Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG.

The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.

Prediction of poststroke cognitive impairment based on the systemic inflammatory response index.

BACKGROUND: Poststroke cognitive impairment (PSCI) is a prevalent complication among stroke survivors. Although the systemic inflammatory response index (SIRI) has been shown to be a reliable predictor of a variety of inflammatory diseases, the association between the SIRI and PSCI is still unclear. Therefore, the purpose of this study was to investigate the relationship between SIRI and PSCI, and to design a nomogram to predict the risk of PSCI in acute ischemic stroke (AIS) patients. METHODS: A total of 1342 patients with AIS were included in the study. Using the Mini-Mental State Examination scale, patients were separated into PSCI and non-PSCI groups within 2 weeks of stroke. Clinical data and SIRI values were compared between the groups. We developed the optimal nomogram for predicting PSCI using multivariate logistic regression. Finally, the nomogram was validated using the receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA). RESULTS: In total, 690 (51.4%) patients were diagnosed with PSCI. After adjusting for potential confounders, the SIRI (OR = 1.226, OR: 1.095-1.373, p < .001) was shown to be an independent risk factor for PSCI in the logistic regression analysis. The nomogram based on patient gender, age, admission National Institutes of Health Stroke Scale scores, education, diabetes mellitus, and SIRI had good discriminative ability with an area under the curve (AUC) of 0.716. The calibration curve and Hosmer-Lemeshow test revealed excellent predictive accuracy for the nomogram. Finally, the DCA showed the good clinical utility of the model. CONCLUSION: Increased SIRI on admission is correlated with PSCI, and the nomogram built with SIRI as one of the predictors can help identify PSCI early.

FANCI serve as a prognostic biomarker correlated with immune infiltrates in skin cutaneous melanoma.

Background: As a member of tumor, Skin cutaneous melanoma (SKCM) poses a serious threat to people's health because of its strong malignancy. Unfortunately, effective treatment methods for SKCM remain lacking. FANCI plays a vital role in the occurrence and metastasis of various tumor types. However, its regulatory role in SKCM is unclear. The purpose of this study was to explore the association of FANCI with SKCM. Methods: This study investigated the expression of FANCI in GSE46517, GSE15605, and GSE114445 from the Gene Expression Omnibus database and The Cancer Genome Atlas (TCGA)-SKCM datasets using the package "limma" or "DESeq2" in R environment and also investigated the prognostic significance of FANCI by utilizing the GEPIA database. Additionally, our research made use of real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) staining to verify FANCI expression between SKCM and normal tissues and developed the knockdown of FANCI in A375 and A875 cells to further analyze the function of FANCI. Finally, this study analyzed the correlation of FANCI and tumor-infiltrating immune cells by CIBERSORT, ESTIMATE, and ssGSEA algorithms. Results: The FANCI level was increasing in SKCM tissues from GSE46517, GSE15605, GSE114445, and TCGA-SKCM. However, high FANCI expression correlated with poor overall survival. The RT-qPCR and IHC confirmed the accuracy of bioinformatics. Knocking down FANCI suppresses A375 and A875 cell proliferation, migration, and invasion. FANCI could be involved in the immunological milieu of SKCM by regulating immune responses and infiltrating numerous immune cells, particularly neutrophils, CD8+ T cells, and B cells. Furthermore, patients with SKCM who have a high FANCI expression level are reported to exhibit immunosuppression, whereas those with a low FANCI expression level are more likely to experience positive outcomes from immunotherapy. Conclusions: The increased FANCI expression in SKCM can be a prognostic biomarker. Knockdown FANCI can reduce the occurrence and progression of SKCM. The FANCI expression provides a foundation for predicting the immune status and treatment of SKCM.

Curcumin Alleviates Epidermal Psoriasis-Like Dermatitis and IL-6/STAT3 Pathway of Mice.

Background: To further investigate why curcumin (CUR) can attenuate psoriasis-like dermatitis of mice. Methods and Results: Sixteen mice were randomized into four groups. The control group used carrier cream, and the model and the CUR group were applied with topical 5% imiquimod in the naked mice skin once a day for 6 days (62.5 mg/day/mice). Meanwhile, the control and model mice were given the same dose of saline by oral means, while mice in the CUR groups received oral drug doses of 50 and 100 mg/kg once a day for 6 days, respectively. CUR could largely improve imiquimod-induced lesions of mice. By using the ELISA and qPCR, we found that the protein and mRNA levels of epidermal TNF-α and IL-6 were inhibited by CUR. The phosphorylation levels of STAT3 and its downstream associated protein levels (eg, Cyclin D1, Bcl-2 and Pim1) in skin tissues of different groups were also inhibited by CUR. Furthermore, the results of immunohistochemistry also showed the repressed effect of CUR for the expression of TNF-α, IL-6 and p-STAT3 in psoriasis-like lesions of mice. Conclusion: CUR can effectively ameliorate the featured lesions of psoriasis mice, which may be closely associated with the involvement of IL-6/STAT3 signaling.

Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis.

Ferroptosis plays a critical role in ischemic stroke, and anti-ferroptosis strategies were regarded as potentially effective measures. Based on ferroptosis-related mechanisms, this study aims to design and prepare anti-ferroptosis exosomes from adipose-derived mesenchymal stem cells (ADSC-Exo) for treating ischemic brain injury via intranasal (IN) administration. According to the bioinformatic analysis, CHAC1 was a key gene in the progress of ferroptosis in ischemic stroke. miR-760-3p can inhibit the expression of CHAC1 and may be abundant in ADSC-Exo. Therefore, ADSC-Exo were successfully isolated and the immunofluorescence showed that they can be efficiently delivered to the brain via IN administration. Additionally, IN administration of ADSC-Exo can effectively improve the neurobehavior function of mice after I/R, and improve the ferroptosis-related outcomes. As the immunofluorescence showed the co-localization of NeuN with CHAC1 obviously, we further evaluated the systematic effect of ADSC-Exo in an oxygen-glucose deprivation (OGD) mouse neuroblastoma cell line N2a model. The results showed that miR-760-3p in ADSC-Exo contributed to their function in inhibiting ferroptosis by targeting CHAC1 in neurons. Collectively, the present study successfully designed and prepared anti-CHAC1 ADSC-Exo and suggested a promising exosome-based strategy for anti-ferroptosis therapy in cerebral ischemia/reperfusion injury.

Risk factors for small intestinal bacterial overgrowth in patients with acute ischaemic stroke.

Introduction. The intestinal flora has become a promising new target in acute ischaemic stroke (AIS), and small intestinal bacterial overgrowth (SIBO) is a common pathological condition of the intestinal flora. Recently, the lactose hydrogen-methane breath test has emerged as a non-invasive and economical method for the detection of SIBO in AIS patients. Exploring the prevalence of SIBO and its associated risk factors will provide a clinical basis for the association between intestinal flora and AIS.Hypothesis/Gap Statement. Given that the prevalence of SIBO and its risk factors in patients with AIS remain to be studied, there is a need to investigate them.Aim. This study aimed to investigate the prevalence and risk factors of SIBO in patients with AISMethodology. Eighty patients tested for SIBO using the lactulose hydrogen-methane breath test were evaluated. Patients were divided into SIBO-positive and SIBO-negative groups according to the presence or absence of SIBO, respectively. The baseline characteristics and clinical biochemical indicators of the patients were compared between the two groups. The independent risk factors and predictive value of SIBO in AIS patients were determined using multivariate logistic regression and receiver operating characteristic (ROC) curve analyses.Results. Of the 80 consecutive patients with AIS, 23 (28.8 %) tested positive for SIBO. Triglyceride (TG) and homocysteine (Hcy) levels were identified as independent risk factors for SIBO in patients with AIS using multivariate logistic regression analysis (P<0.005). ROC curve analysis showed that the area under the curve (AUC) of TG was 0.690 (95 % CI 0.577-0.789, P=0.002). The sensitivity, specificity and optimal cut-off values were 95.7 %, 35.1 % and 1.14 mmol l-1, respectively. The AUC of Hcy was 0.676 (95 % CI 0.562-0.776, P=0.01). The sensitivity, specificity and optimal cut-off values were 73.9 %, 59.7 % and 14.1 µmol-1, respectively. When TG and Hcy levels were combined, the AUC increased to 0.764 (95 % CI 0.656-0.852, P<0.001). The specificity and sensitivity were 61.4 and 82.6 %, respectively. This showed that the combined detection of TG and Hcy levels had a higher predictive valueConclusion. The prevalence of SIBO in patients with AIS was 28.8 %. TG and Hcy levels are independent risk factors for SIBO in patients with AIS. Both markers had good predictive value for the occurrence of SIBO. In the future, we should actively utilize these indicators to prevent intestinal flora imbalance and the occurrence of SIBO.

A broad and potent IgM antibody against tetra-EV-As induced by EVA71 and CVA16 co-immunization.

OBJECTIVE: To determine the potent and broad neutralizing monoclonal antibody (mAb) against enterovirus A (EV-A) in vitro and in vivo induced by enterovirus A71(EVA71) and coxsackievirus 16 (CVA16) co-immunization. METHODS: The mAb was Generated by co-immunization with EVA71 and CVA16 through hybridomas technology. The characteristics and neutralizing ability of mAb were analysed in vitro and in mice. RESULTS: We screened three mAb, the IgM antibody M20 and IgG antibody B1 and C31. All three antibodies showed cross-reactivity against tetra-EV-As. However, M20 showed potent and broad neutralizing ability against tetra-EV-As than B1 and C31. Meanwhile, M20 provided cross-antiviral efficacy in tetra-EV-As orally infected mice. Moreover, M20 binds to a conserved neutralizing epitope within the GH loop of tetra-EV-As VP1. CONCLUSIONS: M20 and its property exhibited potent and broad antiviral activity against tetra-EV-As, and that is expected to be a potential preventive and therapeutic candidate against EV-As.

Dandy-Walker malformation in methylmalonic acidemia: a rare case report.

BACKGROUND: Methylmalonic acidemia is an organic acid metabolism disorder that usually has nonspecific clinical manifestations. CASE PRESENTATION: A 3-month-old female infant was admitted to the hospital for developmental retardation. Her prenatal and birth history was unremarkable. After admission, she developed dyspnea and severe anemia and was subsequently transferred to the intensive care unit. Magnetic resonance imaging of her brain showed a Dandy-Walker malformation, and metabolic screening indicated methylmalonic acidemia. Thus, she was diagnosed with methylmalonic acidemia and Dandy-Walker malformation. The patient underwent treatment including acidosis correction, blood transfusion, antibiotics, mechanical ventilation and heat preservation. Unfortunately, her condition progressively worsened and she died of metabolic crisis. CONCLUSIONS: Dandy-Walker malformation may be a clinical manifestation of methylmalonic acidemia. Additionally, the co-existence of methylmalonic acidemia and Dandy-Walker malformation may be an uncharacterized syndrome which needs to be studied further.

GLIS family zinc finger 3 promoting cell malignant behaviors and NF-κB signaling in glioma.

Glioma is a common tumor in the human central nervous system. However, its molecular mechanism in the pathogenesis and regulation of glioma progression is still unclear. In this study, we found that GLIS3 was up-regulated in glioma tissues, and the increased expression is positively correlated with advanced tumor grade. Survival evaluation disclosed that patients with high expression levels of GLIS3 normally have a poor prognosis. Functional analysis revealed the oncogenic role of GLIS3 in the development of glioma. GLIS3 promotes glioma cells' invasion, migration, and proliferation. Meanwhile, deficiency of GLIS3 produces an inhibitory function upon NF-κB signaling pathway. This work demonstrated that GLIS3, acting as a target and prognostic factor for glioma, may promote the invasion, migration and proliferation of glioma cells involved in regulation of NF-κB signaling pathway.

Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer's Disease.

BACKGROUND: As the most common neurodegenerative disease, Alzheimer's disease (AD) leads to progressive loss of cognition and memory. Presently, the underlying pathogenic genes of AD patients remain elusive, and effective disease-modifying therapy is not available. This study explored novel biomarkers that can affect diagnosis and treatment in AD based on immune infiltration. METHODS: The gene expression profiles of 139 AD cases and 134 normal controls were obtained from the NCBI GEO public database. We applied the computational method CIBERSORT to bulk gene expression profiles of AD to quantify 22 subsets of immune cells. Besides, based on the use of the Least Absolute Shrinkage Selection Operator (LASSO), this study also applied SVM-RFE analysis to screen key genes. GO-based semantic similarity and logistic regression model analyses were applied to explore hub genes further. RESULTS: There was a remarkable significance in the infiltration of immune cells between the subgroups. The proportions for monocytes, M0 macrophages, and dendritic cells in the AD group were significantly higher than those in the normal group, while the proportion of some cells was lower than that of the normal group, such as NK cell resting, T-cell CD4 naive, T-cell CD4 memory activation, and eosinophils. Additionally, seven genes (ABCA2, CREBRF, CD72, CETN2, KCNG1, NDUFA2, and RPL36AL) were identified as hub genes. Then we performed the analysis of immune factor correlation, gene set enrichment analysis (GSEA), and GO based on seven hub genes. The AUC of ROC prediction model in test and validation sets were 0.845 and 0.839, respectively. Eventually, the mRNA expression analysis of ABCA2, NDUFA2, CREBRF, and CD72 revealed significant differences among the seven hub genes and then was confirmed by RT-PCR. CONCLUSION: A model based on immune cell infiltration might be used to forecast AD patients' diagnosis, and it provided a new perspective for AD treatment targets.

Network pharmacology to investigate the pharmacological mechanisms of muscone in Xingnaojing injections for the treatment of severe traumatic brain injury.

BACKGROUND: Xingnaojing injections (XNJI) are widely used in Chinese medicine to mitigate brain injuries. An increasing number of studies have shown that XNJI may improve neurological function. However, XNJI's active ingredients and molecular mechanisms when treating traumatic brain injury (TBI) are unknown. METHODS: XNJI's chemical composition was acquisited from literature and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. We used the "absorption, distribution, metabolism, and excretion" (ADME) parameter-based virtual algorithm to further identify the bioactive components. We then screened data and obtained target information regarding TBI and treatment compounds from public databases. Using a Venn diagram, we intersected the information to determine the hub targets. Cytoscape was used to construct and visualize the network. In accordance with the hub proteins, we then created a protein-protein interaction (PPI) network using STRING 11.0. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed according to the DAVID bioinformatics resource database (ver. 6.8). We validated the predicted compound's efficacy using the experimental rat chronic constriction injury (CCI) model. The neuronal apoptosis was located using the TUNEL assay and the related pathways' hub proteins were determined by PCR, Western blot, and immunohistochemical staining. RESULTS: We identified 173 targets and 35 potential compounds belonging to XNJI. STRING analysis was used to illustrate the protein-protein interactions and show that muscone played a fundamental role in XNJI's efficacy. Enrichment analysis revealed critical signaling pathways in these components' potential protein targets, including PI3K/AKT1, NF-kB, and p53. Moreover, the hub proteins CASP3, BCL2L1, and CASP8 were also involved in apoptosis and were associated with PI3K/AKT, NF-kB, and p53 signaling pathways. We showed that muscone and XNJI were similarly effective 168 h after CCI, demonstrating that the muscone in XNJI significantly attenuated neuronal apoptosis through the PI3K/Akt1/NF-kB/P53 pathway. CONCLUSION: We verified the neuroprotective mechanism in muscone for the first time in TBI. Network pharmacology offers a new approach for identifying the potential active ingredients in XNJI.

Twisted gastrulation signaling modulator 1 promotes the ability of glioma cell through activating Akt pathway.

Glioblastoma is one of the most common primary nervous system tumors and has a high mortality rate. It is necessary to explore a novel biological target and treatment approach. Twisted gastrulation signaling modulator 1 (TWSG1) is expressed in many tumors and closely related to tumor growth and proliferation. However, there is almost no report about the mechanism of TWSG1 in glioma. We used a glioma chip to detect the expression level of TWSG1 by Immunohistochemistry. The overexpression and silence experiments of TWSG1 were performed to assay the biological function of TWSG1 in LN229 and U251 cells. Subcutaneous xenograft mouse model presented the effect of TWSG1 expression on the malignant behavior of tumor cells. Experimental results displayed that the expression level for TWSG1 was substantially elevated in gliomas compared to that in normal brain tissue. The expression knockdown of TWSG1 caused inhibition of glioma cell proliferation. Besides, TWSG1 overexpression enhanced proliferation in glioma cells, and the capacity of proliferation was partly abolished by the PI3K inhibitor LY294002. We found that TWSG1 affected the activity of Akt signaling pathway. In conclusion, TWSG1 is overexpressed in glioma tissue and promotes tumor proliferation through Akt signaling pathway, may serve as a potential target for glioma diagnosis and therapy.

Evaluation of microstructural changes in spinal cord of patients with degenerative cervical myelopathy by diffusion kurtosis imaging and investigate the correlation with JOA score.

BACKGROUND: To explore the feasibility of the metrics of diffusion kurtosis imaging (DKI) for investigations of the microstructural changes of spinal cord injury in patients with degenerative cervical myelopathy (DCM) and the correlation between Japan Orthopaedic Association (JOA) scores and DKI metrics. METHODS: Fifty-seven patients with DCM and 38 healthy volunteers underwent 3.0 T magnetic resonance (MR) imaging with routine MRI sequences and DKI from echo-planar imaging sequence. Based on the JOA score, DCM patients were divided into four subgroups. DKI metrics of the DCM group and control group were obtained and compared, separately for the white matter (WM) and the gray matter (GM). RESULTS: The FA values in WM were significantly lower (P = 0.020) in the DCM group than in the control group. The MK values in GM were lower (P = 0.011) in the DCM group than in the control group. The MD values in WM were significantly higher (P = 0.010) in the DCM group than in the control group. In GM, the JOA score was positively correlated with the MK values (r = 0.768, P < 0.05). In the WM, the JOA score was positively correlated with the FA values (r = 0.612, P < 0.05). CONCLUSION: DKI provides quantitive evaluation to the characters of microstructure of the spinal cord damage in patients with DCM compared to conventional MR. MK values can reflect microstructural abnormalities of gray matter of the cervical spinal cord and provide more information beyond that obtained with routine diffusion metrics. In addition, MK values of GM and FA values of WM may as a be highly sensitive biomarker for the degree of cervical spinal cord damage.

Benefits of Low-Dose CT Scan of Head for Patients With Intracranial Hemorrhage.

OBJECTIVES: For patients with intracranial hemorrhage (ICH), routine follow-up computed tomography (CT) scans are typically required to monitor the progression of intracranial pathology. Remarkable levels of radiation exposure are accumulated during repeated CT scan. However, the effects and associated risks have still remained elusive. This study presented an effective approach to quantify organ-specific radiation dose of repeated CT scans of head for patients with ICH. We also indicated whether a low-dose CT scan may reduce radiation exposure and keep the image quality highly acceptable for diagnosis. METHODS: Herein, 72 patients with a history of ICH were recruited. The patients were divided into 4 groups and underwent CT scan of head with different tube current-time products (250, 200, 150, and 100 mAs). Two experienced radiologists visually rated scores of quality of images according to objective image noise, sharpness, diagnostic acceptability, and artifacts due to physiological noise on the same workstation. Organ-/tissue-specific radiation doses were analyzed using Radimetrics. RESULTS: In conventional CT scan group, signal to noise ratio (SNR) and contrast to noise ratio (CNR) of ICH images were significantly higher than those in normal brain structures. Reducing the tube current-time product may decrease the image quality. However, the predilection sites for ICH could be clearly identified. The SNR and CNR in the predilection sites for ICH were notably higher than other areas. The brain, eye lenses, and salivary glands received the highest radiation dose. Reducing tube current-time product from 250 to 100 mA can significantly reduce the radiation dose. DISCUSSION: We demonstrated that low-dose CT scan of head can still provide reasonable images for diagnosing ICH. The radiation dose can be reduced to ∼45% of the conventional CT scan group.