A Comprehensive Analysis of LYAR in Colorectal Cancer: Prognostic Marker and Therapeutic Target.

Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work aimed to investigate the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.

Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

Identification through machine learning of potential immune- related gene biomarkers associated with immune cell infiltration in myocardial infarction.

BACKGROUND: To investigate the potential role of immune-related genes (IRGs) and immune cells in myocardial infarction (MI) and establish a nomogram model for diagnosing myocardial infarction. METHODS: Raw and processed gene expression profiling datasets were archived from the Gene Expression Omnibus (GEO) database. Differentially expressed immune-related genes (DIRGs), which were screened out by four machine learning algorithms-partial least squares (PLS), random forest model (RF), k-nearest neighbor (KNN), and support vector machine model (SVM) were used in the diagnosis of MI. RESULTS: The six key DIRGs (PTGER2, LGR6, IL17B, IL13RA1, CCL4, and ADM) were identified by the intersection of the minimal root mean square error (RMSE) of four machine learning algorithms, which were screened out to establish the nomogram model to predict the incidence of MI by using the rms package. The nomogram model exhibited the highest predictive accuracy and better potential clinical utility. The relative distribution of 22 types of immune cells was evaluated using cell type identification, which was done by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. The distribution of four types of immune cells, such as plasma cells, T cells follicular helper, Mast cells resting, and neutrophils, was significantly upregulated in MI, while five types of immune cell dispersion, T cells CD4 naive, macrophages M1, macrophages M2, dendritic cells resting, and mast cells activated in MI patients, were significantly downregulated in MI. CONCLUSION: This study demonstrated that IRGs were correlated with MI, suggesting that immune cells may be potential therapeutic targets of immunotherapy in MI.

AZGP1 Up-Regulation is a Potential Target for Andrographolide Reversing Radioresistance of Colorectal Cancer.

Background: Radiation resistance is a challenge that limits the therapeutic benefit of colorectal cancer (CRC) treatment, but the mechanism underlying CRC radiation resistance remains unclear. Andrographolide shows a broad-spectrum anti-tumor effect in various malignancies, including CRC, its effect and how it functions in CRC initiation, and radiation have not been established. This study aimed to explore the mechanism of CRC radiation resistance and the potential mechanisms of andrographolide on CRC radiation. Methods: Two acquired radioresistant cell lines were established and high throughput sequencing was employed to screen out the differentially expressed genes. The expression of AZGP1, which was upregulated in the acquired radioresistant tissues, was verified by microarray data recomputing. The common targets of andrographolide, CRC initiation, and radiation resistance were obtained, and the corresponding functional enrichment and pathway analysis were performed. The interaction between AZGP1 and andrographolide was investigated using molecular docking. Results: AZGP1 was upregulated in both the radioresistant cell model and microarray data. Moreover, AZGP1 was upregulated in cancerous colorectal tissue and displayed a tendency toward elevated expression in patients with an unfavorable prognosis. AZGP1 was identified as the common target of andrographolide, colorectal cancer initiation, and radiotherapy resistance. Ultimately, the protein structure of AZGP1 proved to be closely intertwined with the crystal texture of andrographolide. Conclusion: AZGP1 is recognized as a crucial factor for both CRC initiation and radioresistance. Andrographolide may affect the radioresistance of CRC via the targeting of AZGP1. Thus, the combination of andrographolide and AZGP1 intervention might be a promising strategy for improving the treatment benefit of CRC radiotherapy.

Clinical assessment and molecular mechanism of the upregulation of Toll-like receptor 2 (TLR2) in myocardial infarction.

OBJECTIVE: The prevalence and mortality of cardiovascular diseases remain ranked first worldwide. Myocardial infarction (MI) is the central cause of death from cardiovascular diseases, seriously endangering human health. The clinical implication of toll-like receptor 2 (TLR2) remains contradictory, and its mechanism is still unknown. Hence, the objective of this study was to elucidate the clinical value and molecular mechanism of TLR2 in MI. METHODS: All high-throughput datasets and eligible literature were screened, and the expression levels of TLR2 were collected from the MI. The integrated expression level of TLR2 was displayed by calculating the standardized mean difference (SMD) and the area under the curve (AUC) of the summary receiver operating characteristic curve (sROC). The related TLR2 genes were sent for pathway analyses by gene ontology (GO), Kyoto encyclopedia of genes and genome (KEGG), and disease ontology (DO). Single-cell RNA-seq was applied to ascertain the molecular mechanism of TLR2 in MI. RESULTS: Nine microarrays and four reported data were available to calculate the comprehensive expression level of TLR2 in MI, including 325 cases of MI and 306 cases of controls. The SMD was 2.55 (95% CI = 1.35-3.75), and the AUC was 0.76 (95% CI = 0.72-0.79), indicating the upregulation of TLR2 in MI. The related TLR2 genes were primarily enriched in the pathways of atherosclerosis, arteriosclerotic cardiovascular disease, and arteriosclerosis, suggesting the clinical role of TLR2 in the progression of MI. Afterward, TLR2 was upregulated in myeloid cells in MI. CONCLUSIONS: TLR2 may have a crucial role in progressing from coronary atherosclerosis to MI. The upregulation of TLR2 may have a favorable screening value for MI.

Simplified Chinese version of the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire: cross-cultural adaptation, reliability, and validity for patients with cervical spondylotic myelopathy.

PURPOSE: This study aimed to validate the simplified Chinese version of the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) for Chinese patients with cervical spondylotic myelopathy (CSM). METHODS: The construct validity was conducted using confirmatory factor analysis (CFA). The convergent validity was based on factor loading, composite reliability (CR), and Pearson correlation coefficients (r). Internal consistency reliability was evaluated using Cronbach's α, test-retest reliability using intraclass correlation coefficients (ICC), and the ceiling and floor effects were also examined. RESULTS: A total of 168 native Chinese-speaking patients were enrolled. The CFA indicated that construct validity did not meet the preset criteria to be considered as good. Except for Q 4-1, the factor loading was higher than the standard of 0.5, and the CR values ranged from 0.70 to 0.85. Strong to moderate correlations were found between other scales and the simplified Chinese JOACMEQ. The scale showed good internal consistency reliability (Cronbach's α 0.639-0.821), and test-retest reliability (ICC 0.760-0.916). Moreover, the ceiling effect was displayed from Q1 to Q4. CONCLUSIONS: This study indicates that the simplified Chinese JOACMEQ is a reliable and valid measure of the functional status among Chinese patients with CSM.IMPLICATIONS FOR REHABILITATIONThe JOACMEQ was translated into the simplified Chinese and culturally adapted for Chinese-speaking patients with CSM for the first time.The simplified JOACMEQ demonstrated an excellent level of internal consistency and good test-retest reliability.The simplified Chinese JOACMEQ was reliable and valid for the measurement of the functional status among the patients with CSM.

Astragaloside â £ Protects Against Aß1-42-induced Oxidative Stress, Neuroinflammation and Cognitive Impairment in Rats.

Objective To investigate the neuroprotective action of astragaloside Ⅳ (AS-Ⅳ) on spatial learning and memory impairment induced by amyloid-beta 1-42 (Aß1-42) in rats and elucidate its underlying molecular mechanisms. Methods Adult-male Sprague-Dawley rats (230-250 g) were divided into six groups randomly: control, Aß1-42, AS-Ⅳ, Aß1-42 plus 5 mg/kg·d AS-Ⅳ, Aß1-42 plus 25 mg/kg·d AS-Ⅳ, and Aß1-42 plus 50 mg/kg·d AS-Ⅳ groups. Aß1-42 were delivered by intracerebroventricular injection under the guidance of a brain stereotaxic apparatus. The Morris water maze test (hidden platform test, probe trials, visible platform test) was performed one week after Aß1-42 injection to obtain the ability of rat spatial learning and memory. AS-Ⅳ (5, 25 and 50 mg/kg·d) was administrated intraperitoneally once per day from the 8th day after Aß1-42 injection for 5 consecutive days. Average escape latencies, distances for searching for the platform under water and the percentage of total time elapsed and distance swam in the right quadrant after removing platform were determined by behavior software system. The vision and swim speeds of rats were also determined to exclude the effect of these factors on the parameters of learning and memory. After behavioral tests, the rats were sacrificed immediately by decapitation. Hippocampus were collected. The enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-px) and catalase (CAT) in the hippocampus obtained from different-treated rat brain were measured by following the manufacturer's instructions. The levels of interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) in tissue lysates were assayed with ELISA. Results The water maze test results indicated that chronic treatments with AS-Ⅳ effectively protected the rats from Aß1-42-induced spatial learning and memory impairment. Furthermore, the activities of SOD, GSH-px and CAT decreased by Aß1-42 were also restored by AS-Ⅳ treatment in the hippocampus of rats. In addition, AS-Ⅳ significantly decreased the levels of IL-1ß and TNF-α in the hippocampus of Aß1-42-induced amnesia's rats. Conclusion Our findings suggest that AS-Ⅳ might be a useful chemical in improving the spatial memory and relieving the oxidative stress and neuroinflammation in Alzheimer patients.

[Mechanism of macrophage polarization on spinal cord injury].

Spinal cord injury is a serious trauma of the spinal and nervous system, local tissue destruction and microcirculation disturbance can lead to a more serious spinal cord injury and extensive necrosis of neurons. Spinal cord injury often accompany with Inflammation reaction producing a variety of cytokines and bioactive substances, result in macrophage polarization. M1 macrophages polarization are induced by IFN-γ, LPS, TNF-α and so on, it show the damage and proinflammatory effect. M2 macrophages polarization are caused by IL-4, IL-10, IL-13 and show the recovery and anti-inflammatory effect. However, clinical treatment after spinal cord injury is very limited, inhibition of proinflammatory and promotion of anti-inflammatory by regulating the M1 macrophages and M2 macrophages is a new direction for the treatment of spinal cord injury. The article will review different phenotype and function of macrophages after spinal cord injury.

Simplified Chinese Version of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire: Cross-cultural Adaptation, Reliability, and Validity for Patients With Low Back Pain.

STUDY DESIGN: Cross-cultural adaptation and cross-sectional psychometric testing in a convenience sample of patients with low back pain. OBJECTIVE: The aim of this study was to translate and adapt the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) into a simplified Chinese version, and assess its reliability and validity. SUMMARY OF BACKGROUND DATA: No simplified Chinese version of the JOABPEQ was previously available. METHODS: We translated and culturally adapted the original English JOABPEQ to develop a Chinese version, based on cross-cultural adaptation guidelines. Principal component analysis with varimax rotation was used to confirm the factor structure of each subscale. Internal consistency was evaluated with Cronbach alpha. Test-retest reliability was examined in stable patients, who completed the questionnaire again at 4 days to 2 weeks from baseline. The validity of the translated Chinese version was assessed by examining the relationship between the JOABPEQ and Chinese versions of the Roland-Morris Disability Questionnaire (RMDQ), the Oswestry Disability Index (ODI), the Short Form Health Survey (SF-36), and the Numerical Pain Rating Scale. Ceiling and floor effects were considered present if more than 15% of respondents achieved the lowest or highest possible total score. RESULTS: The JOABPEQ showed excellent internal consistency (α = 0.886). The test-retest reliability (intraclass correlation coefficients) ranged from 0.951 to 0.977. The convergent validity of the Chinese version was supported by its high correlation with other physical functional status measures (RMDQ, ODI, and SF-36 Physical Function; r values from -0.645 to -0.726), and moderate correlation with other measures (SF-36 Bodily pain and Social functioning subscales; r values 0.426-0.546). Q5 Mental health was highly correlated with SF-36 items (r values 0.337-0.640). There was a floor effect in Q1 low back pain (38, 20.65%). CONCLUSION: The results indicate that the simplified Chinese version of the JOABPEQ is a reliable and valid instrument to measure the multidimensional status in patients with low back pain. LEVEL OF EVIDENCE: 4.

A novel antibody targeting sequence 31-35 in amyloid ß protein attenuates Alzheimer's disease-related neuronal damage.

Amyloid ß protein (Aß) plays a critical role in pathogenesis of Alzheimer's disease (AD). Our previous studies indicated that the sequence 31-35 in Aß molecule is an effective active center responsible for Aß neurotoxicity in vivo and in vitro. In the present study, we prepared a novel antibody specifically targeting the sequence 31-35 of amyloid ß protein, and investigated the neuroprotection of the anti-Aß31-35 antibody against Aß1-42 -induced impairments in neuronal viability, spatial memory, and hippocampal synaptic plasticity in rats. The results showed that the anti-Aß31-35 antibody almost equally bound to both Aß31-35 and Aß1-42 , and pretreatment with the antibody dose-dependently prevented Aß1-42 -induced cytotoxicity on cultured primary cortical neurons. In behavioral study, intracerebroventricular (i.c.v.) injection of anti-Aß31-35 antibody efficiently attenuated Aß1-42 -induced impairments in spatial learning and memory of rats. In vivo electrophysiological experiments further indicated that Aß1-42 -induced suppression of hippocampal synaptic plasticity was effectively reversed by the antibody. These results demonstrated that the sequence 31-35 of Aß may be a new therapeutic target, and the anti-Aß31-35 antibody could be a novel immunotheraputic approach for the treatment of AD. © 2016 Wiley Periodicals, Inc.

Exendin-4, a glucagon-like peptide 1 receptor agonist, protects against amyloid-ß peptide-induced impairment of spatial learning and memory in rats.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share specific molecular mechanisms, and agents with proven efficacy in one may be useful against the other. The glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has similar properties to GLP-1 and is currently in clinical use for T2DM treatment. Thus, this study was designed to characterize the effects of exendin-4 on the impairment of learning and memory induced by amyloid protein (Aß) and its probable molecular underlying mechanisms. The results showed that (1) intracerebroventricular (i.c.v.) injection of Aß1-42 resulted in a significant decline of spatial learning and memory of rats in water maze tests; (2) pretreatment with exendin-4 effectively and dose-dependently protected against the Aß1-42-induced impairment of spatial learning and memory; (3) exendin-4 treatment significantly decreased the expression of Bax and cleaved caspase-3 and increased the expression of Bcl2 in Aß1-42-induced Alzheimer's rats. The vision and swimming speed of the rats among all groups in the visible platform tests did not show any difference. These findings indicate that systemic pretreatment with exendin-4 can effectively prevent the behavioral impairment induced by neurotoxic Aß1-42, and the underlying protective mechanism of exendin-4 may be involved in the Bcl2, Bax and caspase-3 pathways. Thus, the application of exendin-4 or the activation of its signaling pathways may be a promising strategy to ameliorate the degenerative processes observed in AD.

Arginine vasopressin remolds the spontaneous discharges disturbed by amyloid ß protein in hippocampal CA1 region of rats.

Beta-amyloid peptide (Aß) aggregated in the brain is the main pathological characteristic of Alzheimer's disease (AD), and a significant decrease in the concentration of arginine vasopressin (AVP) in the brain of AD patients has been reported. Our recent study shows that intracerebroventricular (i.c.v.) injection of AVP protects against Aß-induced impairments of spatial learning and memory. However, it is still unclear whether the Aß-induced cognitive deficit is involved in the alteration of central neuronal discharges, and further whether AVP can modulate the electrophysiological change induced by Aß. The present study thus observed the effects of AVP, Aß and AVP plus Aß on the spontaneous discharges of hippocampal CA1 neurons in rats by using multi-channel extracellular recording technique. The results showed that: (1) the average frequency of spontaneous discharges was decreased by i.c.v. injection of 25 nmol Aß(25-35); (2) 10 nmol AVP induced an increase in spike discharge in the hippocampal CA1 neurons; (3) pretreatment with 10 nmol AVP effectively reversed Aß(25-35) induced suppression of spontaneous discharges in hippocampal CA1 region. These in vivo electrophysiological results indicate that AVP, as a hormone and neurotransmitter, can remold the spontaneous discharges disturbed by Aß and counteract the deleterious effect of Aß(25-35) on neural circuit, suggesting that the activation of central vasopressinergic system may play a beneficial role for the prevention and treatment of cognitive impairments in AD.

[Brain-derived neurotrophic factor prevents against amyloid beta protein-induced impairment of hippocampal in vivo long-term potentiation in rats].

OBJECTIVE: To explore the effects of brain-derived neurotrophic factor (BDNF) pretreatment on beta amyloid protein (Abeta) induced impairment of in vivo hippocampal long-term potentiation (LTP) in the CA1 region of rats. METHODS: Thirty-six adult male SD rats were randomly divided into six groups (n = 6): control, Abeta25-35, BDNF, (0.02 microg, 0.1 microg, 0.5 microg) BDNF + Abeta25-35. A self-made hippocampal local drug delivery catheter and a parallel bound stimulating/recording electrode were used to deliver drugs/stimulation and record field excitatory post-synaptic potentials (fEPSPs) in the hippocampal CA1 region of rats. High-frequency stimulation (HFS) was used to induce in vivo LTP. RESULTS: (1) Abeta25-35 (2 nmol) injection into CA1 region of rats did not affect the baseline fEPSPs, but inhibited the HFS-induced LTP significantly (P < 0.01). (2) Hippocampal CA1 injection of BDNF (0.1 microg) alone did not affect the baseline fEPSPs and HFS-induced LTP. (3) Compared with Abeta25-35 alone group, the averaged amplitude of LTP in BDNF (0.1 microg and 0.5 microg) plus Abeta25-35 groups significantly increased at 0 min, 30 min, and 60 min after HFS (P < 0.01), indicating that pretreatment with BDNF effectively protected against the Abeta,25-35 induced depression of LTP in a dose-dependent manner. CONCLUSION: Intrahippocampal injection of BDNF can protect against the Abeta25-35-induced LTP impairment, suggesting that the up-regulation of BDNF in the brain could maintain the normal hippocampal synaptic plasticity and may contribute to the improvement of learning and memory in Alzheimer's (AD) disease patients.

Arginine vasopressin prevents against Abeta(25-35)-induced impairment of spatial learning and memory in rats.

Amyloid beta protein (Abeta) is thought to be responsible for loss of memory in Alzheimer's disease (AD). A significant decrease in [Arg(8)]-vasopressin (AVP) has been found in the AD brain and in plasma; however, it is unclear whether this decrease in AVP is involved in Abeta-induced impairment of spatial cognition and whether AVP can protect against Abeta-induced deficits in cognitive function. The present study examined the effects of intracerebroventricular (i.c.v.) injection of AVP on spatial learning and memory in the Morris water maze test and investigated the potential protective function of AVP against Abeta-induced impairment in spatial cognition. The results were as follows: (1) i.c.v. injection of 25 nmol Abeta(25-35) resulted in a significant decline in spatial learning and memory; (2) 1 nmol and 10 nmol, but not 0.1 nmol, AVP injections markedly improved learning and memory; (3) pretreatment with 1 nmol or 10 nmol, but not 0.1 nmol, AVP effectively reversed the impairment in spatial learning and memory induced by Abeta(25-35); and (4) none of the drugs, including Abeta(25-35) and different concentrations of AVP, affected the vision or swimming speed of the rats. These results indicate that Abeta(25-35) could significantly impair spatial learning and memory in rats, and pretreatment with AVP centrally can enhance spatial learning and effectively prevent the behavioral impairment induced by neurotoxic Abeta(25-35). Thus, the present study provides further insight into the mechanisms by which Abeta impairs spatial learning and memory, suggesting that up-regulation of central AVP might be beneficial in the prevention and treatment of AD.