PTERIDINES

The degradation of the green plant pigment chlorophyll has fascinated chemists and biologists alike over the last few decades. Bioactivities of the compounds formed in this biochemical degradation pathway, however, have only come to light recently. These natural compounds that are formed from chlorophyll during plant senescence are now called phyllobilins. In this review, we shortly discuss chlorophyll degradation and outline the so-far known bioactivities of selected phyllobilins (phylloleucobilin, dioxobilin-type phylloleucobilin, and phylloxanthobilin), and we also highlight the recently discovered immunomodulatory effects of a yellow phylloxanthobilin.

Objective To investigate the correlation between serum level of homocysteine (Hcy) and ulcerative colitis (UC) and evaluate its diagnostic performance by pooling the open published data. Methods The case–control or cohort studies relevant to serum level of Hcy and UC, published in Pubmed, Medline, EMBASE, China Wanfang and CNKI databases, were systematically screened by using the text word of “homocysteine,” “hcy,” “UC,” “inflammatory bowel disease.” The standard mean difference (SMD) was pooled through random effect model. The diagnostic sensitivity, specificity and area under the receiver operating characteristic (AUC) curve of serum Hcy for UC were also calculated. Results Eighteen relevant case–control studies were identified by electronic searching the related databases. The pooled results indicated that the serum levels of Hcy were statical different between UC and healthy controls with SMD = 0.95 (95% CI: 0.87–1.04). The serum levels of Hcy were 14.30 ± 3.08 (range: 10.10–21.73) and 10.09 ± 1.57 (range: 6.80–12.47) μmol/L for UC and healthy controls, respectively, of the included 18 studies. Using serum Hcy as biomarker for UC identification, the diagnostic sensitivity, specificity and AUC were 94.44% (95% CI: 72.71–99.86%), 72.22% (46.52–90.31%) and 0.88 (95% CI: 0.77–0.99, P < 0.05), respectively. Significant publication bias was identified in the present work. Conclusion Based on the present publications, serum Hcy was elevated in UC cases and can be applied as serological marker for UC diagnosis. However, due to significant publication bias, the diagnostic performance should be further validated by well-designed prospective diagnostic studies.

Because of an increasing incidence of malignant tumours of the head and neck there is an unmet medical need for early diagnosis of the primary disease or precancerous lesions, and timely detection of recurrence by simple non-invasive tests. The analysis of biomarkers in body fluids may be appropriate for this goal. In this review, we compare the data on utilization of neopterin and interleukin-6 (IL-6) measurements in saliva and plasma/serum of patients with oral and oropharyngeal squamous cell carcinoma, indicating the suitability of using saliva as a diagnostic matrix in head and neck cancers on behalf of close anatomical proximity and a potential to study the tumour microenvironment. Salivary neopterin and IL-6 are potential biomarkers of head and neck cancer suitable not only for early diagnosis, but also for monitoring of treatment results and detection of the disease recurrence.

Objective Inconsistent findings have been reported regarding the association between elevated plasma total homocysteine (tHcy) and the risk of different types of strokes. We conducted this meta-analysis to identify the association between tHcy and different kinds of strokes or recurrences of strokes, and provide evidence for preventing. Methods Relevant studies published before May 1, 2022 in databases such as PubMed, EMBASE, the Cochrane Library, CNKI, and Wanfang were retrieved. Two researchers independently searched and extracted the data, and used Stata 16.0 statistical software for analysis. Results were presented as the odds risk (OR) and the corresponding 95% confidence intervals (CI). Results In total, 24 articles were included, involving 51,426 subjects, of which 4,983 had stroke events during follow-up. Relative to lower tHcy, higher tHcy were associated with increased stroke (OR = 1.95, 95% CI: 1.59–2.37), ischemic stroke (OR = 1.71, 95% CI: 1.39–2.11), hemorrhagic stroke (OR = 1.99, 95% CI: 1.03–3.84), and recurrent stroke (OR = 1.25, 95% CI: 1.12–1.39), respectively. Conclusions This study shows that elevated tHcy increases the risk of stroke, including ischemic stroke and hemorrhagic stroke, and is closely related to the recurrence of stroke. It is recommended to pay attention to the detection of tHcy in the management of stroke patients in the future, and take effective measures to prevent and delay the progression of stroke.

Objective The present work aimed to investigate folate receptor (FOLR1, FOLR2, FOLR3) expression, functional enrichment, signaling pathway and prognosis in ovarian cancer patients by integrated bioinformatics analysis. Methods Folate receptor (FOLR1, FOLR2, and FOLR3) mRNA expression level between epithelial ovarian cancer and corresponding normal ovarian tissue of cancer patients was compared through the TCGA database by GEPIA online analysis tool. The protein–protein interaction (PPI) network of FOLR1, FOLR2, FOLR3, and related genes were constructed through the STRING database. GO and KEGG enrichment of FOLR1, FOLR2, FOLR3, and relevant genes were analyzed. Overall survival (OS) and progression-free survival (PFS) between FOLR1, FOLR2, and FOLR3 mRNA high and low expression epithelial ovarian cancer patients were compared by log-rank test. Results FOLR and FOLR3 mRNA expression in epithelial ovarian cancer tissue were significantly higher than that of corresponding normal ovarian tissue of cancer patients ( P < 0.05) The PPI network showed 53 nodes and 298 edges with the average node degree of 11.2. The local clustering coefficient was 0.744, which indicated that the protein–protein enrichment was statistically significant ( P < 1.0 × 10 ⁻¹⁶ ). Folate receptor (FOLR1, FOLR2, and FOLR3) and relevant genes were mainly enriched in folic acid transport, methotrexate transmembrane transporter activity, antifolate resistance for biological process, molecular function, and KEGG pathway, respectively. The PFS of FOLR1 and FOLR3 high expression epithelial ovarian cancer patients was significantly lower compared to low-expression subjects with statistical significance [hazard ratio (HR FOLR1 ) = 1.26, 95% confidence interval (CI): 1.09–1.45, P < 0.05, HR FOLR3 = 1.22, 95% CI: 1.06–1.40, P < 0.05]. However, the OS was not statistically different between FOLR1, FOLR2, and FOLR3 low and high expression groups. Conclusion Folate receptor (FOLR1, FOLR2, and FOLR3) genes were up-regulated in epithelial ovarian cancer and partly associated with patient’s poor prognosis.

Objective To investigate the epithelial nitric oxide synthases (eNOS) 894 G < T polymorphism and diabetic nephropathy (DN) susceptibility by pooling the open published data. Methods Studies relevant to eNOS 894 G < T polymorphism and DN susceptibility published in PubMed, EMBASE, Medline, CNKI, and Wanfang databases were systematically screened by using the text words of endothelial nitric oxide synthase, eNOS, NOS-3, G894T, rs179983, polymorphism, diabetic nephropathy, and DN. The correlation between eNOS 894 G < T polymorphism and DN susceptibility was demonstrated by odds ratio (OR) and corresponding 95% confidence interval (95% CI). The data were combined through fixed or random effect model according to statistical heterogeneity. The publication bias was assessed by Begg’s funnel plot and Egger’s line regression test. Results Twenty-six case-control studies relevant to eNOS 894 G < T polymorphism and DN susceptibility were identified by electronic searching of the related databases. Type 2 diabetes mellitus (T2MD) patients with T allele had increased susceptibility to DN compared with G allele under homologous gene model (TT vs GG) (OR = 1.40, 95% CI: 1.16–1.69, p = 0.001), dominant gene model (TT + GT) vs GG (OR = 1.61, 95% CI: 1.30–2.00, p = 0.000) and recessive gene model TT vs (GT + GG) (OR = 1.39, 95% CI: 1.16–1.66, p = 0.000). Publication bias was not statistically significant for homologous and recessive gene model. Conclusion Based on the present evidence, DN risk was increased in T2MD cases with T allele compared to G allele.

Background Numerous studies indicated that B vitamin supplementation can reduce cardiovascular risk; nonetheless, available proof reported from individual studies have not been consistent, so we performed an updated meta-analysis of randomized controlled trials (RCTs) to evaluate the relationship between B vitamin supplementation and cardiovascular outcomes. Materials and method Relevant studies published before May 2022 were searched from the electronic databases of PubMed, Embase, the Cochrane Library, Chinese Biology Medicine, and the Chinese National Knowledge Infrastructure. Outcomes included major adverse cardiovascular event (MACE), myocardial infarction (MI), stroke, hospitalization for unstable angina, revascularization, total mortality, and cardiovascular death. The strength of the association was examined by risk ratio (RR) with 95% confidence interval (95% CI). Results A total of 17 RCTs involving 31,085 subjects were included in the meta-analysis. The combined supplementation of B vitamins had no significant effect on MACE based on eight RCTs (RR = 0.98, 95% CI = 0.92–1.04), MI based on 13 RCTs (RR = 1.00, 95% CI = 0.92–1.09), and revascularization based on 12 RCTs (RR = 1.02, 95% CI = 0.95–1.10). Ten studies showed that the combined supplementation of B vitamins reduced the risk of stroke by 12% (RR = 0.88, 95% CI = 0.81–0.97). Eleven studies showed that the combined supplementation of B vitamins had no significant effect on the total mortality (RR = 0.99, 95% CI = 0.94–1.05), and nine studies showed that the combined B vitamins had no significant effect on cardiovascular death (RR = 0.96, 95% CI = 0.88–1.05). Besides, with the extension of follow-up duration and those with a history of cardio-cerebrovascular diseases, supplementation of B vitamins could reduce the risk of stroke. Conclusion The supplementation of folic acid, Vitamin B6, and B12 is associated with a reduction in stroke, but not in total mortality, cardiovascular death, MACE, and MI.

Amalgam has been widely used as a restorative dental material for over 150 years. Most standard dental amalgam formulations contain approximately 50% elemental mercury in a mixture of copper, tin, silver, and zinc. Mercury is a highly volatile metal, which can easily vaporize to a colorless and odorless gas. It has been demonstrated that mercury is released from dental amalgam, which is increased by chewing, eating, brushing, and drinking hot liquids. Besides this, amalgam is the main occupational exposure source of mercury for dental workers. It is known that mercury exposure causes immune modulation in humans. In this study, it was aimed to evaluate the changes in neopterin levels and tryptophan (Trp) degradation in dental technicians. It was observed that low levels of occupational mercury exposure resulted in decreased neopterin, kynurenine (Kyn), and Kyn/Trp levels. Moreover, mercury and neopterin levels had a significant positive correlation in workers. The lower neopterin levels and Kyn/Trp in dental technicians compared to an unexposed group indicates a possible immune suppression with low level of occupational mercury exposure during amalgam preparation. The relationship between urinary mercury levels as an indicator of occupational mercury exposure and neopterin reminded an effect on T-cell-mediated immune response.

Background Numerous studies indicated that there exists a relationship between methylenetetrahydrofolate reductase (MTHFR) C667T polymorphism and diabetic nephropathy (DN) susceptibility; nonetheless, available proof reported from individual studies has not been consistent, so we performed an updated meta-analysis to evaluate the relationship between MTHFR C667T variant and DN. Materials and methods Relevant studies published before February 2022 were searched from the electronic databases PubMed, Embase, Scopus, Chinese Biology Medicine and the Chinese National Knowledge Infrastructure. The strength of the association was examined by odds ratio (OR) with 95% confidence interval (CI). Results The findings illustrated that there was a significant relationship between the polymorphism of C677T and DN compared with that to DM controls in allele (OR = 1.59, 95% CI = 1.39–1.82), dominant (OR = 1.76, 95% CI = 1.47–2.11) and recessive (OR = 1.85, 95% CI = 1.56–2.20) models in all populations. Moreover, as compared with the healthy controls, a significant relationship between C677T and DN was found in three genetic comparison models (allele: OR = 1.81, 95% CI = 1.43–2.29; dominant: OR = 2.09, 95% CI = 1.54–2.85; recessive: OR = 2.02, 95% CI = 1.51–2.70). Furthermore, stratifying data by race, diabetes duration and whether in Hardy–Weinberg equilibrium revealed substantially augmented vulnerability to DN in all subgroups. Conclusion The current meta-analysis highlighted conclusive results for the robust association between C677T polymorphisms and DN susceptibility.

Background The authors explore the therapeutic and prophylactic efficacies of Immunopterin (calcium pterin-6-carboxylate chelate) against coronavirus colds and as a therapy against COVID-19. Methods To determine Immunopterin’s therapeutic efficacy against colds and flus, a 5-year observational study was conducted with 34 subjects who took Immunopterin when feeling symptoms of a cold or flu. The mean sample cold recovery time was compared to the US population mean. A review of the Moheno (2014) 2-year observational study was conducted to evaluate the prophylactic efficacy of Immunopterin against colds. Early COVID-19 case studies, treated with Immunopterin, were collected to explore Immunopterin’s efficacy as a therapeutic and prophylactic against COVID19 disease. Results The mean cold recovery time for the therapeutic sample in the cold/flu observational study was 30 h compared to the US population mean of 168 h ( N = 34; p < 0.001). Subjects taking prophylactic Immunopterin reported 0% incidences of colds and flus ( N = 31). Immunopterin successfully treated four confirmed COVID-19 subjects. A fifth clinical nurse case study demonstrates COVID-19 prevention. Conclusions The therapeutic and prophylactic efficacies of Immunopterin against coronavirus colds, along with reported cross-reactivity between coronavirus colds and SARS-CoV-2 strongly suggest Immunopterin can act as a therapy and preventative against COVID- 19 infection associated disease.

Pterins, such as folate and biopterin, and their derivatives hold significant importance given their biological relevance, as well as the numerous pterin-based inhibitors developed for targeting various biological targets. For this reason, pterins can be viewed as a privileged scaffold, as the discovery of new pterin analogs gives rise to a vast array of potential drug candidates. 7-carboxymethyl-pterin (7-CMP) represents a useful scaffold for the rapid generation of structurally diverse pterin amides and has been a key building block in medicinal chemistry. In an effort to facilitate rapid generation of this pterin scaffold, we have explored multiple routes towards 7-CMP to assess the most efficient method of generation. Methods were evaluated based on yield, regioselectivity, reaction time, and hazardous reaction conditions. This work can aide in the synthesis and discovery of new pterin-based drug candidates.

Objective To evaluate the correlation between methylene tetrahydrofolate reductase ( MTHFR ) gene rs1801133 C>T polymorphisms and risk of osteoporosis. Methods We searched the clinical studies related to MTHFR gene rs1801133 C>T polymorphisms and risk of osteoporosis in the electronic databases of PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM) and included the suitable publications in the present meta-analysis according to the inclusion and exclusion criteria. The data of included studies were extracted and pooled by a random or fixed-effect model. The odds ratio (OR) and 95% confidence interval (95% CI) were applied to demonstrate the correlation between MTHFR gene rs1801133 C>T polymorphisms and the risk of osteoporosis. Publication bias was assessed by Begg’s funnel plot and Egger’s line regression test. Results Seven case–control clinical studies were included and a data combination was made. The data was pooled by the fixed effect model because of no obvious statistical heterogeneity. The pooled results indicated that people with the T allele had increased risk of developing osteoporosis under the homologous gene model (TT vs CC) (OR = 2.36, 95% CI: 1.81–3.08, p < 0.05), dominant gene model (TT + CT) vs CC (OR = 1.47, 95% CI: 1.21–1.77, p < 0.05) and recessive gene model TT vs (CC + CT) (OR = 2.16, 95% CI: 1.71–2.74, p < 0.05). Egger’s line regression test indicated no significant publication bias for the present meta-analysis in the above homologous, dominant, and recessive gene models. Conclusion The MTHFR gene rs1801133 C>T polymorphisms are associated with osteoporosis and subjects with the T allele have an increased risk of developing osteoporosis.

Objective Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides, which was involved in the progression of malignant tumors including non-small cell lung cancer (NSCLC). Material/methods Ferroptosis inhibiting gene solute carrier family 7 member 11 (SLC7A11) mRNA expression was investigated in the database of TCGA and Oncomine and compared between the cancer tissue and the normal corresponding tissue of NSCLC patients. SLC7A11 gene mutation of NSCLC was investigated in the TCGA database by the online data analysis tool of Catalog of Somatic Mutations in Cancer (COSMIC) and cBioPortal. The protein–protein interaction (PPI) network of SLC7A11 and associated genes were constructed with the STRING database. Gene ontology (GO) and the KEGG pathway of genes involved in the PPI network were explored and demonstrated by a bubble plot. Progression-free survival (PFS), overall survival (OS) and postprogression survival (PPS) between SLC7A11 high and SLC7A11 low expression groups were compared and demonstrated by the survival curve. Results SLC7A11 mRNA was upregulated in cancer tissues compared to paired normal tissues in colorectal adenocarcinoma, esophageal squamous cell carcinoma, lung squamous cell carcinoma rectum adenocarcinoma and uterine corpus endometrial carcinoma. Missense and synonymous substitutions were 66.67% and 16.67% for lung squamous cell carcinoma. For lung adenocarcinoma, the missense and synonymous substitutions were 66.67% and 33.33% respectively. In the case of single nucleotide mutation, A>T, C>G, G>A, G>T for lung squamous cell carcinoma and G>T, C>A, G>A, T> for lung adenocarcinoma were the most common mutations in the SLC7A11 coding strand. Fifty-one genes were included in the PPI network with an edge number of 287, average node degree of 11.3 and local clustering coefficient of 0.694, which demonstrated that the PPI network was enriched significantly ( p = 1.0 × 10 ⁻¹⁶ ). In terms of the KEGG pathway, the SLC7A11 and PPI-involved genes were mainly enriched in ferroptosis, NSCLC, pathways in cancer, tp53 signaling pathway, etc. The overall survival (OS) in the SLC7A11 high group was significantly lower than those of SLC7A11 low groups in NSCLC (HR = 1.15, 95% CI: 1.02–1.31, p = 0.027). However, the progression-free survival (PFS) (HR = 1.17, 95% CI: 0.97–1.42, p = 0.098) and postprogression survival (PPS) (HR = 1.00, 95% CI: 0.78–1.29, p = 0.97) between SLC7A11 high and SLC7A11 low expression groups were not statistically different. Conclusion SLC7A11 was upregulated in NSCLC and correlated with the patient’s poor overall survival. SLC7A11 may be a potential target for NSCLC treatment through the ferroptosis pathway.

Objective To investigate methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) expression, biological function, and correlation with head and neck squamous cell carcinoma (HNSCC) patient’s prognosis. Methods The relative expression levels of MTHFD2 gene mRNA in tumor tissues of HNSCC and adjacent normal tissues were analyzed in the Cancer Genome Atlas and oncomine database. MTHFD2 protein relative expression in tumor tissue of HNSCC patients was analyzed in human proteome database. Protein–protein interaction (PPI) network of MTHFD2 and correlated genes were constructed in STRING database. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway of MTHFD2 and relevant proteins involved in the PPI network was enriched. The Tumor Immune Estimation Resource database was used to analyze the relationship between MTHFD2 expression and immune infiltration. Overall survival (OS) and progression-free survival (PFS) for MTHFD2 high and low expression groups were investigated in the Kaplan–Meier Plotter database. Results In HNSCC, MTHFD2 mRNA relative expression level in tumor tissue was significantly higher than the corresponding normal tissue with statistical difference ( p < 0.05). In the PPI network, 21 protein coding genes were involved in the network with 124 edges, which indicated that the enrichment was significant ( p < 0.05). MTHFD2 and PPI network involved genes were mainly enriched in tetrahydrofolate metabolic process, one-carbon metabolic process biological process. In KEGG pathway, MTHFD2 and PPI network involved genes were mainly enriched in one-carbon pool by folate, metabolic pathways, glyoxylate, and dicarboxylate metabolism, and carbon metabolism. The relative expression level of MTHFD2 gene was correlated with immune infiltration of macrophage ( r = 0.712, p < 0.05), neutrophil ( r = 0.158, p < 0.05), dendritic cell ( r = 0.1825, p < 0.05), and CD4+ T lymph cell ( r = 0.1825, p < 0.05). HNSCC patients with high expression MTHFD2 had low OS compared to low expression cases (hazard ratio = 1.53, 95% CI: 1.16–2.02, p < 0.05). Conclusion MTHFD2 is overexpressed in HNSCC and correlated with patient’s prognosis. MTHFD2 maybe a potential target for HNSCC target treatment and provides a possible direction for the research and development of related targeted drugs.

The aim of this study was to investigate the changes in circulating concentrations of citrulline, neopterin, kynurenine, and tryptophan during the course of chemoradiation in patients with cervical cancer. Sixteen patients with histologically confirmed carcinoma of the uterine cervix, aged 53 ± 15 years (range 29–76 years), were included in this study. Plasma neopterin, kynurenine, and tryptophan were determined with an enzyme-linked immunosorbent assay. Plasma citrulline was measured with high-performance liquid chromatography. Compared to baseline, citrulline concentration was markedly and statistically significantly decreased at visits 2, 3, and 4, while returning to pretreatment concentrations at visit 5. A significant increase in serum neopterin concentrations was observed at visits 4 and 5. With the exception of decreased kynurenine/tryptophan ratio at visit 3, no significant changes were observed in the concentrations of kynurenine, tryptophan, and kynurenine/tryptophan ratio throughout the course of the treatment. In conclusion, present data demonstrate that citrulline concentrations decrease early and neopterin concentrations increase late during the course of chemoradiation in patients with cervical carcinoma. Citrulline represents a biomarker of intestinal toxicity in this population.

Acute myocardial infarction (AMI) is the most severe manifestation of coronary artery disease. Considerable efforts have been made to elucidate its etiology and pathology, but the genetic factors that play a decisive role in the occurrence of AMI are still unclear. To determine the molecular mechanism of the occurrence and development of AMI, four microarray datasets, namely, GSE29111, GSE48060, GSE66360, and GSE97320, were downloaded from the Gene Expression Omnibus (GEO) database. We analyzed the four GEO datasets to obtain the differential expression genes (DEGs) of patients with AMI and patients with non-AMI and then performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and Protein-protein interaction (PPI) network analysis. A total of 41 DEGs were identified, including 39 upregulated genes and 2 downregulated genes. The enriched functions and pathways of the DEGs included the inflammatory response, neutrophil chemotaxis, immune response, extracellular space, positive regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcription factor activity, response to lipopolysaccharide, receptor for advanced glycation end products (RAGE) receptor binding, innate immune response, defense response to bacterium, and receptor activity. The cytoHubba plug-in in Cytoscape was used to select the most significant hub gene from the PPI network. Ten hub genes were identified, and GO enrichment analysis revealed that these genes were mainly enriched in inflammatory response, neutrophil chemotaxis, immune response, RAGE receptor binding, and extracellular region. In conclusion, this study integrated four datasets and used bioinformatics methods to analyze the gene chips of AMI samples and control samples and identified DEGs that may be involved in the occurrence and development of AMI. The study provides reliable molecular biomarkers for AMI screening, diagnosis, and prognosis.

The naturally occurring stilbenoid oxyresveratrol was shown to influence inflammatory and metabolic processes. During cellular immune activation, tryptophan breakdown and neopterin formation via the enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and GTP-cyclohydrolase, respectively, are induced. Neopterin and the kynurenine to tryptophan ratio are reliable and pertinent biomarkers of Th1-type immune response and are also used in vitro to monitor effects of active plant ingredients on peripheral blood mononuclear cells (PBMCs). We investigated the effects of oxyresveratrol on the activity of the above-mentioned pathways in mitogen-stimulated human PBMC and in the myelomonocytic cell line THP-1. Oxyresveratrol exerted suppressive effects on tryptophan breakdown in both stimulated cell models. Of note, in PBMC, tryptophan breakdown was induced at lower concentrations (5–20 µM) and suppressed at higher treatment concentrations only. Neopterin formation was decreased dose-dependently in stimulated PBMC. In unstimulated PBMC similar, albeit lesser effects were observed. Data indicate that oxyresveratrol exerts distinct and concentration-dependent effects on different immune cell types. IDO-1 is targeted by oxyresveratrol and its activity can be modulated in both directions. Detailed investigations of the interactions would be interesting to fully explore the activity of this phytocompound.

Objective Psychiatric hospitalizations and emergency department (ED) visits are costly, stigmatizing, and often ineffective. Given the immune and kynurenine activation in bipolar disorder (BD) and schizophrenia, as well as the immune-modulatory effects of statins, we aimed to compare the relative risk (RRs) of psychiatric hospitalizations and ED visits between individuals prescribed lipophilic vs. hydrophilic statins vs. no statins. We hypothesized (a) reduced rates of hospitalization and ER utilization with statins versus no statins and (b) differences in outcomes between statins, as lipophilia increases the capability to penetrate the blood–brain barrier with potentially beneficial neuroimmune, antioxidant, neuroprotective, neurotrophic, and endothelial stabilizing effects, and, in contrast, potentially detrimental decreases in brain cholesterol concentrations leading to serotoninergic dysfunction, changes in membrane lipid composition, thus affecting ion channels and receptors. Methods We used VA service utilization data from October 1, 2010 to September 30, 2015. The RRs for psychiatric hospitalization and ED visits, were estimated using robust Poisson regression analyses. The number of individuals analyzed was 683,129. Results Individuals with schizophrenia and BD who received prescriptions for either lipophilic or hydrophilic statins had a lower RR of psychiatric hospitalization or ED visits relative to nonstatin controls. Hydrophilic statins were significantly associated with lower RRs of psychiatric hospitalization but not of ED visits, compared to lipophilic statins. Conclusion The reduction in psychiatric hospitalizations in statin users (vs. nonusers) should be interpreted cautiously, as it carries a high risk of confounding by indication. While the lower RR of psychiatric hospitalizations in hydrophilic statins relative to the lipophilic statins is relatively bias free, the finding bears replication in a specifically designed study. If replicated, important clinical implications for personalizing statin treatment in patients with mental illness, investigating add-on statins for improved therapeutic control, and mechanistic exploration for identifying new treatment targets are natural next steps.

Objective To explore the expression and genotypes of thymidylate synthase (TS) in patients of non-small cell lung cancer (NSCLC) with different clinicopathological characteristics. Methods The expression profiles of TS were examined by immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) in 160 patients with NSCLC. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to detect TS-5′UTR tandem repeats, G/C nucleotide polymorphisms, and 3′UTR 6 bp deletion/insertion polymorphisms. The relationships between clinicopathological characteristics and TS expression or genotypes were investigated through χ ² test. Kaplan–Meier survival analysis was used to analyze the association between TS expression and overall survival (OS) and disease-free survival (DFS) of NSCLC patients. Results The expression levels of TS protein and TS gene in NSCLC tissues were significantly higher than that in paracancerous tissues ( P < 0.05). Furthermore, high expression of TS protein and 5′UTR polymorphism of TS gene showed significant correlation with differentiation, TNM stage, and lymph node metastases. The frequency of −6 bp/−6 bp genotypes in patients with NSCLC was 43.13% (69/160), which was higher than others. In addition, the rate of TS protein overexpression in NSCLC patients with 3R/3R was 79.79%, which was higher than others. Interestingly, high expression of TS protein predicted shorter DFS and OS and lower 3-year DFS rate and 3-year OS rate. Conclusions The expression levels of TS in NSCLC were significantly increased and may help to predict the prognosis of NSCLC, and high expression of TS protein and 5′UTR polymorphism of TS gene were significantly related to differentiation, TNM stage, and lymph node metastases.

Objective The aim of the study is to investigate the correlations among serum homocysteine (Hcy), D-dimer, and the risk of developing deep venous thrombosis (DVT) of the lower extremities in patients who underwent operation for lower limb fracture. Methods Seventy-five cases who underwent operation for lower limb fracture were included and further divided into DVT group ( n = 26) and control group ( n = 49) based on post-DVT diagnostic criteria. The serum Hcy and D-dimer were examined 48 h after operation. The serum Hcy and D-dimer levels were compared between the two groups. The correlation between serum Hcy and D-dimer was investigated by the Pearson correlation test. The receiver-operating characteristic (ROC) curve was applied to evaluate the diagnostic performance of serum Hcy and D-dimer as serological markers for DVT. Results The serum Hcy concentrations were 11.96 ± 3.98 μmol/L and 7.92 ± 3.27 μmol/L for DVT and control groups, respectively, with statistical difference ( t = 4.72, P < 0.01). The serum D-dimer in the DVT group was significantly higher than that of the control group (8.99 ± 4.50 vs 1.70 ± 2.11) μg/mL with statistical difference ( t = 9.56, P < 0.01). Line regression analysis indicated that serum Hcy was positively correlated with serum D-dimer concentration and can be demonstrated by the equation of Y = 0.6651* X + 1.036 for the DVT group. Using serum Hcy as the biomarker for predicting DVT, the prediction sensitivity and specificity were 76.92 and 71.44%, respectively, with the AUC of 0.7804 under the cut-point of 9.54 μmol/L. For serum D-dimer, the prediction sensitivity and specificity were 96.15 and 73.47%, respectively, with the area under the ROC (AUC) of 0.9455 under the cut-point of 1.66 μg/mL. Conclusion Serum Hcy was significantly elevated in DTV patients, and hence, it can be applied as a serological marker for DVT prediction in patients who underwent operation for lower limb fracture. However, the DVT prediction performance of serum Hcy was inferior to D-dimer especially for diagnostic sensitivity.

Objective The aim of this study was to investigate the correlation between MTHFR 677C > T polymorphism and response of pemetrexed-based chemotherapy in advanced non-small-cell lung cancer (NSCLC) by pooling the open published relevant studies. Methods Clinical studies associated with MTHFR 677C > T polymorphism and response of pemetrexed-based chemotherapy in advanced NSCLC were systematically searched in databases of Pubmed, Embase, Cochrance Library, China national knowledge infrastructure (CNKI) and Wanfang. The correlation was expressed by odds ratio (OR) and corresponding 95% confidence interval (95% CI). The publication bias of the included studies was evaluated through Begg’s funnel plot and Egger’s line regression test. Results Ten prospective clinical studies relevant to MTHFR 677C > T polymorphism and response of pemetrexed-based chemotherapy in NSCLC were included in the present meta-analysis. The pooled results indicated that the partial response in NSCLC patients with TT or CT genotype was inferior to CC genotype in a dominant gene model (TT + CT vs CC) (OR = 0.16, 95% CI: 0.06–0.41, P = 0.001). NSCLC cases with T genotype were inferior to C genotype in the objective response rate treated with pemetrexed-based chemotherapy for dominant (OR = 0.28, 95% CI: 0.18–0.45, P = 0.001), recessive (OR = 0.43, 95% CI: 0.19–0.94, P = 0.03) and homozygous models (OR = 0.30, 95% CI: 0.13–0.67, P = 0.003). However, there was no statistical difference in disease control rate, progressive disease between different genotypes of different gene models ( P all > 0.05). Conclusion The pemetrexed-based chemotherapy response was decreased in NSCLC cases with T genotype, which can be applied as a potential pemetrexed-based chemotherapy response marker.

Objective The aim of the study was to determine whether biopterin is present in significantly lower quantities in urine samples of patients with autism spectrum disorder (ASD) compared to healthy individuals. Methods The concentration of biopterin in urine samples was measured by ELISA using commercially available kit. The study involved 53 children aged 3–16 years with ASD and 60 healthy children aged 2–14 years. Results Significantly lower biopterin concentration was observed in autistic patients compared to the control group. However, no significant difference was observed between mild, moderate, and severe ASD. Conclusion One of the potential causes of decrease in urinary biopterin levels may be tetrahydrobiopterin (BH 4 ) deficiency, which has extensive and serious health consequences for the nervous system. The results of measuring biopterin as a fully oxidized form of BH 4 may suggest that biosynthesis or regeneration of BH 4 may be decreased in children with ASD. On the other hand, decreased urinary biopterin levels in children with ASD may be due to BH 4 overuse, a good regeneration process, and decreased urinary excretion; and abnormalities in BH 4 metabolism appear to be related to the aetiology of ASD or may be due to ASD.

Objective The aim of this study was to investigate the clinical significance of serum homocysteine (Hcy) as a biomarker for early diagnosis of diabetic nephropathy (DN) in type 2 diabetes mellitus (T2DM) patients. Methods Fifty-five T2DM patients with DN and 51 T2DM patients without DN were prospectively recruited from January 2016 to May 2020 in our hospital. The serum Hcy was tested by electrochemiluminescence assay in DN and T2DM groups and compared. The diagnostic efficacy of serum Hcy as a biomarker for early diagnosis of DN was evaluated by calculating the diagnostic sensitivity, specificity and area under the ROC curve (AUC). Results The serum levels of Hcy were 15.49 ± 5.40 and 9.23 ± 3.15 μmol/L for DN and T2DM patients, respectively, with statistical difference ( t = 7.21, P < 0.001). In the DN group, the serum Hcy levels for patients with hyperfiltration, intermittent proteinuria, microalbuminuria, macroalbuminuria and uremic were 10.99 ± 2.57, 13.90 ± 2.86, 15.38 ± 4.77, 18.98 ± 4.36 and 23.31 ± 5.22 μmol/L, respectively, which indicated that serum Hcy levels in DN were higher than those of T2DM patients and correlated with patient’s renal damage. Using the serum Hcy level as the reference, the diagnostic sensitivity, specificity and AUC were 84.31 (71.41–92.98)%, 74.55 (61.00–85.33)% and 0.85 (0.78–0.92)%, respectively, with the cutoff value of 12.08 between DN and T2DM. The serum Hcy also had relatively good differential diagnostic efficacy between different DN stages with high sensitivity, specificity and AUC. Conclusion Serum Hcy was obviously elevated in DN compared to T2MD and correlated with the renal damage severity, which can be applied as a potential serological marker for early diagnosis of DN.

Background: To investigate the clinical effects of norepinephrine versus dopamine in treatment of septic shock by pooling the data form open published clinical trials. Material and Methods: The clinical trials relevant to norepinephrine versus dopamine in treatment of septic shock were electronically searched in the databases of Pubmed, Embase, the Cochrane Library, Web of Science, Google scholar and CNKI. The original data related to the treatment effects such as death risk, oxygen metabolism and hemodynamics index were extracted from the included original studies. The death risk was pooled by the effect size of relative risk (RR), the oxygen metabolism and hemodynamics index were pooled by standard mean difference (SMD) and the corresponding 95% confidence interval (95%CI). The publication bias was evaluated by Begg’s funnel plot and Egger’s line regression test. Results: Thirteen clinical trials were included in the meta-analysis. The pooled results demonstrated the death risk was significantly decreased (RR=0.89, 95%CI:0.81 to 0.98, p=0.024) in septic shock patients who received norepinephrine compared to those receiving dopamine. The HR (SMD=-1.84, 95%CI:-2.86 to -0.81, p<0.01) and cardiac index (SMD=-0.74, 95%CI:-1.01 to -0.48, p<0.01) were lower in norepinephrine group compared to dopamine group. The systemic vascular resistance index (SMD=1.33, 95%CI:0.62 to 2.04, p<0.01) in norepinephrine group was higher than those of dopamine group with statistical difference. The Begg’s funnel plot and Egger’s line regression test (t=-0.84, p=0.425) showed no publication bias. Conclusions: Based on the present evidence, norepinephrine was superior to dopamine in the aspects of death risk reducing and hemodynamics.

The new coronavirus SARS-CoV-2 was identified to be responsible for the COVID-19 pandemic. There are striking differences in the response to infection, some people develop no or mild symptoms, while other outcomes are severe of even fatal. For those COVID-19 patients who require hospitalization, prognostic markers could help clinicians to identify patients with a poor outcome early. The serum levels of the immune activation marker neopterin have already been shown to be of prognostic value in patients with SARS-CoV-1 and a similar pattern can be observed for SARS-CoV-2. This comment discusses the biochemical circuits that support the clinical value of neopterin measurements in COVID-19 patients.

In Coronavirus disease 2019 (COVID-19), it is important to evaluate disease activity and investigate possible biomarkers. Therefore, in this study, we investigated the relationship between disease activity and serum levels of possible immune activation marker neopterin in patients with COVID-19. The study enrolled 45 patients (23 females, 51.1%) treated for COVID-19. The patients were divided into two groups according to their clinical presentation: those who recovered quickly (Group 1) and those who worsened progressively (Group 2). The neopterin and C-reactive protein levels were high in all patients on admission. In Group 1, neopterin concentrations and serum neopterin/creatinine ratios were significantly higher on admission compared to Day 14 of the disease, whereas in Group 2, levels were significantly higher at Day 14 of the disease than on admission. Neopterin levels at admission were significantly higher in Group 1. The serum neopterin concentrations at admission were markedly higher in patients with a derived neutrophil–lymphocyte ratio (dNLR) > 2.8 compared to those with a dNLR ≤ 2.8 (p < 0.05). Serum neopterin levels can be used as a prognostic biomarker in predicting disease activity in COVID-19.

Objective The aim of the present work was to investigate the expression of nitric oxide synthase 2 (iNOS/ NOS2) in colorectal and gastric cancers and evaluate its association with patient’s prognosis by integrated bioinformatics analysis. Methods The data for present study was obtained from the TCGA, GTEx, and STRING database. iNOS/NOS2 mRNA expression in normal tissue and colorectal, and gastric cancer tissuea were investigated through the GTEx and TCGA database. iNOS/NOS2 gene mutations and frequency were analyzed in the TCGA database using the cBioPortal online data analysis tool. The protein-protein interaction (PPI) network of iNOS/NOS2 was constructed by STRING database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of iNOS/NOS2 and relevant proteins involved in the PPI network were enriched and demonstrated by the bubble plot. Comparison of the overall survival(OS) and disease free survival(DFS) between samples expressing high and low levels of iNOS/NOS2 was analysis based on the TCGA databases through the GEPIA online data analysis tool. Results For colon adenocarcinoma (COAD) and rectal adenocarcinoma(READ) iNOS/NOS2 mRNA expression levels in tumor tissue were significant higher than those of corresponding normal colorectal tissue (p<0.05). iNOS/NOS2 mutations were identified in both colorectal cancer and gastric cancer. Missense substitutions and synonymous substitution were the top two mutation types for colorectal and gastric cancer. The top positive and negative co-expressed genes correlated with iNOS/ NOS2 were TRIM40 (r pearson =0.56, p<0.05) and GDPD5 (r pearson =-0.41, p<0.05) in colorectal cancer respectively andCASP5 (r pearson =0.63,p<0.05) and PIAS3 (r pearson =-0.43,p<0.05) in gastric cancer. Twenty one proteins were included in the PPI network with 51 nodes and 345 edges which indicated the PPI enrichment wassignificant (p=1.0e-16). The KEGG of the included genes were mainly enriched in metabolic pathway and Jak-STAT signaling pathway. There was a significant difference indisease free survival (DFS) between samples expressing high and low iNOS/NOS2 (HR=0.37, p=0.044) in rectal cancer. The difference was not statistical between iNOS/NOS2 high and low expressing groups for overall survival(OS) or DFS in the colon cancer or gastric cancer(p>0.05). Conclusions iNOS/NOS2 mRNA isup-regulated in tumor tissue compared to corresponding normal tissue in colorectal and gastric cancer which implement it in the development of colorectal and gastric cancers.

Objective Folate deficiency is closely related to the occurrence of human tumors and plays an important role in cell growth, differentiation, repair, and host defense. We studied the effects of folic acid on the apoptosis of breast cancer cells (MDA-MB-231) and on the activity of the PTEN/AKT/P53 signaling pathway in breast cancer cells. Methods Breast cancer cells (MDA-MB-231) were treated with folate alone or in combination with a PTEN specific inhibitor, SF1670. Cell viability was detected by a MTT assay, and the expression levels of apoptosis-related proteins and PTEN/AKT/P53 signaling pathway were detected via Western blot analysis. Rate of apoptosis was measured via cytometry. Results Folic acid inhibited the cell viability of MDAMB-231 cells and the expressions of Bcl-2 and p-AKT proteins and upregulate the expression of Bax, PTEN, and P53 proteins, thereby inducing apoptosis in these cells. SF1670 treatment inhibited the expressions of Bcl-2 and p-AKT protein and upregulate Bax, PTEN, and P53 protein expression. Conclusion Folic acid has cytotoxic effects on MDAMB-231 cells and can induce apoptosis by targeting the PTEN/AKT/P53 signaling pathway.

Background: This study aimed to explore the effect of 5-HT1A receptors (HTR1A) on activation of the anterior cingulate cortex and simultaneous regulation of neural activity in the insular cortex and hippocampus. Methods: The IBS rat model was established via chronic water avoidance stress (WAS). Visceral sensitivity was measured by electromyogram, and anxiety-like behaviours were evaluated by the open field test. HTR1A-specific lentivirus expressing green fluorescent protein was used to overexpress or down-regulate HTR1A expression. Protein expression levels were detected by western blot. Results: Up-regulation of HTR1A in ACC could inhibit ACC sensitization and reverse the visceral hypersensitivity and anxiety-like behaviours induced by chronic psychological stress. In contrast, down-regulation of HTR1A in ACC might promote these behaviors in IBS rats. Additionally, up-regulation of HTR1A in ACC could inhibit IC and hippocampus sensitization, while down-regulation might have the opposite effect. Conclusions: In IBS rats, HTR1A could modulate ACC activation and interactions among the ACC, IC and hippocampus. These effects might in turn contribute to the development of visceral hypersensitivity and anxiety-like behaviours induced by chronic psychological stress.

In patients with metastatic melanoma the advent of targeted therapy and immune checkpoint inhibitors has transformed the management of advanced and metastatic disease, resulting in improved outcomes. Neopterin is a biomarker of immune activation increased in cancer as well as in other conditions associated with immune activation. We present a case of a patient with advanced metastatic melanoma responding to the combination targeted therapy with dabrafenib and trametinib. The treatment was complicated by a fever that was accompanied by a marked rise in serum and urinary neopterin concentrations. Present case report illustrates not only the efficacy of combined targeted therapy, but also the utilization of neopterin measurements in the diagnosis and monitoring of pyrexia in patients with metastatic malignant melanoma.

Objective To evaluate the expression of inducible nitric oxide synthases (iNOS/NOS2) in human glioma and its correlation with patients’ prognoses. Methods IiNOS/NOS2 expression in tumor and corresponding normal tissues of glioma patients was analyzed using the TCGA database and the online analysis tool GEPIA. The mutation statuses of iNOS/NOS2 genes were also explored in the TCGA database using cBioPortal. Co-expressed genes relevant to iNOS/NOS2 were screened by LinkedOmics. Gene ontology (GO) and KEGG pathway enrichment for iNOS/NOS2 and co-expressed genes was performed using LinkedOmics. Overall survival (OS) and disease-free survival (DFS) outcomes between iNOS/NOS2 mRNA high and low expression groups were compared using a log-rank test. Twenty-two glioma patients who underwent operation were included in the present work. A real-time PCR assay was used to detect iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissue. Results There was no statistical difference in iNOS/NOS2 mRNA expression levelss between tumor and normal tissues of glioma. A real-time PCR assay indicated that iNOS/NOS2 mRNA expression in tumor tissue and normal brain tissues were not statistical difference (p>0.05). A mutation rate of 0.8% for the iNOS/NOS2 gene was found using 1044 glioma patients from two datasets. The mutation types include deep deletion (0.4%), truncating (0.2%) and missense (0.2%). The top positive and negative co-expressed gene with iNOS/NOS2 were COL25A1 (r pearson =0.4734, p<0.05) and ALCAM (r pearson =0.4734, p<0.05), respectively. For KEGG pathway analysis, iNOS/NOS2 was mainly enriched in calcium signaling pathway, Wnt signaling pathway, GnRH signaling pathway, HIF-1 signaling pathway and pathways in cancer. The overall survival (HR=2.0, p<0.05) and disease-free survival (HR=1.6, p<0.05) values were significantly different between iNOS/NOS2 high and low expression groups. Conclusion OS and DFS were significantly decreased in high iNOS/NOS2 mRNA expression groups. iNOS/NOS2 can be used as a poor prognostic biomarker for glioma.

Background: Two unique biomarkers, soluble form of the urokinase-type plasminogen activator receptor (suPAR) and neopterin, play a crucial role in inflammatory processes. This study aimed to reveal whether it is possible to utilize these biomarkers in predicting tumor prognosis in patients with lung cancers. Methods: The present study was designed as a single center, prospective, and controlled research. The study was conducted with forty patients with lung cancer (case group) and 41 healthy individuals (control group) in Kırıkkale University, Faculty of Medicine between 2016-2020. The case group was also divided into two of the early and advanced stages. The blood samples were drawn to evaluate suPAR and neopterin levels, and these parameters were compared between the case and control groups. Also, the prognostic effects of age, stage of the tumor, and the levels of mentioned parameters were investigated with the survival analysis. Results : The median duration of the follow-up was 32 (4-75) months. suPAR and neopterin levels were found to be higher in the case group than in the control group. Cox regression showed that the high levels of neopterin and suPAR increased mortality risk [p=0.002, HR: 1.25 (1.08-1.45 95%CI) and p=0.023, HR:1.07 (1.01-1.13), respectively]. Finally, age and stage of the tumor were found to have no relationship with survival. Conclusion: suPAR and neopterin as members of the inflammatory pathway were found to be higher in cancer cases. Furthermore, both suPAR and neopterin levels were found to be predictive for the mortality of patients with lung cancers; therefore, they are thought to be used for the management of cancer.

Objective The aim of the present work was to evaluate the folate-receptor 1 ( FOLR1 ) expression in cervical squamous cell carcinoma and its clinical significance. Methods FOLR1 mRNA expression level was detected in the cancer genome atlas (TCGA) database for multiple carcinomas. The FOLR1 mRNA relative expression between tumor tissue and normal cervix tissue of the cervical squamous cell cancer patients was compared by the online data analysis tool of GEPIA. The overall survival (OS) and progression free survival (PFS) between the FOLR1 high and low expression groups were compared by the log-rank test. Thirty one cervical squamous cancer patients and 20 healthy controls were included in and tested for serum FOLR1 protein level detection. Eighty one cervical squamous cell cancer patients who received surgery were included for FOLR1 protein expression detected by immunohistochemistry assay (IHC). The correlation between FOLR1 protein expression and patients’ clinical features was analyzed. Results FOLR1 mRNA was up-regulated in tumor tissue compared to corresponding normal cervical tissue of cervical squamous cell carcinoma. Top 20 genes interacted with FOLR1 was identified through the network with the edges of 146. UBXN10 (r=0.668, P<0.01) and GBP6 (r-=0.606, P<0.01) were the top 2 genes that most correlated with FOLR1. The serum level of FR-α (FOLR1 coding protein) were 275.50±83.79 and 161.70±66.62 (ng/L) for the cervical cancer and healthy control subjects respectively with significant statistical difference (P<0.05). Using the serum FR-α as serological marker for cervical cancer detection, the diagnostic sensitivity, specificity and AUC were 80.0% (58.40% to 91.93%), 80.65% (63.72% to 90.81%) and 0.85(95%CI:0.74-0.96), respectively. Immunohistochemical assay indicated that of the 81 cancer tissue samples, 45 (55.6%) was FOLR1 protein positive. FOLR1 protein positive expression rate in FIGO stage Ⅲ/Ⅳ was significant higher than in the stage Ⅰ/Ⅱ with statistical difference (P<0.05). The progression free survival (PFS) was significant different between FOLR1 high and low expression group (HR=2.48, 95%CI:1.1-5.58, P=0.023). However, the overall survival (OS) was not statistical different between the two groups (HR=1.34, 95%CI:0.84-2.15, P=0.22). Conclusion: FOLR1 was up-regulated in both serum and cancer tissue of cervical squamous cell carcinoma which may act as diagnostic and prognostic maker for cervical squamous cell cancer.

Chronic Hepatitis B virus (HBV) is still one of the major reasons for liver related mortality and morbidity all around the world. This study aimed to investigate the possible relationship between the immune system activation and presence, as well as progression, of hepatitis B infection by monitoring the tryptophan degradation and serum neopterin levels in patients with HBV. 110 patients with HBV and 23 healthy subjects were included in the study. The patients had significantly higher neopterin levels and increased kynurenine to tryptophan ratios, which were most probably due to enhanced indoleamine 2,3-dioxygenase (IDO) activity compared to healthy control. A strong positive correlation was found between neopterin levels and IDO activity in patient group. Neopterin levels and IDO activity were markedly increased in patients with histological activity index (HAI) ≥4 compared to HAI<4, and a significant correlation was found between neopterin and HAI. Moreover, there was a significant correlation between albumin levels and IDO activity in HBV patients. These findings suggest that tryptophan degradation results from IFN-γ-induced IDO activation, likewise depletion of albumin synthesis in HBV patients may result from diminished tryptophan availability. In conclusion, based on the study results, serum neopterin levels and IDO activity could provide additional immunological information for monitoring liver histological activity and can be used as prognostic markers in HBV disease.

Introduction: Neopterin and 7,8-dihydroneopterin are used as biomarkers of oxidative stress and inflammation, but the effect of kidney function on these measurements has not been extensively explored. We examine the levels of oxidative stress, inflammation and kidney function in intensive patients and compare them to equivalent patients without sepsis. Methods: 34 Intensive care patients were selected for the study, 14 without sepsis and 20 with. Both groups had equivalent levels of trauma, assessed by SAPS II, SOFA, and APACHE II and III scores. Plasma and urinary neopterin and total neopterin (neopterin + 7,8-dihydroneopterin) values were measured. Results: Neopterin and total neopterin were significantly elevated in urine and plasma for multiple days in sepsis versus non-sepsis patients. Plasma neopterin and total neopterin have decreasing relationships with increased eGFR (p<0.008 and p<0.001, respectively). Plasma/urinary neopterin and total neopterin ratios demonstrate that total neopterin flux is more influenced by eGFR than neopterin, with significantce of p<0.02 and p<0.0002 respectively. Conclusion: Sepsis patients present with greater levels of oxidative stress and immune system activation than non-sepsis patients of equal levels of trauma, as measured by neopterin and total neopterin. eGFR may need to be taken into account when accessing the level of inflammation from urinary neopterin measurements.

Objective To investigate the correlation between serum homocysteine (Hcy), Galectin-3 concentration and atrial structural remodeling in atrial fibrillation (AF) patients. Methods Twenty-five patients with persistent atrial fibrillation (PeAF), 24 patients with paroxysmal atrial fibrillation (PaAF) and 23 healthy controls were included in the present work. All subjects received an echocardiography examination. Serum concentration of Hcy and Galectin-3 were also examined by Enzyme Linked Immunosorbent Assay (ELISA). Results Echocardiography examination demonstrated that there were significant differences for LAD (p=0.002), LVEF (p=0.005) and LVAI (p=0.0001) between the control, PaAF and PeAF groups. However, LVSD and LVDD were not significantly different between the three groups (p all >0.05). There was a significant positive correlation between LAVI and serum Hcy level in both PaAF (r pearson =0.49, p=0.016) and PeAF (r pearson =0.51, p=0.009) groups. The correlation between LAVI and serum Galectin-3 concentration was also statistically significant for PaAF (r pearson =0.54, p=0.006) and PeAF (r pearson =0.60, p=0.001) groups. Using serum Hcy as reference, diagnostic sensitivity and specificity were calculated as 72.00 (95%CI: 50.61-87.93) and 62.50 (95%CI: 40.59-81.20), respectively, with an AUC of 0.68 for PaAF and PeAF. For serum Galectin-3, the sensitivity and specificity values were 64.00 (95%CI:42.52-82.03) and 66.67 (95%CI:44.68-84.37), respectively, with an AUC of 0.68. Conclusion: Serum Hcy and Galectin-3 were elevated in AF patients and thus may be potential markers of atrial structural remodeling. However, the diagnostic efficacy of PeAF from PaAF was limited by low AUC values.

Background: Soluble P-selectin (sP-selectin) is associated with risk factors for cardiovascular disease (CVD) but this association has not been evaluated in patients with schizophrenia. This study primarily evaluated the association of sP-selectin with plasma lipids and nitrite (NO 2 -) respectively in overweight/obese adults with schizophrenia. Methods: One-hundred and six patients with schizophrenia (mean age 32.9 years; 71.60% male) were recruited from a psychiatric hospital. Participants completed a structured interview and provided a fasting blood sample. Body mass index (BMI) was used to divide the sample into normal weight and overweight/obese groups. Pearson’s and partial correlation coefficients (controlling for age, sex, race, education, and inflammation) were calculated to examine the association of sP-selectin with plasma lipids, and NO 2 - in the overweight/obese patients (primary analysis), as well as in the normal weight patients and the total sample (exploratory analyses). Results: After controlling for potential confounders, sP-selectin positively correlated with triglycerides ( r = 0.38, p = 0.01) and NO 2 - ( r = 0.40, p < 0.01) in the overweight/ obese group only. Conclusions : Future longitudinal studies should evaluate the utility of sP-selectin as a biomarker of CVD in overweight/obese adults with schizophrenia (for example, by relating sP-selectin to incidence of cardiovascular events).

Background To evaluate sulfentanyl combined with dexmedetomidine hydrochloride on postoperative analgesia in patients who received video-assisted thoracic surgery (VATS) and its effects on serum norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT), and prostaglandin (PGE2). Material and Methods Ninety-nine non-small cell lung cancer (NSCLC) patients who received VATS were included in the study. All the patients received intravenous inhalation compound anesthesia. Of the 99 cases, 49 subjects (control group) received sulfentanyl for patient controlled intravenous analgesia (PICA) and other 50 cases (experiment group) received sulfentanyl combined with dexmedetomidine hydrochloride for PICA after operation of VATS. The analgesic effects of the two groups were evaluated according to Visual Analogue Scales (VAS) and the Bruggrmann Comfort Scale (BCS). The serum pain mediator of NE, DA, 5-HT, and PGE2 were examined and compared between the two groups in the first 24 h post-surgery. Results The VAS scores for the experiment group were significant lower than that of control group on the time points of 8, 16, and 24 h post-surgery (p all <0.05), and the BCS scores of the experiment group in the time points of 8, 16, and 24 h were significantly higher than that of controls (p<0.05). However, the VAS and BCS scores were not statistical differently in the time point of 1, 2, and 4 h post-surgery (p all >0.05). The mean sulfentanyl dosage was 63.01 ± 5.14 μg and 67.12 ± 6.91 μg for the experiment and control groups respectively with significant statistical difference (p<0.05). The mean analgesic pump pressing times were 4.30 ± 1.31 and 5.31 ± 1.46 for experiment and control groups respectively with significant statistical difference (p<0.05). The serum NE, DA, 5-HT, and PGE2 levels were significantly lower in the experimental group compared to that of control group in the time point of 12 h post-surgery (p all <0.05). The side effects of nausea, vomiting, delirium, rash, and hypotension atrial fibrillation were not statistically different between the two groups (p all >0.05). Conclusion Patient controlled intravenous analgesia of sulfentanyl combined with dexmedetomidine hydrochloride was effective in reducing the VAS score and serum pain mediators in NSCLC patients who received VAST.

Objective To investigate folate-receptor 1 ( FOLR1 ) expression in ovarian cancer and its association with patient prognosis. Methods TCGA and Oncomine databases were used to collect data about FOLR1 mRNA expression in multiple carcinomas. FOLR1 mRNA expression levels in ovarian cancer samples and corresponding adjacent normal ovary tissue were compared. A protein-protein interaction (PPI) network was constructed using the STRING database of FOLR1 and relevant genes. The overall survival (OS) and progression free survival (PFS) rates of ovarian cancer patients in high- and low- FOLR1 expression groups were compared by log-rank test. Sixty-six ovarian epithelial carcinoma samples were included in the study, and tumor specimens of the 66 cases were tested for FOLR1 protein expression by an immunohistochemistry assay. ResultsFOLR1 mRNA was significantly elevated in ovarian cancer compared to other carcinomas. FOLR1 mRNA expression levels were significantly higher in tumor tissues than in the corresponding normal tissues (P<0.05) of ovarian cancer patients. The PPI network indicated that the local clustering coefficient was 0.898, indicating that the PPI network was enriched significantly (P<0.05). The median PFS values were 22.39 and 19.00 months for lowand high- FOLR1 expression groups, respectively, with significant statistical difference between the two (HR=1.26, 95%CI:1.09-1.45, P<0.05). FOLR1 protein expression was correlated with tumor differentiation (P<0.05) in ovarian cancer patients. However, its levels were not correlated with patient age, tumor diameter, lymph node metastasis or FIGO stage (P>0.05). ConclusionFOLR1 is upregulated in epithelial ovarian cancer, and its expression is correlated with patients’ progression free survival, making it a valuable biomarker for prognosis.

Immune activation coincides with disturbances in iron and vitamin D metabolism in patients with cardiomyopathy. In this study, we investigated whether there are differences regarding immune activation, iron and vitamin D metabolism between the different cardiomyopathy aetiologies. Patients and methods: Parameters of iron metabolism (haemoglobin, iron, transferrin, transferrin saturation, ferritin, hepcidin), vitamin D metabolism (Ct-FGF23, parathormone, phosphate, vitamin D) and immune activation (C-reactive protein and neopterin) were determined in 149 patients (98 men, 51 women) with non-ischaemic cardiomyopathy. Results: Patients with amyloid cardiomyopathy presented with higher neopterin, ferritin and hepcidin levels than other cardiomyopathy aetiologies. Furthermore, they showed the highest rate of cardiovascular events. C-reactive protein levels were significantly higher in patients with inflammatory cardiomyopathy. Patients with virus positive cardiomyopathy presented with significantly higher ferritin and Ct-FGF23 levels compared to patients with virus negative inflammatory cardiomyopathy. Conclusion: This study indicates that there are some differences regarding the extent of immune activation and inflammation as well as alterations in iron metabolism disorders between different cardiomyopathy aetiologies. Further studies with larger patient cohorts are needed to investigate these findings more precisely.

Objective To investigate the correlation between MTHFR C677T polymorphism and non-traumatic osteonecrosis of the femoral head. Methods Open published studies relevant to MTHFR C677T polymorphism and non-traumatic osteonecrosis of the femoral head were electronic systematic searched in the databases of cochrane central register of controlled trials, EMBSE and CNKI. The correlation between MTHFR C677T polymorphism and non-traumatic osteonecrosis of the femoral head was calculated by odds ratio (OR) and corresponding 95% confidence interval (95%CI). The publication bias for the included studies were assessed by Begg’s funnel plot and Egger’s line regression text. Results After systematic searching the electronic databases, 11 original studies were finally included the present work. The I ² test indicated significant statistical heterogeneity (I ² =53.5%, P =0.018) across the included 11 publications. The polled results indicated that subjects of Caucasians with CC genotype had decreased risk of developing non-traumatic osteonecrosis of the femoral head (OR=0.65,95%CI: 0.44-0.96, P=0.031). However, there was no correlations between MTHFR C677T polymorphism and non-traumatic osteonecrosis of the femoral head in American Jewish and East Asian races(p>0.05). Sensitivity analysis indicated the pooled ORs were not sensitive to any included single study. The Begg’s funnel plot was generally left and right symmetrical which indicated no obviously publications. The Egger’s line regression test also demonstrated no statistical publication bias (t=1.57, P=0.15). Conclusion According to the present evidence, MTHFR C677T polymorphism was correlated with non-traumatic osteonecrosis of the femoral head especially for Caucasians race. Subjects of Caucasians race with CC genotype had decreased risk of developing non-traumatic osteonecrosis of the femoral head.

Objective To investigate the clinical efficacy of 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonists in reducing propofol injection pain, postoperative nausea/ vomiting, and shivering through pooling the available published data. Methods Prospective randomized clinical studies relevant to 5-HT 3 receptor antagonists in reducing propofol injection pain published before June 2019 were identified from four electronic databases, Pubmed, the Cochrane central register of controlled trials, EMBASE and Wanfang. The incidence of propofol injection pain, postoperative nausea/vomiting, and shivering in patients after 5-HT 3 receptor antagonists were compared to relevant control groups by pooling the individual data through random or fixed-effect models. The publication bias was assessed by funnel plot and Egger’s line regression test. Results After screening, a total of 19 publications relevant to 5-HT 3 receptor antagonists in reducing propofol injection pain and prevention of postoperative nausea/vomiting or shivering were included for analysis. The pooled results demonstrated that 5-HT 3 receptor antagonists could significantly reduce the total propofol injection pain compared to placebo (RR=0.49, 95%CI:0.45-0.54, P<0.05). For mild propofol injection pain, there was no statistical difference between 5-HT 3 receptor antagonists and control groups (RR=1.07,95%CI:0.89-1.29, P>0.05). However, for moderate (RR=0.37, 95%CI: 0.31-0.46, P<0.05) and severe (RR=0.19, 95%CI:0.14-0.27, P<0.05) propofol injection pain, the incidence in 5-HT 3 receptor antagonists was significantly lower than that of control groups. The pooled results also indicated that incidence of postoperative nausea/vomiting (RR=0.28, 95%CI:0.17-0.44, P<0.05) and postoperative shivering (RR=0.33, 95%CI:0.23-0.48, P<0.05) were significantly reduced in 5-HT 3 receptor antagonists group compared to control group with a statistical difference. Conclusion: In this meta-analysis, 5-HT3 receptor antagonists effectively reduced propofol injection pain, postoperative nausea/vomiting, and shivering.

Objective To investigate the correlation between the methylenetetrahydrofolate reductase ( MTHFR ) gene 677C> T polymorphism and fetal congenital defects. Method Original studies relevant to the MTHFR gene 677C>T single nucleotide polymorphism and fetal congenital defects were systematically searched in the electronic databases of Medline, EMBSE and China National Knowledge Infrastructure (CNKI). All relevant publications were screened for inclusion in the present work. The correlation between the MTHFR gene 677C > T single nucleotide polymorphism and the occurrence of fetal congenital defects was expressed as an odds ratio (OR) and its 95% confidence interval (95% CI). Publication bias was assessed by Begg’s funnel plot and Egger’s line regression test. Results Nineteen case-control studies were ultimately included in the present meta-analysis. The pooled results indicated that the general risk of fetal congenital defects was significantly elevated in subjects with the 677T allele of the MTHFR gene in dominant (OR=1.07,95%CI:1.03-1.12, P<0.05), homozygous (OR=1.17,95%CI:1.06-1.30, P<0.05) and recessive genetic models (OR=1.16,95%CI:1.03-1.31, P<0.05) through the random effect method. However, significant publication bias was identified upon pooling the individual data and evaluating the correlation. Conclusion According to the present evidence, the MTHFR gene 677C>T single nucleotide polymorphism is correlated with poor pregnancy outcomes, and subjects with the T allele have an increased risk of developing general fetal congenital defects.

Objective This meta-analysis aims to investigate the diagnostic performance of serum homocysteine (Hcy) as a biomarker for diabetic nephropathy (DN). Methods Clinical publications relevant to serum Hcy level and DN were systematic searched in the electronic databases of; Pubmed, Cochrane Library, Embase, Web of science, CNKI and CBM. The diagnostic data from each included original study was extracted and pooled by the effect size of diagnostic sensitivity, specificity, positive likely hood ratio (+LR), negative likely hood ratio (-LR), diagnostic odds ratio (DOR) and area under the symmetric ROC curve (AUC). Results 18 publications relevant to serum Hcy and DN were included in the meta-analysis. The I ² test demonstrated significant statistical heterogeneity across the 18 studies for the effect size of diagnostic. The pooled diagnostic sensitivity, specificity, +LR, -L, DOR, AUC were 0.76 (95%CI: 0.74-0.78), 0.84 (95%CI:0.82-0.86), 5.05 (95%CI:3.52-7.24), 0.27 (95%CI:0.19-0.39), 21.68 (95% CI:11.15to 42.14) and 0.90 respectively in the random effect model. Conclusion Based on the present publications, serum Hcy is a promising serological marker for DN diagnosis.

Objective To investigate the clinical efficacy of serological level homocysteine (Hcy) and cystatin C (Cys-C) as biomarkers for progression of diabetic nephropathy (DN). Methods Seventy-five patients with type 2 diabetes mellitus (DM) hospitalized in Lishui People’s Hospital from January 2015 to May 2018 were included in the present study. Of the 75 cases, 28 were simple DM, 25 were early stage DN (DNe) and other 22 subjects were clinical stage DN (DNc). The serum level of Hcy and Cys-C were detected and compared among the DM, DNe and DNc groups. The efficacy of serological levels of Hcy, and Cys-C as biomarkers for diagnosis of early stage diabetic nephropathy was calculated. Results The serological levels of Hcy were 11.53±3.05 μmol/L, 15.39±4.58 μmol/L and 18.14±7.03 μmol/L for DM, DNe and DNc groups respectively (P<0.001). Serum level of Cys-C, were 0.89±0.23 mg/L, 1.51±0.60 mg/L and 2.63±0.90 mg/L respectively for DM, DNe and DNc groups respectively (P<0.001). Significant positive correlation between serum Cys-C and Hcy was detected in DNe (r pearson =0.55, P=0.004) and DNc (r pearson =0.44, P=0.04) groups. However, there was no significant correlation of serological Cys-C and Hcy in DM group (r pearson =0.08, P=0.70). The sensitivity and specificity in diagnosis of early stage DN were 76.0 (95%CI:54.87-90.64)%, 64.29 (544.07-81.36)% for serological Hcy and 80.0 (559.30-93.17)%, 89.29 (571.77-97.73)% for serum Cys-C respectively. The diagnostic area under the ROC curve (AUC) was 0.76 (0.63 to 0.90) and 0.84 (0.72-0.96) respectively for serum Hcy and Cys-C in detection early stage DN. Conclusion : Serum levels of Hcy and Cys-C in diabetic nephropathy patients were elevated compared to that of simple DM cases, making them potential biomarkers for diagnosis of early DN from DM patients.

OBJECTIVE To investigate the correlation between serum homocysteine (Hcy) and cognitive impairment (CI) in patients with Parkinson’s disease (PD). METHODS Eighty-one PD patients were prospectively recruited in this study from Feb 2015 to Jan 2018 in Gansu Provincial Hospital. Of the subjects, 41 were diagnosed with cognitive impairment (PD-CI) vs. the 40 others without PD (PDN). The clinical characteristic and demographic features were recorded for the two groups. The serum Hcy, folate and vitamin B12 (VitB12) were examined by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA). RESULTS The serum Hcy, folate, VitB12 concentration were 21.7±6.2 (μmol/L), 9.2±3.7 (ng/mL), 354.1±123.5 (pg/mL) for PD-CI group and 14.1±5.7 (μmol/L), 12.4±4.5 (ng/mL), 378.7±128.2 (pg/mL) for PDN group respectively. The serum level of Hcy in PD-CI group was significantly higher than that of PDN group (p<0.05), serum folate was significantly lower than PDN group (p<0.05). The diagnostic sensitivity, specificity and AUC were 77.5% (95%CI:61.6%-89.2%), 78.1% (95%CI:62.4%-89.4%), 0.82 (95%CI:0.73-0.91) for serum Hcy and 72.5% (95%CI:56.1%-85.4%), 63.4% (95%CI:46.9%-77.9%), 0.71(95%CI:0060-0.83) for serum folate respectively as serological markers for cognitive impairment diagnosis in patients with PD. Conclusion Serum Hcy and folate were different between PD-CI and PDN patients, which may play an important role in cognitive impairment development in patients with PD and can be used as promising serological diagnostic marker.

Objective To investigate the clinical efficacy and toxicity of Pemetrexed versus Gefitinib as second-line treatment for advanced non-small cell lung cancer (NSCLC). Methods By systematically searching the electronic databases of Pubmed, CENTRAL, Cochrane, EMBASE, ASCO, and CBM, open published randomized clinical trials (RCTs) relevant to clinical efficacy and toxicity of Pemetrexed versus Gefitinib as second-line treatment of advanced NSCLC were included in the meta-analysis. Data of objective response rate (ORR) and drug related toxicity were extracted from the original publications and pooled by random or fixed effect method. Results Fourteen clinical trials related to Pemetrexed versus Gefitinib as second-line treatment for advanced NSCLC fulfilled the inclusion criteria and were included in the meta-analysis. The pooled results show that the ORR (RR=0.81, 95% CI:0.56–1.16, p=0.25) and DCR (RR=1.11, 95% CI:0.94–1.31, p=0.24) were not statistical different for Pemetrexed versus Gefitinib as second-line treatment of advanced NSCLC. However, the pooled data demonstrated the risk of developing skin rash (RR=0.10, 95% CI:0.03–0.30, p=0.00) and diarrhea (RR=0.31, 95% CI:0.15–0.67, p=0.003) in patients with Pemetrexed was significantly lower than that of Gefitinib through random effect model analysis, but the incidence of neutropenia in Pemetrexed group was significantly higher than that of Gefitinib with statistical difference (RR=7.62, 95% CI:3.71–15.66, p=0.00). Conclusion Pemetrexed was not inferior as second-line treatment for advanced NSCLC compared to Gefitinib for tumor response. However, Pemetrexed had higher incidence of neutropenia but lower risk of developing skin rash and diarrhea.

Objective The aim of the present work was to investigate the prognostic value of serological ferritin, 100A12, procalcitonin (PCT) and APACHEII score in predicting death risk for patients with acute respiratory distress syndrome (ARDS). Methods Forty eight ARDS patients were recruited from Feb. 2016 to Jan. 2019 from Lishui People’s Hospital. According to their prognosis (survival or death within 28 days), these 48 patients were further divided into the survival group (n=28) and death group (n=20). The serological levels of S100A12, PCT and ferritin of the 48 ARDS patients were examined within 24 hours after hospitalization. Demographic characteristics, serum S100A12, PCT and ferritin were compared between the two groups, and diagnostic analysis was performed to evaluate the clinical efficacy of these markers in predicting the death of ARDS patients. Results The serum S100A12, ferritin and APACHEII scores of the death group were significantly higher than those of the survival group (p<0.05). However, serum PCT levels were not statistically different between the two groups (p>0.05). The death prediction sensitivity for serum S100A12, PCT, ferritin and APACHEII score were 65.0 (40.78-84.61)%, 60.00(36.05-80.88) %,75.0(50.90-91.34)% and 85.0(62.11-96.79)% respectively. The death prediction specificity for serum S100A12, PCT, ferritin and APACHEII score were 75.0(55.13-89.31)%, 60.00(36.05-80.88)%, 64.29(44.07-81.36)% and 82.14(63.11-93.94)%, respectively. The area under the ROC curve (AUC) for serum S100A12, PCT, ferritin and APACHEII score were 0.68(0.51-0.84), 0.63(0.46-0.79), 0.71(0.56-0.86) and 0.91(0.83-0.99) respectively. Conclusion Serological ferritin, 100A12, PCT and APACHEII scores can be used as biomarkers to predict the death risk of ARDS patients.