Biological Anti-TNF-α Therapy and Markers of Oxidative and Carbonyl Stress in Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) as a chronic inflammatory disease is associated with oxidative stress. Drugs targeting tumor necrosis factor-alpha (TNF-α) ameliorate inflammation and symptoms of RA in most patients. Whether markers of oxidative stress can be used for monitoring of treatment effects is unknown. The aim of our study was to analyze the effects of anti-TNF-α treatment on oxidative stress in plasma and saliva of patients with RA. Samples were collected from 26 patients with RA at baseline as well as 3 and 6 months after starting the anti-TNF-α treatment. Thiobarbituric acid-reacting substances (TBARS), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), and fructosamine were quantified using spectrophotometry and spectrofluorometry in plasma. TBARS were measured also in saliva. The disease activity score (DAS28) was used to assess the clinical status of patients. No significant dynamic changes were found except plasma TBARS that decreased continuously. At 6 months after starting the treatment, plasma TBARS were lower by 39% in comparison to baseline ( p = 0.006 ). Salivary concentrations of TBARS did not reflect the dynamics in plasma. Although a trend was observed ( r = 0.33 ), a significant correlation between plasma TBARS and DAS28 was not found. Our results indicate that anti-TNF-α treatment decreases plasma TBARS as a marker of lipid peroxidation. However, the lack of a significant correlation with DAS28 suggests that it cannot be used for monitoring of treatment. Other markers of oxidative stress and antioxidant capacity with lower biological variability should be tested in future studies.

Role of Advanced Glycation End-Products and Other Ligands for AGE Receptors in Thyroid Cancer Progression

To date, thyroid cancers (TCs) remain a clinical challenge owing to their heterogeneous nature. The etiopathology of TCs is associated not only with genetic mutations or chromosomal rearrangements, but also non-genetic factors, such as oxidative-, nitrosative-, and carbonyl stress-related alterations in tumor environment. These factors, through leading to the activation of intracellular signaling pathways, induce tumor tissue proliferation. Interestingly, the incidence of TCs is often coexistent with various simultaneous mutations. Advanced glycation end-products (AGEs), their precursors and receptors (RAGEs), and other ligands for RAGEs are reported to have significant influence on carcinogenesis and TCs progression, inducing gene mutations, disturbances in histone methylation, and disorders in important carcinogenesis-related pathways, such as PI3K/AKT/NF-kB, p21/MEK/MPAK, or JAK/STAT, RAS/ERK/p53, which induce synthesis of interleukins, growth factors, and cytokines, thus influencing metastasis, angiogenesis, and cancer proliferation. Precursors of AGE (such as methylglyoxal (MG)) and selected ligands for RAGEs: AS1004, AS1008, and HMGB1 may, in the future, become potential targets for TCs treatment, as low MG concentration is associated with less aggressive anaplastic thyroid cancer, whereas the administration of anti-RAGE antibodies inhibits the progression of papillary thyroid cancer and anaplastic thyroid cancer. This review is aimed at collecting the information on the role of compounds, engaged in glycation process, in the pathogenesis of TCs. Moreover, the utility of these compounds in the diagnosis and treatment of TCs is thoroughly discussed. Understanding the mechanism of action of these compounds on TCs pathogenesis and progression may potentially be the grounds for the development of new treatment strategies, aiming at quality-of-life improvements.

Carnosine, oxidative and carbonyl stress, antioxidants and muscle fiber characteristics of quadriceps muscle of patients with COPD

Background: Oxidative/carbonyl stress is elevated in lower-limb muscles of patients with Chronic Obstructive Pulmonary Disease (COPD). Carnosine is a skeletal muscle antioxidant particularly present in fast-twitch fibers. Aims: To compare muscle carnosine, oxidative/carbonyl stress, antioxidants and fiber characteristics between patients with COPD and healthy controls (HCs), and between patients after stratification for airflow limitation (mild/moderate vs. severe/very-severe). To investigate correlates of carnosine in patients with COPD. Methods: A vastus lateralis muscle biopsy was obtained from 40 patients with stable COPD and 20 age/sex matched HCs. Carnosine, oxidative/carbonyl stress, antioxidants, fiber characteristics, quadriceps strength and endurance (QE), VO2peak (incremental cycle test) and physical activity (PA) were determined. Results: Patients with COPD had a similar carnosine concentration (4.16 mmol/kg wet weight (WW) (SD 1.93)) to HCs (4.64 mmol/kgWW (SD 1.71)) and significantly higher percentage of fast-twitch fibers and lower QE, VO2peak and PA vs. HCs. Patients with severe/very-severe COPD had a 30% lower carnosine concentration (3.24 mmol/kgWW (SD 1.79); n=15) vs. patients with mild/moderate COPD (4.71 mmol/kgWW (SD 1.83); n=25; P=0.02) and significantly lower VO2peak and PA vs. patients with mild/moderate COPD. Carnosine correlated significantly with QE (rs=0.427), VO2peak (rs=0.334), PA (rs=0.379) and lung function parameters in patients with COPD. Conclusion: Despite having the highest proportion of fast-twitch fibers, patients with severe/very-severe COPD displayed a 30% lower muscle carnosine concentration compared to patients with mild/moderate COPD. As no oxidative/carbonyl stress markers, nor antioxidants were affected, the observed carnosine deficiency is thought to be a possible first sign of muscle redox balance abnormalities.

Effect of sugar metabolite methylglyoxal on equine lamellar explants: An ex vivo model of laminitis

Laminitis is one of the most devastating diseases in equine medicine, and although several etiopathogenetic mechanisms have been proposed, few clear answers have been identified to date. Several lines of evidence point towards its underlying pathology as being metabolism-related. In the carbonyl stress pathway, sugars are converted to methylglyoxal (MG)—a highly reactive α-oxoaldehyde, mainly derived during glycolysis in eukaryotic cells from the triose phosphates: D-glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. One common hypothesis is that MG could be synthesized during the digestive process in horses, and excessive levels absorbed into peripheral blood could be delivered to the foot and lead to alterations in the hoof lamellar structure. In the present study, employing an ex vivo experimental design, different concentrations of MG were applied to hoof explants (HE), which were then incubated and maintained in a specific medium for 24 and 48 h. Macroscopic and histological analyses and a separation force test were performed at 24 and 48 h post-MG application. Gene expression levels of matrix metalloproteinase (MMP)-2 and -14 and tissue inhibitor of metalloproteinase (TIMP)-2 were also measured at each time point for all experimental conditions. High concentrations of MG induced macroscopic and histological changes mimicking laminitis. The separation force test revealed that hoof tissue samples incubated for 24 h in a high concentration of MG, or with lower doses but for a longer period (48 h), demonstrated significant weaknesses, and samples were easily separated. All results support that high levels of MG could induce irreversible damage in HEs, mimicking laminitis in an ex vivo model.

Urinary Carnosinase-1 Excretion is Associated with Urinary Carnosine Depletion and Risk of Graft Failure in Kidney Transplant Recipients: Results of the TransplantLines Cohort Study

Carnosine affords protection against oxidative and carbonyl stress, yet high concentrations of the carnosinase-1 enzyme may limit this. We recently reported that high urinary carnosinase-1 is associated with kidney function decline and albuminuria in patients with chronic kidney disease. We prospectively investigated whether urinary carnosinase-1 is associated with a high risk for development of late graft failure in kidney transplant recipients (KTRs). Carnosine and carnosinase-1 were measured in 24 h urine in a longitudinal cohort of 703 stable KTRs and 257 healthy controls. Cox regression was used to analyze the prospective data. Urinary carnosine excretions were significantly decreased in KTRs (26.5 [IQR 21.4–33.3] µmol/24 h versus 34.8 [IQR 25.6–46.8] µmol/24 h; p < 0.001). In KTRs, high urinary carnosinase-1 concentrations were associated with increased risk of undetectable urinary carnosine (OR 1.24, 95%CI [1.06–1.45]; p = 0.007). During median follow-up for 5.3 [4.5–6.0] years, 84 (12%) KTRs developed graft failure. In Cox regression analyses, high urinary carnosinase-1 excretions were associated with increased risk of graft failure (HR 1.73, 95%CI [1.44–2.08]; p < 0.001) independent of potential confounders. Since urinary carnosine is depleted and urinary carnosinase-1 imparts a higher risk for graft failure in KTRs, future studies determining the potential of carnosine supplementation in these patients are warranted.

Glyoxalase I disruption and external carbonyl stress impair mitochondrial function in human induced pluripotent stem cells and derived neurons

Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, we found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger. Our observations can be used for designing an intervention strategy for diseases, particularly those induced by enhanced carbonyl stress or oxidative stress.