Abstract
Through the formation of covalent connections with hyaluronic acid (HA), the inter-α-trypsin inhibitor (IαI) family collaborates to preserve the stability of the extracellular matrix (ECM). The five distinct homologous heavy chains (ITIH) and one type of light chain make up the IαI family. ITIH alone or in combination with bikunin (BK) has been proven to have important impacts in a number of earlier investigations. This implies that BK and ITIH might be crucial to both physiological and pathological processes. The functions of BK and ITIH in various pathophysiological processes are discussed independently in this paper. In the meanwhile, this study offers suggestions for further research on the roles of BK and ITIH in the course of disease and summarizes the plausible mechanisms of the previous studies.
1 Introduction
Members of the ancient and distinctive inter-α-trypsin inhibitor (IαI) family have developed throughout hundreds of millions of years of vertebrate history (1). Hepatocytes are the primary source of the 225 kDa IαI family protein complexes, which are found in the blood at high concentrations of 0.15 to 0.5 mg/mL (2). Human IαI family consists of three different polypeptide chains, namely bikunin (BK), heavy chain 1 and heavy chain 2 (3). IαI family, which makes up the majority of family members in human serum, is thought to be dormant until it enters the target tissue, where it is cleaved by TNF-stimulated gene 6 protein (TSG-6). After that, heavy chains (HCs) are transferred to hyaluronic acid (HA), a significant part of the extracellular matrix (ECM), through the formation of temporary covalent bonds with TSG-6 (4). TSG-6 is essential for the interaction with HA because it facilitates two following ester exchange reactions: it binds HC1 or HC2 of IαI family covalently and then moves them to the HA fraction in this complex, where the heavy chain conjugates and releases free TSG-6 (5, 6). HCs have been found to function as structural proteins that can directly cross-link HA that is secreted (7). IαI HC forms a strong bond with HA produced by fibroblasts in culture (7). In addition, the physiological correlation of HA with members of the IαI HC family has been linked to various cell types that show HA-containing outer membranes. For example, the maturation process of oocytes and experiments in vitro culture of mesothial cells (8). In summary, the IαI family of proteins interacts with HA to maintain the stability of the ECM, which is a critical function in numerous illnesses. This work aims to provide an overview of the mechanisms underlying the occurrence and development of IαI family proteins that have been linked to current disorders. Additionally, it offers suggestions for future research on IαI family proteins.
2 The structure and function of inter-α-trypsin inhibitor family members
2.1 Bikunin
Bikunin (BK), the light chain, and five homologous heavy chains come together to form the IαI family (9) (Figure 1). There are various homologous heavy chains (ITIH), and the one that has been discovered to date has five members (ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), despite the fact that there is only one type of light chain. The α-1-microglobulin/BK precursor (AMBP) encodes the light chain and α-1 microglobulin, a member of the lipid transport protein superfamily independent of the ITI family either physically or functionally (10). The ITI light chain is referred to as “BK” because it has two tandem repeats of a Kunitz-type structural domain (11). Serum proteoglycans generated from liver are known as BK isoforms. They contain chondroitin sulfate (CS) chains, which are mainly esterified by one or two glycoproteins referred to as “heavy chains” (HC). There are three primary serum isoforms that have been extensively documented: pro-alpha-proteinase inhibitor and inter-alpha-trypsin inhibitor, which carry one and two HC, respectively, and urotrypsin inhibitor, which corresponds to BK and is connected to the CS chain (10). These complexes create the characteristic ITI protein-glycosaminoglycan-protein structure (12).
Figure 1
Composition of inter-a-trypsin inhibitors and serum-derived hyaluronan-associated proteins. The IαI family is assembled from light chain-bikunin and five homologous heavy chains.
2.2 ITIH
Apart from BK, the ITI heavy chain also serves biological purposes (13). Numerous diseases, including inflammatory reactions in local tissues, acute inflammation, tumor growth, and problems connected to psychiatry, have been linked to ITIHs, according to studies (13, 14). Subsequent investigations have also revealed that ITIHs, a main constituent of ITI, plays an important role, either by itself or in conjunction with BK (13). The von Willebrand A-type structural domains and the vault are two of the modules that make up the H chain, which can communicate with the ECM. The carboxyl group of the matching H-chain’s C-terminal aspartic acid residue and the C-6 hydroxyl group of the internal N-acetylamino galactose residue of Bk’s chondroitin sulfate component are what link the H-chain to the protein. ITIHs can undergo an ester exchange reaction to covalently conjugate to locally generated HA. Serum-derived hyaluronan-associated protein is made up of D-glucuronic acid and N-acyl-D-glucosamine, which together make up the desialylated polymer known as HA (2). ITIHs bind covalently to HA to stabilize the ECM (15). Many extracellular proteins released by cells make up the ECM, which controls intercellular communication as well as biological activities (16). Many interacting proteins and proteoglycans that control cellular activity have an impact on the stiffness or rigidity of HA (17, 18). One important element of the ECM is HA (19). Together, these molecules of the ECM—HA, proliferating cells, migration, and tumor metastasis—maintain the stability of the ECM by forming a reticular structure (20, 21). A common ECM component, HA is a high molecular weight polymer that does not need to be modified further (21). Numerous biological processes, including wound healing, differentiation, and cell motility, are facilitated by HA-binding proteins, especially membrane-bound receptors like CD44 and RHAMM (22, 23). For instance, during the healing of skin injury, synthesis is elevated. The covalent transfer of heavy chains from IαI to HA is catalyzed by TsG-6, and the resulting HC-HA complex is engaged in remodeling and inflammatory processes in both healthy and pathological contexts (24). Furthermore, HA participates in angiogenic processes. The size of HA affects its angiogenic potential: short segments of HA produced in inflammation and tissue damage are strongly angiogenic (25), while high molecular weight HA possesses vasopressor qualities (26). After degradation, HA becomes a pro-angiogenic ligand (15). For instance, it has been discovered in earlier research that HA stimulates angiogenesis in lung damage and is even linked to abnormal angiogenesis (17). Increased ITIHs protein may prevent the HA-CD44 and ECM pathways from degrading, which would have anti-angiogenic effects. This could be one of the key ways that the protein ITIHs functions as a putative oncogene.
3 Advances in the study of BK and disease
In both physiological and pathological processes, BK has pleiotropic functions. BK appears to be involved in numerous activities, according on genetic studies of mice deficient the protein. Genes related to stress, apoptosis, proteases, aging, cytokines, HA metabolism, and female ovulation processes are dysregulated when BK is absent (27, 28). Subsequent research revealed that female mice deficient the BK gene exhibit considerably lower fertility (28). This results from a malfunction in the lateral protein precursors’ ability to form compounds with hyaluronic acid in the ovarian mound before ovulation. Therefore, hyaluronan, which is necessary for mammalian ovulation and fertilization, requires the delivery of serum-derived hyaluronan-related proteins by the chondroitin sulfate part of BK (29). Concurrently, research has produced intriguing findings on the potential of the medication BK to lower the risk of preterm labor and enhance neonatal outcomes (30).
Furthermore, in pancreatitis, septic shock, and rheumatoid arthritis, it has been demonstrated that the BK core protein inhibits inflammation-associated proteases such trypsin, elastase, and fibrinolytic enzymes (31, 32). As an anti-inflammatory, BK prevents the production of cytokines that are triggered by lipopolysaccharide (LPS). Through extracellular signal-regulated kinase signaling (ERK), calcium endocytosis, and endotoxin receptors, BK suppresses the generation of cytokines. Endotoxin stimulates calcium inward flow, generates phosphorylated ERK, and activates multiple transcription factors, including nuclear factor kappa B and early growth response-1, through endotoxin receptor signaling, all of which support the development of cytokines (33). It was discovered to prevent the generation of pro-inflammatory cytokines in a number of cell types in cellular tests (3, 34). Mice injected BK showed a decrease in multiple inflammatory markers in animal models of inflammatory disorders (35). Furthermore, BK knockout mice, Bik (−/−), were used for in vitro cytokine experiments and in vivo animal models. It was discovered that Bik (−/−) mice induced higher levels of endotoxin-induced death when compared to wild-type (Wt) mice; that application of BK significantly reduced LPS-induced lethality; and that endotoxin significantly increased endotoxin-induced lethality when compared to Wt mice. BK combined with application of BK inhibited the levels of these cytokines; additionally, BK inhibited endotoxin-induced up-regulation of cytokine expression by suppressing macrophage phosphorylation of ERK1/2, JNK, and p38; this implies that BK has a major anti-inflammatory function (36). In different acute and chronic inflammatory reactions, BK is a non-invasive circulating or urine biomarker (37).
BK has been found in cancer studies to inhibit tumor cell invasion through direct inhibition of fibrinolytic activity associated with tumor cells as well as urokinase-type fibrinogen activator (UPA) expression at the gene and protein levels, potentially through inhibition of MAP kinase signaling cascades and/or CD44 dimer. By interacting with different cell types’ cartilage junction proteins and BK receptors, BK can be suppressed in order to prevent cell invasion (38). Furthermore, ovarian cancer cells’ gene expression patterns are changed by BK, which prevents tumor cell invasion (39). In animal investigations, it was discovered that the exogenous injection of BK inhibited the growth of intraperitoneal ovarian tumors as well as peritoneal disseminated metastases (40). Treatment with BK in the adjuvant setting and/or in conjunction with cytotoxic medicines to enhance therapeutic efficacy may be helpful in postponing the beginning of metastases in patients with advanced ovarian cancer (41). Patients with ovarian cancer who had preoperative BK concentrations higher than 11.5 μg/mL were shown to have a significantly better prognosis than those with lower amounts. Patients with pretreatment values of 11.5 μg/mL had 2.2-fold higher Hazard Ratios (risk of mortality) than those with concentrations of more than 11.5 μg/mL of BK. Patients in both groups had a median survival of 26 months and more than 60 months, respectively (42). This implies that BK has a critical function and importance in determining the prognosis of ovarian cancer patients. Remarkably, there has been no report of BK overexpression being linked to human pathology (1).
The above cellular and animal experiments suggest that BK has potential medical value. It also plays a significant role in mammalian ovulation and even directly affects fertility in knockout mice. Additionally, BK has important roles and functions as an anti-inflammatory protein and an anti-tumor invasive protein. These findings may lead to new ideas for diagnostic and therapeutic approaches in the future gene therapy of ovarian cancer, inflammation, and infertility. It might offer suggestions for later gene therapy treatments for ovarian cancer, inflammation, and infertility. Figure 2 presents a summary of the physiological and pathological processes that are mediated by BK.
Figure 2
Stress, apoptosis, proteases, aging, signaling molecules, cytokines, HA metabolism, and female ovulation processes are all impacted by bakunin. Its responsibilities and functions as an anti-inflammatory and anti-tumor invasion protein are also significant.
4 Developments in the understanding of ITIH proteins and illnesses
ITIH has lately been found and thoroughly explained to be involved in several pathophysiological processes, such as inflammation and carcinogenesis (9, 43). Depending on the circumstances, these proteins may be positively or negatively regulated; nonetheless, there is compelling evidence that every member of the ITIH family is crucial to the development of tumors and cellular malignant processes (9, 44). ITIH proteins function as both pre- and anti-inflammatory acute phase proteins during inflammation, which leads to contradictory functions in the process. While the H3 chain is up-regulated and the related molecules behave as positive acute phase proteins, the H2 and BK chains are down-regulated and the associated molecules behave as negative acute phase proteins in acute inflammation, Inflammatory situations do not seem to have an impact on H1 chain (45). Strong evidence suggests that genes in the ITIH family may be tumor suppressors because these genes are highly down-regulated in a range of human solid tumors, including lung cancer, breast cancer and colon cancer (9). ITIH proteins stabilize the ECM in a way that inhibits tumor growth, which plays a significant role in carcinogenesis (46). ITIH’s covalent binding to HA and its capacity to maintain the ECM are two potential pathways. ITIH2 expression and estrogen receptor expression are substantially associated (p = 0.001) in breast cancer, according to a number of prior research. Cancer invasion and motility have been shown to be inhibited by estrogen (47). Because ITIH2 has an estrogen-binding structural domain that profoundly affects ECM integrity and may therefore be crucial for tumor growth and metastasis, there used to be a high correlation between ITIH2 expression levels and estrogen levels (48). ITIH2 is expressed in low-grade CNS cancers and normal brain tissues; however, it is not expressed in glioblastomas, especially glioblastoma multiforme, which is a highly invasive CNS tumor. This suggests that ITIH2 may have an anti-invasive function (49). The ITIH family gene has been linked in certain studies to shared genetic risk factors for schizophrenia and depression, in addition to its significant function in inflammation and malignancies. These findings imply that the ITIH family may potentially be implicated in the pathophysiology of psychiatric disorders (50). Furthermore, aberrant expression of ITIH family proteins has been found in neurodegenerative diseases (51, 52). The following table provides a summary of the roles and possible mechanisms of action of heavy chain participation (see Tables 1–5).
Table 1
| Functions | Mechanisms | References | |
|---|---|---|---|
| ITIH1 | Insulin sensitivity |
|
(16) |
| ITIH1 | Indicators for ankylosing spondylitis diagnosis | Markedly elevated in ankylosing spondylitis patients, p = 0.035 ROC distinguished between ankylosing spondylitis patients (AUC = 0.98) | (53) |
| ITIH1 | Evaluation of hepatic fibrosis | Liver fibrosis development and impaired ECM stability are linked to lower ITIH1 levels | (54) |
| ITIH1 | Control of adherence of leukocytes | Adhesion of the inflammatory HA is regulated by thrombin cleavage of ITIH1 | (55) |
| ITIH1 | Modulator of immunity | Blocks the C3 complement pathway | (56) |
| ITIH1 | Potential biomarker for hepatocellular carcinoma that is both diagnostic and predictive | Hepatocellular carcinoma patients have much lower levels of ITIH1 expression, and this downregulation is detrimental to the prognosis of these patients | (57) |
| ITIH1 | Involved in the development of hepatocellular carcinoma | By stimulating the PI3K/AKT signaling pathway and epigenetically suppressing ITIH1 transcription, KDM5C can encourage the malignant progression of hepatocellular carcinoma | (58) |
| ITIH1 | Markers for radiographic knee osteoarthritis development prediction | Shows promise for enhancing clinical practice radiographic knee osteoarthritis incidence prediction | (59) |
| ITIH1 | Potential biomarkers for ovarian cancer | Variations in expression in the serum of patients with ovarian cancer | (60) |
| ITIH1 | Biomarker for coronary heart disease risk stratification | When paired with additional proteins, ITIH1 exhibits a Lasso-logistic score that is highly effective in categorization (cross-validated area under the curve = 0.74) | (61) |
Functions and potential mechanisms of ITIH1.
Table 2
| Functions | Mechanisms | References | |
|---|---|---|---|
| ITIH2 | Increases intercellular adhesion, suppresses cell proliferation, and prevents glioblastoma invasion | Reduces the activity of the PI3K/AKT signaling pathway | (49) |
| ITIH2 | Biomarker for multiple sclerosis in children | Patients with pediatric multiple sclerosis had considerably reduced serum levels of ITIH2 protein | (62) |
| ITIH2 | Pancreatic cancer diagnostic biomarker | Area under the curve = 0.947; ROC separates pancreatic cancer from chronic pancreatitis | (63) |
| ITIH2 | Potential candidates associated with diabetic retinopathy | Comparing the protein profiles of vitreous humor in patients with idiopathic macular lentigines who are not diabetics, it was discovered that they had significantly decreased expression of ITIH2 protein | (64) |
| ITIH2 | Indicators of serum proteins for osteoarticular. Tuberculosis detection | For the diagnosis of osteoarticular tuberculosis, the AUC of ITIH2 was 0.7167 (95% CI: 0.5846–0.8487) | (65) |
| ITIH2 | Hinders the growth of mother cells in gliomas | Tumor cell contact is inhibited by gonadotropin-releasing hormone interaction | (66) |
Functions and potential mechanisms of ITIH2.
Table 3
| Functions | Mechanisms | References | |
|---|---|---|---|
| ITIH3 | Play in the development of the human brain | Differential spatiotemporal expression of ITIH3 in the developing human brain is shown by analysis of spatiotemporal histology data, which indicates that the SNP locus rs25352629 of ITIH3 is a susceptibility variable for autism | (67) |
| ITIH3 | Intrahepatic cholestasis in pregnancy: diagnostic indicators | For the diagnosis of intrahepatic cholestasis in pregnancy, the AUC of ITIH3 was 0.8163 | (68) |
| ITIH3 | Strongly correlated with a history of attempted suicide in bipolar illness and schizophrenia cases | After multiple testing was taken into account, there was a substantial correlation found between the risk allele for the SNP locus rs2239547 of ITIH3 and a history of suicide attempts | (14) |
| ITIH3 | Strongly correlated with the likelihood of getting schizophrenia | The ITIH3 SNP locus rs3617 may impact neurodevelopment and protein function, raising the risk of schizophrenia | (69) |
| ITIH3 | Potentially forecast ovarian cancer’s susceptibility to cisplatin | Platinum resistance and a poor prognosis are strongly correlated with low expression of ITIH3 protein in ovarian cancer tissues | (70) |
| ITIH3 | Unknown hereditary susceptibility to myocardial infarction | In human atherosclerotic lesions, macrophages and vascular smooth muscle cells express the ITIH3 protein | (71) |
| ITIH3 | It is a helpful biomarker for gastric cancer early detection Assesses the likelihood of gastric cancer |
According to ROC, ITIH3 has a maximum sensitivity of 96% and a maximum specificity of 66% in the identification of gastric cancer. Furthermore, patients with early gastric cancer had considerably greater plasma levels of ITIH3 than non-cancerous patients (p < 0.001) | (72, 73) |
| ITIH3 | Might not be adequate as a potent biomarker for early gastric cancer detection | Between early and advanced gastric cancer, there was no difference in expression; the AUC value was 0.65 (95% CI: 0.55–0.75) | (74) |
| ITIH3 | Enhances acute and chronic heart failure and hypertrophic cardiomyopathy. Treatment with biomarker candidate | Proteomic analysis was used to identify putative core biomarkers | (75) |
| ITIH3 | A biomarker for the detection of pancreatic cancer | In comparison to controls, expression in pancreatic cancer was 1.80 times greater | (76) |
| ITIH3 | It is a biomarker for the early detection of rheumatoid arthritis | Utilizing innovative diagnostic techniques, rheumatoid arthritis diagnosis approaches 100% sensitivity and specificity | (77) |
| ITIH3 | Contributes to the development of synovial joint disease | Significant elevation of ITIH3 in synovial joint diseases | (78) |
Functions and potential mechanisms of ITIH3.
Table 4
| Functions | Mechanisms | References | |
|---|---|---|---|
| ITIH4 | Pro-inflammatory reaction | Activation of the PGK1-ITIH4 axis causes a pro-inflammatory response | (79) |
| ITIH4 | Cholestatic liver disease biomarkers | Cholestatic liver dysfunction was associated with considerably higher plasma ITIH4 values | (80) |
| ITIH4 | Biomarkers that show how NAFLD progresses and how hepatocellular carcinoma develops as a result | Compared to patients with simple steatosis and virus-associated hepatocellular carcinoma, patients with hepatocellular carcinoma-NAFLD had considerably higher serum ITIH4 levels Following hepatectomy, patients with hepatocellular carcinoma-NAFLD who had greater serum ITIH4 levels had a worse prognosis |
(81) |
| ITIH4 | A possible therapeutic target to prevent the spread of tumors | HuH7 cell movement was markedly reduced by ITIH4 overexpression and increased by ITIH4 knockdown, respectively. Patients with hepatocellular carcinoma who had a good prognosis had tumor tissues with higher levels of ITIH4 expression than those who had a bad prognosis | (82) |
| ITIH4 | Distinguishes multisystemic and unisystemic histiocytosis of Langerhans cells | Significant variations in ITIH4 expression were found between the two illness groups by peptideomics analysis | (83) |
| ITIH4 | Participated in repeated abortions | The activation of the IL-6 signaling pathway by ITIH4(ΔN688) promotes inflammatory responses The long isoforms of ITIH4 have different functions in controlling cell invasion, migration, proliferation, and inflammatory responses |
(84) |
| ITIH4 | Beneficial for anticipating and monitoring sepsis | The expression of ITIH4 varies with the stage of sepsis | (85) |
| ITIH4 | Possible prognostic biomarker for psoriasis patients’ liver fibrosis brought on by methotrexate | Patients with psoriasis who had liver fibrosis brought on by methotrexate had abnormally high levels of it in their urine | (86) |
| ITIH4 | Early gastric cancer biomarkers | When compared to patients receiving will-care controls, patients with early gastric cancer had noticeably higher serum levels of ITIH ITIH4 expression increased during Helicobacter pylori infection |
(87, 88) |
| ITIH4 | Biomarkers for ovarian cancer | Patients with ovarian cancer had far lower ITIH4 expression levels in their urine than did controls | (89) |
| ITIH4 | Evaluation of the diagnostic and prognostic importance in individuals with hepatitis B-associated hepatocellular carcinoma and liver cirrhosis caused by the virus | Patients diagnosed with hepatocellular carcinoma had lower serum ITIH4 levels, and those with hepatitis B-associated hepatocellular carcinoma also had shorter survival times | (90) |
| ITIH4 | Associated with autoimmune disease | Prevention of neutrophil recruitment in order to reduce inflammatory autoimmunity | (91) |
| ITIH4 | Prognostic markers for aneurysmal subarachnoid hemorrhage in humans (ASAH) |
|
(92) |
| ITIH4 | Prostate cancer and prostatic hyperplasia identification | Patients with prostate cancer had considerably higher ITIH4 protein levels | (93) |
| ITIH4 | Ischemic acute stroke biomarkers | As the acute ischemic stroke condition progressed, ITIH4 eventually returned to normal | (94) |
| ITIH4 | Preventing the growth of melanoma | A finding not further explained in the text | (95) |
| ITIH4 | Monitoring of patients with postoperative breast cancer | ITH4 was substantially lower in postoperative breast cancer patients than in controls | (96) |
| ITIH4 | Accurately forecasting hyperlipidemia | C/T polymorphism of single nucleotides at IVS17 + 8 of ITIH4. Ninety percent of those missing the T allele went on to develop hypercholesterolemia. Of those with the T allele, only 10% experienced hypercholesterolemia (p < 0.0001) | (97) |
| ITIH4 | Potential Alzheimer’s disease serum biomarkers | Increased intact size of ITIH4 protein and decreased fragmentation of ITIH4; increased ITIH4 expression | (51, 52) |
| ITIH4 | Interstitial cystitis biomarkers | ITIH4 plasma concentrations were greater in the patients (p = 0.019) | (98) |
Functions and potential mechanisms of ITIH4.
Table 5
| Functions | Mechanisms | References | |
|---|---|---|---|
| ITIH5 | Indicator biomarkers for bile duct cancer diagnostics | In comparison to the control group, which included people with hepatocellular carcinoma, benign illness, chronic hepatitis B, and healthy persons, the cholangiocarcinoma group had greater serum ITIH5 levels. The AUC for ITIH5 varied between 0.839 and 0.851, indicating a significant difference between bile duct cancer and the control group | (99) |
| ITIH5 | Prevention of the development of pancreatic cancer | Prevention of the spread of pancreatic cancer | (100) |
| ITIH5 | Prevention of the development of bladder cancer | Overexpression of ITIH5 in bladder cancer cells prevented colony spreading and cell migration | (101) |
| ITIH5 | Prevention of the spread of breast cancer | ITIH5-overexpressing breast cancer cells nearly totally failed to develop lung metastasis in a mouse metastasis model | (102) |
| ITIH5 | Stops the spread of cervical cancer | Reduced the growth and invasiveness of tumor spheres to a large degree, which increased the rate of death in cervical cancer cells | (103) |
| ITIH5 | Adipokine released by adipocytes | By comparing gene expression in subcutaneous and visceral fat microarray investigations in obese and lean subjects, ITIH5 was discovered as a novel adipokine | (104) |
| ITIH5 | Involved in wound healing | The transformation of fibroblasts into myofibroblasts, which is dependent on growth factor β1, requires the interaction of ITIH5 with cell surface HA | (105) |
| ITIH5 | Involved in breast cancer development | Breast cancers exhibit a marked downregulation of ITIH5 expression. While ITIH5 expression is either consistently missing or significantly downregulated in invasive ductal carcinomas, normal breast epithelial cells express ITIH5 substantially. Both benign breast cell lines and breast cancer cell lines did not exhibit ITIH5 gene expression. Breast cancer development may be linked to the lack of ITIH5 expression | (106) |
| ITIH5 | Prevention of the development of cervical cancer | ITIH5 overexpression resulted in a marked decrease in cell migration and clone formation as well as a considerable inhibition of cervical cancer cell proliferation | (107) |
| ITIH5 | Prevents the growth of colon cancer cell | Colon cancer cells were unable to proliferate when ITIH5 was overexpressed | (108) |
| ITIH5 | Prevention of the development of pancreatic cancer | ITIH5 may obstruct many oncogenic signaling pathways, including as the PI3K/AKT pathway. Changes in cell migration and the creation of local adhesions may result from this. These alterations in the cells could be connected to ITIH5’s ability to prevent metastasis in pancreatic cancer | (109) |
| ITIH5 | Prevention of the development of non-small cell lung cancer | Lower expression of ITIH5 is linked to a worse prognosis in non-small cell lung cancer | (110) |
| ITIH5 | Responsible for the emergence of clinical metabolic abnormalities and obesity | Obese people express ITIH5 more than lean people do, and dieting-induced weight loss reduces ITIH5 expression | (111) |
| ITIH5 | Contribute to the pathophysiology of congenital megacolon | Elevated ITIH5 expression prevents cell migration and proliferation | (112) |
Functions and potential mechanisms of ITIH5.
The ITIH family has five homologous variants that are encoded by various genes. Through an overview of current research pertaining to the ITIH family, we discovered that ITIH plays a role in numerous pathophysiological mechanisms. These comprise immunological responses, tumor growth, psychological issues, and inflammation. These protein families play a role in the modification of extracellular structures necessary for cell migration and the growth of malignant tumors. ITIH family has intricate functions. Various disease processes may involve distinct heavy chain proteins. Different diseases may involve the same heavy chain protein. This implies that ITIH family may not be as accurate a diagnostic or prognostic marker for some disorders. Large-scale multicenter clinical trials are required in the future to assess if ITIH family may be used as a prognostic or diagnostic biomarker for specific illnesses. Despite the fact that numerous studies have demonstrated that the ITIH family prevents the growth of different types of solid tumors. The ITIH family is a putative oncogene, but further investigation and analysis are required, and it’s still unclear how it works.
5 Summary
To jointly preserve the stability of the ECM, members of the IαI family bind covalently to HA. Hence the characteristics play a role in several physiological and pathological processes. The IαI family contains the protein BK, which is important for mammalian ovulation and human cancer. It is also an anti-invasive protein. The ITIH family is important for inflammation, immunity, psychiatric disorders, tumorigenesis, and development. Although BK has been extensively researched, its exact mechanism of action in the pathophysiological processes involving the ITIH family is still unclear. In order to examine the possible mechanisms and offer a theoretical foundation for targeted therapy of the associated disorders, a significant amount of research is required going forward. In addition, existing studies have shown that BK and ITIH family have been found to play a role in both inflammation and tumors, but whether there is an interaction between the two remains unclear.
Statements
Author contributions
X-fZ: Investigation, Writing – original draft, Data curation. X-lZ: Writing – original draft, Data curation, Investigation. LG: Writing – original draft. Y-pB: Writing – original draft. YT: Supervision, Writing – review & editing. H-yL: Supervision, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. Related research was funded by Huang Changming Expert Workstation in Yunnan Province (202105AF150040).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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Summary
Keywords
inter-α-trypsin inhibitor (IαI) family, bikunin (BK), ITIHs, hyaluronic acid (HA), extracellular matrix (ECM)
Citation
Zhang X-f, Zhang X-l, Guo L, Bai Y-p, Tian Y and Luo H-y (2024) The function of the inter-alpha-trypsin inhibitors in the development of disease. Front. Med. 11:1432224. doi: 10.3389/fmed.2024.1432224
Received
13 May 2024
Accepted
15 July 2024
Published
01 August 2024
Volume
11 - 2024
Edited by
Ian James Martins, University of Western Australia, Australia
Reviewed by
Xiaolei Li, University of Pennsylvania, United States
Xianfang Rong, IMiracle, China
Updates
Copyright
© 2024 Zhang, Zhang, Guo, Bai, Tian and Luo.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yan Tian, 905790434@qq.comHua-you Luo, km-lhy@qq.com
†These authors have contributed equally to this work and share first authorship
Disclaimer
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