TsMS combined with EA promotes functional recovery and axonal regeneration via mediating the miR-539-5p/Sema3A/PlexinA1 signalling axis in sciatic nerve-injured rats.

Enhancing axonal regeneration is one of the most important processes in treating nerve injuries. Both magnetic and electrical stimulation have the effect of promoting nerve axon regeneration. But few study has investigated the effects of trans-spinal magnetic stimulation (TsMS) combined with electroacupuncture (EA) on nerve regeneration in rats with sciatic nerve injury. In this study, we compared the improvement of neurological function in rats with sciatic nerve crush injuries after 4 weeks of different interventions (EA, TsMS, or TsMS combined with EA). We further explored the morphological and molecular biological alterations following sciatic nerve injury by HE, Masson, RT-PCR, western blotting, immunofluorescence staining and small RNA transcriptome sequencing. The results showed that TsMS combined with EA treatment significantly promoted axonal regeneration, increased the survival rate of neurons, and suppressed denervation atrophy of the gastrocnemius muscle. Subsequent experiments suggested that the combination treatment may play an active role by mediating the miR-539-5p/Sema3A/PlexinA1 signaling axis.

Bisdemethoxycurcumin, a curcumin derivative, ameliorates adjuvant-induced arthritis by suppressing inflammatory reactions and macrophage migration.

Rheumatoid arthritis (RA) is a highly prevalent and chronic inflammatory synovial joint disease manifested by hyperplasia and continuous inflammation. Curcumin (Cur) has been studied for alleviating RA. However, poor stability and oral bioavailability restrict its therapeutic value. Bisdemethoxycurcumin (BDMC), a curcumin (Cur) derivative, exerts better stability and oral bioavailability than Cur. However, the efficacy of BDMC on RA has not been fully clarified. The aim of the study was to investigate the therapeutic effects and underlying mechanisms of BDMC on RA. The in-vivo anti-arthritic activity of BDMC was determined via adjuvant-induced arthritis (AIA) rat model. Paw swelling, body weight, arthritic index, and histopathological assessments were performed. RAW264.7 cell was stimulated by lipopolysaccharides (LPS) in vitro. The cell viability were determined by CCK8 assay, while the migration ability was determined using cell wound healing and transwell assays. Furthermore, in-vivo and in-vitro levels of pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) were assayed by ELISA, and that of IκBα, p-NF-κB, NF-κB, and COX-2 were assessed via Western blot or immunofluorescence. In AIA rat model, it suggested a higher anti-arthritic activity of BDMC than Cur, including amelioration of swelling in hind paws, reduced arthritic index, and alleviated histopathological injury in rats. Furthermore, BDMC also substantially decreased the levels of the aforementioned pro-inflammatory cytokines in both in-vivo and in-vitro, inhibited the IκBα degradation, down-regulated the COX-2 levels and p-NF-κB/NF-κB ratio in AIA rats and LPS-stimulated RAW264.7 cells. Additionally, BDMC showed an inhibitory effect on the migration of LPS-stimulated RAW264.7 cells. BDMC could effectively ameliorate RA by suppressing inflammatory reactions and inhibiting macrophage migration, more potentially than Cur.

Exosomal Non-coding RNAs: A New Approach to Melanoma Diagnosis and Therapeutic Strategy.

Malignant melanoma (MM) is a highly aggressive cancer with a poor prognosis. Currently, although a variety of therapies are available for treating melanoma, MM is still a serious threat to the patient's life due to numerous factors, such as the recurrence of tumors, the emergence of drug resistance, and the lack of effective therapeutic agents. Exosomes are biologically active lipid-bilayer extracellular vesicles secreted by diverse cell types that mediate intercellular signal communication. Studies found that exosomes are involved in cancer by carrying multiple bioactive molecules, including non-- coding RNAs (ncRNAs). The ncRNAs have been reported to play an important role in regulating proliferation, angiogenesis, immune regulation, invasion, metastasis, and treatment resistance of tumors. However, the functional role of exosomal ncRNAs in MM remains unknown. Therefore, this review summarizes the current state of melanoma diagnosis, treatment, and the application of exosomal ncRNAs in MM patients, which may provide new insights into the mechanisms involved in melanoma progression and serve as biomarkers for diagnosis and therapeutic targets.

Exploring the ability of vocal biomarkers in distinguishing depression from bipolar disorder, schizophrenia, and healthy controls.

Background: Vocal features have been exploited to distinguish depression from healthy controls. While there have been some claims for success, the degree to which changes in vocal features are specific to depression has not been systematically studied. Hence, we examined the performances of vocal features in differentiating depression from bipolar disorder (BD), schizophrenia and healthy controls, as well as pairwise classifications for the three disorders. Methods: We sampled 32 bipolar disorder patients, 106 depression patients, 114 healthy controls, and 20 schizophrenia patients. We extracted i-vectors from Mel-frequency cepstrum coefficients (MFCCs), and built logistic regression models with ridge regularization and 5-fold cross-validation on the training set, then applied models to the test set. There were seven classification tasks: any disorder versus healthy controls; depression versus healthy controls; BD versus healthy controls; schizophrenia versus healthy controls; depression versus BD; depression versus schizophrenia; BD versus schizophrenia. Results: The area under curve (AUC) score for classifying depression and bipolar disorder was 0.5 (F-score = 0.44). For other comparisons, the AUC scores ranged from 0.75 to 0.92, and the F-scores ranged from 0.73 to 0.91. The model performance (AUC) of classifying depression and bipolar disorder was significantly worse than that of classifying bipolar disorder and schizophrenia (corrected p < 0.05). While there were no significant differences in the remaining pairwise comparisons of the 7 classification tasks. Conclusion: Vocal features showed discriminatory potential in classifying depression and the healthy controls, as well as between depression and other mental disorders. Future research should systematically examine the mechanisms of voice features in distinguishing depression with other mental disorders and develop more sophisticated machine learning models so that voice can assist clinical diagnosis better.

Diagnostic efficiency and psychometric properties of CBCL DSM-oriented scales in a large sample of Chinese school-attending students aged 5-16.

BACKGROUND: Children and adolescents are vulnerable to various psychiatric disorders during the critical phase of individual development. In China, the child behavior checklist (CBCL) is a widely employed psychometric questionnaire for assessing children and adolescents. However, further validation of the psychometric properties and diagnostic effectiveness of the CBCL DSM-oriented scales is necessary. These scales were developed based on DSM diagnosis and require evaluation using a substantial sample of Chinese individuals. METHODS: This study involved the analysis of a substantial dataset consisting of 72,109 samples collected from five provinces in China. Data was gathered using the CBCL (Parent Rating Scale), and rigorous assessments of reliability and validity were conducted. The mini-international neuropsychiatric interview for children and adolescents (MINI-KID) and the diagnostic and statistical manual of mental disorders-IV (DSM-IV) interview were employed to diagnose the participants. To ensure the accuracy of the diagnoses, receiver operating characteristic curve (ROC curves) were utilized, and the Youden Index was calculated to determine the appropriate diagnostic cut-off point for each specific target diagnosis. RESULTS: The study included a total sample of 72,109 cases, out of which 19,782 cases underwent MINI-KID assessment and structured or semi-structured interviews based on DSM-IV to clarify the diagnosis. Reliability and validity analyses showed that the reliability of the subscales and total scales was good, except for Anxiety Problems. The Cronbach's alpha for the CBCL DSM-oriented scales was 0.92. In addition, the validity of all scales was good (CFI = 0.80). For the sample with a clear diagnosis, all five subscales of the CBCL DSM-oriented scales showed fair diagnostic efficiency for the target diagnosis. Among them, the area under curves (AUC) of Mood disorder, Anxiety, Attention deficit and hyperactivity disorder (ADHD), Oppositional defiant disorder (ODD) and Conduct disorder (CD) are 0.80, 0.74, 0.75, 0.74, 0.74. Among the three sample groups, the highest diagnostic efficiency was found in Affective Problems to Mania. The diagnostic cut-off point for each subscale on target diagnoses was clearly defined. CONCLUSION: Overall, the reliability, validity and diagnostic efficiency of CBCL DSM-oriented scales in Chinese children and adolescents were within acceptable limits. In addition, we used ROC curves and cut-off points to predict the cut-off values of common child and adolescent psychiatric disorders mentioned in the CBCL DSM-oriented scales. This provides an important reference for the clinical application of the CBCL DSM-oriented scales in Chinese samples.

Spectral characteristics of the correlation between elemental arsenic and vegetation stress in the Yueliangbao gold mining.

Some soils in the Yueliangbao gold mining area have been contaminated by heavy metals, resulting in variations in vegetation. Hyperspectral remote sensing provides a new perspective for heavy metal inversion in vegetation. In this paper, we collected ground truth spectral data of three dominant vegetation species, Miscanthus floridulus, Equisetum ramosissimum and Eremochloa ciliaris, from contaminated and healthy non-mining areas of the Yueliangbao gold mining region, and determined their heavy metal contents. Firstly, we compared the spectral characteristics of vegetation in the mining and non-mining areas by removing the envelope and derivative transformation. Secondly, we extracted their characteristic identification bands using the Mahalanobis distance and PLS-DA method. Finally, we constructed the inverse model by selecting the vegetation index (such as the PRI, DCNI, MTCI, etc.) related to the characteristic band combined with the heavy metal content. Compared to previous studies, we found that the pollution level in the Yueliangbao gold mining area had greatly reduced, but arsenic metal pollution remained a serious issue. Miscanthus floridulus and Eremochloa ciliaris in the mining area exhibited obvious arsenic stress, with a large "red-edge blue shift" (9 and 6 nm). The extracted characteristic wavebands were around 550 and 680-740 nm wavelengths, and correlation analysis showed significant correlations between vegetation index and arsenic, allowing us to construct a prediction model for arsenic and realize the calculation of heavy metal content using vegetation spectra. This provides a methodological basis for monitoring vegetation pollution in other gold mining areas.

Long-term iTBS Improves Neural Functional Recovery by Reducing the Inflammatory Response and Inhibiting Neuronal Apoptosis Via miR-34c-5p/p53/Bax Signaling Pathway in Cerebral Ischemic Rats.

To investigate intermittent theta-burst stimulation (iTBS) effect on ischemic stroke and the underlying mechanism of neurorehabilitation, we developed an ischemia/reperfusion (I/R) injury model in Sprague-Dawley (SD) rats using the middle cerebral artery occlusion/reperfusion (MCAO/r) method. Next, using different behavioral studies, we compared the improvement of the whole organism with and without iTBS administration for 28 days. We further explored the morphological and molecular biological alterations associated with neuronal apoptosis and neuroinflammation by TTC staining, HE staining, Nissl staining, immunofluorescence staining, ELISA, small RNA sequencing, RT-PCR, and western blot assays. The results showed that iTBS significantly protected against neurological deficits and neurological damage induced by cerebral I/R injury. iTBS also significantly decreased brain infarct volume and increased the number of surviving neurons after 28 days. Additionally, it was observed that iTBS decreased synaptic loss, suppressed activation of astrocytes and M1-polarized microglia, and simultaneously promoted M2-polarized microglial activation. Furthermore, iTBS intervention inhibited neuronal apoptosis and exerted a positive impact on the neuronal microenvironment by reducing neuroinflammation in cerebral I/R injured rats. To further investigate the iTBS mechanism, this study was conducted using small RNA transcriptome sequencing of various groups of peri-infarcted tissues. Bioinformatics analysis and RT-PCR discovered the possible involvement of miR-34c-5p in the mechanism of action. The target genes prediction and detection of dual-luciferase reporter genes confirmed that miR-34c-5p could inhibit neuronal apoptosis in cerebral I/R injured rats by regulating the p53/Bax signaling pathway. We also confirmed by RT-PCR and western blotting that miR-34c-5p inhibited Bax expression. In conclusion, our study supports that iTBS is vital in inhibiting neuronal apoptosis in cerebral I/R injured rats by mediating the miR-34c-5p involvement in regulating the p53/Bax signaling pathway.

Swimming training combined with fecal microbial transplantation protects motor functions in rats with spinal cord injury by improving the intestinal system.

Spinal cord injury (SCI) leads to severe intestinal dysfunction and decreased motility. There is an interaction between the intestine and the nervous system, intestinal intervention through microbial regulation and exercise is a potential treatment option for spinal cord injury. We investigated the effects of swimming rehabilitation training combined with fecal microbial transplantation on intestinal as well as neurological functions in rats with spinal cord injuries, and explored the potential mechanisms. The animals were randomly divided into five groups: sham-operated control group (Sham), spinal cord injury only group (SCI), swimming training group (Swimming), fecal microbial transplantation group (FMT) and combined interventions group (Combined). Behavioral assessments, pathological and immunological analyses were performed after the interventions. Compared to rats in the spinal cord injury group, rats subjected to swimming training, fecal microbial transplantation and combined interventions group exhibited improved intestinal transit, barrier functions, motility, and motor conduction pathway conductivity(P < 0.05). The combined interventions group had better outcomes(P < 0.01). In addition, combined interventions significantly suppressed inflammatory factor levels (P < 0.05) in the colon and spinal cords and significantly protected forefoot motor neurons (NeuN) in the spinal cord injury area, inhibiting astrocyte activation and reducing the expressions of the signature glial fibrillary acidic protein (GFAP) and markers of microglia (Iba-1) at the lesion site(P < 0.05). In conclusion, all effects of combined swimming training and fecal microbial transplantation interventions were superior to swimming training or fecal microbial transplantation alone. Swimming training and fecal microbial transplantation interventions have a synergistic effect on the recovery of intestinal function and motility after spinal cord injury. The mechanism of mutual facilitation between gut function and motility may be related to the brain-gut axis interaction.

Linguistic Analysis for Identifying Depression and Subsequent Suicidal Ideation on Weibo: Machine Learning Approaches.

Depression is one of the most common mental illnesses but remains underdiagnosed. Suicide, as a core symptom of depression, urgently needs to be monitored at an early stage, i.e., the suicidal ideation (SI) stage. Depression and subsequent suicidal ideation should be supervised on social media. In this research, we investigated depression and concomitant suicidal ideation by identifying individuals' linguistic characteristics through machine learning approaches. On Weibo, we sampled 487,251 posts from 3196 users from the depression super topic community (DSTC) as the depression group and 357,939 posts from 5167 active users on Weibo as the control group. The results of the logistic regression model showed that the SCLIWC (simplified Chinese version of LIWC) features such as affection, positive emotion, negative emotion, sadness, health, and death significantly predicted depression (Nagelkerke's R2 = 0.64). For model performance: F-measure = 0.78, area under the curve (AUC) = 0.82. The independent samples' t-test showed that SI was significantly different between the depression (0.28 ± 0.5) and control groups (-0.29 ± 0.72) (t = 24.71, p < 0.001). The results of the linear regression model showed that the SCLIWC features, such as social, family, affection, positive emotion, negative emotion, sadness, health, work, achieve, and death, significantly predicted suicidal ideation. The adjusted R2 was 0.42. For model performance, the correlation between the actual SI and predicted SI on the test set was significant (r = 0.65, p < 0.001). The topic modeling results were in accordance with the machine learning results. This study systematically investigated depression and subsequent SI-related linguistic characteristics based on a large-scale Weibo dataset. The findings suggest that analyzing the linguistic characteristics on online depression communities serves as an efficient approach to identify depression and subsequent suicidal ideation, assisting further prevention and intervention.

Protocol of a randomized controlled trial to investigate the efficacy and neural correlates of mindfulness-based habit reversal training in children with Tourette syndrome.

Background: Tourette syndrome (TS) is a developmental neuropsychiatric disorder. Behavior therapy, especially habit reversal training (HRT), has gradually become regarded as one of the core therapies for TS. Mindfulness approaches can improve psychological adjustment and reduce stress and anxiety, suggesting potential benefits when incorporated into behavior therapy. To improve the efficacy of HRT, we combined it with mindfulness, an approach named mindfulness-based habitual reversal training (MHRT). The aim of this protocol is to investigate the efficacy and neural mechanisms of MHRT for TS. Methods/design: We will perform a randomized control trial (RCT) to evaluate the efficacy and neural mechanisms of MHRT. The sample will include 160 participants (including 120 patients with TS and 40 healthy controls). The patient sample will be randomly divided into three groups exposed to three different types of training: MHRT, HRT, and psychoeducation and supportive therapy (PST). Participants will be assessed and undergo resting-state fMRI scans at baseline and at the end of the 12-week training. The Yale Global Tic Severity Scale (YGTSS) and Premonitory Urge for Tic Scale (PUTS) will be used to assess the severity of tic symptoms and premonitory urges. The primary outcomes are change scores on the YGTSS and other assessments from baseline and the end of the training. The secondary outcomes are the neural correlates of these trainings among these groups based on graph theory, which is used to characterize brain functional connectivity networks. The default mode network (DMN) and the salience network (SN) will be assessed (which have been associated with mindfulness as well as the generation of tic symptoms) by network parameters, including clustering coefficients and shortest path lengths. Changes in these network parameters will be regarded as the neural correlates of the behavioral training. Discussion: MHRT was newly developed for the treatment of TS. MHRT may lead to greater reductions in tic severity than traditional HRT. Changes in the network parameters of the DMN and SN may show associations with the efficacy of MHRT. Clinical trial registration: http://www.chictr.org.cn, ChiCTR2100053077, China.

Systemic sclerosis patients with negative antinuclear antibodies have distinctive clinical manifestations: a multicenter CRDC cohort in China.

BACKGROUND: The presence of circulating antinuclear antibodies (ANAs) is a hallmark of immune dysregulation in patients with systemic sclerosis (SSc). OBJECTIVE: A variety of ANAs are associated with unique sets of disease manifestations and are widely used in clinical practice in SSc. This study aimed to investigate the clinical features of SSc patients negative for ANAs in a Chinese Rheumatism Data Center (CRDC) multicenter cohort in China. METHODS: Patients were prospectively recruited between April 2008 and June 2019 from 154 clinical centers nationwide, and all cases fulfilled the 2013 ACR/EULAR classification criteria for systemic sclerosis. Results for antinuclear antibodies were intensively collected. Demographic, clinical, and laboratory data were compared between ANA-positive SSc patients and those negative for ANAs. RESULTS: Antinuclear antibodies were detected in 2129 of 2809 patients enrolled in the study; 4.2% of patients were negative. There were more males among ANA-negative SSc patients (29/60 vs. 294/1746, p < 0.001). The incidence of certain critical organ involvement, including gastroesophageal reflux (5.6% vs. 18.5%, p = 0.002), interstitial lung disease (65.2% vs. 77.9%, p = 0.015), and pulmonary arterial hypertension (11.5% vs. 29.0%, p = 0.006) was significantly lower in ANA-negative patients than in ANA-positive patients. The proportion of abnormal erythrocyte sedimentation rate (32.4% vs. 47.6%, p = 0.013) and IgG elevation (14.3% vs. 37.0%, p = 0.003), an indicator of disease activity, was significantly lower in ANA-negative patients than in ANA-positive patients. CONCLUSION: Antinuclear antibodies are strongly associated with the clinical manifestations of systemic sclerosis, with ANA-negative SSc patients tending to exhibit relatively milder disease.

Bisdemethoxycurcumin Inhibits VEGF-Induced HUVECs Proliferation, Migration and Invasion through AMPK/mTOR Pathway-Dependent Autophagy Activation and Cell Cycle Arrest.

Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, which plays a key role in the proliferation, migration and invasion of endothelial cell. Bisdemethoxycurcumin (BDMC) is a natural demethoxy curcumin derivative. In this study, we explored the mechanisms whereby BDMC is able to influence the proliferative, migratory and invasive activity of human umbilical vein endothelial cells (HUVECs) in response to VEGF treatment. These experiments revealed that BDMC at 10 and 20 µM suppressed HUVECs proliferation in response to VEGF (10 ng/mL) without impacting the proliferation in absence of VEGF. BDMC treatment also signifantly suppressed VEGF-induced migratory and invasive activity in HUVECs. However, the selective AMP-activated protein kinase (AMPK) inhibitor compound C (3 µM) treatment signifantly reversed all of these effects. Flow cytometric assay showed BDMC treatment was found to induce G0/G1 phase cell cycle arrest. Western blotting further indicated that BDMC treatment increased the ratios of p-AMPK/AMPK and LC3B/LC3A, up-regulated the expression of Beclin-1, decreased the ratio of p-mammalian target of rapamycin (mTOR)/mTOR, down-regulated the expression of cyclin D1 and CDK4. Overall, these data suggested that BDMC may exert benefical effect on HUVECs activation by activating autophagy and inducing cell cycle arrest through regulation of the AMPK/mTOR pathway, which could provide a potential compound candidate for the treatment of diseases related to VEGF overproduction.

Development of pH-sensitive dextran-based methotrexate nanodrug for rheumatoid arthritis therapy through inhibition of JAK-STAT pathways.

Rheumatoid arthritis (RA) is a chronic and symmetrical autoimmune disease that primarily characterized with articular synovial hyperplasia, joint swelling, cartilage and bone destruction. The in-depth understanding of the role of immune signaling pathway inhibitors provides inspiration for the construction of new and more effective strategy for RA therapy. In this study, by loading methotrexate (MTX) into an acetalated dextran biopolymer, AcDEX, we developed a pH-sensitive, MTX-loaded and molecularly targeted nanodrug MTX@pH-AcDEX NPs) to decrease the toxicity of MTX and simultaneously enhance its therapeutic effect. The resultant MTX@pH-AcDEX NPs showed the spherical morphology and notable pH-responsiveness with high drug loading of 88.32%. As demonstrated in vitro and in vivo, the reduced cytotoxicity of both RAW264.7 cells and LPS-activated RAW264.7 cells treated with MTX@pH-AcDEX NPs was found compared to free MTX. Upon intravenous administration into adjuvant-induced arthritis (AIA) rat model, the nanodrug had potent pharmacokinetic and pharmacodynamic profiles, which can accumulate in RA lesions and release MTX inhibitors for regulating the JAK-STAT pathways. As a result, the MTX@pH-AcDEX NPs achieved the cartilage and bone protective and a better anti-inflammatory effect with negligible systemic toxicity, suggesting the strong potential of safe and effective nanodrug for RA therapy as well as other autoimmune diseases.

Treadmill training improves respiratory function in rats after spinal cord injury by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway.

OBJECTIVE: To investigate the effects of treadmill training on lung injury and HMGB1/TLR4/NF-κB after spinal cord injury (SCI) in rats. METHODS: A total of 108 female SD rats were randomly divided into three groups: sham operation group, SCI brake group, and SCI exercise group. The rats in the SCI exercise group began treadmill training on the 3rd day after the operation. The rats in the SCI brake group underwent braking treatment. The lung tissues were obtained on the 3rd, 7th, and 14th days after exercise. Locomotor functional recovery was determined using the BBB scores and inclined plane test. Respiratory function was determined via abdominal aortic blood gas analysis. HE staining was used to detect pathological changes in rat lung tissue. RNA sequencing was used to identify differentially expressed genes at different phases in each group of lung tissues. HMGB1, TLR4, and NF-κB in lung tissue were detected using immunohistochemistry and immunofluorescence. Detection of HMGB1 levels in serum, spinal cord tissues and lung tissues by ELISA. HMGB1, TLR4, NF-κB, IL-1ß, IL-6, TNF-α mRNA, and protein expression levels were detected via qRT PCR and western blot. RESULTS: Motor and respiratory functions significantly decreased after SCI (P < 0.05). However, locomotion and respiratory functions were significantly improved after treadmill training intervention (P < 0.05). HE staining showed that interstitial thickening, inflammatory cells, and erythrocyte infiltration occurred in lung tissue of rats after SCI (P < 0.05). Moreover, inflammatory reaction in lung tissue was significantly reduced after treadmill training intervention (P < 0.05). A total of 428 differentially expressed mRNAs [(|log2(FC)| > 2, P < 0.05)] were identified in the intersection of the three groups. KEGG analysis identified five enriched signal pathways, including NF-kappa B. ELISA results showed that treadmill training could significantly reduce the levels of HMGB1 in serum, spinal cord tissue and lung tissue that were elevated after SCI (P < 0.05). Immunohistochemistry, immunofluorescence, qRT PCR, and Western blot showed that HMGB1, TLR4, IL-1ß, IL-6, TNF-α, and NF-κB expressions were significantly up-regulated at the 3rd, 7th and 14th days after SCI, compared with the sham group. Besides, inflammatory cytokines were significantly lower in the SCI exercise group than in the SCI brake group at all time points after intervention (P < 0.05). CONCLUSION: Treadmill training alleviates lung tissue inflammation and promotes recovery of motor and respiratory functions by inhibiting the HMGB1/TLR4/NF-κB signaling pathway after SCI in rats.

CircRNA and miRNA expression profiles during remote ischemic postconditioning attenuate brain ischemia/reperfusion injury.

Remote ischemic postconditioning (RIPostC) is a protective procedure for brain damage caused by ischemia/reperfusion (IR), yet the mechanism of this treatment remains to be elucidated. Circular RNAs (circRNAs) are endogenous non-coding RNAs that have recently been recognized to play vital roles in ischemic brain injury. The aim of this study was to explore the role of circRNAs in the protective mechanism of RIPostC and to analyze the circRNA-microRNA (miRNA) regulation network in RIPostC. Nine rats were assigned randomly into three groups (three rats per group): sham, IR, and RIPostC. Their brain tissues were extracted for next-generation RNA sequencing and bioinformatics analysis was performed for two comparisons: sham vs. IR and IR vs. RIPostC. The expression patterns of selected circRNAs and miRNAs were validated by quantitative real-time PCR (qPCR). We detected 82 upregulated and 51 downregulated circRNAs and 137 upregulated and 127 downregulated miRNAs in the IR group compared with the sham group, and 41 upregulated and 100 downregulated circRNAs and 45 upregulated and 64 downregulated miRNAs in the RIPostC group compared with the IR group. The proposed competitive endogenous RNA (ceRNA) network, which included 24 circRNAs, 20 miRNAs, and 145 mRNAs, indicated that the dysregulated circRNAs played important roles in brain IR injury. On the basis of the expression patterns of selected circRNAs, miRNAs, and mRNAs obtained by qPCR, we proposed a circRNA_0002286-miR-124-3p-VLCAD pathway. In PC12 cell, the expression level of miR-124-3p was significantly upregulated when the expression of circRNA_0002286 was repressed and the expression level of VLCAD (very-long chain acyl-CoA dehydrogenase) was significantly downregulated, which suggested that circRNA_0002286 may act as a miRNA sponge for miR-124-3p to regulate the expression of VLCAD. We found that upregulation of circRNA_0002286 attenuated IR injury and was associated with downregulation of miR-124-3p and upregulation of VLCAD. This is the first time that circRNAs have been shown to be closely related to brain IR injury and RIPostC and suggests that targeting the circRNA_0002286-miR-124-3p-VLCAD pathway might attenuate brain IR injury.

Novel Insights into the Emerging Role of Neat1 and Its Effects Downstream in the Regulation of Inflammation.

Nuclear paraspeckle assembly transcript 1 (Neat1) located at chromosome 11 is a long non-coding RNA that is widely expressed in mammalian cell types, and which is overexpressed in several inflammation-related disorders. Inflammation implies a plethora of mutual interactions between both soluble factors and cells due to various stimuli including tissue injury. Although there is no doubt that inflammation is critically involved in multiple biological and pathological processes alike, the precise mechanisms being involved are still open for debate. In this context, the role of Neat1 as a regulator of inflammation, microglial activation, and lipid accumulation under various inflammatory conditions remains elusive. Herein, we review the regulation of Neat1 and how it modulates the expression of its target genes. Thereafter, we will review the impact of Neat1 on inflammation by activating or inhibiting various signaling pathways, such as microRNAs, AKT, TLR4, TRAF6, and NF-κB.

Negative regulation by proBDNF signaling of peripheral neurogenesis in the sensory ganglia of adult rats.

Neurogenesis in the adult brain is well recognized and plays a critical role in the maintenance of brain function and homeostasis. However, whether neurogenesis also occurs in the adult peripheral nervous system remains unknown. Here, using sensory ganglia (dorsal root ganglia, DRGs) as a model, we show that neurogenesis also occurs in the peripheral nervous system, but in a manner different from that in the central nervous system. Satellite glial cells (SGCs) express the neuronal precursor markers Nestin, POU domain, class 4, transcription factor 1, and p75 pan-neurotrophin receptor. Following sciatic nerve injury, the suppression of endogenous proBDNF by proBDNF antibodies resulted in the transformation of proliferating SGCs into doublecortin-positive cells in the DRGs. Using purified SGCs migrating out from the DRGs, the inhibition of endogenous proBDNF promoted the conversion of SGCs into neuronal phenotypes in vitro. Our findings suggest that SGCs are neuronal precursors, and that proBDNF maintains the SGC phenotype. Furthermore, the suppression of proBDNF signaling is necessary for neuronal phenotype acquisition by SGCs. Thus, we propose that peripheral neurogenesis may occur via the direct conversion of SGCs into neurons, and that this process is negatively regulated by proBDNF.

Prognostic Signature of Osteosarcoma Based on 14 Autophagy-Related Genes.

Background: Osteosarcoma is a common malignancy of bone with inferior survival outcome. Autophagy can exert multifactorial influence on tumorigenesis and tumor progression. However, the specific function of genes related to autophagy in the prognosis of osteosarcoma patients remains unclear. Herein, we aimed to explore the association of genes related to autophagy with the survival outcome of osteosarcoma patients. Methods: The autophagy-associated genes that were related to the prognosis of osteosarcoma were optimized by LASSO Cox regression analysis. The survival of osteosarcoma patients was forecasted by multivariate Cox regression analysis. The immune infiltration status of 22 immune cell types in osteosarcoma patients with high and low risk scores was compared by using the CIBERSORT tool. Results: The risk score model constructed according to 14 autophagy-related genes (ATG4A, BAK1, BNIP3, CALCOCO2, CCL2, DAPK1, EGFR, FAS, GRID2, ITGA3, MYC, RAB33B, USP10, and WIPI1) could effectively predict the prognosis of patients with osteosarcoma. A nomogram model was established based on risk score and metastasis. Conclusion: Autophagy-related genes were identified as pivotal prognostic signatures, which could guide the clinical decision making in the treatment of osteosarcoma.