Inhibition of complement C3 signaling ameliorates locomotor and visual dysfunction in autoimmune inflammatory diseases.

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by transverse myelitis and optic neuritis. The pathogenic serum IgG antibody against the aquaporin-4 (AQP4) on astrocytes triggers the activation of the complement cascade, causing astrocyte injury, followed by oligodendrocyte injury, demyelination, and neuronal loss. Complement C3 is positioned as a central player that relays upstream initiation signals to activate downstream effectors, potentially stimulating and amplifying host immune and inflammatory responses. However, whether targeting the inhibition of C3 signaling could ameliorate tissue injury, locomotor defects, and visual impairments in NMO remains to be investigated. In this study, using the targeted C3 inhibitor CR2-Crry led to a significant decrease in complement deposition and demyelination in both slice cultures and focal intracerebral injection models. Moreover, the treatment downregulated the expression of inflammatory cytokines and improved motor dysfunction in a systemic NMO mouse model. Similarly, employing serotype 2/9 adeno-associated virus (AAV2/9) to induce permanent expression of CR2-Crry resulted in a reduction in visual dysfunction by attenuating NMO-like lesions. Our findings reveal the therapeutic value of inhibiting the complement C3 signaling pathway in NMO.

Determination of Mouth Width for Facial Reconstruction Based on Statistical Regression Model.

INTRODUCTION: It is important to generate predictable statistical models by increasing the number of variables on the human skeletal and soft tissue structures on the face to increase the accuracy of human facial reconstructions. The purpose of this study was to determine mouth width 3-dimensionally based on statistical regression model. MATERIAL AND METHODS: Cone-beam computed tomography scan data from 130 individuals were used to measure the horizontal and vertical dimensions of orbital and nasal structures and intercanine width. The correlation between these hard tissue variables and the mouth width was evaluated using the statistical regression model. RESULTS: Orbital width, nasal width, and intercanine width were found to be strong predictors of the mouth width determination and were used to generate the regression formulae to find the most approximate position of the mouth. CONCLUSION: These specific variables may contribute to improving the accuracy of mouth width determination for oral and maxillofacial reconstructions.

Remyelination in neuromyelitis optica spectrum disorder is promoted by edaravone through mTORC1 signaling activation.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)-derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO-IgG-induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO-IgG-treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.

hnRNPA2B1 promotes the occurrence and progression of hepatocellular carcinoma by downregulating PCK1 mRNA via a m6A RNA methylation manner.

BACKGROUND: N6-methyladenosine (m6A) is the most prevalent RNA modification. Although hnRNPA2B1, as a reader of m6A modification, has been reported to promote tumorigenesis in a few types of tumors, its role in hepatocellular carcinoma (HCC) and the underlying molecular mechanism remains unclear. METHODS: Multiple public databases were used to analyze the expression of hnRNPA2B1 in HCC and its correlation with survival prognosis. We employed a CRISPR-Cas9 sgRNA editing strategy to knockout hnRNPA2B1 expression in HCC cells. The biological function of hnRNPA2B1 in vitro in HCC cells was measured by CCK8, colony formation, migration, and invasion assay. The tumorigenic function of hnRNPA2B1 in vivo was determined by a subcutaneous tumor formation experiment and a HCC mouse model via tail injection of several plasmids into the mouse within 5s-7s. RNA binding protein immunoprecipitation (RIP) experiment using hnRNPA2B1 was performed to test the target genes of hnRNPA2B1 and methylated RNA immunoprecipitation (MeRIP) assay was performed to explore the m6A methylated mRNA of target genes. RESULTS: hnRNPA2B1 highly expressed in HCC tissues, correlated with high grades and poor prognosis. Its knockout reduced HCC cell proliferation, migration, and invasion in vitro, while overexpression promoted these processes. hnRNPA2B1-knockout cells inhibited tumor formation in graft experiments. In HCC mice, endogenous knockout attenuated hepatocarcinogenesis. RNA-seq showed downregulated gluconeogenesis with high hnRNPA2B1 expression. hnRNPA2B1 negatively correlated with PCK1, a key enzyme. RIP assay revealed hnRNPA2B1 binding to PCK1 mRNA. hnRNPA2B1 knockout increased m6A-methylation of PCK1 mRNA. Interestingly, PCK1 knockout partially counteracted tumor inhibition by hnRNPA2B1 knockout in mice. CONCLUSION: Our study indicated that hnRNPA2B1 is highly expressed in HCC and correlated with a poor prognosis. hnRNPA2B1 promotes the tumorigenesis and progression of HCC both in vitro and in vivo. Moreover, hnRNPA2B1 downregulates the expression of PCK1 mRNA via a m6A methylation manner. More importantly, the ability of hnRNPA2B1 to induce tumorigenesis and progression in HCC is dependent on its ability to decrease the expression of PCK1. Therefore, this study suggested that hnRNPA2B1 might be a diagnostic marker of poor prognosis of HCC and a potential therapeutic target for HCC patients.

Design of compact off-axis freeform imaging systems based on optical-digital joint optimization.

Using a freeform optical surface can effectively reduce the imaging system weight and volume while maintaining good performance and advanced system specifications. But it is still very difficult for traditional freeform surface design when ultra-small system volume or ultra-few elements are required. Considering the images generated by the system can be recovered by digital image processing, in this paper, we proposed a design method of compact and simplified off-axis freeform imaging systems using optical-digital joint design process, which fully integrates the design of a geometric freeform system and the image recovery neural network. This design method works for off-axis nonsymmetric system structure and multiple freeform surfaces with complicated surface expression. The overall design framework, ray tracing, image simulation and recovery, and loss function establishment are demonstrated. We use two design examples to show the feasibility and effect of the framework. One is a freeform three-mirror system with a much smaller volume than a traditional freeform three-mirror reference design. The other is a freeform two-mirror system whose element number is reduced compared with the three-mirror system. Ultra-compact and/or simplified freeform system structure as well as good output recovered images can be realized.

Prevalence and associated factors of minimally invasive facial cosmetic surgery in Chinese college students.

BACKGROUND: Minimally invasive facial cosmetic surgery (MIFCS) is becoming more and more popular and acceptable in Chinese young people, and it influences people in many aspects. However, there is little research on the associations between MIFCS and psychopathology in Chinese college students. The purpose of this study was to identify the prevalence of MIFCS and its associated factors among Chinese college students. METHODS: A cross-sectional design was applied in this study. A total of 8089 students completed an online questionnaire on demographic data, depressive symptoms (Self-Rating Depression Scale), anxiety symptoms (Self-Rating Anxiety Scale) and MIFCS. Logistic regression was used to identify independent factors associated with MIFCS. RESULTS: The prevalence of MIFCS in Chinese college students was 2.7% (221/8098). Students with MIFCS were more likely to be from urban areas, from a single child household, experience depression or anxiety and have a history of smoking (all p < 0.05). They were also less likely to be right-handed or have a good relationship with father or mother (all p < 0.05). Binary logistic regression showed that older age (OR,1.162; 95%CI [1.061,1.273]), female sex (OR,1.837; 95%CI [1.352, 2.497]), community (urban) (OR,0.601; 95%CI [0.441,0.818]), right-handedness (OR,0.668; 95%CI [0.454,0.985]), depressive symptoms (OR, 4.708; 95%CI [1.690,13.112]), family income (30,000-70,000 yuan per year) (OR,0.572; 95%CI [0.403,0.812]) and smoking (OR,1.571; 95%CI [1.09,2.423]) were independently associated with MIFCS. CONCLUSIONS: Minimally invasive facial cosmetic surgery (MIFCS) is very common in Chinese college students, indicating the importance of paying attention to MIFCS. This study provides valuable evidence for college counselors and doctors in the cosmetic department to provide better and healthier services to students who undergo MIFCS, especially those with depressive symptoms.

Define Mesenchymal Stem Cell from Its Fate: Biodisposition of Human Mesenchymal Stem Cells in Normal and Concanavalin A-Induced Liver Injury Mice.

The pharmaceutical industry and clinical trials have been revolutionized mesenchymal stem cell-based therapeutics. However, the pharmacokinetics of transplanted cells has been little characterized in their target tissues under healthy or disease condition. A quantitative polymerase chain reaction analytical method with matrix effect was developed to track the biodistribution of human mesenchymal stem cells in normal mice and those with Concanavalin A (Con A)-induced liver injury. Mesenchymal stem/stromal cell (MSC) disposition in blood and different organs were compared, and relevant pharmacokinetic parameters were calculated. Human MSCs (hMSCs) and mouse MSCs (mMSCs) displayed a very similar pharmacokinetic profile in all tested doses: about 95% of the detected hMSCs accumulated in the lung and 3% in the liver, and almost negligible cells were detected in other tissues. A significant double peak of hMSC concentration emerged in the lung within 1-2 hours after intravenous injection, as with mMSCs. Prazosin, a vasodilator, could eliminate the second peak in the lung and increase its Cmax and area under the concentration-time curve (AUC) by 10% in the first 2 hours. The injury caused by Con A was significantly reduced by hMSCs, and the Cmax and AUC0-8 (AUC from time 0 to 8 hours) of cells in the injured liver decreased by 54 and 50%, respectively. The Cmax and AUC would be improved with the alleviation of congestion through the administration of heparin. The study provides a novel insight into the pharmacokinetics of exogenous MSCs in normal and Con A-induced liver injury mice, which provides a framework for optimizing cell transplantation. SIGNIFICANCE STATEMENT: Mesenchymal stem/stromal cells (MSCs) are known for their potential as regenerative therapies in treating several diseases, but an insufficient understanding of the pharmacokinetics of MSCs restricts their future application. The current study was the first to elucidate the pharmacokinetics and possible factors, including dosage, species, and derived sources, in a systematic way. The study further revealed that Concanavalin A-induced liver injury significantly prevented cells from entering the injury site, which could be reversed by the diminished congestion achieved by heparin.

Involvement of α7nAChR in the Protective Effects of Genistein Against ß-Amyloid-Induced Oxidative Stress in Neurons via a PI3K/Akt/Nrf2 Pathway-Related Mechanism.

Abnormal excessive production and deposition of ß-amyloid (Aß) peptides in selectively susceptible brain regions are thought to be a key pathogenic mechanism underlying Alzheimer's disease (AD), resulting in memory deficits and cognitive impairment. Genistein is a phytoestrogen with great promise for counteracting diverse Aß-induced insults, including oxidative stress and mitochondrial dysfunction. However, the exact molecular mechanism or mechanisms underlying the neuroprotective effects of genistein against Aß-induced insults are largely uncharacterized. To further elucidate the possible mechanism(s) underlying these protective effects, we investigated the neuroprotective effects of genistein against Aß-induced oxidative stress mediated by orchestrating α7 nicotinic acetylcholine receptor (α7nAChR) signaling in rat primary hippocampal neurons. Genistein significantly increased cell viability, reduced the number of apoptotic cells, decreased accumulation of reactive oxygen species (ROS), decreased contents of malondialdehyde (MDA) and lactate dehydrogenase (LDH), upregulated BCL-2 expression, and suppressed Caspase-3 activity occurring after treatment with 25 µM Aß25-35. Simultaneously, genistein markedly inhibited the decreases in α7nAChR mRNA and protein expression in cells treated with Aß25-35. In addition, α7nAChR signaling was intimately involved in the genistein-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt and Nrf2/keap1 signaling. Thus, α7nAChR activity together with the PI3K/Akt/Nrf2 signaling cascade likely orchestrates the molecular mechanism underlying the neuroprotective effects of genistein against Aß-induced oxidative injury.

Decreased immunomodulatory and secretory capability of aging human umbilical cord mesenchymal stem cells in vitro.

Mesenchymal stem cell therapy has drawn much attention as a promising therapeutic option for the treatment of different diseases. Due to insufficient cell population derived from freshly isolated tissues, in vitro propagation is required prior to clinical use. However, reduced cell viability of aging mesenchymal stem cell (MSCs) with repeated propagations has yet not be fully investigated, especially for the biological characteristics of immunoregulatory ability and paracrine factors. In this study, we compared the biological properties of human umbilical cord-MSCs (hUC-MSCs) at different passages, especially for immunomodulatory ability and secretions. Our results showed that hUC-MSCs at early passage (P2) and late passage (P8) exhibited similar morphology and surface marker expression, but hUC-MSCs at P8 displayed reduced proliferation and differentiation potential, immunoregulatory and secretory ability. In particular, hUC-MSCs at P2 and P5 could significantly suppress the population of proinflammatory Th1 and Th17 cell subsets and upregulate Treg cells, but not with hUC-MSCs at P8. For paracrine mechanism, higher level of secretions such as growth factors, cell adhesions, anti-inflammatory factors of hUC-MSCs were observed at P2 and P5 compared to that at P8. Therefore, it is essential to verify and validate the biological characteristics of hUC-MSCs that possess a good vitality before they are released for clinical use. Altogether, this study provides a rationale and two important parameters for how to select appropriate passage and vitality of MSCs for cell therapy.

Internet addiction among college students in a Chinese population: Prevalence, correlates, and its relationship with suicide attempts.

BACKGROUND: Internet addiction is common, but its relationship with suicide attempts is rarely reported among Chinese college students. This study aimed to investigate the prevalence and correlates of internet addiction among Chinese college students. METHODS: A cross-sectional study was conducted among 8,098 college students in Hunan province, China. We collected the following data: demographic variables, suicidal behaviors, internet addiction (Revised Chinese Internet Addiction Scale), depression (Self-reporting Depression Scale), and anxiety (Self-Rating Anxiety Scale). RESULTS: The prevalence of internet addiction was 7.7% in these Chinese college students. Logistic regression analysis showed that good relationship with mother (1.730 [1.075, 2.784]), good relationship with father (0.615 [0.427, 0.885]), family history of mental disorders (2.291 [1.122, 4.676]), anxiety (1.987 [1.382, 2.857]), depression (2.016 [1.384, 2.937]), suicidal ideation (2.266 [1.844, 2.784]), and suicide attempts (1.672 [1.258, 2.224]) were independent correlates for internet addiction, the adjusted R square for this model is 13.7%. Furthermore, the prevalence of suicide attempts among internet addiction participants was 21.4%, and anxiety (3.397 [1.058, 10.901]), suicidal ideation (26.984 [11.538, 63.112]), and suicide plans (8.237 [3.888, 17.451]) were the independent predictors for suicide attempts, the adjusted R square for this model is 51.6%. CONCLUSION: Our results show that internet addiction is common among Chinese college students. In addition, suicide attempts are very common among internet addicts, suggesting that special measures and attention should be provided to these students according to risk factors to prevent their suicidal behavior.

A multi-institutional and cross-sectional study on empathy in Chinese medical students: differences by student cadre or not, future career preference, and father's education status.

BACKGROUND: The aims of this study were to examine the factor structure of the Chinese version of the Jefferson Scale of Empathy for medical students (JSE-S) and investigate differences in empathy scores among Chinese medical students according to gender, student cadre or not, future career preference, and parents' education. METHODS: Medical students from three universities completed an online questionnaire containing the JSE-S. Exploratory factor analysis was conducted to determine the factor structure, and group comparisons of empathy scores were examined via t-tests and analysis of variance. RESULTS: Four factors emerged from the factor analysis: "perspective taking," "compassionate care," "standing in the patient's shoes," and an uninterpretable factor. The results indicated that students who were female, held positions as student cadres, preferred to become a doctor, and whose fathers had a high school education or below tended to have more empathy. CONCLUSIONS: Overall, the findings provide information on the dimensions of empathy applicable to Chinese medical students and confirm the factors found in the original measure. The dimensions have implications for developing empathy among medical students throughout the world. Educators can use the information to design interventions to foster empathy among students in the context of medical education reform in many countries, including China.

Patients with suspected benign tumors and glial fibrillary acidic protein autoantibody: an analysis of five cases.

Aim: To investigate the clinical features of five glial fibrillary acidic protein (GFAP) antibody positive patients with suspected benign tumors and explore its underlying pathogenesis. Materials and methods: Overall, 1018 serum and cerebrospinal fluid (CSF) samples were tested by indirect immunofluorescence assay and data from five patients with suspected tumors and positive for GFAP autoantibody in the CSF were analyzed retrospectively. Results: The positive rate of GFAP antibody in the serum and CSF was 3.93% by indirect immunofluorescence assay. Tumors were diagnosed before or after neurologic onset in 5 of 40 patients (12.5%) and no deterioration of the tumors was found during the long-term follow-up. Of the five patients, one patient suffered a thyroid nodule, one patient had a small nodule in the left lung, two patients suffered meningiomas, and one patient had a suspicious eosinophilic granuloma. Conclusion: GFAP autoimmunity may be a paraneoplastic immune response with a low frequency of tumor in Chinese patients with GFAP astrocytopathy.

Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer.

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using γ-secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa.

Glutamic Acid Decarboxylase Antibody in a Patient with Myelitis: A Retrospective Study.

OBJECTIVE: The aim of this study was to evaluate the positive rate of serum glutamic acid decarboxylase (GAD) autoantibody in patients with myelitis and to describe the clinical findings in patients with positive GAD antibody. METHODS: Serum samples were collected from 390 patients with myelitis, including 210 patients positive for aquaporin 4 (AQP4) antibody and 180 patients negative for AQP4. GAD65 antibody was measured by an indirect immunofluorescence assay. RESULTS: Only 1 serum and cerebral spinal fluid sample from 390 patients (0.26%) was positive for anti-GAD antibodies. The patient was a female with relapsing myelitis and a thymic mass. Thymic resection was undertaken, and pathological examination revealed a benign thymic cyst. Extensive infiltration of lymphocytes positive for CD3, CD4, CD8 and CD20 was found. Immunohistochemistry showed positive expression of GAD65 in the cyst. CONCLUSIONS: Although serum GAD65 antibodies were present in a patient, it is not recommended to routinely screen for GAD65 antibodies in patients with myelitis because of their rare occurrence. However, screening for GAD65 antibodies should be considered in patients who have been diagnosed with cancer or a thymic abnormality.

Empathy in Chinese eight-year medical program students: differences by school year, educational stage, and future career preference.

BACKGROUD: To examine the psychometric properties of a Chinese translation of the Jefferson Scale of Empathy (Student-version, JSE-S), and to study differences in empathy scores among eight-year undergraduate medical students across gender, year of study, and future career preference. METHODS: The JSE-S was administered to 442 participants from December 2016 to July 2017, who were all first- to seventh-year students on an eight-year medical education course at Fudan University. Factor analysis was used to examine the underlying components of the Chinese version of the JSE-S. The data analyses comprised a t-test and analyses of variance. RESULTS: Factor analysis confirmed four components: perspective taking, compassionate care, ability to stand in patient's shoes, and difficulties in adopting patient's perspective. The lowest empathy score was found in the seventh-year students (99.5), while a decline was found across school years. Students in clinical training (sixth/seventh year) had lower empathy than students in premedical study (first/second year), basic medicine (third/fourth year), and clinical medicine (fifth year). Statistically significant differences in empathy mean scores were found in respect of future career preference but not gender. Students who preferred not to become doctors had lower empathy than students who preferred to become doctors, who were undecided, and who did not specify. CONCLUSIONS: The findings support the construct validity and reliability of the Chinese version of the JSE-S for medical students. The study also revealed the features of empathy in eight-year program students, and provided a reliable reference to design interventions to cultivate empathy among Chinese medical students.

Treatment of Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: Follow-Up in 7 Cases.

OBJECTIVE: The aim of this work was to report an autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy with long-term follow-up in 7 patients. METHODS: Antibodies were detected by indirect immunofluorescence assay and patient data were analyzed retrospectively. RESULTS: Seven patients (4 female, 3 male) with ≥1 year follow-up were included. All patients had positive GFAP antibodies in their cerebral spinal fluid (CSF). Their median age at disease onset was 56 years (range 27-69) and the median disease duration was 1 year (range 1-4). In the initial attack, all patients received intravenous methylprednisolone (IVMP) followed by oral steroids, which were tapered. Six patients received intravenous immunoglobulin (IVIg). One patient had no response to IVIg and IVMP. Four patients received immunosuppressive agents. Five patients underwent the second lumbar puncture after treatment. CSF white blood cell counts, protein levels, and antibody titers were significantly decreased. CSF protein levels correlated positively with the Expanded Disability Status Scale score, which was elevated at each lumbar puncture. Four patients experienced relapse. To date, 6 patients had a bad prognosis, of which 2 died. CONCLUSIONS: Some patients with GFAP astrocytopathy experienced a poor response to treatment although they received steroids and immunosuppressive agents.

Chemical conversion of mouse fibroblasts into functional dopaminergic neurons.

Ectopic expression of lineage-specific transcription factors facilitates the conversion of mammalian somatic cells into dopaminergic (DA) neurons, which is a promising strategy for cell therapy of Parkinson's disease (PD). However, this approach still has some drawbacks limiting its clinical application due to the potential risks of integrating vectors into the host genome. Therefore, it is critical to seek a more desired approach to generate DA neurons derived from mammalian somatic cells. Here, we report that mouse embryonic fibroblasts (MEFs) can be efficiently converted into DA neurons by using small molecules along with specific growth factors. These neuron-like cells generate DA neuronal morphology, and acquire immunocytochemical and calcium imaging special for neuronal electrophysiological profile. More importantly, these converted cells can secrete dopamine, indicating that they are functionally similar to DA neurons. Taken together, our study might provide a promising cell source for treating PD by using chemical approach without introduction of exogenous transcription factors.

Anti-KIR4.1 Antibodies in Chinese Patients with Central Nervous System Inflammatory Demyelinating Disorders.

OBJECTIVES: The aim of this study was to explore the frequency of KIR4.1 antibodies in patients with multiple sclerosis (MS) and in control groups using a cell-based assay. MATERIALS AND METHODS: A transfected HEK-293A cell line expressing KIR4.1 was established to test for the presence of KIR4.1 antibodies in blood serum. We tested 904 subjects, including 188 patients with MS, 264 patients with neuromyelitis optica spectrum disorders (NMOSD), 209 patients with other inflammatory neurologic disease (OIND), 203 patients with other noninflammatory neurological disease (OND), and 40 healthy controls. RESULTS: KIR4.1 antibodies were present in 23 of the 188 (12.2%) MS patients, 42 of the 264 (15.9%) NMOSD patients, 32 of the 209 (15.3%) OIND patients, 24 of the 203 (11.8%) OND patients, and 2 of the 40 (5%) healthy controls. There were no significant differences among the MS and control groups (p = 0.279). CONCLUSIONS: Anti-KIR4.1 antibody, as determined by a cell-based assay, is not a specific biomarker for MS.

Unfolded protein response is required for the definitive endodermal specification of mouse embryonic stem cells via Smad2 and ß-catenin signaling.

Tremendous efforts have been made to elucidate the molecular mechanisms that control the specification of definitive endoderm cell fate in gene knockout mouse models and ES cell (ESC) differentiation models. However, the impact of the unfolded protein response (UPR), because of the stress of the endoplasmic reticulum on endodermal specification, is not well addressed. We employed UPR-inducing agents, thapsigargin and tunicamycin, in vitro to induce endodermal differentiation of mouse ESCs. Apart from the endodermal specification of ESCs, Western blotting demonstrated the enhanced phosphorylation of Smad2 and nuclear translocation of ß-catenin in ESC-derived cells. The inclusion of the endoplasmic reticulum stress inhibitor tauroursodeoxycholic acid to the induction cultures prevented the differentiation of ESCs into definitive endodermal cells even when Activin A was supplemented. Also, the addition of the TGF-ß inhibitor SB431542 and the Wnt/ß-catenin antagonist IWP-2 negated the endodermal differentiation of ESCs mediated by thapsigargin and tunicamycin. These data suggest that the activation of the UPR appears to orchestrate the induction of the definitive endodermal cell fate of ESCs via both the Smad2 and ß-catenin signaling pathways. The prospective regulatory machinery may be helpful for directing ESCs to differentiate into definitive endodermal cells for cellular therapy in the future.

AhR-STAT3-HO-1/COX-2 signalling pathway may restrict ferroptosis and improve hMSC accumulation and efficacy in mouse liver.

BACKGROUND AND PURPOSE: The low efficacy of mesenchymal stem cells (MSCs) has restricted their application in the treatment of liver disease. Emerging evidence suggested that ferroptosis may provoke hepatocyte dysfunction and exacerbate damage to the liver microenvironment. Here, we have investigated the contribution of liver ferroptosis to the elimination and effectiveness of human MSC (hMSC). Furthermore, potential links between liver ferroptosis and aryl hydrocarbon receptors (AhR) were explored. EXPERIMENTAL APPROACH: Two mouse models, iron supplement-induced hepatic ferroptosis and hepatic ischaemia/reperfusion (I/R) injury, were used to identify effects of ferroptosis on hMSC pharmacokinetics (PK)/pharmacodynamics (PD). KEY RESULTS: AhR inhibition attenuated hepatic ferroptosis and improved survival of hMSCs. hMSC viability was decreased by iron supplementation or serum from I/R mice. The AhR antagonist CH223191 reversed iron overload and oxidative stress induced by ferroptosis and increased hMSC concentration and efficacy in mouse models. Effects of CH223191 were greater than those of deferoxamine, a conventional ferroptosis inhibitor. Transcriptomic results suggested that the AhR-signal transducer and activator of transcription 3 (STAT3)-haem oxygenase 1/COX-2 signalling pathway is critical to this process. These results were confirmed in a mouse model of hepatic I/R injury. In mice pre-treated with CH223191, hMSC exhibited more potent protective effects, linked to decreased hepatic ferroptosis. CONCLUSION AND IMPLICATIONS: Our findings showed that ferroptosis was a critical factor in determining the fate of hMSCs. Inhibition of AhR decreased hepatic ferroptosis, thereby increasing survival and therapeutic effects of hMSCs in mouse models of liver disease.