MiR-1290: a potential therapeutic target for regenerative medicine or diagnosis and treatment of non-malignant diseases

MicroRNAs are a set of small non-coding RNAs that could change gene expression with post-transcriptional regulation. MiRNAs have a significant role in regulating molecular signaling pathways and innate and adaptive immune system activity. Moreover, miRNAs can be utilized as a powerful instrument for tissue engineers and regenerative medicine by altering the expression of genes and growth factors. MiR-1290, which was first discovered in human embryonic stem cells, is one of those miRNAs that play an essential role in developing the fetal nervous system. This review aims to discuss current findings on miR-1290 in different human pathologies and determine whether manipulation of miR-1290 could be considered a possible therapeutic strategy to treat different non-malignant diseases. The results of these studies suggest that the regulation of miR-1290 may be helpful in the treatment of some bacterial (leprosy) and viral infections (HIV, influenza A, and Borna disease virus). Also, adjusting the expression of miR-1290 in non-infectious diseases such as celiac disease, necrotizing enterocolitis, polycystic ovary syndrome, pulmonary fibrosis, ankylosing spondylitis, muscle atrophy, sarcopenia, and ischemic heart disease can help to treat these diseases better. In addition to acting as a biomarker for the diagnosis of non-malignant diseases (such as NAFLD, fetal growth, preeclampsia, down syndrome, chronic rhinosinusitis, and oral lichen planus), the miR-1290 can also be used as a valuable instrument in tissue engineering and reconstructive medicine. Consequently, it is suggested that the regulation of miR-1290 could be considered a possible therapeutic target in the treatment of non-malignant diseases in the future.


Introduction
MicroRNAs (miRNAs) are a group of small non-coding RNAs (∼21 nucleotides) that could regulate post-transcriptionally gene expression by degrading mRNAs or inhibiting their translation. MiRNAs have a significant effect on regulating molecular signaling pathways so that disorder in miR-NAs expression can lead to the progression and development of malignant and non-malignant diseases [1,2]. Moreover, the expression of miRNAs plays an essential role in regulating innate and adaptive immune system activity [3,4].
Differentiation of stem cells (totipotent, pluripotent, multipotent, oligopotent) into a specific cell type depends on overexpression of particular genes and decreasing or inhibition of non-specific genes. For example, gene delivery of RUNX2 and BMP-2 or TGF-β3 and SOX9 plays an essential role in differentiating mesenchymal stem cells into bone or cartilage [5]. MiRNAs can be considered a potent target for cell differentiation and tissue engineers [5]. Induced pluripotent stem cells (iPS) can differentiate into almost any cell type. Previous studies have shown that the miR-302/367 cluster can reprogram somatic cells directly into iPS cells. In contrast, miR-449a and miR-211, by downregulating their target genes, can stimulate osteoblast differentiation from iPS cells [6]. Dicer-null mice studies have shown that the absence of endogenous 1 3 miRNA processing could be responsible for the premature death of mutated embryos. Moreover, embryonic stem cells lacking Dicer are unable to differentiate [7]. In addition, miRNAs (such as miR-290-295-17-92-106a-363) play an essential role in the cell cycle regulation of pluripotent stem cells by inhibiting the expression of cyclin E, cyclin D, PTEN, p53, p21, and RB genes [8].
Exosomes are vesicles secreted into the extracellular environment by almost all mammalian cells for cellular communication via protein and RNA delivery [9]. Valadi et al. for the first time demonstrated that cells could secrete miRNAs via exosomes [10]. Moreover, Lawrie et al. found that circulating miRNAs could be used as a diagnostic biomarker for diffuse large B-cell lymphoma patients [11]. Therefore, circulating miRNAs and exosomal miRNAs (such as miR-1290) can be used as potential biomarkers for the prognosis and diagnosis of various diseases [12].
Our previous study shows that miR-1290 is overexpressed in numerous cancers such as colorectal, breast, stomach, esophageal squamous cell carcinoma, pancreatic, and lung cancer [2]. Moreover, the serum level measurement of miR-1290 can be employed for the early detection of various cancers [2]. According to the literature, no review article has been published yet about the function of miR-1290 in non-malignant diseases. In a systematic study, we focused on the importance of miR-1290 expression in normal physiological conditions and non-malignant diseases. Therefore, this present study aimed to determine whether the expression of miR-1290 is vital for preserving human health to be employed for gene therapy or tissue engineering and can also be used as a biomarker for diagnosing non-malignant diseases.

Methodology for search and selection of the literature
A systematic search was accomplished in electronic databases such as PubMed, Scopus, Cochrane Library, and Science Direct to identify published original articles regarding miR-1290 by following keywords: (microRNA-1290 OR miRNA-1290 OR miR-1290) based on ʺtitle and abstract.ʺ All articles from 1993 to 15 January 2022 were evaluated. To categorize related articles, the two authors screened the search results individually, including 1,241 articles. Finally, 42 original research articles regarding the potential function of miR-1290 in the development, diagnosis, or treatment of non-malignant diseases in humans were selected and entered into this study (Fig. 1). Articles that studied the function of miR-1290 in human cancer were excluded. Furthermore, review articles, letters to the editor, case reports, non-English language, and brief communication articles were excluded [13]. Additional points regarding the literature search procedure and choosing appropriate articles are displayed in Figs. 1 and 2.

Biogenesis of miR-1290
Based on the NCBI database, hsa-miR-1290 is located in the first intron of the aldehyde dehydrogenase 4 family member A1 (ALDH4A1) gene, which is discovered on the negative strand of chromosome 1 (1p36.13) [14]. This miRNA was first found in human embryonic stem cells, which plays an essential role in developing the fetal nervous system [15]. Since miR-1290 is located in the intronic region of the ALDH4A1 gene, it is classified as a mirtron. Mirtrons are non-canonical miRNAs that originate from intronic regions. The molecular mechanisms involved in the processed of Mirtrons are Drosha-independent and splicing-dependent [16]. After transcription of the ALDH4A1gene by RNA polymerase, introns are removed by the spliceosome, and a mirtron lariat is formed during this splicing process. DBR1, a lariat debranching enzyme, then converts the mirtron lariat into a pre-miRNA which subsequently enters the canonical biogenesis pathways involving Exportin-5, RanGTP, and Dicer to generate a mature miRNA [17,18]. Finally, the mature miRNA mediates gene silencing by promoting target mRNA degradation and repressing translation through association with Argonaute proteins (miRISCs) [19]. The amount of complement between mature miR-1290 (UGG AUU UUU GGA UCA GGG A) and 3'UTR of the target gene determines the fate of the target mRNA [20]. Figure 3 schematically displays the above steps.

Role of miR-1290 in human viral and bacterial infections
MiRNAs (viral and host miRNAs) play a significant role in the pathogenesis and development of viral and bacterial infections. The first viral miRNAs were detected in the Epstein-Barr virus (EBV). By producing at least 44 miRNAs, this virus can inhibit apoptosis and hide infected cells from host immune responses [21]. KSHV miR-K12-7 and miR-K12-3 induce the expression of IL-6 and IL-10 in human myelomonocyte cell lines by inhibiting an isoform of the transcription factor C/EBPβ from helping KSHV escape from the immune system [22]. Major histocompatibility complex class I-related chain B (MICB) gene is a critical gene for the virus-infected cells killing depended on the NK cell. Human cytomegalovirus-encoded miR-UL112 by downregulation MICB contributes to reduced killing by NK cells [23].
Host miRNAs are classified into antiviral or proviral according to their role and function. Hence, antiviral miR-NAs exert their antiviral function via reducing viral RNA production, suppressing viral proteins, preventing virus replication, or causing the virus to enter the latency stage. In contrast, proviral miRNAs help the virus escape the host immune response by suppressing antiviral interferons (IFN) [24]. In return, some viruses modulate the host's signaling pathways and innate immune system with their miRNAs to provide suitable conditions for their replication and survival [25]. The first miRNA-based antiviral therapy was published in 2014 by Gebert and colleagues. They used miravirsen (SPC3649) in a second-phase clinical trial as a miR-122 inhibitor. Indeed, through hybridizing to mature miR-122, miravirsen prevents the interaction of miR-122 with HCV RNA and can help better treat chronic hepatitis C infection [26].
Acquired immunodeficiency syndrome (AIDS) is an immunodeficiency disease caused by a virus of the lentivirus family called human immunodeficiency virus (HIV). By inserting its genome into human chromosomes, HIV-1 can remain dormant in latently infected cells for years to escape from viral treatment and increase the viral load when discontinuing the antiviral drugs [27]. The results of previous studies suggest that many human cellular miRNAs can modulate HIV-1 expression by targeting host gene transcripts or viral RNAs [28]. One of the miRNAs that increased in HIV-1latently infected cells compared to productively infected cells is miR-1290. Studies by Wang et al. showed that miR-1290 has two target sites in 3' UTR of HIV-1 and that upregulation has a suppressing effect on infectivity and viral production via downregulation expression of HIV-1 RNA. They also found that blocking miR-1290 with anti-miR could reduce the HIV-1 latency in T cells (HLA-DR − CD4 + ) directly isolated from HIV-1-infected individuals and increase the production and infectivity of the HIV-1 [29]. Therefore, simultaneous use of miR-1290 inhibitor with antiretroviral drugs can lead to more satisfactory therapeutic results by reducing latent HIV-1.
Influenza A virus (IAV) is a pathogenic respiratory virus belonging to the Orthomyxoviridae family, whose genome is a negative single-stranded RNA with a negative polarity enclosed in an envelope. Infection with the virus causes cough, fever, fatigue, headache, sore throat, and runny nose, sometimes leading to death in people with underlying diseases or old age [30]. Recently, it has been reported in many studies that IAV infection alters the expression profile of some host miRNAs, which target its viral genome. Here, it suggests the role of miRNAs in the influenza virus infection process [31]. MiR-1290 is one of the miRNAs involved in the influenza virus replication cycle. High-throughput sequencing and microarray analyses of mRNA and miRNA expression profiling in A549 cells contaminated by avianorigin influenza A virus H3N2 (AVI_9990), swine-origin influenza A virus H1N1 (SW_3861), and human-origin seasonal influenza A virus H3N2 (Human_Br07) reveal IAV infection increased the expression of miR-1290 to decreased its target gene, including NDRG1, TFRC, EGLN3, and FGA [32]. Influenza A virus ribonucleoproteins (vRNPs) consist of eight genomic RNAs, and each of the RNAs binds to several viral nucleoproteins. The influenza virus's life cycle depends on vRNPs that bind to RNA-dependent RNA polymerase (RdRp) and facilitate transcription and replication of the viral genome [33]. Studies by Huang et al. showed that IAV could upregulate miR-1290 through the extracellular signal-regulated kinase (ERK) pathway. Thereby miR-1290 enhances viral replication and viral polymerase activity by targeting and reducing the expression of the host vimentin gene and retaining vRNPs in the cell nucleus. Moreover, suppressing miR-1290 by an antagonist (LNA-1290) could significantly reduce IAV viral titers in the armored animal model and human cells [34]. Also, dysregulation of miRNAs has been identified in neurological disorders and neurodegenerative diseases. Borna disease virus (BDV) is a group of single-stranded RNA viruses belonging to the Bornaviridae family in Mononegavirales, inducing human neuropsychiatric disease and mental disorders [35]. Investigating miRNAs expression in human oligodendrocytes infected with the BDV strain (Hu-H1) reveals that miR-1290 and six other miRNAs are out of control, so miR-1290 is significantly downregulated [36].
Leprosy, also known as Hansen's disease, is a chronic infectious disease caused by Mycobacterium leprae that damages the peripheral nerves and can affect the eyes, skin, muscles, and nose [37]. Leprosy is another contagious disease that has an adverse effect on miR-1290 expression. Soares et al. has done a study to identify miRNAs that might play an essential role in the molecular pathogenesis of leprosy. Analyzing the expression differences of miR-NAs in sixty-seven samples of leprosy lesions compared with nine skin samples from healthy individuals showed that miR-1290 decreased up to 6.4-fold in leprosy lesions while expressing seven (miR-142-3p, miR-142-5p, miR-146b-5p, miR-342-3p, miR-361-3p, miR-3653, and miR-484) other miRNAs has increased. These miRNAs may play an essential role in regulating the immune system, and their dysregulation can change the pathogenesis of leprosy [38]. Therefore, finding dysregulated miRNAs and related signaling pathways can be used as identification tools or therapeutic markers to develop drug therapies to treat leprosy.

Role of miR-1290 in cellular differentiation
Mesenchymal stem cells (MSCs) are a group of pluripotent cells that exit in multiple tissues such as fat tissue, umbilical cord, and bone marrow. They can differentiate from various mesodermal origin tissues, including connective tissue, cartilage, and bone. Previously, transcription factors have been identified as the main factor regulating cell differentiation. However, recent studies have revealed that miRNAs also play a vital role in cell differentiation due to their ability in alter gene expression [39,40]. Indeed, miR-1290 is one of the miRNAs specifically overexpressed during human mesenchymal stem cells (hMSCs) differentiation into hepatocytes, and downregulation of miR-1290 can inhibit HGF-induced hepatic differentiation. As a result, overexpression of miR-1290 not only induces hepatocyte properties in hMSCs but also transforms hMSCs cells into mature functional hepatocytes [41]. Moreover, miR-1290 is needed for developing and maintaining neurons, and its expression plays a vital role in regulating the differentiation and proliferation of nerve cells during neurogenesis. Upregulation of miR-1290 in undifferentiated immature neurons (progenitor cells) slows the cell cycle to induce neuronal differentiation; in contrast, the knockdown of miR-1290 in (differentiated) mature neurons induced cell proliferation and subsequently cell death [42]. The study of Zhuang et al. on MSCs isolated from the Wharton's jelly of the human umbilical cord showed that during the differentiation of MSCs into neuron-like cells, the expression of miR-1290 increased up to eightfold [43]. Also, Moore et al. demonstrate that the expression of miR-1290 is an essential factor in controlling neuronal differentiation during initial brain development and is significantly downregulated in idiopathic autism spectrum disorder-derived neural stem cells [44].
Stroke is a severe and deadly complication that occurs due to the oxygen and nutrient deprivation in brain cells after ischemia, leading to necrotic and apoptotic neuronal cell death. Therefore, protective and regeneration therapies of nerve cells are urgently required [45]. A previous study showed that human umbilical vein endothelial cell-derived exosomes could promote proliferation, regeneration, and suppress apoptosis of neural stem cells in mice; therefore, endothelial cells could participate in the post-injury neural regeneration of the stroke [46]. A study of extracellular vesicles derived from human umbilical cord endothelial cells (HUVEC) effect on oxygen-glucose-deprived neurons showed that HUVECs could reduce apoptosis in these neurons. Further studies revealed that the reduction in apoptosis rate was due to the overexpression of miR-1290 in HUVECderived extracellular vesicles (EVs). [47].
Achieving the ability to regenerate cartilage using mesenchymal stem cells can play an essential role in treating arthritis. Comparison of miRNA expression among exosomes from human bone mesenchymal stem cells (hBMSCs) with and without chondrogenic differentiation induction showed that miR-1290 and 34 other miRNAs were increased in chondrogenic induced cells. Overexpression of these miRNAs promotes chondrocyte migration and proliferation and increases chondrogenesis formation of hBMSCs. This finding suggests these miRNAs, including miR-1290, may play a crucial role in differentiating hBMSCs into cartilage [48]. Sarcopenia is a common skeletal disease that loses skeletal muscle mass and function and is related to myogenic disorders and muscle atrophy [49]. Investigating the serum expression level of miR-1290 in muscle atrophy patients showed miR-1290 was downregulated, and a reverse association was also discovered between the severity of muscle atrophy and expression of miR-1290. In vitro and in vivo studies revealed overexpression of miR-1290 could inhibit myotube atrophy and enhance myoblast differentiation via decreasing the protein levels of atrogin-1 and MuRF1. Indeed, the function of miR-1290 in myoblast differentiation, controlling myogenesis and myotube atrophy, is via the regulation Akt/p70/FoxO3 pathway [50]. According to previous findings (Fig. 4), the use of miR-1290 in tissue engineering may play a critical role in treating various diseases based on tissue regeneration.

The potential of miR-1290 as a novel diagnostic biomarker for non-malignant disease distinguishing
Exosomes are small vesicles secreted by cells in the extracellular environment to facilitate intercellular communication and the transmission of biological information [9]. MiR-NAs could be secreted as exosomal miRNAs to control the expression of genes in distant cells [10]. Although the analysis of the expression of blood-based miRNAs is not as valid and reliable as that of tissue-based miRNAs, blood-based miRNAs can be operated as a sensitive and non-invasive method for screening and early detection of diseases [51]. Therefore, based on the results of previous studies, exosomal and circulating miRNAs can be used as a prospective biomarker for the diagnosis of different diseases [12]. An overview of the possible uses of miR-1290 as a biomarker in diagnosing various non-malignant diseases is presented in Table 1.
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by the abnormal accumulation of fat, especially triglycerides, in the liver [1]. Lack of proper NAFLD treatment develops into serious liver diseases, including non-alcoholic steatohepatitis (NASH), cirrhosis, and liver carcinoma. Current studies have shown that changes in microRNA expression play an essential role in the occurrence and development of NAFLD [1]. Comparison of serum miRNA expression profile in samples of NAFLD patients with healthy individuals showed that a miRNA panel consisting of miR-1290 and several other miRNAs could detect NAFLD. In addition, the results revealed that the expression of miR-1290 in NAFLD patients increased up to fourfold, and ROC analysis showed that this panel of miR-NAs was more sensitive and specific than FIB-4 and ALT for the diagnosis of NAFLD [52]. For further investigation, Di Mauro et al. decided to create NASH and NAFLD model cells using the treatment of HepG2 cells with Palmitate and Oleate-Palmitate, respectively. The differentially expressed (DE) study of intracellular and extracellular miRNAs in the context of in vitro model of NAFLD (up to fivefold) and NASH (up to 20-fold) showed expression of miR-1290 increased in the context of cells, and this upregulation was higher in the NASH model [53].
Polycystic ovary syndrome (PCOS) is a common disease in women characterized by polycystic ovarian morphology, ovulatory dysfunction, and hyperandrogenism. Women with polycystic PCOS are at risk for several diseases, including infertility, endometrial cancer, and metabolic disorders (such as insulin resistance and compensatory hyperinsulinemia) [69]. Sorensen et al. tried to find miRNAs that could be used to detect metabolic syndrome and hyperandrogenism in women with PCOS. The results reveal that PCOS women with hyperandrogenic were more insulin resistant than PCOS women with normal androgenic, and PCOS women with hyperandrogenic had a higher prevalence of metabolic syndrome [54]. Also, differentially expressed serum micro-RNAs showed that miR-1290 is one of the miRNAs that is increased in PCOS women compared to the control group. Moreover, miR-1290 expression is also associated with hyperandrogenism, metabolic syndrome, and an increased risk of developing polycystic ovary syndrome [54].
Endometrial receptivity is the primary step in the normal physiological state of the uterus for embryo implantation. Several factors, including hormones, anatomical compatibility, and miRNA expression, play an essential role in regulating endometrial acceptance [70]. The interaction between the uterus and the embryo is vital for the successful implantation and development of the embryo during pregnancy. Endometrial tissue biopsy in cows before implantation of embryos at days 3 and 7 of the estrous cycle (similar to the human menstrual cycle) showed that the expression of several miRNAs changed during this period so that the expression of miR-1290 increased up to tenfold on day 7 of the estrous cycle under normal conditions [71]. Therefore, more studies are needed on human samples to determine whether the expression of miR-1290 is important for embryo implantation and normal pregnancy. Given these ambiguities, Shi et al. investigated how exosomal miRNAs derived from placental trophoblast cells by promoting the EMT and angiogenesis in the endometrial epithelial cells could manage the interaction between endometrium and embryo toward successful embryo implantation. Their results showed that miR-1290 is one of the most enriched miRNAs in these exosomes. MiR-1290 can increase EMT and migration via of LHX6 (as a specific target gene), E-cadherin, and upregulation of Fibronectin, Vimentin, Zeb1, and Zeb2. Furthermore, although angiogenesis is a multifactorial process, the results of this study confirmed that miR-1290 could increase angiogenesis [72].
During pregnancy, the number of EVs in the bloodstream of pregnant mothers increases significantly compared to nonpregnant women so that their contents can affect the growth rate of the fetus [73]. Analyzing the relationship between fetal growth and exomiRNAs circulating in the mother's blood in the second trimester showed that exomiRNA levels in mothers with large-for-gestational fetuses were higher than mothers with appropriate-for-gestational age infants. In contrast, exomiRNA levels in mothers with small-for-gestational fetuses were lower than in infants with appropriatefor-gestational age. Moreover, the low expression level of miR-1290 in the second-trimester mother's blood was associated with lower birth weight for gestational age z-score [55]. Nevertheless, a study by Rahman et al. on placentaderived miRNAs in Bangladesh pregnant women showed a significant relationship between miR-1290 expression and birth weight through its effect on gestational age. Due to a binding site for miR-1290 in the MT1G, NAT-1, CYP4F11, MT1H genes, this miRNA can reduce their expression. Also, the expression of miR-1290 in the placenta is associated with birth weight and a shortage of gestational age [56]. One of the particular disorders of pregnancy is preeclampsia (PE), which is associated with proteinuria and high blood pressure. Therefore, early prediction and accurate diagnosis using reliable biomarkers are fundamental for precise disease management [74]. Studies on serum samples of patients with PE showed that the expression of several miRNAs, including miR-31-5p, miR-155-5p, miR-214-3p, and miR-1290-3p, was altered compared to healthy pregnant women. This study indicated a strong correlation between the downregulation of miR-1290-3p and upregulation of other miRNAs (miR-31-5p, miR-155-5p, miR-214-3p) with clinical symptoms such as hypertension and proteinuria. Analysis of the ROC curve using the ratios of miR-214-3p, miR-155-5p, and miR-31-5p to miR-1290-3p shows that this panel has more than 95% accuracy for PE distinguishing, and miR-1290 has 94.57% sensitivity and 84.78% specificity for PE [57].
Down syndrome (DS) is a congenital chromosomal abnormality caused by an extra copy of chromosome 21 (47xy or 47xx) or by a partial duplication (q21) of chromosome 21, in which mental retardation is one of its complications [75]. The study of miRNA expression levels in the plasma of pregnant women with DS fetuses led to designing a panel of miRNA as a non-invasive method for early detection of DS. In their study, Kretowska et al. found that in the plasma samples of women with fetal DS, seven miRNA decreased and six miRNA increased. Evaluation of miR-1290 expression indicated that it decreased up to -1.8-fold compared to pregnant women with healthy fetuses [58]. Given that miR-1290 expression plays an essential role in neuronal cell differentiation, it is likely that one of the reasons for mental retardation in people with DS is decreased miR-1290 expression during their fetal period.
Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinonasal mucosa and paranasal sinuses. CRS, based on the absence or presence of nasal polyps, is classified into two different phenotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP) [76]. Expression profiling analysis of miRNAs in adult dendritic cells differentiated from monocytes (CD141 +) of CRS patients showed miR-1290 was upregulated in both atopic CRSwNP and non-atopic CRSwNP but downregulated in CRSsNP [60]. In this regard, Cha et al. investigated the expression of miRNAs in extracellular vesicles (EVs) obtained from nasal lavage fluid (NLF) in patients with chronic rhinosinusitis. Their results showed that the expression of EV miRNA in CRSwNP was different from CRSsNP. Moreover, miR-1290 and seven other miR-NAs in the NLF-EVs of CRSwNP patients increased more than twofold compared with CRSsNP patients. Given that these miRNAs can regulate mucin-type O-glycan biosynthesis and the TGF beta signaling pathway, they may play an essential role in advancing CRS and aggravating CRSwNP [59].
Necrotizing enterocolitis (NEC) is a disease that is mainly seen in premature infants. In addition to very high mortality, cholestasis, intestinal strictures and adhesions, stunted growth, short bowel syndrome, and delayed neural development are among its long-term complications [77]. Although not much progress has been made in NEC treatment, the study of pathophysiology and its early detection using predictive biomarkers can improve individual prevention and treatment strategies. Investigation of molecular networks and comparison of miRNAs expression profiles in the small intestinal tissues of infants with necrotizing enterocolitis indicated an increase in 80 miRNAs and a decrease in the expression of another 27 miRNAs. MiR-1290 is one of the miRNAs whose expression is increased up to 12.88-fold compared to control samples. A comparison of the expression levels of miRNAs and their target genes showed an inverse correlation between the expression of miR-1290 and its target mRNAs, such as THBS1 and FOXA1. However, there is very little knowledge on the possible role of miRNA in NEC by influencing the expression of downstream gene expression and regulatory pathways. MiR-1290 and other miRNAs may play an essential role in modulating the inflammatory response induced by bacterial receptors (TLR4) and hypoxia/oxidative stress [61]. Previous examinations have shown that FOXA1 is involved in gastrointestinal epithelial maintenance, endocrine cell differentiation, ion channel integrity, and Muc2 expression by its transcription factor activity [78,79]. It is prominent that miRNAs released from intestinal tissues into the bloodstream or intestinal tract can be used as biomarkers to detect NEC and intestinal damage early. In a case-control and cohort study, Ng et al. investigated whether circulating miRNAs could distinguish NEC from inflammatory conditions or neonatal sepsis. Their results showed that serum miR-1290 expression in plasma of the NEC group was 6.78-and 17.34-fold higher than the septicemia and non-NEC groups, respectively. Therefore, miR-1290 could act as a valuable diagnostic biomarker for identifying severe and mild cases of surgical NEC [62].
Delayed cerebral infarction (DCI) is a complication of days 4 to 7 after aneurysmal subarachnoid hemorrhage (SAH) in up to 44% of SAH patients. Factors such as initial neurological impairment, age, intraventricular hemorrhage, aneurysm size, and SAH load are associated with DCI incidence [80]. A comparison of circulating miRNAs in SAH patients with and without DCI revealed that downregulation of miR-1290, along with three other miRNAs, can differentiate SAH patients with DCI beside an area under the curve (AUC) of 100% (95% CI) from patients without DCI. Interestingly, the miR-1290 with an AUC of 95.3% (95% CI 0.897-1) has 90% specificity and 85% sensitivity for differentiation of SAH patients with DCI from patients without DCI [63].
Celiac disease (CD) is a chronic autoimmune disease. Consumption of gluten in barley, rye, or wheat abnormally activates the immune response to damage small intestinal tissue. Therefore, a lifelong gluten-free diet is a primary treatment [81]. Previous studies have shown that the expression of miRNAs in small intestinal fibroblasts in people with CD is different from the control group [82,83]. A survey of fresh specimens and formalin-fixed endoscopic duodenal biopsies in patients with celiac disease showed that seven miRNAs were out of control, so the expression of miR-1290 was upregulated in the sample of CD patients compared to the control group. Also, treating primary fibroblasts of CD patients with immune gliadin peptides could significantly reduce the miRNAs expression [83]. With this evidence, screening for miRNA expression profiling can help implement patient-appropriate management, thus promising that the overall clinical approach for CD patients will become a personal approach in the future.

Potential of miR-1290 regulation for diseases therapy
Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints (SIJs), the spine joints, and the tendons and ligaments adjacent to them, the progression of which leads to fusion and calcification of the spine [84]. Li et al. reported that the expression level of circ_0056558 in AS tissue was significantly higher than in healthy samples, and hsa_circ_0056558 via suppressing miR-1290 expression could upregulate CDK6 and suppress cell proliferation and differentiation. Additionally, overexpression of hsa_circ_0056558 or CDK6 could enhance protein levels of p-NF-κB, p-AKT, p-IκBα, and p65. At the same time, upregulation of miR-1290 could significantly reverse the effects of hsa_circ_0056558 or CDK6 on protein levels of p-NF-κB, p-AKT, p-IκBα, and p65. Therefore, upregulation of miR-1290 in AS has therapeutic properties and could enhance cell proliferation and differentiation while suppressing apoptosis [85]. Ischemic heart disease, also known as coronary artery disease, is caused by narrowing the arteries. During ischemia, not enough blood and oxygen can reach the heart tissue. As a result, ischemia leads to myocardial infarction (MI) by inducing hypoxia and the death of myocardial cells [86]. The hypoxia-inducible transcription factors 1 and 2 (HIF1/2) play an essential role in the response of cells to hypoxia by regulating the expression of many genes, which protects cells against hypoxia and ischemic damage [87]. In contrast, HIF3A has been shown to play a negative role in adaptability with hypoxia, so its expression inhibition leads to increased cell endurance against ischemia [88]. Wu et al. showed that miR-1290 could be a potential target in preventing ischemia-induced death and reperfusion injury of the myocardial cell line. Moreover, overexpression of miR-1290 in AC16 human myocardial cell line under hypoxic conditions showed miR-1290 via downregulation of HIF3A, and upregulation of HIF1A could decrease hypoxia-induced apoptosis [89].
Although miR-1290 expression can be helpful for several pathologies such as ankylosing spondylitis and myocardial infarction, it is not beneficial in lung cells by inducing fibrosis. Pulmonary fibrosis (PF) is one of the most common chronic lung diseases whose pathological mechanisms are due to an imbalance between proliferation and apoptosis of fibroblasts and impaired accumulation and breakdown of the extracellular matrix (ECM) [90]. Previous studies have indicated that TGF-β1 is related to liver fibrosis via the AKT pathway [91]. Analysis of blood samples from PF patients and TGF-β1-stimulated A549 cells revealed that miR-1290 was upregulated, and its expression was negatively correlated with Napsin A expression. Molecular studies have demonstrated that TGF-β1 significantly increases transcription of miR-1290 through CREB1, so miR-1290 promotes fibrotic changes in A549 cells by inhibiting Napsin A expression [92].

Conclusions and perspectives
Since the discovery of miRNAs in 1993, much research has been done to determine the function of these macromolecules. Our previous study showed that miR-1290 is out of control in many cancers. Its oncogenic role predominates over tumor suppressor function and can be utilized as a clinical biomarker for the early diagnosis of various cancers. Studies on the function of miR-1290 in infectious diseases such as HIV, IAV, BDV, and leprosy suggest that the deregulation of miR-1290 may be helpful in the treatment of these diseases. Also, downregulation of miR-1290 1 3 in non-infection diseases such as celiac, necrotizing enterocolitis NASH, NAFLD, polycystic ovary syndrome, and pulmonary fibrosis and upregulation miR-1290 in ankylosing spondylitis, muscle atrophy, sarcopenia, and ischemic heart disease will help treat patients better (Fig. 5). Moreover, studying the expression level of exosomal miR-1290 can distinguish people with various diseases from healthy individuals (Table1). Therefore, it seems that miR-1290 can be used as a promising biomarker to diagnose nonmalignant diseases. Finally, since miR-1290 can differentiate mesenchymal stem cells into mature cell lines such as hepatocyte and cartilage, it can be used as a powerful tool in tissue engineering and regenerative medicine (Fig. 4).
Undoubtedly, further in vitro and in vivo studies are needed to identify specific binding sites of miR-1290 on target genes and evaluate the molecular mechanisms of miR-1290 in the development or treatment of non-malignant diseases. But in general, changing miR-1290 expression and monitoring the correlation of its expression with patient prognosis can help us achieve better treatment for non-malignant patients. Accordingly, it is suggested that the deregulation of miR-1290 and its combination with drugs could be considered a promising therapeutic target in clinical medicine for the treatment of non-malignant diseases in the future. Also, we suggest long-term studies for clinical follow-up of miR-1290 expression in nonmalignant patients to determine whether miR-1290 can employ as a promising biomarker. Availability of data and materials Not Applicable.

Conflict of interests
The authors have no relevant financial or nonfinancial interests to disclose.
Ethical Approval. This article does not contain any studies with human participants or animals performed by the authors.
Consent for publication Not Applicable.