induced mechanical hypersensitivity, persistent spontaneous nociception, and macrophage recruitment in the sciatic nerve. Mechanistically, we found that redox effector factor-1 (Ref-1) secreted by breast cancer cells activated hypoxia inducible factor-1α (HIF-1α) expression and inhibited reactive oxygen species (ROS) production in Schwann cells, ultimately inducing CXCL2 expression in Schwann cells. In brief, the present study expands new insights into cancer pain mechanisms from promising animal models to provide new strategies for the control of cancer pain.

Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury.

BACKGROUND: Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI. METHODS: PNI models were constructed with 8-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1ß, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents. RESULTS: MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 or DRG neurons collected from MaR1 treated mice revealed that MaR1 regulated neurite outgrowth through the PI3K-AKT-mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice. CONCLUSIONS: Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.

Distribution, co-existing metals, and potential health risk of fluorine in farmland soil in different anthropogenic activity dominated districts in a county-level city in Sichuan province, Southwest China, in 2015.

Continuous fluorine (F) accumulation in soil by anthropogenic activities leads to variously global environmental and health issues. Herein, 300 farmland soil samples were collected from different anthropogenic activity dominated districts for studying the distribution and related health risk of F in soils. Co-existing metal concentrations in soil samples were also analysed to evaluate the relationship between the distribution of F and metals in soil. The median value of the total F concentration of 488 mg kg-1 in the present samples was higher than the median background F concentration in topsoil in Sichuan province of China (261 mg kg-1). Concentration of water-soluble F (1.33-26.2 mg kg-1) was two or three orders of magnitude less than that of total F in soil. Levels of total and water-soluble F in soils collected from the district with longer contamination history were higher than that from other districts with shorter contamination period, indicating a historical contribution of anthropogenic activities to F accumulation in soil. Notable positive correlation between the total F and vanadium (V) concentration in soil can be partly linked to the usually negative charged form or a common source of F and V in soil (e.g. coal combustion). Compared with inhalation and dermal contact, present human exposure of F in soil was mainly caused by oral ingestion, and the health risks posed by F in soil for both children and adults were acceptable. However, considering the higher potential risk for children than adults, the accumulation of F in soil induced by anthropogenic activities should not be neglect.

Overexpression of P2X4 receptor in Schwann cells promotes motor and sensory functional recovery and remyelination via BDNF secretion after nerve injury.

Of the seven P2X receptor subtypes, P2X4 receptor (P2X4R) is widely distributed in the central nervous system, including in neurons, astrocytes, and microglia. Accumulating evidence supports roles for P2X4R in the central nervous system, including regulating cell excitability, synaptic transmission, and neuropathic pain. However, little information is available about the distribution and function of P2X4R in the peripheral nervous system. In this study, we find that P2X4R is mainly localized in the lysosomes of Schwann cells in the peripheral nervous system. In cultured Schwann cells, TNF-a not only enhances the synthesis of P2X4R protein but also promotes P2X4R trafficking to the surface of Schwann cells. TNF-a-induced BDNF secretion in Schwann cells is P2X4R dependent. in vivo experiments reveal that expression of P2X4R in Schwann cells of injured nerves is strikingly upregulated following nerve crush injury. Moreover, overexpression of P2X4R in Schwann cells by genetic manipulation promotes motor and sensory functional recovery and accelerates nerve remyelination via BDNF release following nerve injury. Our results suggest that enhancement of P2X4R expression in Schwann cells after nerve injury may be an effective approach to facilitate the regrowth and remyelination of injured nerves.

The beneficial effect of chitooligosaccharides on cell behavior and function of primary Schwann cells is accompanied by up-regulation of adhesion proteins and neurotrophins.

Chitosan-based tissue engineered nerve grafts are successfully used for bridging peripheral nerve gaps. The biodegradation products of chitosan are water-dissolvable chitooligosaccharides (COSs), which have been shown to support peripheral nerve regeneration. In this study, we aimed to examine in vitro interactions between COSs and Schwann cells (SCs), the principal glial cells in the peripheral nervous system. Treatment of primary SCs with COSs enhanced cell survival and promoted cell proliferation in a dose-dependent manner (0.25-1.0 mg/ml), as determined by real-time cell analyzer-based assay, cell growth assay, cell cycle analysis, and EdU incorporation. Western blot analysis and immunocytochemistry with antibodies against MBP and MAG (two myelin-specific markers) showed that COSs enhanced axonal myelination in a co-culture system consisting of SCs and dorsal root ganglia (DRGs). Furthermore, we observed that COSs enhanced the protein expression of N-cadherin and ß-catenin in primary SCs, and also increased the release of BDNF and NGF in co-culture of SCs with DRGs. And we also noted that knockdown of N-cadherin in primary SCs reduced COSs-induced increase in cell proliferation. Our findings suggested that beneficial effects of COSs on cell behavior and functions of primary SCs might be accompanied by up-regulation of adhesion proteins and neurotrophins, thus providing a new insight into the supportive role of COSs during peripheral nerve regeneration.

Fermentation of DaiDai fruit and its biological activity.

DaiDai fruit, a medicinal and edible plant fruit, is abundant in biologically active compounds and has a long history of use in traditional Chinese medicine. This research focuses on utilizing fermentation to develop a functional DaiDai fruit fermentation broth. Lactobacillus, Bacillus subtilis and Saccharomyces cerevisiae were employed in the fermentation process. By conducting screenings of bacterial strains, single factor experiments, and response surface methodology, the total flavonoids, polysaccharides, polyphenols, and 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radical scavenging rate were used as the index for selection, ultimately identifying Lactobacillus L-13 as the optimal fermentation strain. The optimal fermentation conditions were determined to be a time of 108 h, a temperature of 43.6°C, and a solid-liquid ratio of 1:15.157 (w/v). Under these conditions, the total flavonoid content reached 412.01 mg/g, representing a 36.71% increase compared to conventional extraction methods. The contents of polysaccharides and polyphenols and the DPPH scavenging rate were also increased. The fermentation broth of DaiDai fruit exhibited inhibitory effects on tyrosinase and melanin production in mouse melanoma cells B16-F10 induced by α-MSH and anti-inflammatory properties in a zebrafish inflammation model. These indicate that the DaiDai fruit fermentation broth possesses anti-melanoma, whitening, and anti-inflammatory properties, showcasing significant potential for applications in medicine, cosmetics, and other industries.

The Schwann cell-specific G-protein Gαo (Gnao1) is a cell-intrinsic controller contributing to the regulation of myelination in peripheral nerve system.

Myelin sheath abnormality is the cause of various neurodegenerative diseases (NDDs). G-proteins and their coupled receptors (GPCRs) play the important roles in myelination. Gnao1, encoding the major Gα protein (Gαo) in mammalian nerve system, is required for normal motor function. Here, we show that Gnao1 restricted to Schwann cell (SCs) lineage, but not neurons, negatively regulate SC differentiation, myelination, as well as re-myelination in peripheral nervous system (PNS). Mice lacking Gnao1 expression in SCs exhibit faster re-myelination and motor function recovery after nerve injury. Conversely, mice with Gnao1 overexpression in SCs display the insufficient myelinating capacity and delayed re-myelination. In vitro, Gnao1 deletion in SCs promotes SC differentiation. We found that Gnao1 knockdown in SCs resulting in the elevation of cAMP content and the activation of PI3K/AKT pathway, both associated with SC differentiation. The analysis of RNA sequencing data further evidenced that Gnao1 deletion cause the increased expression of myelin-related molecules and activation of regulatory pathways. Taken together, our data indicate that Gnao1 negatively regulated SC differentiation by reducing cAMP level and inhibiting PI3K-AKT cascade activation, identifying a novel drug target for the treatment of demyelinating diseases.

Improvement of antioxidant activity and active ingredient of Dendrobium officinale via microbial fermentation.

This study used brewer's yeast to ferment Dendrobium officinale and single-factor and orthogonal experiments were conducted to determine the optimal fermentation conditions. The antioxidant capacity of Dendrobium fermentation solution was also investigated by in vitro experiments, which showed that different concentrations of fermentation solution could effectively enhance the total antioxidant capacity of cells. The fermentation liquid was found to contain seven sugar compounds including glucose, galactose, rhamnose, arabinose, and xylose using gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography-quadrupole-time of flight mass spectrometry (HPLC-Q-TOF-MS), with the highest concentrations of glucose and galactose at 194.628 and 103.899 µg/ml, respectively. The external fermentation liquid also contained six flavonoids with apigenin glycosides as the main structure and four phenolic acids including gallic acid, protocatechuic acid, catechol, and sessile pentosidine B.

Corrigendum: Improvement of antioxidant activity and active ingredient of Dendrobium officinale via microbial fermentation.

[This corrects the article DOI: 10.3389/fmicb.2023.1061970.].

Expression, characterization, and immobilization of a novel SGNH esterase Est882 and its potential for pyrethroid degradation.

The widely-used pyrethroid pesticides have attracted public attention because of their potentials to cause environmental pollution and toxic effects on non-target organisms. Esterase is a kind of hydrolytic enzyme that can catalyze the cleavage or formation of ester bonds. it plays a pivotal role in the decomposition of pyrethroids and esters containing industrial pollutants through the hydrolysis of ester bonds. Here, a new esterase gene est882 was successfully screened, which encodes Est882, a SGNH family esterase composed of 294 amino acids. It was heterogeneously expressed, identified and immobilized. Multiple sequence alignment showed that Est882 had a typical GDS(X) conserved motif and a catalytic triad composed of Ser79, Asp269 and His275. Phylogenetic analysis showed that Est882 shall belong to a new esterase family. Biochemical characterization demonstrated that the optimum condition was 40°C and pH 9.0. Est882 immobilization was studied with mesoporous silica SBA-15 as the carrier and found to significantly improve the tolerance and stability of Est882. Its optimum pH increased to 10.0 and stabilized within pH 8.0-11.0. Free Est882 can effectively degrade various pyrethroids within 30 min, with a degradation rate above 80%. The immobilized Est882 yet degraded more than 70% of pyrethroids within 30 min. The present study indicated that Est882 has outstanding potential in bioremediation of a pyrethroid-polluted environment. These characteristics endow Est882 with potential values in various industrial applications and hydrolysis of pyrethroid residues.

The Etv1/Er81 transcription factor coordinates myelination-related genes to regulate Schwann cell differentiation and myelination.

Background: Axonal myelination is critical for the functioning of vertebrate nervous system. Myelin sheath malformation or degeneration can cause a variety of neurological diseases. Our previous study identified multiple potential myelination-related transcriptional factors (TFs), including expressed sequence tag (ETS) variant transcription factor 1 (Etv1)/Er81, via gene microarray analysis of Schwann cells (SCs) at various myelination stages. Etv1 is known to be involved in the regulation of neuronal specialization, muscle spindle differentiation, and sensorimotor connectivity. However, to our knowledge, to date, there are no relevant studies that Etv1 regulates SC myelination. Methods: To investigate the roles of Etv1 in SC re-myelination, an in vivo mouse myelination model was used, in which the sciatic nerve is crushed. Etv1 in nerves was knocked down via in situ injection of cholesterol-modified Etv1-small interfering (si)RNA. The expression of myelin-associated glycoprotein (MAG) was evaluated by Western blotting (WB) and immunohistochemistry (IHC). Myelination was assessed by transmission electron microscopy (TEM). The effects of Etv1 on SC proliferation, migration, and differentiation were assessed in vitro using the EdU cell proliferation kit, a culture-insert scratch assay, a SC aggregate sphere migration assay on the axons of dorsal root ganglions (DRGs), and a SC differentiation model. Chromatin immunoprecipitation (ChIP) united with quantitative real-time PCR (qPCR), known as ChIP-qPCR, and luciferase activity reporter assays were performed to explore the possible mechanisms by which Etv1 controls SC differentiation and myelination. Results: The results demonstrated that Etv1 promoted myelination by facilitating SC proliferation, migration, and differentiation. Etv1 expression in SCs was upregulated during re-myelination, and knocking down Etv1 expression dramatically abrogated SC re-myelination in the crushed sciatic nerves. Moreover, silencing of Etv1 by siRNA in SCs in vitro inhibited its migration, proliferation, and differentiation. The results of ChIP-qPCR and luciferase reporter assay showed that Etv1 may regulate SC differentiation and myelination by binding to the promoters of myelination-related genes, such as MAG and Runx2, to initiate their transcription. Conclusions: Taken together, these findings demonstrated a previously unknown role of Etv1 in SC differentiation and myelination, providing a candidate molecular target for clinical interventions in demyelinating diseases.

Decellularization alters the unfavorable regenerative adverse microenvironment of the injured spinal cord to support neurite outgrowth.

Background: Acellular tissue has been transplanted into the injury site as an external microenvironment to intervene with imbalance microenvironment that occurs after spinal cord injury (SCI) and stimulating axonal regeneration, although the mechanism is unclear. Given decellularization is the key means to obtain acellular tissues, we speculated changes in the internal components of tissue caused by decellularization may be the key reason why acellular tissues affect remodeling of the microenvironment. Methods: Complete spinal cord crush in a mouse model was established, and the dynamic of extracellular matrix (ECM) expression and distribution during SCI was studied with immunohistochemistry (IHC). Normal spinal cord (NSC) and 14-day injury spinal cord (ISC) were obtained to prepare the decellularized NSC (DNSC) and decellularized ISC (DISC) through a well-designed decellularization method, and the decellularization effects were evaluated by residual DNA content determination, hematoxylin and eosin staining (H&E), and IHC. Rat dorsal root ganglia (DRG) were co-cultured with NSC, ISC, DNSC, and DISC to evaluate their effect on neurite outgrowth. Furthermore, the mechanisms by which decellularized tissue promotes axonal growth were explored with proteomics analysis of the protein components and function of 14-day ISC and DISC. Results: We found the expression of the four main ECM components (collagen type I and IV, fibronectin, and laminin) gradually increased with the progression of SCI compared to NSC, peaking at 14 days of injury then slightly decreasing at 21 days, and the distribution of the four ECM proteins in the ISC also changed dynamically. H&E staining, residual DNA content determination, and IHC showed decellularization removed cellular components and preserved an intact ECM. The results of co-cultured DRG with NSCs, ISCs, DNSCs, and DISCs showed DNSCs and DISCs had a stronger ability in supporting neurite outgrowth than NSC and ISC. We found through proteomics that decellularization could remove proteins associated with inflammatory responses, scarring, and other pathological factors, while completely retaining the ECM proteins. Conclusions: Taken together, our findings demonstrate decellularization can optimize the imbalanced microenvironment after SCI by removing components that inhibit spinal cord regeneration, providing a theoretical basis for clinical application of acellular tissue transplantation to repair SCI.

Expression, Characterization, Fermentation, Immobilization, and Application of a Novel Esterase Est804 From Metagenomic Library in Pesticide Degradation.

Esterase, as a type of powerful catabolic enzyme for the degradation of pyrethroid pesticides (PYRs), appears promising in improving the quality of crops and the environment contaminated by pesticide residues. The purpose of this research is to provide a detailed introduction to the enzymatic properties, optimal production and immobilization conditions, and the degradation ability of Est804 for PYRs. The study on enzymatic properties indicated that Est804 was an alkaline esterase with an optimal pH of 8.0 and a broad optimal temperature in the range of 35-50°C. The optimal activity of free Est804 was calculated to be 112.812 U, and the specific enzyme activity was 48.97 U/mg. The kinetic parameters of Est804 were K m = 0.613 mM, k cat = 12,371 s-1, and V m = 0.095 mM/min. The results of the fermentative optimization demonstrated that the optimal conditions included 1.5% of inoculation amount, 30 mL of liquid volume, 28°C of the fermentation temperature, and 18 h of the fermentation time. The optimal medium consists of 15.87 g of yeast powder, 8.00 g of glycerol, and 9.57 g of tryptone in 1 L of liquid. The optimized enzyme activity was 1.68-fold higher than that before optimization. Immobilized Est804 exhibited the highest activity under the optimum preparation conditions, including 0.35 g of chitosan dosage, 0.4 mL of an enzyme, and 4 h at 40°C for adsorption. The degradation rates of Cypermethrin (CYP), fenpropathrin (FE), and lambda-cyhalothrin (LCT) by Est804 within 30 min were 77.35%, 84.73%, and 74.16%, respectively. The present study indicated that Est804 possesses great potential for the treatment of pesticide residues on crops and environmental remediation, conducive to the development of SGNH family esterase against pyrethroid accumulation.

The Effect of Schwann Cells/Schwann Cell-Like Cells on Cell Therapy for Peripheral Neuropathy.

Peripheral neuropathy is a common neurological issue that leads to sensory and motor disorders. Over time, the treatment for peripheral neuropathy has primarily focused on medications for specific symptoms and surgical techniques. Despite the different advantages of these treatments, functional recovery remains less than ideal. Schwann cells, as the primary glial cells in the peripheral nervous system, play crucial roles in physiological and pathological conditions by maintaining nerve structure and functions and secreting various signaling molecules and neurotrophic factors to support both axonal growth and myelination. In addition, stem cells, including mesenchymal stromal cells, skin precursor cells and neural stem cells, have the potential to differentiate into Schwann-like cells to perform similar functions as Schwann cells. Therefore, accumulating evidence indicates that Schwann cell transplantation plays a crucial role in the resolution of peripheral neuropathy. In this review, we summarize the literature regarding the use of Schwann cell/Schwann cell-like cell transplantation for different peripheral neuropathies and the potential role of promoting nerve repair and functional recovery. Finally, we discuss the limitations and challenges of Schwann cell/Schwann cell-like cell transplantation in future clinical applications. Together, these studies provide insights into the effect of Schwann cells/Schwann cell-like cells on cell therapy and uncover prospective therapeutic strategies for peripheral neuropathy.

Delayed inhibition of ERK and p38 attenuates neuropathic pain without affecting motor function recovery after peripheral nerve injury.

Peripheral nerve injuries (PNIs) often result in persistent neuropathic pain, seriously affecting quality of life. Existing therapeutic interventions for PNI-induced neuropathic pain are far from satisfactory. Extracellular signal-regulated kinases (ERKs) and p38 have been found to participate in triggering and maintaining PNI-induced neuropathic pain. However, ERK and p38 also contribute to axonal regeneration and motor function recovery after PNI, making it difficult to inhibit ERK and p38 for therapeutic purposes. In this study, we simultaneously characterized neuropathic pain and motor function recovery in a mouse sciatic nerve crush injury model to identify the time window for therapeutic interventions. We further demonstrated that delayed delivery of a combination of ERK and p38 inhibitors at three weeks after PNI could significantly alleviate PNI-induced neuropathic pain without affecting motor function recovery. Additionally, the combined use of these two inhibitors could suppress pain markedly better than either inhibitor alone, possibly reducing the required dose of each inhibitor and alleviating the side effects and risks of the inhibitors when used individually.

Transcriptome Analysis of Schwann Cells at Various Stages of Myelination Implicates Chromatin Regulator Sin3A in Control of Myelination Identity.

Enhancing remyelination after injury is of utmost importance for optimizing the recovery of nerve function. While the formation of myelin by Schwann cells (SCs) is critical for the function of the peripheral nervous system, the temporal dynamics and regulatory mechanisms that control the progress of the SC lineage through myelination require further elucidation. Here, using in vitro co-culture models, gene expression profiling of laser capture-microdissected SCs at various stages of myelination, and multilevel bioinformatic analysis, we demonstrated that SCs exhibit three distinct transcriptional characteristics during myelination: the immature, promyelinating, and myelinating states. We showed that suppressor interacting 3a (Sin3A) and 16 other transcription factors and chromatin regulators play important roles in the progress of myelination. Sin3A knockdown in the sciatic nerve or specifically in SCs reduced or delayed the myelination of regenerating axons in a rat crushed sciatic nerve model, while overexpression of Sin3A greatly promoted the remyelination of axons. Further, in vitro experiments revealed that Sin3A silencing inhibited SC migration and differentiation at the promyelination stage and promoted SC proliferation at the immature stage. In addition, SC differentiation and maturation may be regulated by the Sin3A/histone deacetylase2 (HDAC2) complex functionally cooperating with Sox10, as demonstrated by rescue assays. Together, these results complement the recent genome and proteome analyses of SCs during peripheral nerve myelin formation. The results also reveal a key role of Sin3A-dependent chromatin organization in promoting myelinogenic programs and SC differentiation to control peripheral myelination and repair. These findings may inform new treatments for enhancing remyelination and nerve regeneration.

Effects of novel cellulase (Cel 906) and probiotic yeast fermentation on antioxidant and anti-inflammatory activities of vine tea (Ampelopsis grossedentata).

Vine tea (Ampelopsis grossedentata) is a plant resource with good nutritional and medicinal, and is widely consumed in China. This study aimed to develop a functional vine tea fermentation broth using microbial fermentation and cellulase degradation. First, the most suitable probiotics for vine tea fermentation were screened, and the fermentation conditions were optimized. Then, a new cellulase (Cel 906, MW076177) was added to evaluate the changes in the contents of effective substances and to study its efficacy. The results show that saccharomyces cerevisiae Y-401 was identified as the best strain, the optimal fermentation conditions were a time of 94.60 h, feeding concentration of 115.21 g/L, and temperature of about 34.97°C. The vine tea fermentation broth has a strong inhibitory ability on 2,2'-azinobis3-ethylbenzothiazoline-6-sulfonic acid (ABTS) (99.73%), peroxyl (53.15%), superoxide anion radicals (84.13%), and 1,1-Diphenyl-2-trinitrophenylhydrazine (DPPH) (92.48%). It has a decent inhibitory impact on the cell viability, tyrosinase activity (32.25%), and melanin synthesis (63.52%) of B16-F10 melanoma cells induced by α-MSH. Inflammatory cell recruitment was reduced in a zebrafish inflammation model. Therefore, this vine tea fermented broth has strong antioxidant, anti-melanoma, and anti-inflammatory effects, and has healthcare potential as a probiotic tea.

Pannexin 1, a large-pore membrane channel, contributes to hypotonicity-induced ATP release in Schwann cells.

Pannexin 1 (Panx 1), as a large-pore membrane channel, is highly permeable to ATP and other signaling molecules. Previous studies have demonstrated the expression of Panx 1 in the nervous system, including astrocytes, microglia, and neurons. However, the distribution and function of Panx 1 in the peripheral nervous system are not clear. Blocking the function of Panx 1 pharmacologically (carbenoxolone and probenecid) or with small interfering RNA targeting pannexins can greatly reduce hypotonicity-induced ATP release. Treatment of Schwann cells with a Ras homolog family member (Rho) GTPase inhibitor and small interfering RNA targeting Rho or cytoskeleton disrupting agents, such as nocodazole or cytochalasin D, revealed that hypotonicity-induced ATP release depended on intracellular RhoA and the cytoskeleton. These findings suggest that Panx 1 participates in ATP release in Schwann cells by regulating RhoA and the cytoskeleton arrangement. This study was approved by the Animal Ethics Committee of Nantong University, China (No. S20180806-002) on August 5, 2018.

Emerging Role of Schwann Cells in Neuropathic Pain: Receptors, Glial Mediators and Myelination.

Neuropathic pain caused by nerve injury or disease remains a major challenge for modern medicine worldwide. Most of the pathogenic mechanisms underlying neuropathic pain are centered on neuronal mechanisms. Accumulating evidence suggests that non-neuronal cells, especially glial cells, also play active roles in the initiation and resolution of pain. The preponderance of evidence has implicated central nervous system (CNS) glial cells, i.e., microglia and astrocytes, in the control of pain. The role of Schwann cells in neuropathic pain remains poorly understood. Schwann cells, which detect nerve injury and provide the first response, play a critical role in the development and maintenance of neuropathic pain. The cells respond to nerve injury by changing their phenotype, proliferating and interacting with nociceptive neurons by releasing glial mediators (growth factors, cytokines, chemokines, and biologically active small molecules). In addition, receptors expressed in active Schwann cells have the potential to regulate different pain conditions. In this review article, we will provide and discuss emerging evidence by integrating recent advances related to Schwann cells and neuropathic pain.