Statins may exert protective effects against oxidative stress by upregulating specific antioxidant mechanisms. We conducted a systematic review and meta-analysis of the effect of statins on three key ...antioxidant enzymes: glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. The electronic databases PubMed, Web of Science, and Scopus were searched from inception to July 2021. The risk of bias was assessed with the Joanna Briggs Institute Critical Appraisal Checklist and certainty of evidence was assessed using the GRADE framework. In 15 studies, reporting 17 treatment arms in 773 patients (mean age 53 years, 54% males), statins significantly increased the concentrations of both GPx (standardized mean difference, SMD = 0.80, 95% confidence interval, CI 0.13 to 1.46, p = 0.018; high certainty of evidence) and SOD (SMD = 1.54, 95% CI 0.71 to 2.36, p < 0.001; high certainty of evidence), but not catalase (SMD = −0.16, 95% CI −0.51 to 0.20, p = 0.394; very low certainty of evidence). The pooled SMD values were not altered in sensitivity analysis. There was no publication bias. In conclusion, statin treatment significantly increases the circulating concentrations of GPx and SOD, suggesting an antioxidant effect of these agents (PROSPERO registration number: CRD42021271589).
We describe the development and validation of an HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards ...dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple-negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30 mg/Kg daily) in six-week-old severe combined immunodeficiency disease (SCID) mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 h (6.47 and 9.01 μM, respectively) and 24 h (0.13 and 0.16 μM, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 h (15.06 and 8.72 μM, respectively) and 24 h (0.17 and 0.17 μM, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-life after acute and chronic treatment ranged between 4.4-7.1 h (plasma) and 4.5-5.0 h (tumour) for ZST316, and 4.2-5.3 h (plasma) and 3.6-4.9 h (tumour) for L-257. The results of our study demonstrate the (a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, (b) rapid conversion of ZST316 into L-257, (c) good intra-tumour penetration of both compounds, and (d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. Compared to a previous method developed by our group to investigate ZST316 in plasma, the main advantages of the new method include a wider range of linearity which reduces the need for dilutions and the combined assessment of ZST316 and L-257 in plasma and tumour tissue which limits the required amount of matrix. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.
The identification of robust circulating biomarkers of stroke may improve outcomes. We conducted a systematic review and meta-analysis of serum concentrations of ischaemia-modified albumin (IMA) in ...subjects with or without acute ischaemic stroke (AIS), intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH). We searched PubMed, Web of Science, Scopus, and Google Scholar from inception to March 2022. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 17 studies, IMA concentrations were significantly higher in patients with AIS (standard mean difference, SMD = 2.52, 95% CI 1.92 to 3.12; p < 0.001), ICH (SMD = 3.13, 95% CI 1.00 to 5.25; p = 0.004), and SAH (SMD = 4.50, 95% CI 0.91 to 7.01; p = 0.014) vs. controls (very low certainty of evidence). In AIS, the effect size was associated with the male gender, and was relatively larger in studies conducted in Egypt and India and those using enzyme-linked immunosorbent assays. IMA concentrations were progressively higher, by direct comparison, in SAH, ICH, and AIS. In sensitivity analysis, the pooled SMDs were not altered when individual studies were sequentially removed. Our meta-analysis suggests that IMA concentrations might be useful to diagnose stroke and discriminate between AIS, ICH, and SAH (PROSPERO registration number: CRD42021320535).
There is an intense focus on the identification of novel biomarkers of chronic obstructive pulmonary disease (COPD) to enhance clinical decisions in patients with stable disease and acute ...exacerbations (AECOPD). Though several local (airway) and circulatory inflammatory biomarkers have been proposed, emerging evidence also suggests a potential role for routine haematological parameters, e.g., the red cell distribution width (RDW). We conducted a systematic literature search in PubMed, Web of Science, and Scopus, from inception to April 2022, for articles investigating the diagnostic and prognostic role of the RDW in stable COPD and AECOPD. The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist. Significant associations between the RDW and the presence and severity of disease, outcomes (mortality, hospital readmission), and other relevant clinical parameters (right heart failure, pulmonary arterial hypertension) were reported in 13 out of 16 studies in stable COPD (low risk of bias in 11 studies), and 17 out of 21 studies of AECOPD (low risk of bias in 11 studies). Pending further research, our systematic review suggests that the RDW might be useful, singly or in combination with other parameters, for the diagnosis and risk stratification of patients with stable COPD and AECOPD (PROSPERO registration number: CRD42022348304).
Introduction
The identification of novel, easily measurable disease biomarkers might enhance the diagnosis and management of patients with rheumatic diseases (RDs). We conducted a systematic review ...and meta‐analysis of ischemia‐modified albumin (IMA), a marker of oxidative stress, acidosis, and ischemia, in RD patients and healthy controls.
Methods
We searched PubMed, Web of Science, and Scopus from inception to January 15, 2024. The risk of bias and the certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively.
Results
In 20 studies investigating a total of 1188 RD patients (mean age 45 years, 64% females) and 981 healthy controls (mean age 44 years, 66% females), RD patients had significantly higher IMA concentrations when compared to controls (standard mean difference, SMD = 0.50, 95% CI: 0.18−0.83, p = .003; I2 = 92.4%, p < .001; low certainty of evidence). In subgroup analysis, the pooled SMD was significantly different in studies investigating ankylosing spondylitis (p < .001), Behçet's disease (p < .001), and rheumatoid arthritis (p = .033), but not familial Mediterranean fever (p = .48). Further associations were observed between the pooled SMD and the broad classification of autoimmune and/or autoinflammatory diseases, the study country, and the method used to measure IMA.
Conclusion
Our study suggests that IMA is a promising biomarker of oxidative stress, acidosis, and ischemia, as it can effectively discriminate between patients with different types of RDs and healthy controls. Our results warrant confirmation in longitudinal studies of patients with different types of RDs and different ethnicities (PROSPERO registration number: CRD42024509126).
Our study suggests that ischemia‐modified albumin is a promising biomarker of oxidative stress, acidosis, and ischemia in different types of rheumatic diseases. Our results warrant confirmation in longitudinal studies of patients with different types of rheumatic diseases and different ethnicity.
Cutaneous angiosarcoma (CAS) is the most common type of angiosarcoma that predominantly affects older Caucasians. The outcomes of immunotherapy in CAS are currently under investigation in relation to ...the expression of programmed death ligand 1 (PD-L1) and other biomarkers. We performed a systematic review and metanalysis of data from the current literature reporting on PD-L1 immunohistochemistry expression. A systematic search of publications in the electronic databases PubMed, Web of Science, and Scopus was conducted using the following terms: "PD-L1" and "angiosarcomas". A total of ten studies reporting on 279 cases were identified and included in the meta-analysis. The pooled prevalence of PD-L1 expression in CAS was 54% (95% CI 36-71%), with high heterogeneity (I
= 84.81%,
< 0.001). In sub-group analysis, the proportion of PD-L1 expression in CAS was significantly (
= 0.049) lower in Asian studies (ES = 35%, 95% CI 28-42%, I
= 0.0%,
= 0.46) than in European studies (ES = 71%, 95% CI 51-89%, I
= 48.91%,
= 0.12).
There is an increasing interest in biomarkers of nitric oxide dysregulation and oxidative stress to guide management and identify new therapeutic targets in patients with chronic obstructive ...pulmonary disease (COPD). We conducted a systematic review and meta-analysis of the association between circulating metabolites within the arginine (arginine, citrulline, ornithine, asymmetric, ADMA, and symmetric, SDMA dimethylarginine), transsulfuration (methionine, homocysteine, and cysteine) and folic acid (folic acid, vitamin B6, and vitamin B12) metabolic pathways and COPD. We searched electronic databases from inception to 30 June 2023 and assessed the risk of bias and the certainty of evidence. In 21 eligible studies, compared to healthy controls, patients with stable COPD had significantly lower methionine (standardized mean difference, SMD = −0.50, 95% CI −0.95 to −0.05, p = 0.029) and folic acid (SMD = −0.37, 95% CI −0.65 to −0.09, p = 0.009), and higher homocysteine (SMD = 0.78, 95% CI 0.48 to 1.07, p < 0.001) and cysteine concentrations (SMD = 0.34, 95% CI 0.02 to 0.66, p = 0.038). Additionally, COPD was associated with significantly higher ADMA (SMD = 1.27, 95% CI 0.08 to 2.46, p = 0.037), SDMA (SMD = 3.94, 95% CI 0.79 to 7.08, p = 0.014), and ornithine concentrations (SMD = 0.67, 95% CI 0.13 to 1.22, p = 0.015). In subgroup analysis, the SMD of homocysteine was significantly associated with the biological matrix assessed and the forced expiratory volume in the first second to forced vital capacity ratio, but not with age, study location, or analytical method used. Our study suggests that the presence of significant alterations in metabolites within the arginine, transsulfuration, and folic acid pathways can be useful for assessing nitric oxide dysregulation and oxidative stress and identifying novel treatment targets in COPD. (PROSPERO registration number: CRD42023448036.)
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•Intracellular ZST316 and ZST152 can be quantified using a sensitive UPLC-MS assay.•ZST316 and ZST152 inhibit DDAH1 activity in MDA-MB-231 breast cancer cells.•DDAH1 inhibition by ...ZST316 or ZST152 increases intracellular ADMA concentrations.•DDAH1 inhibition by ZST316 or ZST152 decreases intracellular l-citrulline concentrations.•ZST316 and ZST152 significantly inhibit MDA-MB-231 cell migration and VM.
Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a key enzyme involved in the metabolism of the endogenous nitric oxide synthase (NOS) inhibitors asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA). Increased DDAH1 expression and subsequent increased NO production have been recently linked to cancer. Specifically, DDAH1 is implicated in establishment of a vascular network by tumour cells, vasculogenic mimicry (VM), which is strongly associated with tumour progression and poor patient prognosis. The use of DDAH1 inhibitors as potential therapeutic agents thus represents a growing field of interest. Here we describe a UPLC-MS assay to quantify stability and intracellular concentration of two small molecule DDAH1 inhibitors synthesised by our group, ZST316 and ZST152, following incubation with MDA-MB-231 breast cancer cells. In an in vitro assay of VM, both DDAH1 inhibitors significantly attenuated formation of capillary-like tube structures in a dose-dependent fashion. This was not due to cell toxicity or altered cell proliferation, but may be due in part to inhibition of cell migration. Mechanistically, we demonstrate significant modulation of the endogenous DDAH/ADMA/NO pathway following exposure of 100 μM ZST316 or ZST152: a 40% increase in the DDAH1 substrate ADMA, and a 38% decrease in the DDAH1 product l-citrulline. This study represents the first evidence for therapeutic inhibition of DDAH1 by small molecules in breast cancer.
Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The ...initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.
The pleiotropic effects of statins might involve preventing inflammatory cell adhesion to the endothelium, which is a critical step in the pathogenesis of atherosclerosis. We conducted a systematic ...review and meta-analysis of the effects of statins on the circulating cell adhesion molecules E-Selectin, L-Selectin, and P-Selectin. A literature search was conducted in PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 61 studies, statins significantly reduced P-selectin (standard mean difference, SMD = −0.39, 95% CI −0.55 to −0.22, p < 0.001; moderate certainty of evidence), L-selectin (SMD = −0.49, 95% CI −0.89 to −0.10, p = 0.014; very low certainty of evidence), and E-Selectin (SMD = −0.73, 95% CI −1.02 to −0.43, p < 0.001; moderate certainty of evidence), independently of baseline lipid profile and other study and patient characteristics. The corresponding pooled SMD values in sensitivity analysis were not substantially altered when individual studies were sequentially removed. Simvastatin had a significant lowering effect on both P-selectin and E-selectin. Therefore, statins significantly reduce circulating selectins. Further studies are required to investigate whether selectin lowering mediates cardiovascular risk reduction with these agents. (PROSPERO registration number: CRD42021282778).
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