Macular edema after siponimod treatment for multiple sclerosis: a case report and literature review.

BACKGROUND: As a modulator of the sphingosine 1-phosphate receptor, siponimod is administered as a therapeutic intervention for multiple sclerosis. A previous phase 3 study first reported siponimod-associated macular edema. Since that report, there were only few relevant reports in clinical settings. Here, we report a case of secondary progressive multiple sclerosis developed macular edema after siponimod treatment. We also review the progress of sphingosine 1-phosphate receptor modulators, elaborate on accepted mechanisms in treating multiple sclerosis, and discuss the causation of siponimod-associated macular edema. CASE PRESENTATION: A 38-year-old Chinese female patient with secondary progressive multiple sclerosis, who had recurrent numbness of the limbs and right leg fatigue, developed mild macular edema following 4 months of siponimod treatment. The macular edema resolved after discontinuing the medication, and did not recur after resuming siponimod. CONCLUSION: Although siponimod-associated macular edema may be rare, mild, transitory, and manageable, it cannot be ignored and requires ongoing vigilance.

Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis.

Mesenchymal stem cell (MSC) transplantation is a promising treatment strategy for spinal cord injury, but immunological rejection and possible tumor formation limit its application. The therapeutic effects of MSCs mainly depend on their release of soluble paracrine factors. Exosomes are essential for the secretion of these paracrine effectors. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-EXOs) can be substituted for BMSCs in cell transplantation. However, the underlying mechanisms remain unclear. In this study, a rat model of T10 spinal cord injury was established using the impact method. Then, 30 minutes and 1 day after spinal cord injury, the rats were administered 200 µL exosomes via the tail vein (200 µg/mL; approximately 1 × 106 BMSCs). Treatment with BMSC-EXOs greatly reduced neuronal cell death, improved myelin arrangement and reduced myelin loss, increased pericyte/endothelial cell coverage on the vascular wall, decreased blood-spinal cord barrier leakage, reduced caspase 1 expression, inhibited interleukin-1ß release, and accelerated locomotor functional recovery in rats with spinal cord injury. In the cell culture experiment, pericytes were treated with interferon-γ and tumor necrosis factor-α. Then, Lipofectamine 3000 was used to deliver lipopolysaccharide into the cells, and the cells were co-incubated with adenosine triphosphate to simulate injury in vitro. Pre-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival rate. These findings suggest that BMSC-EXOs may protect pericytes by inhibiting pyroptosis and by improving blood-spinal cord barrier integrity, thereby promoting the survival of neurons and the extension of nerve fibers, and ultimately improving motor function in rats with spinal cord injury. All protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16, 2019.

[Effect of p65 gene inhibited by siRNA on differention of rat marrow mesenchymal stem cells into neurons].

OBJECTIVE: To investigate the effect of p65 gene inhibited by siRNA on neuronic differentiation in the marrow mesenchymal stem cells (MSCs). METHODS: The MSCs were transfected with Rn-p65-siRNA. Fasudil hydrochloride induced MSCs differentiating into neurons. The non-transfected group and negative control group (transfected with negative control siRNA marked by Cy3) were used as controls. The fluorescence expressed by transfected MSCs were observed under inverted fluorescence microscope at 24 h,48 h and 72 h after transfected with negative control siRNA. The viability of MSCs was detected by MTT at 24 h, 48 h and 72 h after transfected with Rn-p65-siRNA. The expressions of p65 mRNA and protein in MSCs were detected by RT-PCR and Western blot respectively. The expressions of p65 protein, NSE, MAP-2 and glial fibrillary acidic protein (GFAP) were detected by immunocytochemical method after transfection for 6 h. RESULTS: The fluorescence of MSCs was mostly displayed after transfection of 72 hours and the efficiency of transfection was up to 83.3% ± 3.8%. Meanwhile, the p65 mRNA and p65 protein expressed by MSCs of transfected group were significantly decreased (P < 0.05); MTT displayed that the viability of MSCs was also significantly reduced (P < 0.05). The best efficiency of induction was observed in the transfected group. There were higher expressions of NSE and MAP-2 than the other group (P < 0.05). CONCLUSION: The p65 gene inhibited by siRNA can promote the marrow mesenchymal stem cells to differentiate into neurons.

[Clinical research of electroacupuncture at acupoints of qijie area combined with spine balance-regulating massage on posterior circulation ischemia].

OBJECTIVE: To compare the clinical efficacy difference between electroacupuncture (EA) at qijie area combined with spine balance-regulating massage and medication for posterior circulation ischemia (PCI). METHODS: One hundred cases of PCI were randomly divided into a treatment group (50 cases) and a medication group (50 cases). The treatment group was treated with EA at Baihui (GV 20), Sishencong (EX-HN 1), Fengchi (GB 20), Shenshu (BL 23), Danzhong (CV 17), etc. in qijie area combined with spine muscle-relieving massage and comprehensive chiropractic. The medication group was treated with oral administration of nimodipine (30 mg per time, three treatments per day) and vinpocetine injection with 500 mL of glucose injection or intravenous drip of 500 mL 0.9% sodium chloride injection, once a day. Ten treatments were taken as one course in both groups, and two courses were given. The symptom score, mean resistance index (RI) of vertebral artery (VA) and basilar artery (BA), mean velocity of blood flow (Vm) and comprehensive clinical efficacy were compared before and after treatment in two groups. RESULTS: The cured and markedly effective rate was 79.6% (39/49) in the treatment group, which was superior to 54.7% (23/42) in the medication group (P<0.05). The symptom score was both significantly improved after treatment in two groups (both P<0.05), which was more obvious in the treatment group (P<0.05). The RI of VA and BA, Vm of VA and BA were significantly improved after treatment in two groups (all P<0.05), which were more obvious in the treatment group (all P<0.05). CONCLUSION: The electroacupuncture combined with spine balance-regulating massage has superior effect on improving mean velocity of blood flow and resistance index of vertebral artery and basilar artery as well as symptom score to medication, and is believed to be a safe and effective treatment for posterior circulation ischemia.

[Screening on antiosteoporotic active parts of dipsacus radix based on zebrafish model].

OBJECTIVE: Prednisolone-induced osteoporosis model using zebrafish was used to screen the antiosteoporotic active parts of Dipsacus Radix, in order to investigate the applicability and rationality of the zebrafish model of osteoporosis. METHODS: Zebrafish larvae at 5 days post fertilization (dpf) were exposed with 25 micromol/L prednisolone and 0.5% DMSO for 48 h, then except one group of 25 micromol/L prednisolone, other groups of 25 micromol/L prednisolone were treated with a range of concentration (0.025, 0.25, 2.5, 25 microg crude drug/mL) of extract of Dipsacus Radix and its different concentration ethanol elution parts of macroporous resin with 25 micromol/L prednisolone. All groups were incubated in 24-well plates (28.5 degrees C) until 10 dpf. Zebrafish skeleton at 10 dpf were anesthetized and fixed for staining with alizarin red. Quantitative analysis of the stained area was performed by microscopic inspection and digital imaging methods to reflect the amount of zebrafish head skeleton mineralization. RESULTS: The results indicated that head skeleton mineral area and integrated optical density (IOD) of 25 micromol/L prednisolone model group were significantly decreased when compared with vehicle control group, and the extract of Dipsacus Radix and its 30%, 50%, 70% and 90% ethanol elution parts of macroporous resin rescued the further bone loss of zebrafish induced by prednisolone when compared with the model group. HPLC analysis indicated that components of 30%, 50%, 70% and 90% ethanol elution parts of macroporous resin containing saponins and nonsaponins components. CONCLUSION: Both saponins and nonsaponins can prevent bone loss of zebrafish induced by prednisolone. This novel osteoporosis zebrafish model was successfully used to screen antiosteoporotic active parts of Dipsacus Radix, which had advantages of simple, high efficiency and easy to perform.

[Ideas and methods of two-dimensional zebrafish model combined with chromatographic techniques in high-throughput screening of active anti-osteoporosis components of traditional Chinese medicines].

OBJECTIVE: To break through the restrictions of the evaluation model and the quantity of compounds by using the two-dimensional zebrafish model combined with chromatographic techniques, and establish a new method for the high-throughput screening of active anti-osteoporosis components. METHOD: According to the research group-related studies and relevant foreign literatures, on the basis of the fact that the zebrafish osteoporosis model could efficiently evaluate the activity, the zebrafish metabolism model could efficiently enrich metabolites and the chromatographic techniques could efficiently separate and analyze components of traditional Chinese medicines, we proposed that the inherent combination of the three methods is expected to efficiently decode in vivo and in vitro efficacious anti-osteoporosis materials of traditional Chinese medicines. RESULT AND CONCLUSION: The method makes it simple and efficient in the enrichment, separation and analysis on components of traditional Chinese medicines, particularly micro-components and metabolites and the screening anti-osteoporosis activity, fully reflects that efficacious materials of traditional Chinese medicines contain original components and metabolites, with characteristic of "multi-components, multi-targets and integral effect", which provides new ideas and methods for the early and rapid discovery of active anti-osteoporosis components of traditional Chinese medicines.

[Significance of soluble DLL1 in diagnosis of intracranial infectious diseases in children].

OBJECTIVE: To investigate the significance of soluble DLL1 (Delta-like-1) levels of cerebrospinal fluid (CSF) and serum in the diagnosis of intracranial infection in children. METHODS: Fifty children with intracranial infection, including 20 cases of tuberculous meningitis (TM), 20 cases of viral meningitis (VM) and 10 cases of purulent meningitis (PM), and 20 children without intracranial infection (control group) were enrolled. The levels of soluble DLL1 in CSF and serum were measured using ELISA. RESULTS: The level of CSF soluble DLL1 in the TM group was significantly higher than that in the VM, PM and control groups (2.89 ± 1.72 ng/mL vs 0.14 ± 0.14 ng/mL, 0.27 ± 0.21 ng/mL, 0.13 ± 0.12 ng/mL; P<0.01). The level of serum soluble DLL1 in the TM group was also significantly higher than that in the VM, PM and control groups (12.61 ± 6.45 ng/mL vs 2.28 ± 2.27 ng/mL, 2.38 ± 1.79 ng/mL, 2.26 ± 2.10 ng/mL; P<0.01). The levels of soluble DLL1 in the CSF and serum in the VM and PM groups were not significantly different from those in the control group. CONCLUSIONS: Soluble DLL1 as a novel indicator might have potentially important value in the diagnosis of TM.

Expression and significance of DSCAM in the cerebral cortex of APP transgenic mice.

Down syndrome cell adhesion molecule (DSCAM) plays important roles in the regulation of synaptogenesis, neurite outgrowth, axon guidance and synapse formation. Overexpression of DSCAM in Down syndrome (DS) may be involved in the pathogenesis of mental retardation through an inhibitory action on synaptogenesis/neurite outgrowth, and in the precocious dementia associated with an amyloid precursor protein (APP) dosage effect with enhanced plaque formation. In this report we examined the expression of DSCAM in the cerebral cortex of APP transgenic mice versus age-matched wild-type mice. We found that the level of DSCAM expression increased with increasing age in both groups of mice, up to a maximum at 3 months old. The level of DSCAM expression in APP transgenic mice was significantly higher than in the age-matched wild types. We propose that overexpression of DSCAM in the cerebral cortex might play an important role in the learning and memory defects of APP transgenic mice.

[Effect of notch signaling on differentiation of rat marrow mesenchymal stem cells into neurons induced by fasudil hydrochloride].

OBJECTIVE: To investigate the effect of notch signaling on differentiation of rat bone marrow mesenchymal stem cells (MSCs) into neurons induced by fasudil hydrochloride. METHODS: The experiments were divided into non-transfected group, transfected group (transfected with Rn-Notch1-siRNA), positive control group (transfected with Rn-MAPK-1 Control siRNA) and negative control group (transfected with negative control siRNA). Fasudil hydrochloride induced MSCs differentiating into neurons. The fluorescence expressed by transfected MSCs were observed under inverted fluorescence microscope. The expression of notch1 mRNA, Hes1 mRNA and MAPK1 mRNA in MSCs was detected by RT-PCR. The expression of Notch1 protein, NSE, neurofilament M (NF-M) and glial fibrillary acidic protein(GFAP)was detected by immunocytochemical method. The viability of MSCs was detected by MTT. RESULTS: (1) The fluorescence of MSCs was mostly displayed after transfection for 72 h and the efficiency of transfection was up to 91.3% +/- 4.2%. Meanwhile, the notch1 mRNA and Hes1 mRNA expressed by MSCs of transfected group were significantly decreased (P < 0.05) and MTT displayed that the viability of MSCs was also significantly reduced (P < 0.05). (2) Fasudil hydrochloride could induce MSCs differentiate into neurons and the best efficiency of induction was observed in the transfected group. There was higher expression of NSE and neurofilament-M (NF-M) than the other groups (P < 0.05). CONCLUSION: There may be notch1 signaling and Rho/Rho GTPase signaling synergy on differentiation of rat bone marrow stromal cell into neurons induced by fasudil hydrochloride and they jointly promote the differentiation of MSCs into neurons.