Downregulation of lncRNA XIST may promote Th17 differentiation through KDM6A-TSAd pathway in neuromyelitis optica spectrum disorders.

BACKGROUNDS: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease with significant female preponderance. X inactive specific transcript (XIST) is a long non-coding RNA (lncRNA) and a key regulator of X-chromosome inactivation which is related to the sex-bias of autoimmunity. And Th17 cell proportion was significantly elevated in NMOSD according to our previous study. OBJECTIVES: This study aimed to explore the expression levels of lncRNA XIST-KDM6A-TSAd pathway in lymphocytes of female NMOSD patients, and investigate its possible relationship with pathogenesis of NMOSD. METHODS AND RESULTS: The study enrolled 30 acute-phase untreated female NMOSD patients and 30 age-matched female healthy controls, their lymphocytes were collected for experiments. Microarray as well as validation experiments showed lncRNA XIST was significantly downregulated in the NMOSD group. And the levels of lysine demethylase 6A (KDM6A) decreased in NMOSD and showed significant positive correlation with XIST. The levels of T cell-specific adapter (TSAd) mRNA and protein levels were significantly lower in NMOSD. And Chromatin immunoprecipitation assay demonstrated that NMOSD had more H3K27me3 modification than control at TSAd promoter region. CONCLUSIONS: The present study introduced a potential pathway that following lncRNA XIST downregulation, which process may promote Th17 differentiation in NMOSD. These findings shed new light on the immune regulation mechanism about lncRNA XIST and related epigenetic features, which may contribute to develop female-specific treatment plans.

Exosomal miR-23b-3p from bone mesenchymal stem cells alleviates experimental autoimmune encephalomyelitis by inhibiting microglial pyroptosis.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system and is marked by inflammation and damage to the myelin sheath surrounding nerve fibers. Recent studies have highlighted the therapeutic value of exosomes (Exos) obtained from bone marrow mesenchymal stem cells (BMSCs) in MS treatment. These BMSC-Exos contain biologically active molecules that show promising results in preclinical evaluations. The aim of this study was to investigate the mechanism of BMSC-Exos containing miR-23b-3p in both LPS-stimulated BV2 microglia and in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Exos were isolated from BMSCs, and their effects were evaluated in vitro by co-culturing with BV2 microglia. The interaction between miR-23b-3p and its downstream targets was also explored. The efficacy of BMSC-Exos was further verified in vivo by injecting the Exos into EAE mice. The results showed that BMSC-Exos containing miR-23b-3p reduced microglial pyroptosis in vivo by specifically binding to and suppressing the expression of NEK7. In vivo, BMSC-Exos containing miR-23b-3p alleviated the severity of EAE by decreasing microglial inflammation and pyroptosis via the repression of NEK7. These findings provide new insights into the therapeutic potential of BMSC-Exos containing miR-23b-3p for MS.

Mesenchymal stem cell-derived exosomal microRNA-367-3p alleviates experimental autoimmune encephalomyelitis via inhibition of microglial ferroptosis by targeting EZH2.

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disorder of the central nervous system. Accumulating evidence has underscored the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-Exos) containing bioactive compounds in MS. Herein, the current study sought to characterize the mechanism of BMSC-Exos harboring miR-367-3p both in BV2 microglia by Erastin-induced ferroptosis and in experimental autoimmune encephalomyelitis (EAE), a typical animal model of MS. Exosomes were firstly isolated from BMSCs and identified for further use. BV2 microglia were co-cultured with miR-367-3p-containing BMSC-Exos, followed by an assessment of cell ferroptosis. Mechanistic exploration was furthered by the interaction of miR-367-3p and its downstream regulators. Lastly, BMSC-Exos harboring miR-367-3p were injected into EAE mice for in vivo validation. BMSC-Exos carrying miR-367-3p restrained microglial ferroptosis in vitro. Mechanistically, miR-367-3p could bind to Enhancer of zeste homolog 2 (EZH2) and restrain EZH2 expression, leading to the over-expression of solute carrier family 7 member 11 (SLC7A11). Meanwhile, over-expression of SLC7A11 resulted in Glutathione Peroxidase 4 (GPX4) activation and ferroptosis suppression. Ectopic expression of EZH2 in vitro negated the protective effects of BMSC-Exos. Furthermore, BMSC-Exos containing miR-367-3p relieved the severity of EAE by suppressing ferroptosis and restraining EZH2 expression in vivo. Collectively, our findings suggest that BMSC-Exos carrying miR-367-3p brings about a significant decline in microglia ferroptosis by repressing EZH2 and alleviating the severity of EAE in vivo, suggesting a possible role of miR-367-3p overexpression in the treatment strategy of EAE. AVAILABILITY OF DATA AND MATERIALS: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Pterostilbene Protects the Optic Nerves and Retina in a Murine Model of Experimental Autoimmune Encephalomyelitis via Activation of SIRT1 Signaling.

Optic neuritis and retinal damage are common manifestations of multiple sclerosis (MS). Pterostilbene (PT) has been used to treat multiple diseases for its anti-inflammatory, anti-apoptosis and neuroprotective activities. This study aimed to investigate whether PT exerts a therapeutic effect on optic neuritis and retinal damage triggered by MS. Here, experimental autoimmune encephalomyelitis (EAE), an experimental model for MS, was induced in female C57BL/6 mice by immunizing with MOG35-55 peptide and treating with pertussis toxin. The mice were intraperitoneally injected with 20 mg/kg and 40 mg/kg PT once daily for 25 days at 24 h post immunization. We found that PT alleviated EAE severity and delayed EAE onset. Moreover, PT mitigated EAE-induced optic nerves and retinal inflammation, as indicated by the decreased Iba-1+ and GFAP+ cells and mRNA levels of interleukin-6, tumor necrosis factor-α and interleukin-1ß and the increased Iba-1+sirtuin 1 (SIRT1)+ and GFAP+SIRT1+ cells in the optic nerves and retina. PT also protected the optic nerves against demyelination and axonal loss and the retina against disorders in retinal morphology and apoptosis of retinal ganglion cells. High-dose PT had a more significant effect on protection of the optic nerves and retina in EAE than low-dose PT. In addition, PT activated SIRT1 signaling in the optic nerves and retina. Notably, EX-527, an inhibitor of SIRT1, reversed the effect of high-dose PT on the optic nerves and retina, indicating that PT exerted the protective effect via activating SIRT1 signaling. This study provides a potential candidate for treating MS.

Clustered regularly interspaced short palindromic repeats as an advanced treatment for Parkinson's disease.

Recently, genome-editing technology like clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 has improved the translational gap in the treatments mediated through gene therapy. The advantages of the CRISPR system, such as, work in the living cells and tissues, candidate this technique for the employing in experiments and the therapy of central nervous system diseases. Parkinson's disease (PD) is a widespread, disabling, neurodegenerative disease induced by dopaminergic neuron loss and linked to progressive motor impairment. Pathophysiological basis knowledge of PD has modified the PD classification model and expresses in the sporadic and familial types. Analyses of the earliest genetic linkage have shown in PD the inclusion of synuclein alpha (SNCA) genomic duplication and SNCA mutations in the familial types of PD pathogenesis. This review analyzes the structure, development, and function in genome editing regulated through the CRISPR/Cas9. Also, it explains the genes associated with PD pathogenesis and the appropriate modifications to favor PD. This study follows the direction by understanding the PD linking analyses in which the CRISPR technique is applied. Finally, this study explains the limitations and future trends of CRISPR service in relation to the genome-editing process in PD patients' induced pluripotent stem cells.

Protective effect and mechanism of nicotinamide adenine dinucleotide against optic neuritis in mice with experimental autoimmune encephalomyelitis.

Patients with multiple sclerosis (MS) are commonly accompanied by optic neuritis (ON) that causes retinal ganglion cell (RGC) death and even vision loss. Nicotinamide adenine dinucleotide (NAD+) can protect against cell apoptosis and attenuate MS-triggered symptoms. However, the effect of NAD+ on MS-triggered ON remains unclear. Herein, experimental autoimmune encephalomyelitis (EAE) was established by immunizing female C57BL/6 mice with MOG35-55 peptide. To investigate the effect of NAD+ on ON prevention and treatment, EAE mice received 250 mg/kg NAD+ daily via intraperitoneal injection after immunization and EAE onset, respectively. EX-527 (10 mg/kg, SIRT1 inhibitor) was intraperitoneally injected every two days to explore the role of SIRT1 in NAD+-induced therapeutic effect on EAE. NAD+ intervention attenuated the severity of EAE in mice. NAD+ intervention relieved inflammatory infiltration and CD3+ and CD4+ cell infiltration and decreased the number and activation of microglia and astrocytes in the optic nerve. NAD+ intervention also attenuated demyelination, axonal loss, oligodendrocyte apoptosis and oligodendrocyte progenitor cell recruitment and proliferation in the optic nerve and protected against RGC apoptosis in the retina. NAD+ intervention decreased pro-inflammatory cytokine mRNA and pro-apoptotic protein expression and enhanced anti-inflammatory cytokine mRNA expression and the SIRT1 signaling in the optic nerve and retina and regulated the Th1/Th17/Tregs immune response in the spleen. In addition, EX-527 reversed the therapeutic effect of NAD+ on EAE, suggesting that NAD+ prevented MS-triggered ON by activating the SIRT1 signaling pathway. This study shows the potential of NAD+ to be used as a drug in preventing and treating MS-related ON.

[Effects of Arbuscular Mycorrhizal Fungi on the Growth of Reeds in Wetland Soils with Different Salt Content].

A greenhouse pot experiment was conducted to investigate the effects of arbuscular mycorrhizal (AM) fungi Claroideoglomus etunicatum (CE), Rhizophagus intraradices (RI), Funneliformis mosseae (FM) and Glomus versiforme (GV) on AM colonization rate, biomass, mineral nutrient uptake, C: N: P ratios and Na and Cl- concentrations of reeds (Phragmites australis) grown in saline and non-saline wetland soils. The aim was to provide a technical basis for the ecological revegetation and salinity restoration of wetland ecosystem. The results indicated that symbiotic associations were successfully established between the four isolates and reeds grown in the two types of wetland soils. The average AM colonization rates ranged from 2.5% to 38%. The mean root colonization rate of CE was significantly higher than those of the other three isolates. There were no significant differences in root colonization rates between saline and non-saline wetland soils. The biomass and nutrient contents of reeds grown in non-saline wetland soils were significantly higher than those grown in saline wetland soils. However, Na+ and Cl- concentrations of reeds grown in non-saline wetland soils were significantly lower than those grown in saline wetland soils. In non-saline wetland soils, inoculation with GV significantly increased the shoot dry weight and the shoot N, P, K, Ca and Mg contents of reeds. Inoculation with GV and RI significantly improved the root P and K contents of reeds. Inoculation with the four AM fungi significantly reduced the shoot N: P ratios. Inoculation with FM and GV significantly reduced the root C : N and C : P ratios. Inoculation with the four AM fungi significantly reduced the shoot Cl- concentrations. Inoculation with RI significantly reduced the shoot Na+ concentrations. In saline wetland soils, inoculation with AM fungi had no significant effect on the biomass, mineral nutrient uptake and Na+ and Cl- concentrations of reeds. The results demonstrated that the four AM fungi isolates had different effects on the growth of reeds in wetland soils with different salt contents. Inoculation with AM fungi played a more positive role in improving the growth of reeds in non-saline wetland soil than those in saline wetland soil. Further experiments should be conducted to screen optimal AM fungi isolates under field conditions and to evaluate the practical effects of AM fungi on the growth of reeds in wetland soils with different salt contents.

Contribution of arbuscular mycorrhizal fungi to the development of maize (Zea mays L.) grown in three types of coal mine spoils.

Coal mine spoils are usually unfavorable for plant growth and have different properties according to dumping years, weathering degree, and the occurrence of spontaneous combustion. The establishment of plant cover in mine spoils can be facilitated by arbuscular mycorrhizal fungi (AMF). A greenhouse pot experiment was conducted to evaluate the importance of AMF in plant adaptation to different mine spoils and the potential role of AMF for revegetation practices. We investigated the effects of Glomus aggregatum, Rhizophagus intraradices (syn. Glomus intraradices), and Funneliformis mosseae (syn. Glomus mosseae) on the growth, nutritional status, and metal uptake of maize (Zea mays L.) grown in recent discharged (S1), weathered (S2), and spontaneous combusted (S3) coal mine spoils. Symbiotic associations were successfully established between AMF and maize in three substrates. Mycorrhizal colonization effectively promoted plant growth by significantly increasing the uptake of nitrogen (N), phosphorus (P), and potassium (K), adjusting C:N:P stoichiometry and alleviating toxic effects of heavy metals. G. aggregatum, R. intraradices, and F. mosseae exhibited different mycorrhizal effects in response to mine spoil types. F. mosseae was the most effective in the development of maize in S1 and may be the most appropriate for revegetation of this substrate, while R. intraradices played the most beneficial role in S2 and S3. Our results suggest that inoculation with AMF can enhance plant adaptation to different types of coal mine spoils and play a positive role in the revegetation of coal mine spoil banks.

[Distribution characteristic and current situation of soil rare earth contamination in the Bayan Obo mining area and Baotou tailing reservoir in Inner Mongolia].

The pollution status and distribution characteristic of rare earth elements in soil were analyzed around Bayan Obo mining area and Baotou tailing reservoir located in Inner Mongolia grassland ecosystem, aiming at grasping the overall situation of grassland ecosystem pollution caused by rare earth elements and providing basic information as well as theoretical basis. The results indicated that seven rare earth elements in soils from different directions of Baotou tailing reservoir accumulated to a certain extent compared to the soil background value of Inner Mongolia. The pollution degree was Ce > La > Nd > Pr > Sm > Y > Eu. Within 50 m from the edge of tailing reservoir, soil rare earth contamination was the most serious, with the concentrations of La, Ce, Pr, Nd, Sm, Eu and Y reaching 11,45.0 mg x kg(-1), 23,636.0 mg x kg(-1), 4568.16 mg x kg(-1) , 6855.51 mg x kg(-1), 582.18 mg x kg(-1), 94.21 mg x kg(-1)), and 136.25 mg x kg(-1), respectively. Owing to the dominant wind direction of northwest, soils from the southeast were contaminated most seriously. For Bayan Obo mining area, the concentrations of seven rare earth elements in soil from the mining area were significantly higher than those of other areas investigated, with the concentrations of La, Ce, Pr, Nd, Sm, Eu and Y reaching 3112.56 mg x kg(-1), 7142.12 mg x kg(-1), 1467.12 mg x kg(-1), 2552.80 mg x kg(-1), 210.80 mg x kg(-1), 36.20 mg x kg(-1) and 63.22 mg x kg(-1), respectively. The soils of six areas of Bayan Obo mining area were all contaminated by rare earth elements, and the contamination degree was in the order of mining area > outside the dump > east side of the railway > the dump > outside the urban area > west side of the railway. Besides, the transportation of rare earth ore led to the soil rare earth contamination along the railway, and the distribution characteristic of rare earth elements in soils along the railway was affected by the dominant wind direction of northwest. Baotou tailing reservoir and Bayan Obo mining area had the same contamination characteristic, and the concentrations of rare earth elements were in accordance with those in the tailings. The health and stabilization of local grassland ecosystem are being threatened by excessive soil rare earth elements.

[Effects of arbuscular mycorrhizal fungi on the growth and rare earth elements uptake of soybean grown in rare earth mine tailings].

A greenhouse pot experiment was conducted to investigate the influence of arbuscular mycorrhizal (AM) fungi Glomus versiforme on the plant growth, nutrient uptake, C: N: P stoichiometric, uptake of heavy metals and rare earth elements by soybean (Glycine max) grown in rare earth mine tailings. The aim was to provide a basis for the revegetation of rare earth mine tailings. The results indicated that soybean had a high mycorrhizal colonization and symbiotic associations were successfully established with G. versiforme, with an average rate of approximately 67%. The colonization of G. versiforme significantly promoted the growth of soybean, increased P, K contents, and decreased C: N: P ratios, supporting the growth rate hypothesis. Inoculation with G. versiforme significantly decreased shoots and roots La, Ce, Pr and Nd concentrations of soybean compared to the control treatment. However, inoculation with G. versiforme had no significant effect on the heavy metal concentrations, except for significantly decreased shoot Fe and Cr concentrations and increased root Cd concentrations. The experiment demonstrates that AM fungi have a potential role for soybean to adapt the composite adversity of rare earth tailings and play a positive role in revegetation of rare earth mine tailings. Further studies on the role of AM fungi under natural conditions should be conducted.

[Effects of arbuscular mycorrhizal fungi on the vegetation restoration of different types of coal mine spoil banks].

A greenhouse pot experiment was conducted to investigate the influence of arbuscular mycorrhizal (AM) fungi Glomus etunicatum (GE) and Glomus versiforme (GV) on the plant growth, nutrient uptake, C: N: P stoichiometric, uptake of heavy metals by maize (Zea mays L.) grown in three types of coal mine spoil banks. The aim was to provide a technical basis for the revegetation of coal mine spoil banks in grassland ecosystem. The results indicated that the symbiotic associations were successfully established between two isolates and maize grown in the three substrates, with an average mycorrhizal colonization rate ranging from 36% to 54%. The colonization of two AM fungi significantly increased the dry weight of maize grown in recent discharged and weathered coal mine spoils and GE increased those grown in weathered coal mine spoil. Inoculation with AM fungi promoted the uptake of N, P and K by maize to varying degrees. In addition, inoculation with GE and GV also decreased C: N: P ratios, supporting the growth rate hypothesis, and had significantly differences on concentrations of Cu, Fe, Mn and Zn in shoots and roots of maize. The results indicated that GE and GV had different mycorrhizal effects on maize in the three types of substrates. GV was more suitable for the revegetation of recent discharged coal mine spoil and weathered coal mine spoil, while GE was more suitable for the revegetation of spontaneous combusted coal mine spoil. The experiment demonstrates that AM fungi have a potential role for maize to enhance the ability to adapt the composite adversity of different types of coal mine spoil and play a positive role in the revegetation of different coal mine spoil banks. Further field experiments should be conducted to evaluate the practical effects of AM fungi on the vegetation restoration of different types of coal mine spoil under field conditions.