INTRODUCTION:

Homeostasis is a self-regulatory process in which the system in the body maintains stability while adapting to changing external conditions¹. It is important for every organism to maintain more or less constant internal conditions so as to enable it to adapt and survive in dealing with a changing, and sometimes, dangerous external environment¹.

Stress occurs when homeostatic conditions are threatened². Activation of the stress system causes behavioral and physical changes that will increase the individual's ability to adjust homeostasis and increase the chances of survival³.

However, stress is often considered to have undesirable effects by most people. Strategies to combat stress in humans often rely on early detection of stress-induced damage. Various indicators have been identified as strong markers of different biological processes, such as pathogenic or pharmacological responses, which are referred to as biomarkers^4,5,6. These include normal physiological biomarkers that are within the normal range in healthy subjects. However, stress markers indicate that a person is not feeling physiologically comfortable and different energy consumption mechanisms operate in their body to maintain homeostasis^7,8 involving multiple biomarkers. Therefore, biomarkers are characteristics that can be measured and evaluated objectively as indicators of physiological and pathological processes or pharmacological responses to therapeutic interventions⁹.

According to the FDA, the ideal biomarker should be specific for a particular disease and should be able to distinguish different physiological conditions, safe and easy to measure, quick so that the determination of the diagnosis becomes faster and able to provide accurate and consistent results in various ethnic groups and gender¹⁰.

MATERIALS AND METHODS:

Methodology:

In this literature review, the author used a scoping review approach. The sources of information used to find and identify various studies and meta-analyses published in English and related to the theme of this scoping review. the author used electronic/internet search with three databases used, namely Google scholar, Pubmed and Science direct from 2000 to 2022. Furthermore, the search for articles or journals used keywords and boolean operators (AND, OR NOT or AND NOT) to to make searching easier. The search strategy is defined as ―(stress)) OR (biomarker stress) AND (diagnostic biomarker) OR (stress-Related diseases)) AND (prognostic biomarker)". Publication (from 2000-2022) and Language (English and Indonesian). The inclusion criteria in this scoping review are biomarker stress-related diseases and original research in English published from 2000 to 2022. Therefore, based on the results of the selection, there were 86 publications retrieved from the database. Duplicate articles that did not meet the inclusion criteria were removed, bringing 62 articles. And I screened and assessed titles excluded from each study against the inclusion criteria, leaving 62 full-text articles eligible for scoping review.

Figure 1. Literature review flowchart

RESULT AND DISCUSSION:

Stress System:

The entire central nervous system (CNS) is directly or indirectly involved in maintaining and reorganizing the body's overall homeostasis. Certain areas of the brain have important roles and different functions in regulating the stress response². Thus, the central components of the stress system are located in the hypothalamus and brainstem and include parvocellular corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) neurons from the paraventricular nucleus (PVN) of the hypothalamus, and CRH neurons from the paragigantocellular and parabranchial nuclei of the hypothalamus. The medulla, as well as the locus coeruleus (LC) and other groups of catecholaminergic, norepinephrine (NE) synthesizing cells in the medulla and pons (central sympathetic nervous system)^1-2,11. Peripheral paralysis of the hypothalamic-pituitary-adrenal (HPA) axis, together with the sympathetic / adrenomedullary efferent system, are peripheral components of this interconnected system¹¹.

Biomarker Type:

According to their application, biomarkers can be classified into diagnostic, prognostic, and therapeutic biomarkers¹². Diagnostic biomarkers are biomarkers that help in the diagnosis or determination of disease, prognostic biomarkers help in forecasting or possibly predict disease outcomes and therapeutic biomarkers help in monitoring the progress of disease treatment¹². Another classification divides biomarkers into prognostic biomarkers, which help in knowing or predicting disease and can tell the likely outcome of disease in untreated individuals, and predictive biomarkers are used to identify patients who can respond positively to the given treatment¹².

Regardless of the classification, biomarkers have relevance to any stress mechanism, disease, organ or system involved. Therefore, descriptions of individual biomarkers can be useful in elucidating their diagnostic, pathophysiological, and clinical significance¹².

Utilization of Biomarkers in Clinical Disease:

Stress related diseases explain the role of stress in the emergence of disease in individuals when a person experiences chronic stress. Stress will cause biochemical and functional changes in the body and, if this continues, it can cause disease. Stress can trigger suppression of the immune system by increasing the production of catecholamines and the number of suppressor T cells¹¹. A study conducted by Liu et al showed that stress can increase the allergic inflammatory response. Chronic stress can also change the concentration of acid in the stomach so that it can trigger peptic ulcers or colitis¹⁶. From this, it is known that stress can increase or decrease the level of biomarkers in the body which affects the incidence of disease in individuals. Various important molecular markers have been identified in relation to stress-related diseases, but for their recommendation as a unique biomarker for each condition depends on the clinical relevance as well as the cost-effectiveness, sensitivity and specificity of the diagnostic tool. Table 1 provides a summary of the various biomolecules that take on diagnostic/prognostic value along with their association with various diseases.

Table 1: Molecular biomarkers for diagnosis/prognosis in stress-related diseases

Molecular Biomarkers	Molecule Category	Molecule Function	Association with Disease	Markers for Diagnosis/Prognosis	Detection module	Ref
Glutamate	Mitochondrial phosphate-dependent glutaminase converts glutamine to glutamate and ammonia	Important for protein synthesis, muscle formation, regulation of acid-base balance in the kidneys, ureagenesis in the liver, hepatic and renal gluconeogenesis, oxidative fuel for gut and immune system cells, precursors for the synthesis of neurotransmitters, nucleotides, nucleic acids and glutathione production	Central obesity and associated metabolic changes	Diagnostic markers for central obesity and altered metabolism	Targeted metabolomics using the IDQ Absolute p180 kit	¹³
Chromogranin-A (CgA)	Present in the secretory granules of most endocrine and neuroendocrine cells	Precursor molecules for biologically active peptides	Neuroendocrine tumors	Diagnostic and prognostic markers for survival	Solid phase, two-site immuno-radiometric assay, CGA-RIA kit	^14,15
Urinary 8-hydroxy-2-deoxyguanosine (8-OH-dG)	Oxidized DNA nucleosides	Excreted in urine after DNA repair	Cancer, atherosclerosis, diabetes, diabetic nephropathy and retinopathy	Diagnostic and prognostic markers	Alkaline comet assay	^16,17
Liver-type fatty acid-binding protein (L-FABP)	Expressed in the proximal tubule of the human kidney, participates in fatty acid metabolism	Reduces cellular oxidative stress through binding to fatty acid oxidation products, and limits the toxic effects of oxidative intermediates	Acute kidney injury	Effective diagnostic marker in estimating the severity of kidney injury/oxidative stress biomarker	Sandwich enzyme-linked immunosorbent assay (ELISA) kit	^18,19
Renal Wilms' tumor-1 (WT-1)	WT-1 is expressed on podocytes in healthy adult kidneys	Maintain normal podocyte function	Focal segmental glomerulosclerosis, steroid sensitive nephrotic syndrome, acute kidney injury	Prognostic markers for podocyte injury	Differential centrifugation followed by lysis and immunoblotting	^20,21
N-acetyl-beta-D-glucosaminidase	Lysosomal enzymes that are abundant in the cells of the proximal renal tubule	Indications of renal tubular function, patients with tubular and interstitial renal impairment, increased urine total NAG activity	Chronic heart failure, acute kidney injury	Prognostic markers for death and rehospitalization of patients with heart failure and renal impairment	Fluorimetric assay based on fluorescent substrate 4-methylumbelliferyl-N-acetyl-β-D-glucosamine or spectrophotometric method based on highly soluble and stable 4-nitrophenyl-N-acetyl-β-D-glucosamine as substrate	^22-24
D-serine	Formed by serine racemase enzyme-mediated conference of L-serin	Anti-depressants	Schizophrenia, Alzheimer's disease	Prognostic markers for antidepressant response to ketamine	High performance liquid chromatography/ amperometric, biosensor-based method	^25,26
Osteocalcin	Only secreted by osteoblasts	Pro-osteoblastic, responsible for bone mineralization and calcium ion homeostasis	Chronic rheumatic disease, bone metastases	Prognostic markers for bone metastases	ELISA	^27-29
Cathepsin-D	Lysosomal aspartate protease	Protein degradation and cell death and regulation of trypsinogen activation	Cystic fibrosis, pancreatitis through inflammatory cells	Prognostic markers for poor prognosis in glioma patients	Real-time -reverse transcription-PCR analysis	^30-31
Urease, ammonia/urea (napas)	Neutralizes stomach acid by producing ammonia from urea which spreads from the blood	Hydrolysis of urea to form ammonia and carbon dioxide	Gastritis, gastric ulcer, and gastric cancer	Diagnostic markers for the presence of H. pylori	apid urease test, urea breath test	^32-33
Calcitonin gene-related peptide (CGRP), daa substance P (SP)	Pronociceptive role	Involved in the development of pain and hyperalgesia	Colonic hypersensitivity	Diagnostic markers of neurogenic inflammation	Capillary Isoelectric Focusing (CIEF) immunoassay	^34-36
Brain-derived neurotropic factor (BDNF)	Neurotropins have a role in the survival and development of neurons	Involved in hyperalgesia mechanism	Associated with pain in chronic pancreatitis	Diagnostic markers of chronic pancreatitis	Immunohistochemistry	³⁷
Galectin-3	β-galactoside binding lectin	Activates various profibrotic factors, promotes fibroblast proliferation and transformation, and mediates collagen production	Fibrotic disease, heart disorders, asthma, atherosclerosis, atopic dermatitis	Prognostic markers in patients with heart failure	ELISA, BGM Gal-3 assay; RCHITECT Gal-3 assay	^38,39
Mucin	A proline, threonine and serine rich protein containing a tandem repeat motif	Physical barrier that limits epithelial damage and attenuates activation of innate and adaptive immune responses	Deficiency causes colitis and superficial erosions consistent with ulcerative colitis	Diagnostic and prognostic markers of gastrointestinal disease, cancer	Solid-phase sandwich ELISA	^40-43
Neutrophil gelatinase associated lipocalin and cystatin C	Expression is induced in liver, spleen and immune cells in response to ischemic damage or other renal impairment; cysteine protease inhibitor expressed by nucleated cells		Indications of kidney damage	Diagnostic markers for tubular damage	ELISA	⁴⁴
Lactoferrin	ransferrin group of iron-binding glycoprotein	Components of the innate immune system, binds to iron with high affinity thereby controlling inflammation	Obesity, type 2 diabetes, and cardiovascular disease	Non-specific diagnostic markers of inflammation	Immunoassay	⁴⁵
Tumor M2-pyruvate kinase (Tumor M2-PK)/M2-pyruvate kinase	Tissue-specific isoenzymes are replaced by M2-PK	In tumor cells there is a shift from the tetrameric form to the almost inactive dimeric form	Increased in some human cancers, diabetes mellitus, coronary heart disease, chronic kidney failure	Prognostic markers for pancreatic cancer, GIT disease	ELISA	^46,47
Catestatin (CST)	Peptide derived from the neuroendocrine protein chromogranin A	Autocrine inhibitor of catecholamine secretion, regulates hypertension	Cardiovascular disorders	Diagnostic markers of psychological stress associated with increased mortality in cardiac patients	ELISA	⁴⁸
Fecal secretogranin	A protein found in the secretory cells of the enteric, endocrine, and immune systems	Describe the activity of the enteric, endocrine, and immune systems	Ulcerative colitis, irritable bowel syndrome	Prognostic markers	Commercial radioimmunoassay	^49-50
Cystatin-C	Cysteine protease inhibitor group	Produced mainly through nucleated cells	Chronic kidney disease	Diagnostic markers for glomerular filtration	Particle-enhanced turbidmetric immunoassay	^51,52
Urinary activin A	Belongs to the TGF-beta superfamily which correlates with the degree of tubular damage	Stimulated by inflammatory mediators	Ischemic kidney	Diagnostic markers of acute kidney injury	ELISA	⁵³
Cardiac troponin (cTn)	Cardiac-specific protein that is part of the troponin complex of the contractile apparatus	Released in the blood followed by acute myocardial infarction (AMI) and other types of acute myocardial injury	Heart injury	Diagnostic markers for IMA	Troponin I assay	⁵⁴
Visfatin	Endocrine, autocrine and paracrine peptides	Participates in the promotion of increased cell proliferation, biosynthesis of nicotinamide mono- and dinucleotides, and hypoglycemic effects	Endometrial cancer, diabetes	Diagnostic markers	Multiplex fluorescent bead-based immunoassays	^55-57
Interleukin-6	Pleiotropic, pro-inflammatory cytokine	Plays an important role in inflammation, immunity, reproduction, metabolism, hematopoiesis, neurodevelopment, bone remodeling and angiogenesis	Albuminuria, retinopathy, and cardiovascular disease	Diagnostic and prognostic markers	SignaturePLUS Protein Array Imaging and Analysis System	^58-59
Fibrinogen	Glycoproteins that are enzymatically converted to fibrin and subsequently form fibrin-based blood clots	Inflammatory markers	Chronic kidney disease	Prognostic markers	Immunonephelometry	⁵⁸
C-reactive protein (CRP)	Acute phase reactants of the pentraxin family	During pathogen-independent inflammation, CRP binds to DNA and histones and scavenges nuclear material released from damaged circulating cells to activate innate immune cells	Solid tumor	Prognostic markers	Turbidmetric immunoassay	^60-61
Natriuretic peptide	Polypeptide hormone secreted by cardiac muscle cells	Lowers blood pressure, diuretics, sympathetic outflow, and vascular smooth muscle and endothelial cell proliferation	Acute (decompensated) and chronic heart failure, kidney disease, hyperthyroidism, lung disease	Diagnostic and prognostic markers	Single-epitope sandwich assay	^62-64
Carbohydrate antigen 125 (CA 125)	Glycoprotein product of MUC16 gene	Produced as a consequence of mechanical stress, such as fluid overload/serous effusion and/or inflammation	Ovarian cancer, heart failure	Diagnostic and prognostic markers	Quantitative ELISA kit	^65-66
Endothelin-1	Potent vasoconstrictor peptide	Secreted from endothelial cells	Systemic sclerosis, cardiac or spontaneous respiratory disease	Diagnostic and prognostic markers	Radioimmunoassay (RIA)	^67-68
Angiogenin	Member of the specific vertebrate secreted ribonuclease A superfamily	Induces the formation of blood vessels	Colorectal cancer, acute myeloid leukemia, multiple myeloma, myelodysplastic syndrome cardiovascular disease	Diagnostic and prognostic markers	ELISA	⁶⁹
β2-Microglobulin	A 100-amino acid protein encoded by a gene present on human chromosome 15	The tertiary structure is similar to the immunoglobulin constant domain and is associated with human leukocyte antigen I (HLA-I) on the surface of all nucleated cells. Interaction is essential for antigen presentation	Acute kidney injury, familial hypercatabolic hypoproteinemia, solid organ malignancies, lymphoproliferative disorders, such as myeloma and chronic lymphoblastic leukemia, and many autoimmune diseases, tubulointerstitial nephritis and uveitis (TINU) syndrome	Diagnostic markers	BN ProSpec Nephelometer	^70-71

When a person is under stress, the first thing that occurs is the hypothalamus will release corticotropin-releasing hormone (CRH) which then will stimulate the pituitary gland to secrete Adrenocorticotropic hormone (ACTH) then stimulate the adrenal gland to release glucocorticoids, then the stressor will activate the hypothalamus, which then will controls the sympathetic nervous system, and stimulates the spinal nerves and then goes to the adrenal cortex system. The sympathetic nervous system will then signal to the adrenal medulla to release epinephrine and norepinephrine into the bloodstream. In addition, the hypothalamus will secrete ACTH which will stimulate the adrenal cortex to stimulate a group of hormones including cortisol, so that cortisol levels will increase. Through this mechanism, it can be seen that stress increases or decreases catecholamine levels in the body, which is a biomarker to see the severity of a disease. One study of stress biomarkers showed that oxidative biomarkers could be a promising approach for controlling the enantioselective toxicity of chiral pesticides⁷². Di-tyrosine bound to plasma proteins is used as a biomarker of oxidative stress in end-stage renal disease patients on routine hemodialysis⁷³. Strong associations were also demonstrated by oxidative stress and antioxidant biomarkers in circulatory, cellular, and urinary anatomic compartments in Guatemalan children from the western highlands⁷⁴. The study concluded that excessive oxidation was associated with increased urinary biomarkers of oxidative stress F2-Iso and 8-OHdG and urinary excretion of oxidative biomarkers and was directly related to antioxidant enzyme activity and inversely related to vitamin concentration^75-80. Studies on the relationship between lipid peroxidation biomarkers provide promising results to assist clinicians in early disease diagnosis, initiation of effective treatment and reliable disease monitoring^81-90. It implies that using biomarkers to identify stress levels in individuals can allow us to find out the severity of the disease and help decide the course of action to take and to monitor and evaluate the outcome.

CONCLUSION:

Stress biomarkers have enormous potential in therapeutic approaches to patients in monitoring prognosis and the accuracy of therapy. Current quantitation based largely on immunological assessment, chromatography, and mass spectrophotometry has yielded fairly reliable results. However, some variability and low reproducibility are significant obstacles in its implementation. Further studies are needed so that biomarker identification can be carried out optimally and specifically for each disorder, both physiological and pathological.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to express their gratitude to the Faculty of Pharmacy, Universitas Padjajaran for the financial support during the preparation of this manuscript.

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Received on 05.01.2023 Modified on 10.04.2023

Research J. Pharm. and Tech 2024; 17(2):471-478.

DOI: 10.52711/0974-360X.2024.00074