Efficacy and safety of tocilizumab versus standard care/placebo in patients with COVID-19; a systematic review and meta-analysis of randomized clinical trials.

AIMS: Tocilizumab has emerged as an important therapy in treating patients with coronavirus disease (COVID-19). Our purpose was to evaluate the efficacy and safety of tocilizumab versus standard care/placebo in patients with COVID-19. METHODS: We searched a variety of sources from 1 January 2020 to 5 May 2021. All randomized controlled trials that reported tocilizumab efficacy as a primary agent in COVID-19 patients were considered. RCTs had to include mortality events, incidence of mechanical ventilation and serious adverse events. Two reviewers were independently responsible for data extraction. Assessment of bias and certainty of evidence was carried out using the Cochrane Risk of Bias Tool and GRADE methodology. RR for mortality events was evaluated using a fixed-effects model. RESULTS: A total of 6837 patients were included from 10 RCTs, of which nine were peer-reviewed. Pooled risk ratio (RR) for all-cause mortality in patients with tocilizumab administration was RR = 0.88 (95% CI: 0.81-0.95, P = .0009). RR for incidence of mechanical ventilation at 28-30 days was 0.79 (95% CI: 0.71-0.88). Serious adverse events (SAE) with tocilizumab use were associated with lower RR (RR = 0.91, 95% CI: 0.76-1.09) but the certainty of evidence was downgraded to moderate due to serious risk of bias. CONCLUSION: In COVID-19 patients with moderate to critical COVID-19, use of tocilizumab reduces all-cause mortality and progression to mechanical ventilation. This efficacy was not associated with higher number of serious adverse events.

Iron in the Tumor Microenvironment.

Cancer metabolism is a well-known target of cancer therapeutics. Classically, cancer metabolism has been studied in terms of the dependence of cancer cells on crucial metabolites, such as glucose and glutamine. But, the accumulating data show that iron metabolism in tumor microenvironment is also an important factor in preserving the survival of cancer cells. Cancer cells have a distinct phenotype of iron metabolism, which secures the much-needed iron for these metabolically active cells. In order to use this iron efficiently, cancer cells need to increase their iron supply and decrease iron loss. As recent research suggests, this is not only done by modifying the expression of iron-related proteins in cancer cells, but also by interaction of cancer cells with other cells from the tumor milieu. Tumor microenvironment is a dynamic environment characterized with intricate relationship between cancer cells, tumor-associated macrophages, fibroblasts, and other cells. Some of the mechanistic aspects of this relationship have been elucidated, while others are yet to be identified. In any case, identifying the details of the iron phenotype of the cells in tumor microenvironment presents with a new therapeutic opportunity to treat this deadly disease.

Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology.

Hepcidin is the main regulator of iron metabolism in tissues. Its serum levels are mostly correlated with the levels of hepcidin expression from the liver, but local hepcidin can be important for the physiology of other organs as well. There is an increasing evidence that this is the case with cardiac hepcidin. This has been confirmed by studies with models of ischemic heart disease and other heart pathologies. In this review the discussion dissects the role of cardiac hepcidin in cellular homeostasis. This review is complemented with examination of the role of systemic hepcidin in heart disease and its use as a biochemical marker. The relationship between systemic vs local hepcidin in the heart is important because it can help us understand how the fine balance between the actions of two hepcidins affects heart function. Manipulating the axis systemic/cardiac hepcidin could serve as a new therapeutic strategy in heart diseases.

Low hepcidin in liver fibrosis and cirrhosis; a tale of progressive disorder and a case for a new biochemical marker.

Liver fibrosis is a precursor of liver cirrhosis, which is associated with increased mortality. Though liver biopsy remains the gold standard for the diagnosis of fibrosis, noninvasive biochemical methods are cost-effective, practical and are not linked with major risks of complications. In this respect, serum hepcidin, has emerged as a new marker of fibrosis and cirrhosis. In this review the discussion uncovers molecular links between hepcidin disturbance and liver fibrosis/cirrhosis. The discussion also expands on clinical studies that suggest that hepcidin can potentially be used as a biochemical parameter of fibrosis/cirrhosis and target of therapeutic strategies to treat liver diseases. The debatable issues such as the complicated nature of hepcidin disturbance in non-alcoholic liver disease, serum levels of hepcidin in acute hepatitis C virus infection, cause of hepcidin disturbance in autoimmune hepatitis and hepatic insulin resistance are discussed, with potential solutions unveiled in order to be studied by future research.

Hepcidin, an emerging and important player in brain iron homeostasis.

Hepcidin is emerging as a new important factor in brain iron homeostasis. Studies suggest that there are two sources of hepcidin in the brain; one is local and the other comes from the circulation. Little is known about the molecular mediators of local hepcidin expression, but inflammation and iron-load have been shown to induce hepcidin expression in the brain. The most important source of hepcidin in the brain are glial cells. Role of hepcidin in brain functions has been observed during neuronal iron-load and brain hemorrhage, where secretion of abundant hepcidin is related with the severity of brain damage. This damage can be reversed by blocking systemic and local hepcidin secretion. Studies have yet to unveil its role in other brain conditions, but the rationale exists, since these conditions are characterized by overexpression of the factors that stimulate brain hepcidin expression, such as inflammation, hypoxia and iron-overload.

Insulin treatment corrects hepcidin but not YKL-40 levels in persons with type 2 diabetes mellitus matched by body mass index, waist-to-height ratio, C-reactive protein and Creatinine.

BACKGROUND: It has been shown that hepcidin and YKL-40 levels change in persons with insulin resistance in different circumstances. However, variations of the levels of these parameters through the stages of prediabetes and type 2 diabetes mellitus are unclear. We hypothesized that hepcidin levels will decrease in persons with prediabetes, while these levels will tend to correct when persons with diabetes are treated with insulin. Finally we sought to determine the levels of YKL-40 in all groups of participants included in the study. METHODS: Serum hepcidin levels and YKL-40 levels were measured in control group (n = 20), persons with prediabetes (n = 30) and persons with diabetes on insulin therapy (n = 30) using ELISA method. Patients in all three groups were matched by Body Mass Index, Waist-to-Height Ratio, C-Reactive Protein and creatinine levels. RESULTS: Hepcidin levels were lower in persons with prediabetes compared to control, while persons with diabetes on insulin therapy had higher values than those with prediabetes (p = 0,00001). YKL-40 levels showed no significant changes. CONCLUSIONS: Serum hepcidin levels in matched persons with prediabetes are a stronger marker of early changes in glucose metabolism compared to YKL-40 levels. Also, treatment with insulin corrects hepcidin levels, but not YKL-40 levels. Correcting levels of hepcidin is important for reducing iron-overload, which is a risk factor for diabetes.

Left ventricular markers of global dyssynchrony predict limited exercise capacity in heart failure, but not in patients with preserved ejection fraction.

BACKGROUND: The aim of this study was to prospectively examine echocardiographic parameters that correlate and predict functional capacity assessed by 6 min walk test (6-MWT) in patients with heart failure (HF), irrespective of ejection fraction (EF). METHODS: In 147 HF patients (mean age 61 ± 11 years, 50.3% male), a 6-MWT and an echo-Doppler study were performed in the same day. Global LV dyssynchrony was indirectly assessed by total isovolumic time - t-IVT [in s/min; calculated as: 60 - (total ejection time + total filling time)], and Tei index (t-IVT/ejection time). Patients were divided into two groups based on the 6-MWT distance (Group I: ≤ 300 m and Group II: >300 m), and also in two groups according to EF (Group A: LVEF ≥ 45% and Group B: LVEF < 45%). RESULTS: In the cohort of patients as a whole, the 6-MWT correlated with t-IVT (r = -0.49, p < 0.001) and Tei index (r = -0.43, p < 0.001) but not with any of the other clinical or echocardiographic parameters. Group I had lower hemoglobin level (p = 0.02), lower EF (p = 0.003), larger left atrium (p = 0.02), thicker interventricular septum (p = 0.02), lower A wave (p = 0.01) and lateral wall late diastolic myocardial velocity a' (p = 0.047), longer isovolumic relaxation time (r = 0.003) and longer t-IVT (p = 0.03), compared with Group II. In the patients cohort as a whole, only t-IVT ratio [1.257 (1.071-1.476), p = 0.005], LV EF [0.947 (0.903-0.993), p = 0.02], and E/A ratio [0.553 (0.315-0.972), p = 0.04] independently predicted poor 6-MWT performance (<300 m) in multivariate analysis. None of the echocardiographic measurements predicted exercise tolerance in HFpEF. CONCLUSION: In patients with HF, the limited exercise capacity, assessed by 6-MWT, is related mostly to severity of global LV dyssynchrony, more than EF or raised filling pressures. The lack of exercise predictors in HFpEF reflects its multifactorial pathophysiology.

Keeping heart homeostasis in check through the balance of iron metabolism.

Highly active cardiomyocytes need iron for their metabolic activity. In physiological conditions, iron turnover is a delicate process which is dependent on global iron supply and local autonomous regulatory mechanisms. Though less is known about the autonomous regulatory mechanisms, data suggest that these mechanisms can preserve cellular iron turnover even in the presence of systemic iron disturbance. Therefore, activity of local iron protein machinery and its relationship with global iron metabolism is important to understand cardiac iron metabolism in physiological conditions and in cardiac disease. Our knowledge in this respect has helped in designing therapeutic strategies for different cardiac diseases. This review is a synthesis of our current knowledge concerning the regulation of cardiac iron metabolism. In addition, different models of cardiac iron dysmetabolism will be discussed through the examples of heart failure (cardiomyocyte iron deficiency), myocardial infarction (acute changes in cardiac iron turnover), doxorubicin-induced cardiotoxicity (cardiomyocyte iron overload in mitochondria), thalassaemia (cardiomyocyte cytosolic and mitochondrial iron overload) and Friedreich ataxia (asymmetric cytosolic/mitochondrial cardiac iron dysmetabolism). Finally, future perspectives will be discussed in order to resolve actual gaps in knowledge, which should be helpful in finding new treatment possibilities in different cardiac diseases.

Systemic and local hepcidin as emerging and important peptides in renal homeostasis and pathology.

Recent data suggest that the importance of hepcidin goes beyond its classical role in controlling systemic iron metabolism. Local hepcidins are emerging as important peptides for organ homeostasis in the brain, heart, blood vessels, and in cancer as well. Similarly, accumulating data indicate that hepcidin does seem to be an important factor in renal homeostasis. This review encompasses present knowledge concerning the role of hepcidin in renoprotection and its use as a biomarker of kidney diseases. Understanding the role of hepcidin in kidneys is important due to its relevance for kidney physiology and its potential therapeutic application in kidney pathologies. © 2018 BioFactors, 45(2):118-134, 2019.

The Dual Role of Hepcidin in Brain Iron Load and Inflammation.

Hepcidin is the major regulator of systemic iron metabolism, while the role of this peptide in the brain has just recently been elucidated. Studies suggest a dual role of hepcidin in neuronal iron load and inflammation. This is important since neuronal iron load and inflammation are pathophysiological processes frequently associated with neurodegeneration. Furthermore, manipulation of hepcidin activity has recently been used to recover neuronal damage due to brain inflammation in animal models and cultured cells. Therefore, understanding the mechanistic insights of hepcidin action in the brain is important to uncover its role in treating neuronal damage in neurodegenerative diseases.

Iron Metabolism in Prostate Cancer; From Basic Science to New Therapeutic Strategies.

An increasing amount of research has recently strengthened the case for the existence of iron dysmetabolism in prostate cancer. It is characterized with a wide array of differential expression of iron-related proteins compared to normal cells. These proteins control iron entry, cellular iron distribution but also iron exit from prostate cells. Iron dysmetabolism is not an exclusive feature of prostate cancer cells, but it is observed in other cells of the tumor microenvironment. Disrupting the machinery that secures iron for prostate cancer cells can retard tumor growth and its invasive potential. This review unveils the current understanding of the ways that prostate cancer cells secure iron in the tumor milieu and how can we exploit this knowledge for therapeutic purposes.

Differential regulation of hepcidin in cancer and non-cancer tissues and its clinical implications.

Hepcidin is a crucial peptide for regulating cellular iron efflux. Because iron is essential for cell survival, especially for highly active cells, such as tumor cells, it is imperative to understand how tumor cells manipulate hepcidin expression for their own metabolic needs. Studies suggest that hepcidin expression and regulation in tumor cells show important differences in comparison with those in non-tumorous cells. These differences should be investigated to develop new strategies to fight cancer cells. Manipulating hepcidin expression to starve cancer cells for iron may prove to be a new therapy in the anticancer arsenal.

Low Hepcidin in Type 2 Diabetes Mellitus: Examining the Molecular Links and Their Clinical Implications.

The relationship between iron and glucose metabolism has been evidenced strongly, but the molecular mediation of this connection is just being revealed. The discovery of hepcidin as the prime controller of iron metabolism has paved the way for understanding the main actors behind this mediation. Recent data suggest that insulin therapy and probably other diabetes drugs can influence hepcidin production, thus influencing the iron load in cells. Correcting iron load through hepcidin expression could be a novel and important mechanism of action of antidiabetes drugs. This effect would further establish the protective role of antidiabetes therapy and might even affect prevention strategies in diabetes. In this review, we summarize the recent data about iron-glucose links through hepcidin expression, the molecular mediation of this interplay and the clinical implications of these findings.

The Role of Insulin Therapy in Correcting Hepcidin Levels in Patients with Type 2 Diabetes Mellitus.

OBJECTIVES: Iron overload can cause or contribute to the pathogenesis of type 2 diabetes mellitus (T2DM), but how the major parameters of iron metabolism change in different settings of diabetes are still unclear. The aim of this study was to determine the relationship between iron, ferritin, and hepcidin levels in diabetic patients and the effect of insulin treatment. METHODS: The study included 80 subjects, 60 with T2DM and 20 without (control group). Serum hepcidin, insulin, ferritin, and iron levels were determined as well as other clinical parameters. The associations between these parameters were analyzed between both groups. RESULTS: Hepcidin levels expressed as mean± standard deviation between groups showed no significant changes (14.4±6.7 ng/mL for the control group, and 18.4±7.9 ng/mL for patients with diabetes, p = 0.069). Parameters of iron metabolism showed modest correlation with the parameters of glucose metabolism. However, the correlation between ferritin and insulin in both groups was statistically significant (p = 0.032; ρ = 0.480 vs. p = 0.011; ρ = 0.328). CONCLUSIONS: Our study showed that hepcidin levels in patients with T2DM on insulin therapy do not change, which might be a result of treatment with insulin. In this context, insulin treatment can be used as a novel method for correction of hepcidin levels. By correcting hepcidin levels, we can prevent cellular iron overload and reduce the risk of diabetes.