Systemic oxidative stress and antioxidant capacity in cancer patients

Various factors impact the outcome of patients with the diagnosis of cancer. Common treatment modalities of cancer, including surgery, radiation therapy and cytostatic agents, all lead to a systemic inflammatory reaction. In particular, this reaction is of physiological importance as it is crucial for patient recovery. However, in some patients, a self-perpetuating inflammatory response develops due to the presence of unfavorable risk factors, several of which are still unknown, but might lead to a worse disease prognosis. Inflammation has been intimately associated with oxidative stress, that is characterized by an imbalance between pro-oxidants, also termed reactive species, and antioxidants. Systemically, oxidative stress can be quantified by measuring thiols (R-SH, sulfhydryl compounds), which are considered to be regulatory nodes within the extracellular antioxidant network. Most importantly, thiol measurements in serum or plasma form a robust and powerful read-out of the in vivo reduction-oxidation (redox) status as thiols are highly redox-active and thus readily oxidized by circulating reactive species. Therefore, systemic quantification of thiols might be a valuable addition to the clinically available diagnostic and prognostic armamentarium as it is able to reliably capture the overall balance between oxidants and the antioxidant capacity of patients. In this review, we summarized the currently available literature on thiol levels as amendable markers for oxidative stress in patients with lung, prostate and colorectal cancer. Total thiols, native (free) thiols and disulfide levels are significantly altered in these patients compared to healthy individuals. In general, these findings indicate that the extracellular antioxidant capacity is severely affected in patients with these types of cancer. Moreover, lower thiol levels are associated with a lowered overall survival. Future research should focus on exploration of the clinical significance of thiols in cancer

Spatiotemporal regulation of hydrogen sulfide signaling in the kidney

Hydrogen sulfide (H2S) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, H2S is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. H2S-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, H2S is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of H2S are not precisely understood. H2S modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, H2S affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by H2S. H2S enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of H2S anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal H2S levels. Together, H2S is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of H2S not only expands fundamental insight in the regulation of functional effects mediated by H2S, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury

Unsuitability of the Oxidation-Reduction Potential Measurement for the Quantification of Fecal Redox Status in Inflammatory Bowel Disease

Oxidative stress is a key pathophysiological process associated with the development and progression of inflammatory bowel disease (IBD). Biomarkers for oxidative stress, however, are scarce, as are diagnostic tools that can interrogate an individual’s gut redox status. This proof- of-concept study aimed to evaluate the potential utility of an oxidation-reduction potential (ORP) measurement probe, to quantify redox status in the feces of both patients with IBD and healthy controls. Previous studies using this ORP measurement probe demonstrated promising data when comparing ORP from severely malnourished individuals with that of healthy controls. To date, ORP analyses have not been performed in the context of IBD. We hypothesized that measuring the ORP of fecal water in patients with IBD might have diagnostic value. The current study, however, did not show significant differences in ORP measurement values between patients with IBD (median [IQR] 46.5 [33.0–61.2] mV) and healthy controls (25 [8.0–52.0] mV; p = 0.221). Additionally, ORP measurements were highly unstable and rapidly fluctuated throughout time, with ORP values varying from +24 to +303 mV. Due to potential biological processes and limitations of the measuring equipment, this study was unable to reliably measure ORP. As a result, our findings indicate that ORP quantification may not be a suitable method for assessing fecal redox status and, therefore, does not currently support further exploration as a diagnostic or monitoring tool

Heart failure-associated anemia: bone marrow dysfunction and response to erythropoietin

Heart failure (HF)-associated anemia is common and has a poor outcome. Because bone marrow (BM) dysfunction may contribute to HF-associated anemia, we first investigated mechanisms of BM dysfunction in an established model of HF, the transgenic REN2 rat, which is characterized by severe hypertrophy and ventricular dilatation and SD rats as controls. Secondly, we investigated whether stimulation of hematopoiesis with erythropoietin (EPO) could restore anemia and BM dysfunction. After sacrifice, erythropoietic precursors (BFU-E) were isolated from the BM and cultured for 10 days. BFU-E were quantified and transcript abundance of genes involved in erythropoiesis were assayed. Number of BFU-E were severely decreased in BM of REN2 rats compared to SD rats (50 ± 6.2 vs. 6.4 ± 1.7, p < 0.01). EPO treatment increased hematocrit in the SD-EPO group (after 6 weeks, 49 ± 1 vs. 58 ± 1%, p < 0.01); however, in the mildly anemic REN2 rats, there was no effect (43 ± 1 vs. 44 ± 1%). This was paralleled by a 67% decrease in BFU-E in BM of REN2 rats compared to SD (p < 0.01). EPO significantly improved BFU-E in both SD and REN2 but could not restore this to control levels in the REN2 rats. Expression of several genes involved in differentiation (LMO2), mobilization (SDF-1), and iron incorporation (transferrin receptor) of the BM were differentially expressed in REN2 rats compared to SD rats, and EPO did not normalize this. Altogether, these results suggest that BM dysfunction is an important contributor to HF-associated anemia and that EPO is not an effective agent to treat HF-associated anemia

Hypomagnesaemia and its determinants in a contemporary primary care cohort of persons with type 2 diabetes

AIMS: Among persons with type 2 diabetes mellitus (T2DM) hypomagnesaemia has been reported in 14-48% of patients. This may be of significance given the emerging associations of hypomagnesaemia with glucometabolic disturbances and possibly even complications. We assessed the prevalence of hypomagnesaemia and its determinants, in a well-defined cohort of persons with T2DM treated in primary care. METHODS: Observational cohort study among persons with T2DM treated in primary care in the Northeast of the Netherlands. Magnesium was measured using a colorimetric endpoint assay (Roche). Hypomagnesaemia was defined as a serum magnesium level <0.70 mmol/L. Pearson correlations were performed to correlate variables with serum magnesium. Next, a stepwise backward regression model was made. RESULTS: Data of 929 persons (55% male) with a mean age of 65 (± 10) years, diabetes duration 6.5 [3.0-10.1] years, and HbA1c concentration 6.7 (± 0.7)% (50 (± 9) mmol/mol) were analysed. Serum magnesium was 0.79 (± 0.08) mmol/L. The percentage of persons with magnesium deficiency was 9.6%. Age, diabetes duration, BMI, HbA1c, use of metformin, sulfonylurea derivatives, and DPP4 inhibitors were negatively associated with magnesium concentrations. In contrast, LDL cholesterol and serum creatinine were positively associated serum magnesium. CONCLUSIONS: Hypomagnesaemia was present in 9.6% of T2DM patients treated in primary care. This percentage is remarkably lower than reported previously, possibly due to the unselected nature of our population. Concerning T2DM-related factors, only BMI, HbA1c and the use of metformin, sulfonylurea derivatives and DPP4 inhibitors correlated negatively with magnesium concentrations

Prolonged Organ Extraction Time Negatively Impacts Kidney Transplantation Outcome

Main Problem: Following cold aortic flush in a deceased organ donation procedure, kidneys never reach the intended 0–4°C and stay ischemic at around 20°C in the donor’s body until actual surgical retrieval. Therefore, organ extraction time could have a detrimental influence on kidney transplant outcome. Materials and Methods: We analyzed the association between extraction time and kidney transplant outcome in multicenter data of 5,426 transplant procedures from the Dutch Organ Transplantation Registry (NOTR) and 15,849 transplant procedures from the United Network for Organ Sharing (UNOS). Results: Extraction time was grouped per 10-min increment. In the NOTR database, extraction time was independently associated with graft loss [HR 1.027 (1.004–1.050); p = 0.022] and with DGF [OR 1.043 (1.021–1.066); p 80 min was associated with a 27.4% higher hazard rate of graft failure [HR 1.274 (1.080–1.502); p = 0.004] and such kidneys had 43.8% higher odds of developing DGF [OR 1.438, (1.236–1.673); p 30 min was associated with 14.5% higher odds of developing DGF [OR 1.145 (1.063–1.233); p < 0.005]. Discussion: Prolonged kidney extraction time negatively influenced graft survival in Dutch donors and increased DGF risk in all deceased donor recipients

Intra-arterial tert-Butyl-Hydroperoxide Infusion Induces an Exacerbated Sensory Response in the Rat Hind Limb and is Associated with an Impaired Tissue Oxygen Uptake

The objective of this study was to investigate oxidative stress and oxygen extraction mechanisms in an animal model of continuous intra-arterial infusion of a free radical donor and in an in vitro model using isolated mitochondria. tert-Butyl-hydroperoxide (tert-BuOOH, 25 mM) was infused for 24 h in the left hind limb of rats to induce soft tissue damage (n = 8). After 7 days, we assessed local sensory response, tissue oxygen consumption, oxygen radicals, and antioxidant levels. In vitro mitochondrial function was measured after stimulation of isolated mitochondria of skeletal muscle cells with increasing doses of tert-BuOOH. tert-BuOOH infusion resulted in an increased skin temperature (p = 0.04), impaired function, and a significantly increased pain sensation (p = 0.03). Venous oxygen saturation levels (p = 0.01) and the antioxidant ceruloplasmin (p = 0.04) were increased. tert-BuOOH inhibited mitochondrial function in vitro. Induction of free radical formation in the rat hind limb results in an exacerbated sensory response and is associated with impaired oxygen extraction, which likely results from mitochondrial dysfunction caused by free radicals

N-acetylcysteine (NAC) and Hydrogen Sulfide (H₂S) in Coronavirus Disease 2019 (COVID-19)

Significance: Hydrogen sulfide (H2S) is one of the three main gasotransmitters which is endogenously produced in humans and is protective against oxidative stress. Recent findings from studies focusing on coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shifted our attention to a potential modulatory role of H2S in this viral respiratory disease. Recent Advances: H2S levels at hospital admission may be of importance since this gasotransmitter has been shown to be protective against lung damage through its antiviral, antioxidant and anti-inflammatory actions. Furthermore, many COVID-19 cases have been described demonstrating remarkable clinical improvement upon administration of high doses of N-acetylcysteine (NAC). NAC is a renowned pharmacological antioxidant substance acting as a source of cysteine, thereby promoting endogenous glutathione (GSH) biosynthesis as well as generation of sulfane sulfur species when desulfurated to H2S. Critical Issues: Combining H2S physiology and currently available knowledge of COVID-19, H2S is hypothesized to target three main vulnerabilities of SARS-CoV-2: 1) cell entry through interfering with functional host receptors, 2) viral replication through acting on RNA-dependent RNA-polymerase (RdRp), and 3) the escalation of inflammation to a potentially lethal hyperinflammatory cytokine storm (TLR4 pathway and NLRP3 inflammasome). Future Directions: Dissecting the breakdown of NAC reveals the possibility of increasing endogenous H2S levels, which may provide a convenient rationale for the application of H2S-targeted therapeutics. Further randomized controlled trials (RCT) are warranted to investigate its definitive role

Different routes of insulin administration do not influence serum free thiols in type 1 diabetes mellitus

Aims: Intraperitoneal (IP) insulin administration is a last-resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As the IP route of insulin administration mimics the physiology more closely than the subcutaneous (SC) route, we hypothesized that IP insulin would result in less oxidative stress (expressed as systemic level of free sulphydryl (R-SH) content) compared to SC insulin in subjects with T1DM.Materials and methods: Prospective, observational case-control study. Serum thiol measurements were performed at baseline and at 26 weeks in age- and gender-matched patients with T1DM. Serum-free thiols, compounds with a R-SH group that are readily oxidized by reactive oxygen species, are considered to be a marker of systemic redox status.Results: A total of 176 patients, 39 of which used IP and 141 SC insulin therapy were analysed. Mean baseline R-SH concentration was 248 (31) μmol/L. In multivariable analysis, the route of insulin therapy had no impact on baseline R-SH levels. The estimated geometric mean concentrations of R-SH did not differ significantly between both groups: 264 (95% CI 257, 270) for the IP group and 258 (95% CI 254, 261) for the SC group with a difference of 6 (95% CI -2, 14) μmol/L.Conclusions: Based on R-SH as a marker of systemic oxidative stress, these findings demonstrate that the route of insulin administration, IP or SC, does not influence systemic redox status in patients with T1DM.</p