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Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values

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Review

Biomarkers in Stress Related Diseases/Disorders: Diagnostic, Prognostic, and Therapeutic Values

Kuldeep Dhama et al. Front Mol Biosci.

Abstract

Various internal and external factors negatively affect the homeostatic equilibrium of organisms at the molecular to the whole-body level, inducing the so-called state of stress. Stress affects an organism's welfare status and induces energy-consuming mechanisms to combat the subsequent ill effects; thus, the individual may be immunocompromised, making them vulnerable to pathogens. The information presented here has been extensively reviewed, compiled, and analyzed from authenticated published resources available on Medline, PubMed, PubMed Central, Science Direct, and other scientific databases. Stress levels can be monitored by the quantitative and qualitative measurement of biomarkers. Potential markers of stress include thermal stress markers, such as heat shock proteins (HSPs), innate immune markers, such as Acute Phase Proteins (APPs), oxidative stress markers, and chemical secretions in the saliva and urine. In addition, stress biomarkers also play critical roles in the prognosis of stress-related diseases and disorders, and therapy guidance. Moreover, different components have been identified as potent mediators of cardiovascular, central nervous system, hepatic, and nephrological disorders, which can also be employed to evaluate these conditions precisely, but with stringent validation and specificity. Considerable scientific advances have been made in the detection, quantitation, and application of these biomarkers. The present review describes the current progress of identifying biomarkers, their prognostic, and therapeutic values.

Keywords: acute phase proteins; biomarkers; diagnosis; heat shock proteins; miRNAs; prognosis; stress; therapeutic values.

Figures

Figure 1
Figure 1
Schematic representation of various endogenous and exogenous factors that act as stressors and lead to the generation of ROS and oxidative stress/modification. In response, various molecular and cellular redox-sensitive processes start that can be tracked as biomarkers of oxidative stress. For instance, major biomarkers include (1) markers of DNA/RNA damage/oxidation, (2) markers of protein damage/oxidation, and (3) markers of lipid damage via the oxidation of membrane components and available lipids, etc.
Figure 2
Figure 2
Heat shock proteins as stress biomarkers. HSP70 has been reported as a biomarker in monitoring environmental diseases, such as mycotoxicoses. HSP27 was characterized as a potent marker for thermal stress, facilitating the effective re-orientation of misfolded proteins. HSP27 inhibits the intrinsic and mitochondrial apoptotic pathways via its action on Bax and cytochrome c. HSP60 and HSP70 was demonstrated to have neuroprotective function in arsenic-induced neurotoxicity in red jungle fowl. HSP30, HSP60, HSP70, and HSP90 were elevated in an Avermectin toxicity model in the cardiac tissues of pigeons.
Figure 3
Figure 3
Acute phase proteins as stress biomarkers. Increased level of haptoglobin was noticed in cattle in conditions like fatty liver syndrome and stress induced by parturition, starvation, or transportation. There was also increase in SAA and fibrinogen in cattle during chronic inflammation and associated stress. Haptoglobin exerts its anti-oxidant role by stabilizing ferric irons to prevent oxidative damage to hemoglobin. Haptoglobin protects albumin from oxidative damage by inhibiting the exchange of heme between hemoglobin and albumin. Haptoglobin scavenges nitric oxide through rapid and irreversible bonding, thereby limiting its bioavailability and preventing oxidative damage from reactive nitrogen species. Haptoglobin and SAA are synthesized in the bovine mammary epithelium, and the substantial increase in their secretion into milk was observed during mastitis. SAA has been found to increase in sera of foals during infections with bacteria, i.e., Rhodocoocus equi and Streptococcus equi and viruses, i.e., H3N8 influenza virus and serotype 1 herpes virus. Streptococcus suis type 2 infection in pigs, transthyretin showed a negative acute phase response. CRP is the primary APP in canines, along with haptoglobin and SAA, whose concentrations are elevated in bacterial infections, inflammation, and stress.
Figure 4
Figure 4
IL-22 signaling pathway for expression of acute phase response proteins. 1. IL-22 receptor is a heterodimer of IL-22R1 and IL-10R2. Initially IL-22 binds to IL-22R1. 2. Upon binding, conformational change in IL-22 enhances its affinity toward IL-10R2. 3. leading to formation of heterodimeric receptor intracellularly, IL-22R1 is associated with JAK1 and STAT3 (STAT3 is recruited through tyrosine-independent recruitment) and IL-10R2 is associated with tyrosine kinase 2 (TYK2). 4. Binding of ligand with receptor initiates the phosphorylation of JAK1 and TYK2. 5. Receptor bound STAT3 is phosphorylated by JAK1. 6. Phosphorylation of STAT3 leads to dimerization of STAT3. 7. Dimerized STAT3 translocates to nucleus; in nucleus, it binds to response elements and regulate associated proteins. 8. STAT3 binds to different genes coding for acute phase proteins by different cells, viz. to viz. a). Epithelial cell (β-defensin 2, β-defensin 3, lipocalin 2, MMP1 and MMP3, S100A7, S100A8, S100A9 b). tracheal epithelial cells (CXCL5); c). synovial fibroblast (CCL2/RANKL); d). hepatic and pancreatic cells (Bcl-2, Bcl-xL, MCL-1, Cyclin D1, p21, CDK4).
Figure 5
Figure 5
Various stresses affecting the salivary stress biomarkers: cortisol, chromogragranin A and α-amylase are increased whilst salivary IgA and lysozyme are decreased with an increase in level of stress.
Figure 6
Figure 6
An overview on renal stress biomarkers: various biomarkers, such as urea, creatinine, 8-hydroxy-2-deoxyguanosine, cystatin-C, and others are used to assess the status of renal system.
Figure 7
Figure 7
Biomarkers in prognosis of stress related diseases/disorders.

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