Association of MicroRNA-146a with Type 1 and 2 Diabetes and their Related Complications

Ghaffari, Mahyar; Razi, Sara; Zalpoor, Hamidreza; Nabi-Afjadi, Mohsen; Mohebichamkhorami, Fariba; Zali, Hakimeh

doi:https://doi.org/10.1155/2023/2587104

Journal of Diabetes Research

On this page

Abstract Introduction Conclusion Abbreviations Conflicts of Interest Authors’ Contributions References Copyright Related Articles

Review Article | Open Access

Volume 2023 | Article ID 2587104 | https://doi.org/10.1155/2023/2587104

Association of MicroRNA-146a with Type 1 and 2 Diabetes and their Related Complications

Mahyar Ghaffari,¹Sara Razi,²Hamidreza Zalpoor,^3,4Mohsen Nabi-Afjadi,⁵Fariba Mohebichamkhorami,⁶and Hakimeh Zali⁶

Academic Editor: Ilaria Campesi

Received18 Jul 2022

Revised17 Jan 2023

Accepted04 Feb 2023

Published03 Mar 2023

Abstract

Most medical investigations have found a reduced blood level of miR-146a in type 2 diabetes (T2D) patients, suggesting an important role for miR-146a (microRNA-146a) in the etiology of diabetes mellitus (DM) and its consequences. Furthermore, injection of miR-146a mimic has been confirmed to alleviate diabetes mellitus in diabetic animal models. In this line, deregulation of miR-146a expression has been linked to the progression of nephropathy, neuropathy, wound healing, olfactory dysfunction, cardiovascular disorders, and retinopathy in diabetic patients. In this review, besides a comprehensive review of the function of miR-146a in DM, we discussed new findings on type 1 (T1MD) and type 2 (T2DM) diabetes mellitus, highlighting the discrepancies between clinical and preclinical investigations and elucidating the biological pathways regulated through miR-146a in DM-affected tissues.

1. Introduction

Diabetes mellitus (DM) is one of the serious persistent concerns confronting healthcare systems across the world [1, 2]. According to the International Diabetes Federation (IDF), this disorder will impact 642 million individuals until 2040 [3]. Diabetes affects 8.8 percent of the adult population globally, pursuant to the IDF. T2DM is the more common type of diabetes; only 10–15 percent of people with diabetes have T1DM [4]. Diabetes is responsible for 6.8 percent of worldwide mortality in the 20–79 age range and is a primary reason for decreased life expectancy [5, 6]. About 10% of diabetic patients have type 1 diabetes (T1D), which is characterized by an uncontrolled and destructive immune response to pancreatic beta cells [7, 8], whereas the remaining DM patients have type 2 diabetes (T2D), whose main risk factors include overweight, insufficient physical activity, and smoking [9, 10]. Numerous clinical studies have shown that lifestyle modifications may successfully prevent the progression of T2D. Genetic variables, on the other hand, have been found to be key regulators of individual vulnerability to T2D development and responsiveness to lifestyle treatments [11]. These findings suggest the need for further study into the molecular roots of diabetes and the identification of additional variables implicated in the disease’s etiology. In this regard, microRNAs (miRNAs) have received a lot of attention recently as unique fine modulators of gene expression [12]. miRNAs attach to the mRNA 3’UTR and inhibit translation or assist mRNA cleavage, suppressing gene expression [13].

Several mRNAs of mammals have been shown to be suppressed by miRNAs, and dozens of such bindings have been identified so far. A large body of evidence suggests that miRNAs play critical roles in human development and illness by fine-tuning gene expression [14]. The importance of miRNAs in regulating immune cell differentiation and function is underscored by the phenotypic disturbances that occur when miRNA expression is altered. Considering the role of miRNAs in modulating immune responses, it is likely that any disruption in the expression of miRNAs contributes to the pathogenesis of autoimmune diseases, chronic inflammation, and malignancies. Currently, dysregulated miRNA expression is associated with several human diseases [15, 16]. MiR-146a has recently been shown to be an important modulator of innate as well as adaptive immune cell differentiation and function. miR146a participates in the regulation of multiple physiological responses by targeting specific messenger RNAs to repress their translation. Also, by acting as a negative regulator of transcription, it plays an important role in inhibiting the escalation of inflammatory responses and maintaining immune homeostasis [17]. In summary, in this review, we aimed to review the potential pathological functions of miR-146a in the pathogenesis of DM and its related complications.

2. Biogenesis of miR-146a

MicroRNA 146a, which is encoded by the MIR146A gene located on chromosome 5q33.3, is a small noncoding RNA [18].

Like the maturation process of other miRNAs, miR-146 has the same standard procedure of miRNA biosynthesis pathways (Figure 1), which begins with transcription of pri-miRNA and is accompanied through its cleavage with the microprocessor complex in the nucleus, including the DGCR8 and Drosha proteins, that results in the generation of a precursor miRNA with 60–70 nucleotides and stem-loop form as pre-miR-146a [19]. Pre-miR-146a molecules are cleaved once more by Dicer after being exported by exportin-5 from the nucleus into the cytosol, leading to the generation of RNA ~22 nucleotide duplexes [20]. TAR-RNA binding protein (TRBP), also termed TARBP2, and then interacts with DICER1. DICER1 is not involved in pre-miRNA maturation, whereas TRBP enhances the precision of DICER1-mediated cleavage of pre-miRNAs in a structure-dependent way and alters the identification of miRNA guide strands by forming iso-miRNAs that are one nucleotide longer than regular miRNAs [21]. Argonaute protein interacts with short duplexes of RNA, creating the backbone of a multi-sub-assemblies complex known as the RNA-induced silencing complex (RISC) and producing single-stranded RNAs, having the ability of mRNA interaction [22]. Interleukin-1 receptor-related kinase 1, tumor necrosis factor transcript, interleukin-1-beta, TNF receptor-related factor 6, and complement factor H are some of the targets of miR-146a [23] (Figure 1).

2.1. miR-146a and Type 1 Diabetes Mellitus (T1DM)

T1DM results from uncontrolled and extended immune responses of immune cells on β-cells, and resultant diabetes progresses due to the gradual loss of insulin-producing cells [24]. MicroRNA 146a is a small noncoding RNA that in humans is encoded by the MIR146A gene, which is located on Chr 5: 160.49–160.49 Mb. MicroRNAs are short noncoding RNAs that are involved in posttranscriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs [25]. miR-146a is a key regulator of inflammatory processes. Expression of miR-146a is altered in target organs of diabetic complications, and deficiency of miR-146a has been implicated in their pathogenesis [26]. In human monocytes, miR-146a, which is encoded by the locus of the LOC285628 gene located on chromosome 5, reacts to lipopolysaccharide (LPS) stimulation, and its activation is reliant on nuclear factor kappa B (NF-κB) [27]. The presumptive function of miR-146a is based on this pathway, in which its upregulation via NF-κB signaling provokes it to direct downregulation of its target genes such as TNF receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1), leading to the dampening or termination of an excess inflammatory response through a negative control feedback loop [28]. The NF-κB response to LPS in monocytes and DCs is a phenotypic and probable pathogenic marker for human T1DM [29]. In T1D animal models, TRAF6 mediated high glucose-induced endothelium damage through NF-κB and AP-1-dependent signaling [30].

Because T1D is frequently associated with other autoimmune diseases (AID), some studies have also been published on the role of epigenetics in autoimmune diseases and T1D extrapancreatic autoimmune disease. For instance, Milluzzo et al. investigated 115 T1D patients that were sporadic cases (S-T1D) and 115 familial cases (F-T1D). The results indicated that the F-T1D group had a higher percentage of AIDs, a significant earlier onset of AIDs at Cox regression analysis, and the highest prevalence of both additional organ-specific antibodies and overt AIDs than the S-T1D group [31]. These observations could be due to the miRNAs as crucial modulators of immune cell functions, thus representing major players in the regulation of immune homeostasis. In particular, miRNAs are associated with many facets of immune responses such as development, activation, and differentiation [32, 33]. To prove this statement, some studies deleted the factor genes associating in miRNAs maturation in immune cells. For example, in a study, Dicer, Drosha, or Argonaute deletion in T cells lead to block interferon-γ (IFN-γ) production [32, 33].

It is also worth noting that miR-146a expression has been linked to elevated levels of glutamic acid decarboxylase antibodies (GADA) and is lowered in peripheral blood mononuclear cells (PBMC) of individuals affected with T1DM. Furthermore, lncRNA SRA was shown to have a role in T1D pathogenesis by inhibiting miR-146b in β-cells and increasing the IRAK1/LDHA/pLDHA signaling pathway, terminating in increased reactive oxygen species (ROS) generation [34]. Liu et al. established that miR-146a may operate as a possible circulating biomarker by demonstrating a decreased expression pattern in the blood of T1DM patients in comparison with normal controls in bioinformatics and clinical analysis [35]. Table 1 summarizes multiple clinical studies about the association of miR-146a with T1D.

The correlation between miR-146a and T1D has recently ended in research concerning its polymorphisms. In this case, case-control research found that the C/G allele for the polymorphism of rs2910164 in miR-146a was linked with protection against T1D [36]. The rs2910164 (G/C) polymorphism is found in the seed sequence of pre-miR-146a [37]. Because miR-146a was reduced, its target genes, such as IRAK-1 and TRAF-6, were less effectively inhibited. This polymorphism, however, was not linked to diabetic retinopathy in T1DM patients [36]. Barutta et al. also discovered a negative and independent correlation between miR-146a-5p and diabetic-related chronic complications, including cardiovascular disorders and diabetic retinopathy, indicating that miR-146a-5p can be potentially considered a biological marker in T1DM complications [26].

2.2. miR-146a and T2DM

In patients with T2D, deregulation of miR-146a has been frequently reported, however, there is conflicting information about the direction of deregulation events (up or down). In this section, we focus on investigating the functional role of miR-146a in T2D, innate immunity, the inflammatory response, viral infection, and human diseases. These studies on the expression pattern of miR-146a in T2DM individuals yielded contradictory findings. Balasubramanyam et al. discovered that individuals with T2D had a two-fold drop in miR-146a levels, leading to dramatically elevated TRAF-6 mRNA expression. The presence of the elevated miR-146a expression in the PBMC of T2D patients suggests that the circulating expression of miR-146a can be considered as a prognostic and diagnostic marker in these individuals [39]. Baldeo’n et al. also found that miR-146a expression in blood considerably decreased in patients with T2D compared to nondiabetic controls in a study of Ecuadorian T2D cohorts. They also discovered that this drop was related to augmented amount of proinflammatory blood cytokines including HGF and IL-8 (a vascular/insular repair factor) as distinguishing indicators of glucose control dysfunction. Alipoor et al. in a meta-analysis study found the same reduced level of miR-146a in PBMC and plasma of patients with T2D; however, it was not seen in the patients’ serum or plasma samples [40]. García-Jacobo et al. verified the reduced expression of miR-146a. They also addressed miR-34a’s connection to miR-146a and resistance to insulin. Furthermore, they stated that the expression of miR-146a in individuals susceptible to diabetes, patients with T2D tolerating insulin therapy, high obesity/glycemia, and T2D patients with diabetic foot ulcers and nephropathy was reduced in serum but was not linked with cell functionality [41]. Habibi et al. also found a substantial drop in miR-146a and a rise in IRAK1, NF-κB, and TRAF6 gene mRNAs in the hippocampus part of rats with diabetes, along with enhanced activity of NF-κB and apoptosis levels in this group in comparison with the control group [42]. In addition, Yavari et al. found that troxerutin pretreatment of rats lowered the levels of mRNAs for IRAK-1, NF-κB, and TRAF-6 in the hippocampus of both diabetic and nondiabetic animals, potentially because of a negative control feedback loop mediated by miR-146a [43].

The expression level of miR-146a is variable in response to physical/medical treatments, age, sex, or the presence of a specific polymorphism. In this example, older T2D patients were given acute strength and cardiovascular exercise, and the amount of miR-146a expression in their blood was examined. As a result, diabetic patients had a greater drop in serum blood glucose than nondiabetics, with a significant reduction following the strength training intervention, which was accompanied by a favorable change in the whole blood circulation levels of miR-146a but not the other miRNAs [44, 45]. In this respect, it is possible to infer that miR-146a levels in peripheral blood leukocytes are inversely related to insulin resistance. In an in vivo study, Alipour et al. discovered a substantial rise in the expression levels of miR-146, NF-κB, and inflammatory cytokines (TNF-α, IL-6, and IL-1), while a significant reduction in the pancreatic expression levels of TRAF6 and IRAK1 was found in the diabetes group in comparison with the control group. Swimming exercise, on the other hand, led to a substantial drop in the expression levels of miR-146a, NF-κB, and inflammatory cytokines and a significant rise in the expression levels of TRAF6 and IRAK1 in the exercise-diabetes group as compared to the diabetic group [46]. On the other hand, microRNA (miRNA) polymorphisms, as a new mechanism, are linked to pathological conditions through interference with miRNA activities [47]. Investigating the rs2910164 polymorphism in miR-146a generated contradictory results. In this situation, Ciccacci et al. and Wang et al. in independent cohort studies on Italian and Chinese T2D patients, respectively, reported that miR-146a had no significant link with illness initiation and that polymorphism in the-miR-146a had no significant differences between cases and controls [47, 48]. Alipoor et al., on the other hand, revealed that the polymorphism of rs2910164 in miR-146a may be related to T2D and its cardiovascular risk factors in an Iranian population [49]. Additionally, Shankaran et al. demonstrated in a meta-analysis that the existence of the C allele in the miR-146ars2910164 polymorphism may have a function as a risk factor in the Indian population of T2D patients via modifying miR-146a maturation [50]. Eventually, a complete meta-analysis of the aforementioned studies revealed that the polymorphism rs2910164 is not associated with T2D susceptibility [51]. In terms of the rs2910164 polymorphism (G/C), it was discovered that the rs2910164-C allele is related to lower levels of expression of miR-146a [52]. Mirzaie et al. found that levels of miR-146a were considerably decreased in diabetes affected patients than in healthy controls that are negatively associated with levels of HbA1c and fasting blood glucose in males when they looked at the association of age and sex with miR-146a expression in T2D patients [53]. Furthermore, in women, miR-146a circulating levels correlated negatively with uric acid, azotemia, ferritin, and waist/hip ratio. Circulating miR-146a might be employed being age-related, potential biomarker in the aging rout of healthy/unhealthy individuals in this scenario [54]. LncRNAs may also negatively or positively affect the development of certain diseases. Chen et al. discovered that LncRNA PTGS2 overexpression is observable in T2D patients. They also discovered that this overexpression may impair islet-cell function and that knocking it down can result in an increase in miR-146a-5p expression. The miR-146a-5p overexpression may limit RBP4 expression through a cascade route. The elevated RBP4 plasma levels were linked to diabetic retinopathy and vision-threatening diabetic retinopathy in Chinese T2D patients, suggesting a role for RBP4 in the pathophysiology of diabetic retinopathy problems [55]. Concerning contradicting findings, Shokri-Mashhadi et al. reported the enhanced level of miR-146a in plasma levels of T2D patients and that astaxanthin supplementation might lower plasma levels of this miRNA [56]. On the other hand, Zeinali et al. discovered that mir-146a levels were decreased in T2DM patients and prediabetic individuals related to healthy controls by assessing the plasma expression level of mir-146ain diabetic patients and prediabetic individuals [57].

Endothelial-derived miR-146a regulates the increased production of ECM proteins and inflammatory cytokines in the retina and kidneys in diabetes [58, 59]. According to Qin et al. study, the miR-146a level in exosome of bone marrow derived mesenchymal stem cells can restore β-cell function in T2D rats through the NUMB/β-catenin signaling pathway. All of these suggest that miR-146a overexpression might be a unique method for treating T2D [60]. The usage of bone marrow mesenchymal stem cells (BM-MSCs)-derived exosomes containing miR-146a has also been shown to contribute to the healing of the hippocampus damage induced by diabetes and, as a result, to the recovery of cognitive impairment [61].

2.3. miR-146a and Diabetic Patients with COVID-19

Nowadays, the pandemic of coronavirus disease-2019 (COVID-19) is a serious hazard for the healthcare system and patients with primary diseases [62–68]. It has been revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has the ability to lead to an increased host immune system response and severity of multiple diseases, such as diabetes, hypertension, cardiovascular, and neurological complications [69–73]. During human coronavirus infection, miRNAs have a critical role in regulating the host’s innate immune system [70].

It is intriguing that the relationship between diabetes, miR-146a, and COVID-19 may be a hot point. In this regard, it is indicated that individuals with diabetes, overweight, and high blood pressure have lower levels of circulating miR-146a, which may be aggravated by SARS-CoV-2 infection since the virus may interact with miR-146. Downregulation of miR-146a might be one of the mechanisms generating severe COVID-19 because of an insufficient host antiviral response, characterized by more protracted and inappropriate cytokine production and an absence of a feedback mechanism to control inflammatory damage to tissues. As a result, miR-146 reduction in diabetes can cause excessive inflammation (due to inadequate inhibition of IRAK1/TRAF6), increased fibrosis (due to fibronectin overexpression), and increased MCP-1 production, followed by further reduction of miR-146a (due to enhanced TGF-β1/ErbB4/Notch1 signaling), which can eventually terminate in severe COVID-19 [70]. To further elucidate its molecular pathways, it should be noted that factors responsible for entrance of SARS-CoV-2 in to cells are expressed at varying levels in masticatory mucosa (tongue) and salivary glands, which are equivalent to those observed in the bronchi and tonsil [74].

Consequently, diabetes-induced increasing in miR-146a, which is plays and important role in cell entrance regulation of SARS-CoV-2 elements and overexpression of angiotensin-converting enzyme 2 (ACE2). It regulates genes associated with host immune response, is expected to upregulate angiotensin-converting enzyme 2 expression, a crucial receptor for the entrance of SARS-CoV-2, and modulate the response of host against viruses.

3. Pathological Roles of miR-146a in Diabetes Mellitus Complications

Various investigations have shown that miR-146a possess a significant role in progression of diabetes complications including nephropathy, wound healing, diabetic olfactory dysfunction, neuropathy, and retinopathy (Figure 2).

3.1. Diabetic Nephropathy Pathogenesis and miR-146a

Uncontrolled hyperglycemia is a key cause of renal dysfunction in diabetes, activating the glomerular endothelium and causing podocyte activity failure [75]. The inflammatory reaction leads to the activation and proliferation of mesangial cells of the renal glomeruli, which causes the excess generation of ECM. This results in the contraction of podocytes and capillaries and then, decreases filtration rate of glomeruli [76]. Glomerulosclerosis consequently causes destruction of epithelium in tubules with permanent fibrotic alterations [77]. According to Feng et al., an animal investigation found that miR-146a was lowered in the renal tissue of type 1 and 2 diabetic rats, resulting in increased expression of fibronectin, an essential component of the extracellular matrix. However, they demonstrated that intravenous injection of miR-146a mimics in type 1 and 2 diabetic rats may reinstate retinal miR-146a expression and reduce fibronectin rate in diabetes but not kidneys, and additional investigations are needed to establish this therapeutic method in diabetic nephropathy [58, 78]. Wang et al. identified nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase 4 as a new target for miR-146a (NOX4). They discovered that decreased expression of miR-146a and consequent upregulation of NOX4 expression can result in an augmented rate of ROS production, oxidative stress, and inflammation, as well as suppressed expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) proteins, leading to diabetic nephropathy pathogenesis in diabetic rats [79]. Lee et al. validated this decreased expression in diabetic kidneys in the glomeruli podocytes of T2D humans and diabetic mice, which correlates with higher albuminuria and glomerular damage [80]. This decreased expression has been linked to downstream targets of miR-146a, including Notch-1, ErbB4, and EFGR. This downregulated expression pattern was found to be up to five times more expressed in diabetic nephropathy patients’ kidney samples as compared to controls. In vitro investigations on human renal glomerular endothelial cells revealed that hyperglycemia elevated TGF-β1, TNF-α, and NF-κB expression [81] (Figure 3). Not only do renal endothelial cells and podocytes have lower expression of miR-146a in diabetic nephropathy, but other immune cells may also have this expression profile and potentially harm the kidney by creating a proinflammatory microenvironment. Keeping this in mind, Bhatt et al. discovered that in diabetes animal models, miR-146a expression was enhanced in both peritoneal and intrarenal macrophages. Remarkably, miR-146a reduction throughout diabetes resulted in enhanced expression of M1 activation markers and repression of M2 markers in macrophages [82]. In contrast to the above studies, Alipour et al. revealed contradictory findings in which miR-146a was elevated in diabetic kidneys of rats compared to normal controls [83]. The C allele of rs2910164 in miR-146a was reported to be related to microvascular diabetic nephropathy problems in T1D patients in Caucasian individuals. The results show that this is mostly due to a deficiency in the pre-maturation level of miR-146a [84].

3.2. miR-146a and Pathogenesis of Diabetic Neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most common complications of T2DM [85]. The reported prevalence of DPN ranges from less than 5% to 60%, with an average of 26.4 percent [86]. The inflammatory responses have been linked to the evolution of diabetic nephropathy, with significant levels of inflammatory cytokines seen in peripheral nerve tissues in diabetic nephropathy models of rats [87]. Reduced production of an anti-inflammatory miRNA, such as miR-146a, might be a critical piece of this complex puzzle. It has been demonstrated that the hyperglycemia leads to reduced expression of miR-146a while it causes increasing levels of TRAF6 and IRAK1 in neurons of dorsal root ganglion (DRG) [88] (Figure 4.). In vitro studies have been demonstrated that miR-146a mimics may significantly inhibit hyperglycemia-induced neuronal death [89]. The same findings were obtained from diabetic rats’ sciatic nerves, confirming its protective action against diabetic neuropathy and DPN. Wang et al. discovered that a small polypeptide with acidic phase called thymosin-4, which has numerous roles such as neurorestoration and anti-inflammation, may raise miR-146a levels and overcome the impact of diabetes on DRG neurons in diabetic mice. This beneficial effect was attributed to neurovascular reorganization and the suppression of proinflammatory signals [90]. Similar findings were obtained by Luo et al. using the nanoparticle–miRNA-146a-5p polyplexes in addition to thymosin-4. In this scenario, nano-miR-146a-5p was proven to increase nerve conduction velocity while also alleviating demyelination and morphological injuries in the sciatic nerve of the DPN rats. The protective effects of nano-miR-146a-5p against neural cell death were attributable to reduced production of proinflammatory cytokines and caspase-3 in sciatic nerve cells, as well as enhanced expression of myelin basic protein. Furthermore, systemic injection of miR-146a mimics to diabetic mice was demonstrated to slow the course of DPN, resulting in increased intraepidermal nerve fibers, myelin thickness, and axonal diameters of sciatic nerves [91]. In silico investigation revealed that lncRNAs XR 598132, XR 351905, XR 357013, XR 589615, XR 589933, XR 600244, XR 353891, and XR 595664 control miR-146a in sciatic nerve cells. It is hypothesized that dysregulation of the aforementioned lncRNAs may contribute to the etiology of DPN [92]. In addition, dysregulation of neuronal regulatory lncRNAs miR-146a in may halt the progression of diabetic neuropathy; it can accelerate the disease too. According to it, lncRNA HCG18 has been demonstrated to increase M1 macrophage polarization by targeting miR-146a and upregulating TRAF6 expression, hence enabling DPN development [85]. The overexpression of miR-146a seems to slow the course of diabetic neuropathy, and exosomes have been proposed as potential therapeutically means for delivering miRNAs. Fan et al. discovered that MSC-exosomes containing miR-146a may reduce peripheral blood inflammatory monocytes and endothelial cell activation through inhibiting the signaling pathway of Toll-like receptor (TLR)-4/NF-κB [93].

3.3. miR-146a and Wound Healing

Diabetic wound healing has been defined by diminished chemokine production, poor angiogenesis, and an aberrant inflammatory response [94, 95]. A growing amount of available data shows that continuous elevation of inflammatory gene expression may lead to the pathophysiology of chronic diabetic wounds by activating inflammatory pathways. Delayed wound healing can also affect the diabetic eye (cornea), resulting in vision impairment [96]. Unlike prior findings, Winkler et al. demonstrated that miR-146a has enhanced in diabetes limbus compared to the normal limbus, resulting in delayed wound healing of epithelial cells in limbal in vitro and faster wound healing in cultured human diabetic derived corneas [97]. Unlike previous research, Xinling et al. discovered that skin wound healing was delayed in miR-146a knocked-out mice by boosting inflammatory responses, indicating that it can be targeted to expedite wound healing [98]. Additionally, it has been found that miR-146a is dramatically downregulated in diabetic mouse wounds. This downregulation was found to be closely associated with the enhanced level of gene expression of its proinflammatory target genes. Employing the mesenchymal stem cell (MSC) therapy, Xu et al. discovered that MSC medication was related to a sharp rise in expression of miR-146a and reduced expression level of its proinflammatory target genes [99]. Nanotechnology-based treatment appears to be promising because nanoparticles are among the most effective biological vehicles for delivering noncoding RNAs. Dewberry et al. also found that coupling miR-146a to cerium oxide nanoparticles effectively improved wound healing [100]. The team of Lindel et al. also confirmed the previous study and mentioned that intradermal injection of conjugated miR-146a to cerium oxide nanoparticles increases wound collagen production, improves angiogenesis, and reduces inflammation and oxidative stress, promoting faster wound repair in diabetic wounds [101]. Curcumin is an excellent wound healing medication [102]. Huang et al. discovered that a curcuminoid derivative can expedite diabetic mice’s skin wound healing by boosting miR-146a and blocking the NF-κB-mediated inflammatory pathway [103].

3.4. miR-146a and Diabetic Retinopathy

Diabetic retinopathy (DR) affects roughly 80% of people with T1D or T2D who have been diagnosed for at least 20 years [104]. In several studies, miRNAs have been shown to play different roles in developing DR and have also shown an association between some miRNAs with the grade of DR [105–107]. DR begins with lesions that are nonproliferative such as changed permeability of vessels and blood flow in retina, and thickening of basement membrane, depletion of pericytes, and the creation of capillaries with no cells, producing macular edema. Later, the illness progresses into a pathological proliferative and neovascularization stage: the arteries expand into the vitreous evoking retinal detachment and hemorrhage which leads to vision loss [108]. For the first time, Feng et al. verified that miR-146a was concentrated in endothelial cells of the retina and was lowered in diabetes. Intravenous injection of miR-146amimics recovered miR-146a in retina and lowered fibronectin synthesis in diabetes [78]. Besides that, Wang et al. stated that diabetes-induced deregulation of miR-146a daily rhythms and inflammatory pathways under miR-146a control has potential implications for the development of DR, implying that miR-146a as a biomarker could be a novel therapeutically target in the DN treatment [109]. Gong et al. discovered a new target of miR-146ain DR pathogenesis from a molecular mechanism standpoint. Roundabout 4 (ROBO4), a major component of angiogenesis, and hypoxia-inducible factor-1 alpha (HIF-1α) are targets for miR-146a, and decreased miR-146a may result in decreased cell survival, augmented permeability, and enhanced cell motility [110]. Rasoulinejad et al. also introduced Nrf2, which may contribute to higher inflammation and oxidative stress rate in diabetic retinopathy [111]. Elevated extracellular matrix protein synthesis (such as collagen IIV and fibronectin) in diabetic mice retina was another involvement of miR-146a in the etiology of diabetic retinopathy. This is because retinal tissue dysfunction was minimized in miR-146a overexpressing transgenic mice [58]. Barutta et al. also revealed that blood levels of miR-146a-5p were lowered in diabetic retinopathy patients, which may be used as a new biological marker in the early identification of these individuals [26].

3.5. Association of miR-146a and Other Diabetic-Related Complications

Olfaction plays an important function in an individual’s diet and social behaviors. The olfactory bulb (OB) is an essential brain lube for odor sensing in which sensory neurons of the olfactory epithelium connect with mitral cells and convey information to other areas for odor interpretation such as the piriform cortex, amygdala, and entorhinal cortex [112]. T2DM patients also have olfactory changes, such as an increased odor perception threshold, decreased odor identification, and a proclivity to develop anosmia. Jiménez et al. discovered that olfactory impairment in T2DM rats is related with IL-1-mediated inflammation and miR-146a overexpression, implying that high levels of IL-1 might cause miR-146a upregulation as negative feedback to inflammatory response in the T2DM rats’ olfactory lobe [113].

4. Conclusion and Future Directions

One of the most significant long-term challenges facing global healthcare systems is DM. In addition, during the COVID-19 pandemic, diabetic patients are more prone to experience severe symptoms of COVID-19. During multiple studies, microRNAs have been identified as key regulators of DM and related complications [105, 106, 114]. Biological samples and laboratory procedures need to be standardized, and the obtained data need to be confirmed in independent cohorts. For instance, in clinical practice, instruments (fundus oculi, fluorangiography, and optical coherence tomography) are used to detect DR early, even though the timing and modalities of such screening procedures are often not applied properly. However, teleretinal evaluations could improve patients’ compliance with screening programs, particularly during the COVID-19 pandemic [105]. It is undeniable that integrating different epigenetic biomarkers, potentially correlated with clinical, instrumental, and biochemical features, will be helpful to identify accurate panels for DR and other DM-related complications prediction. In the future, further prospective studies are required to achieve this aim. Based on the evidence, miR-146a can reduce the progression of diabetes complications, such as nephropathy, retinopathy, neuropathy, olfactory dysfunction, cardiovascular disorders, and wound healing. In diabetic patients, the miR-146a levels are low, which may be aggravated by SARS-CoV-2 infection, since the virus may interact with miR-146a. It is possible to use miR-146a as a marker to predict diabetes clinical outcomes. Therefore, a better understanding of the multiple pathological mechanisms that inhibit miR-146a expression could open new windows in the treatment of diabetes and related complications. Furthermore, we suggest that combinational therapy of miR-146a with conventional and unconventional antidiabetic drugs potentially can be beneficial to combat T1D and T2D and related complications. In this line, Zgheib et al. have found that miR-146a conjugated with cerium oxide nanoparticles (CNP-miR146a) can play a significant role in the treatment of diabetic wounds [100]. Thus future investigations are needed to evaluate the effects of miR-146a combinational therapies.

Abbreviations

DM:	Diabetes mellitus
T1MD:	Type 1 diabetes mellitus
T2DM:	Type 2 diabetes mellitus
miRNA:	MicroRNA
lncRNAs:	Long noncoding RNAs
TRBP:	TAR-RNA binding protein
RISC:	RNA-induced silencing complex
NF-κB:	Nuclear factor kappa B
TRAF6:	TNF receptor-associated factor 6
IRAK1:	IL-1 receptor-associated kinase 1.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

Mahyar Ghafari and Sara Razi conceptualized the research. All authors wrote the manuscript text. HZ and MN-A edited the manuscript. SR, HZ, and MN-A revised the manuscript. HZ supervised the study. All authors read and approved the final manuscript.

References

W. H. Herman, “The global burden of diabetes: an overview,” in Diabetes mellitus in developing countries and underserved communities, S. Dagogo-Jack, Ed., pp. 1–5, Springer, Cham, 2017.
View at: Publisher Site | Google Scholar
M. Babaei, S. Alizadeh-Fanalou, A. Nourian et al., “Evaluation of testicular glycogen storage, FGF21 and LDH expression and physiological parameters of sperm in hyperglycemic rats treated with hydroalcoholic extract of Securigera securidaca seeds, and Glibenclamide,” Reproductive Biology and Endocrinology, vol. 19, no. 1, 2021.
View at: Publisher Site | Google Scholar
K. Ogurtsova, J. D. da Rocha Fernandes, Y. Huang et al., “IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040,” Diabetes Research and Clinical Practice, vol. 128, pp. 40–50, 2017.
View at: Publisher Site | Google Scholar
E. Standl, K. Khunti, T. B. Hansen, and O. Schnell, “The global epidemics of diabetes in the 21st century: current situation and perspectives,” European Journal of Preventive Cardiology, vol. 26, Supplement 2, pp. 7–14, 2019.
View at: Publisher Site | Google Scholar
G. Roglic and N. Unwin, “Mortality attributable to diabetes: estimates for the year 2010,” Diabetes Research and Clinical Practice, vol. 87, no. 1, pp. 15–19, 2010.
View at: Publisher Site | Google Scholar
E. Bahreini, Y. Rezaei-Chianeh, and M. Nabi-Afjadi, “Molecular mechanisms involved in intrarenal renin-angiotensin and alternative pathways in diabetic nephropathy-a review,” Review of Diabetic Studies, vol. 17, no. 1, pp. 1–10, 2021.
View at: Publisher Site | Google Scholar
Y. Zheng, Z. Wang, and Z. Zhou, “miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes,” Cellular & Molecular Immunology, vol. 14, no. 6, pp. 488–496, 2017.
View at: Publisher Site | Google Scholar
B. Kiani, S. Yarahmadi, M. Nabi-Afjadi et al., “A comprehensive review on the metabolic cooperation role of nuclear factor E2-related factor 2 and fibroblast growth factor 21 against homeostasis changes in diabetes,” Clinical Diabetology, vol. 11, no. 6, pp. 409–419, 2022.
View at: Publisher Site | Google Scholar
D. Y. Zhou, X. Mou, K. Liu, W. Liu, Y. Xu, and D. Zhou, “In silico prediction and validation of potential therapeutic genes in pancreatic β‑cells associated with type 2 diabetes,” Experimental and Therapeutic Medicine, vol. 20, no. 5, pp. 1–1, 2020.
View at: Publisher Site | Google Scholar
S. Pouriamehr, H. Barmaki, M. Rastegary, F. Lotfi, and M. Nabi Afjadi, “Investigation of insulin-like growth factors/insulin-like growth factor binding proteins regulation in metabolic syndrome patients,” BMC Research Notes, vol. 12, no. 1, pp. 1–5, 2019.
View at: Publisher Site | Google Scholar
M. M. Sirdah and N. S. Reading, “Genetic predisposition in type 2 diabetes: a promising approach toward a personalized management of diabetes,” Clinical Genetics, vol. 98, no. 6, pp. 525–547, 2020.
View at: Publisher Site | Google Scholar
X. Tang, G. Tang, and S. Özcan, “Role of microRNAs in diabetes,” Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 1779, no. 11, pp. 697–701, 2008.
View at: Publisher Site | Google Scholar
J. Jia, P. Yao, A. Arif, and P. L. Fox, “Regulation and dysregulation of 3UTR-mediated translational control,” Current Opinion in Genetics & Development, vol. 23, no. 1, pp. 29–34, 2013.
View at: Publisher Site | Google Scholar
J. Krol, I. Loedige, and W. Filipowicz, “The widespread regulation of microRNA biogenesis, function and decay,” Nature Reviews Genetics, vol. 11, no. 9, pp. 597–610, 2010.
View at: Publisher Site | Google Scholar
L. Gramantieri, C. Giovannini, F. Piscaglia, and F. Fornari, “MicroRNAs as modulators of tumor metabolism, microenvironment, and immune response in hepatocellular carcinoma,” Journal of Hepatocellular Carcinoma, vol. 8, pp. 369–385, 2021.
View at: Publisher Site | Google Scholar
M. Karami Fath, A. Azargoonjahromi, A. Kiani et al., “The role of epigenetic modifications in drug resistance and treatment of breast cancer,” Cellular & Molecular Biology Letters, vol. 27, no. 1, article 52, 2022.
View at: Publisher Site | Google Scholar
E. Sonkoly and A. Pivarcsi, “microRNAs in inflammation,” International Reviews of Immunology, vol. 28, no. 6, pp. 535–561, 2009.
View at: Publisher Site | Google Scholar
L. Li, X. P. Chen, and Y. J. Li, “MicroRNA-146a and human disease,” Scandinavian Journal of Immunology, vol. 71, no. 4, pp. 227–231, 2010.
View at: Publisher Site | Google Scholar
M. Ha and V. N. Kim, “Regulation of microRNA biogenesis,” Nature Reviews Molecular Cell Biology, vol. 15, no. 8, pp. 509–524, 2014.
View at: Publisher Site | Google Scholar
K. Felekkis, E. Touvana, C. Stefanou, and C. Deltas, “MicroRNAs: a newly described class of encoded molecules that play a role in health and disease,” Hippokratia, vol. 14, no. 4, pp. 236–240, 2010.
View at: Google Scholar
S. R. N. Pullagura, TARBP2-Mediated Post-Transcriptional Regulation of Gene Expression during Murine Embryonic Development and Spermatogenesis, The University of Maine, 2018.
K. Nakanishi, “Anatomy of RISC: how do small RNAs and chaperones activate Argonaute proteins?” WIREs RNA, vol. 7, no. 5, pp. 637–660, 2016.
View at: Publisher Site | Google Scholar
G. Mathonnet, M. R. Fabian, Y. V. Svitkin et al., “MicroRNA inhibition of translation initiation in vitro by targeting the cap-binding complex eIF4F,” Science, vol. 317, no. 5845, pp. 1764–1767, 2007.
View at: Publisher Site | Google Scholar
S. Song and S. Roy, “Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: cells, biomaterials, and devices,” Biotechnology and Bioengineering, vol. 113, no. 7, pp. 1381–1402, 2016.
View at: Publisher Site | Google Scholar
S. Y. Simbo, Effects of Exercise and Diet-Induced Weight Loss in Overweight/Obese Women on Characterization of Serum/White Blood Cells, microRNAs and Cytokine Gene Transcription, 2013, https://hdl.handle.net/1969.1/151753.
F. Barutta, B. Corbetta, S. Bellini et al., “MicroRNA 146a is associated with diabetic complications in type 1 diabetic patients from the EURODIAB PCS,” Journal of Translational Medicine, vol. 19, no. 1, pp. 1–10, 2021.
View at: Publisher Site | Google Scholar
K. D. Taganov, M. P. Boldin, K. J. Chang, and D. Baltimore, “NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 33, pp. 12481–12486, 2006.
View at: Publisher Site | Google Scholar
H. M. Larner-Svensson, A. E. Williams, E. Tsitsiou et al., “Pharmacological studies of the mechanism and function of interleukin-1β-induced miRNA-146a expression in primary human airway smooth muscle,” Respiratory Research, vol. 11, no. 1, pp. 1–13, 2010.
View at: Publisher Site | Google Scholar
Z. U. Mollah, S. Pai, C. Moore et al., “Abnormal NF-κB Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes,” The Journal of Immunology, vol. 180, no. 5, pp. 3166–3175, 2008.
View at: Publisher Site | Google Scholar
R. Liu, H. Shen, T. Wang et al., “TRAF6 mediates high glucose-induced endothelial dysfunction,” Experimental Cell Research, vol. 370, no. 2, pp. 490–497, 2018.
View at: Publisher Site | Google Scholar
A. Milluzzo, A. Falorni, A. Brozzetti et al., “Risk for coexistent autoimmune diseases in familial and sporadic type 1 diabetes is related to age at diabetes onset,” Endocrine Practice, vol. 27, no. 2, pp. 110–117, 2021.
View at: Publisher Site | Google Scholar
G. Ventriglia, L. Nigi, G. Sebastiani, and F. Dotta, “MicroRNAs: novel players in the dialogue between pancreatic islets and immune system in autoimmune diabetes,” BioMed Research International, vol. 2015, Article ID 749734, 11 pages, 2015.
View at: Publisher Site | Google Scholar
S. A. Muljo, K. M. Ansel, C. Kanellopoulou, D. M. Livingston, A. Rao, and K. Rajewsky, “Aberrant T cell differentiation in the absence of dicer,” The Journal of Experimental Medicine, vol. 202, no. 2, pp. 261–269, 2005.
View at: Publisher Site | Google Scholar
Y.-N. Huang, S. L. Chiang, Y. J. Lin et al., “Long, noncoding RNA SRA induces apoptosis of β-cells by promoting the IRAK1/LDHA/lactate pathway,” International Journal of Molecular Sciences, vol. 22, no. 4, p. 1720, 2021.
View at: Publisher Site | Google Scholar
Y. Liu, M. Ma, J. Yu et al., “Decreased serum microRNA-21, microRNA-25 , microRNA-146a, and microRNA-181a in autoimmune diabetes: potential biomarkers for diagnosis and possible involvement in pathogenesis,” International Journal of Endocrinology, vol. 2019, Article ID 8406438, 9 pages, 2019.
View at: Publisher Site | Google Scholar
T. S. Assmann, G. C. K. Duarte, L. A. Brondani et al., “Polymorphisms in genes encoding miR-155 and miR-146a are associated with protection to type 1 diabetes mellitus,” Acta Diabetologica, vol. 54, no. 5, pp. 433–441, 2017.
View at: Publisher Site | Google Scholar
P. Ramkaran, S. Khan, A. Phulukdaree, D. Moodley, and A. A. Chuturgoon, “miR-146a polymorphism influences levels of miR-146a, IRAK-1, and TRAF-6 in young patients with coronary artery disease,” Cell Biochemistry and Biophysics, vol. 68, no. 2, pp. 259–266, 2014.
View at: Publisher Site | Google Scholar
G. Wang, Y. Gu, N. Xu, M. Zhang, and T. Yang, “Decreased expression of miR-150, miR146a and miR424 in type 1 diabetic patients: association with ongoing islet autoimmunity,” Biochemical and Biophysical Research Communications, vol. 498, no. 3, pp. 382–387, 2018.
View at: Publisher Site | Google Scholar
M. Balasubramanyam, S. Aravind, K. Gokulakrishnan et al., “Impaired miR-146a expression links subclinical inflammation and insulin resistance in type 2 diabetes,” Molecular and Cellular Biochemistry, vol. 351, no. 1-2, pp. 197–205, 2011.
View at: Publisher Site | Google Scholar
B. Alipoor, H. Ghaedi, R. Meshkani et al., “Association of miR-146a expression and type 2 diabetes mellitus: a meta-analysis,” International journal of molecular and cellular medicine, vol. 6, no. 3, pp. 156–163, 2017.
View at: Publisher Site | Google Scholar
R. E. García-Jacobo, E. E. Uresti-Rivera, D. P. Portales-Pérez et al., “Circulating miR-146a, miR-34a and miR-375 in type 2 diabetes patients, pre- diabetic and normal-glycaemic individuals in relation to β-cell function, insulin resistance and metabolic parameters,” Clinical and Experimental Pharmacology and Physiology, vol. 46, no. 12, pp. 1092–1100, 2019.
View at: Publisher Site | Google Scholar
F. Habibi, F. Ghadiri Soufi, R. Ghiasi, A. M. Khamaneh, and M. R. Alipour, “Alteration in inflammation-related miR-146a expression in NF-KB signaling pathway in diabetic rat hippocampus,” Advanced pharmaceutical bulletin, vol. 6, no. 1, pp. 99–103, 2016.
View at: Publisher Site | Google Scholar
R. Yavari, R. Badalzadeh, M. R. Alipour, and S. M. Tabatabaei, “Modulation of hippocampal gene expression of microRNA-146a/microRNA-155-nuclear factor-kappa B inflammatory signaling by troxerutin in healthy and diabetic rats,” Indian Journal of Pharmacology, vol. 48, no. 6, pp. 675–680, 2016.
View at: Publisher Site | Google Scholar
G. S. Morais Jr., V. C. Souza, W. Machado-Silva et al., “Acute strength training promotes responses in whole blood circulating levels of miR-146a among older adults with type 2 diabetes mellitus,” Clinical Interventions in Aging, vol. 12, pp. 1443–1450, 2017.
View at: Publisher Site | Google Scholar
F. Olivieri, F. Prattichizzo, A. Giuliani et al., “miR-21 and miR-146a: the microRNAs of inflammaging and age-related diseases,” Ageing Research Reviews, vol. 70, article 101374, 2021.
View at: Publisher Site | Google Scholar
M. R. Alipour, N. Yousefzade, F. M. Bavil, R. Naderi, and R. Ghiasi, “Swimming impacts on pancreatic inflammatory cytokines, miR-146a and NF-кB expression levels in Type-2 diabetic rats,” Current Diabetes Reviews, vol. 16, no. 8, pp. 889–894, 2020.
View at: Publisher Site | Google Scholar
T.-T. Wang, Y. J. Chen, L. L. Sun, S. J. Zhang, Z. Y. Zhou, and H. Qiao, “Affection of single-nucleotide polymorphisms in miR-27a, miR-124a, and miR-146a on susceptibility to type 2 diabetes mellitus in Chinese Han people,” Chinese Medical Journal, vol. 128, no. 4, pp. 533–539, 2015.
View at: Publisher Site | Google Scholar
C. Ciccacci, D. di Fusco, L. Cacciotti et al., “MicroRNA genetic variations: association with type 2 diabetes,” Acta Diabetologica, vol. 50, no. 6, pp. 867–872, 2013.
View at: Publisher Site | Google Scholar
B. Alipoor, R. Meshkani, H. Ghaedi, Z. Sharifi, G. Panahi, and T. Golmohammadi, “Association of miR-146a rs2910164 and miR-149 rs2292832 variants with susceptibility to type 2 diabetes,” Clinical Laboratory, vol. 62, no. 8, pp. 1553–1561, 2016.
View at: Publisher Site | Google Scholar
Z. S. Shankaran, C. E. J. Walter, K. Ramachandiran, V. B. Gurramkonda, and T. Johnson, “Association of microRNA-146a rs2910164 polymorphism with type II diabetes mellitus in a South Indian population and a meta-analysis,” Gene Reports, vol. 18, article 100567, 2020.
View at: Publisher Site | Google Scholar
L. Cheng, M. Zhou, D. Zhang, and B. Chen, “Association of miR-146a polymorphism rs2910164 and type 2 diabetes risk: a meta-analysis,” Journal of International Medical Research, vol. 48, no. 8, 2020.
View at: Publisher Site | Google Scholar
B. Alipoor, H. Ghaedi, R. Meshkani, M. D. Omrani, Z. Sharifi, and T. Golmohammadi, “The rs2910164 variant is associated with reduced miR-146a expression but not cytokine levels in patients with type 2 diabetes,” Journal of Endocrinological Investigation, vol. 41, no. 5, pp. 557–566, 2018.
View at: Publisher Site | Google Scholar
M. Mirzaei, M. Rahmaninan, M. Mirzaei, A. Nadjarzadeh, and A. A. Dehghani tafti, “Epidemiology of diabetes mellitus, pre-diabetes, undiagnosed and uncontrolled diabetes in Central Iran: results from Yazd health study,” BMC Public Health, vol. 20, no. 1, pp. 1–9, 2020.
View at: Publisher Site | Google Scholar
E. Mensà, A. Giuliani, G. Matacchione et al., “Circulating miR-146a in healthy aging and type 2 diabetes: age- and gender- specific trajectories,” Mechanisms of Ageing and Development, vol. 180, pp. 1–10, 2019.
View at: Publisher Site | Google Scholar
Q. Chen, Y. He, X. Wang et al., “LncRNA PTGS2 regulates islet β-cell function through the miR-146a-5p/RBP4 axis and its diagnostic value in type 2 diabetes mellitus,” American Journal of Translational Research, vol. 13, no. 10, pp. 11316–11328, 2021.
View at: Google Scholar
N. Shokri-mashhadi, M. Tahmasebi, J. Mohammadi‐asl, M. Zakerkish, and M. Mohammadshahi, “The antioxidant and anti-inflammatory effects of astaxanthin supplementation on the expression of miR-146a and miR-126 in patients with type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled clinical trial,” International Journal of Clinical Practice, vol. 75, no. 5, article e14022, 2021.
View at: Publisher Site | Google Scholar
F. Zeinali, S. M. Aghaei Zarch, A. Jahan-Mihan et al., “Circulating microRNA-122, microRNA-126-3p and microRNA-146a are associated with inflammation in patients with pre-diabetes and type 2 diabetes mellitus: a case control study,” PLoS One, vol. 16, no. 6, article e0251697, 2021.
View at: Publisher Site | Google Scholar
S. Chen, B. Feng, A. A. Thomas, and S. Chakrabarti, “miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes,” PLoS One, vol. 12, no. 3, article e0173918, 2017.
View at: Publisher Site | Google Scholar
M. Karami Fath, J. Azami, N. Jaafari et al., “Exosome application in treatment and diagnosis of B-cell disorders: leukemias, multiple sclerosis, and arthritis rheumatoid,” Cellular & Molecular Biology Letters, vol. 27, no. 1, 2022.
View at: Publisher Site | Google Scholar
Q. He, J. Song, C. Cui et al., “Retracted article: mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation,” Stem Cell Research & Therapy, vol. 12, no. 1, pp. 1–16, 2021.
View at: Publisher Site | Google Scholar
K. Kubota, M. Nakano, E. Kobayashi et al., “An enriched environment prevents diabetes-induced cognitive impairment in rats by enhancing exosomal miR-146a secretion from endogenous bone marrow-derived mesenchymal stem cells,” PLoS One, vol. 13, no. 9, article e0204252, 2018.
View at: Publisher Site | Google Scholar
H. Zalpoor, M. Bakhtiyari, M. Liaghat, M. Nabi-Afjadi, and M. Ganjalikhani-Hakemi, “Quercetin potential effects against SARS-CoV-2 infection and COVID-19-associated cancer progression by inhibiting mTOR and hypoxia- inducible factor-1α (HIF-1α),” Phytotherapy Research, vol. 36, no. 7, pp. 2679–2682, 2022.
View at: Publisher Site | Google Scholar
H. Zalpoor, H. Shapourian, A. Akbari, S. Shahveh, and L. Haghshenas, “Increased neuropilin-1 expression by COVID-19: a possible cause of long-term neurological complications and progression of primary brain tumors,” Human Cell, vol. 35, no. 4, pp. 1301–1303, 2022.
View at: Publisher Site | Google Scholar
P. Samidoust, M. S. Esmaeili Delshad, R. Navid Talemi et al., “Incidence, characteristics, and outcome of COVID-19 in patients on liver transplant program: a retrospective study in the north of Iran,” New Microbes and New Infections, vol. 44, article 100935, 2021.
View at: Publisher Site | Google Scholar
M. Aghajanzadeh, M. Haghighi, S. Rimaz et al., “Pneumomediastinum, pneumopericardium pneumothorax and subcutaneous emphysema in Iranian COVID-19 patients,” Journal of Current Biomedical Reports, vol. 2, no. 4, pp. 201–205, 2021.
View at: Publisher Site | Google Scholar
M. Nabi-Afjadi, M. Heydari, H. Zalpoor et al., “Lectins and lectibodies: potential promising antiviral agents,” Cellular & Molecular Biology Letters, vol. 27, no. 1, pp. 1–25, 2022.
View at: Publisher Site | Google Scholar
N. Sedighimehr, J. Fathi, N. Hadi, and Z. S. Rezaeian, “Rehabilitation, a necessity in hospitalized and discharged people infected with COVID-19: a narrative review,” Physical Therapy Reviews, vol. 26, no. 3, pp. 202–210, 2021.
View at: Publisher Site | Google Scholar
F. Khomari, M. Nabi-Afjadi, S. Yarahmadi, H. Eskandari, and E. Bahreini, “Effects of cell proteostasis network on the survival of SARS-CoV-2,” Biological Procedures Online, vol. 23, no. 1, pp. 1–10, 2021.
View at: Publisher Site | Google Scholar
H. Zalpoor, A. Akbari, A. Samei et al., “The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies,” Cellular & Molecular Biology Letters, vol. 27, no. 1, pp. 1–21, 2022.
View at: Publisher Site | Google Scholar
J. Roganović, “Downregulation of microRNA-146a in diabetes, obesity and hypertension may contribute to severe COVID-19,” Medical Hypotheses, vol. 146, article 110448, 2021.
View at: Publisher Site | Google Scholar
H. Zalpoor, A. Akbari, and M. Nabi-Afjadi, “Ephrin (Eph) receptor and downstream signaling pathways: a promising potential targeted therapy for COVID‑19 and associated cancers and diseases,” Human Cell, vol. 35, no. 3, pp. 952–954, 2022.
View at: Publisher Site | Google Scholar
Z. Payandeh, N. Mohammadkhani, M. Nabi Afjadi et al., “The immunology of SARS-CoV-2 infection, the potential antibody based treatments and vaccination strategies,” Expert Review of Anti-Infective Therapy, vol. 19, no. 7, pp. 899–910, 2021.
View at: Publisher Site | Google Scholar
H. Zalpoor, A. Akbari, M. Nabi-Afjadi et al., “Hypoxia‐inducible factor 1 alpha (HIF‐1α) stimulated and P2X7 receptor activated by COVID-19, as a potential therapeutic target and risk factor for epilepsy,” Human Cell, vol. 35, no. 5, pp. 1338–1345, 2022.
View at: Publisher Site | Google Scholar
J. R. Roganović, “microRNA-146a and ‐155, upregulated by periodontitis and type 2 diabetes in oral fluids, are predicted to regulate SARS-CoV-2 oral receptor genes,” Journal of Periodontology, vol. 92, no. 7, pp. e35–e43, 2021.
View at: Publisher Site | Google Scholar
T. Wendt, N. Tanji, J. Guo et al., “Glucose, glycation, and rage,” Journal of the American Society of Nephrology, vol. 14, no. 5, pp. 1383–1395, 2003.
View at: Publisher Site | Google Scholar
F. J. López-Hernández and J. M. López-Novoa, “Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects,” Cell and Tissue Research, vol. 347, no. 1, pp. 141–154, 2012.
View at: Publisher Site | Google Scholar
S. Djudjaj and P. Boor, “Cellular and molecular mechanisms of kidney fibrosis,” Molecular Aspects of Medicine, vol. 65, pp. 16–36, 2019.
View at: Publisher Site | Google Scholar
B. Feng, S. Chen, K. McArthur et al., “miR-146a–mediated extracellular matrix protein production in chronic diabetes complications,” Diabetes, vol. 60, no. 11, pp. 2975–2984, 2011.
View at: Publisher Site | Google Scholar
H.-J. Wang, Y. L. Huang, Y. Y. Shih, H. Y. Wu, C. T. Peng, and W. Y. Lo, “MicroRNA-146a decreases high glucose/thrombin-induced endothelial inflammation by inhibiting NAPDH oxidase 4 expression,” Mediators of Inflammation, vol. 2014, Article ID 379537, 12 pages, 2014.
View at: Publisher Site | Google Scholar
H. W. Lee, S. Q. Khan, S. Khaliqdina et al., “Absence of miR-146a in podocytes increases risk of diabetic glomerulopathy via up-regulation of ErbB4 and notch-1,” Journal of Biological Chemistry, vol. 292, no. 2, pp. 732–747, 2017.
View at: Publisher Site | Google Scholar
Y. Huang, Y. Liu, L. Li et al., “Involvement of inflammation-related miR-155 and miR-146a in diabetic nephropathy: implications for glomerular endothelial injury,” BMC Nephrology, vol. 15, no. 1, pp. 1–12, 2014.
View at: Publisher Site | Google Scholar
K. Bhatt, L. L. Lanting, Y. Jia et al., “Anti-inflammatory role of microRNA-146a in the pathogenesis of diabetic nephropathy,” Journal of the American Society of Nephrology, vol. 27, no. 8, pp. 2277–2288, 2016.
View at: Publisher Site | Google Scholar
M. R. Alipour, A. M. Khamaneh, N. Yousefzadeh, D. Mohammad-nejad, and F. G. Soufi, “Upregulation of microRNA-146a was not accompanied by downregulation of pro-inflammatory markers in diabetic kidney,” Molecular Biology Reports, vol. 40, no. 11, pp. 6477–6483, 2013.
View at: Publisher Site | Google Scholar
G. Kaidonis, M. C. Gillies, S. Abhary et al., “A single-nucleotide polymorphism in the MicroRNA-146a gene is associated with diabetic nephropathy and sight-threatening diabetic retinopathy in Caucasian patients,” Acta Diabetologica, vol. 53, no. 4, pp. 643–650, 2016.
View at: Publisher Site | Google Scholar
W. Ren, G. Xi, X. Li et al., “Long non-coding RNA HCG18 promotes M1 macrophage polarization through regulating the miR-146a/TRAF6 axis, facilitating the progression of diabetic peripheral neuropathy,” Molecular and Cellular Biochemistry, vol. 476, no. 1, pp. 471–482, 2021.
View at: Publisher Site | Google Scholar
M. Davies, S. Brophy, R. Williams, and A. Taylor, “The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes,” Diabetes Care, vol. 29, no. 7, pp. 1518–1522, 2006.
View at: Publisher Site | Google Scholar
Y. Fang, X. Tian, S. Bai et al., “Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signaling pathway,” International Journal of Molecular Medicine, vol. 30, no. 1, pp. 85–92, 2012.
View at: Publisher Site | Google Scholar
L. Wang, M. Chopp, A. Szalad et al., “The role of miR-146a in dorsal root ganglia neurons of experimental diabetic peripheral neuropathy,” Neuroscience, vol. 259, pp. 155–163, 2014.
View at: Publisher Site | Google Scholar
X. S. Liu, B. Fan, A. Szalad et al., “MicroRNA-146a mimics reduce the peripheral neuropathy in type 2 diabetic mice,” Diabetes, vol. 66, no. 12, pp. 3111–3121, 2017.
View at: Publisher Site | Google Scholar
L. Wang, M. Chopp, X. R. Lu et al., “miR-146a mediates thymosin β4 induced neurovascular remodeling of diabetic peripheral neuropathy in type-II diabetic mice,” Brain Research, vol. 1707, pp. 198–207, 2019.
View at: Publisher Site | Google Scholar
Q. Luo, Y. Feng, Y. Xie et al., “Nanoparticle-microRNA-146a-5p polyplexes ameliorate diabetic peripheral neuropathy by modulating inflammation and apoptosis,” Nanomedicine: Nanotechnology, Biology and Medicine, vol. 17, pp. 188–197, 2019.
View at: Publisher Site | Google Scholar
Y. Feng, Y. Ge, M. Wu et al., “Long non-coding RNAs regulate inflammation in diabetic peripheral neuropathy by acting as ceRNAs targeting miR-146a-5p,” Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, vol. 13, pp. 413–422, 2020.
View at: Publisher Site | Google Scholar
B. Fan, M. Chopp, Z. G. Zhang, and X. S. Liu, “Treatment of diabetic peripheral neuropathy with engineered mesenchymal stromal cell-derived exosomes enriched with microRNA-146a provide amplified therapeutic efficacy,” Experimental Neurology, vol. 341, article 113694, 2021.
View at: Publisher Site | Google Scholar
S. C.-S. Hu and C.-C. E. Lan, “High-glucose environment disturbs the physiologic functions of keratinocytes: focusing on diabetic wound healing,” Journal of Dermatological Science, vol. 84, no. 2, pp. 121–127, 2016.
View at: Publisher Site | Google Scholar
O. Ochoa, F. M. Torres, and P. K. Shireman, “Chemokines and diabetic wound healing,” Vascular, vol. 15, no. 6, pp. 350–355, 2007.
View at: Publisher Site | Google Scholar
A. V. Ljubimov and M. Saghizadeh, “Progress in corneal wound healing,” Progress in Retinal and Eye Research, vol. 49, pp. 17–45, 2015.
View at: Publisher Site | Google Scholar
M. A. Winkler, C. Dib, A. V. Ljubimov, and M. Saghizadeh, “Targeting miR-146a to treat delayed wound healing in human diabetic organ-cultured corneas,” PLoS One, vol. 9, no. 12, article e114692, 2014.
View at: Publisher Site | Google Scholar
X. Bi, L. Zhou, Y. Liu, J. Gu, and Q. S. Mi, “MicroRNA-146a deficiency delays wound healing in normal and diabetic mice,” Advances in Wound Care, vol. 11, no. 1, pp. 19–27, 2022.
View at: Publisher Site | Google Scholar
J. Xu, W. Wu, L. Zhang et al., “The role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment: correction with mesenchymal stem cell treatment,” Diabetes, vol. 61, no. 11, pp. 2906–2912, 2012.
View at: Publisher Site | Google Scholar
C. Zgheib, S. A. Hilton, L. C. Dewberry et al., “Use of cerium oxide nanoparticles conjugated with microRNA-146a to correct the diabetic wound healing impairment,” Journal of the American College of Surgeons, vol. 228, no. 1, pp. 107–115, 2019.
View at: Publisher Site | Google Scholar
L. C. Dewberry, S. M. Niemiec, S. A. Hilton et al., “Cerium oxide nanoparticle conjugation to microRNA-146a mechanism of correction for impaired diabetic wound healing,” Nanomedicine: Nanotechnology, Biology and Medicine, vol. 40, article 102483, 2022.
View at: Publisher Site | Google Scholar
S. Tejada, A. Manayi, M. Daglia et al., “Wound healing effects of curcumin: a short review,” Current Pharmaceutical Biotechnology, vol. 17, no. 11, pp. 1002–1007, 2016.
View at: Publisher Site | Google Scholar
J. Huang, J. Fu, B. Liu, R. Wang, and T. You, “A synthetic curcuminoid analog,(2E, 6E)-2, 6-bis (2-(trifluoromethyl) benzylidene) cyclohexanone, ameliorates impaired wound healing in streptozotocin-induced diabetic mice by increasing miR-146a,” Molecules, vol. 25, no. 4, p. 920, 2020.
View at: Publisher Site | Google Scholar
P. J. Kertes and T. M. Johnson, Evidence-Based Eye Care, Lippincott Williams & Wilkins, 2007.
A. Milluzzo, A. Maugeri, M. Barchitta, L. Sciacca, and A. Agodi, “Epigenetic mechanisms in type 2 diabetes retinopathy: a systematic review,” International Journal of Molecular Sciences, vol. 22, no. 19, p. 10502, 2021.
View at: Publisher Site | Google Scholar
Z. Liang, K. P. Gao, Y. X. Wang et al., “RNA sequencing identified specific circulating miRNA biomarkers for early detection of diabetes retinopathy,” American Journal of Physiology-Endocrinology and Metabolism, vol. 315, no. 3, pp. E374–E385, 2018.
View at: Publisher Site | Google Scholar
H.-L. Zou, Y. Wang, Q. Gang, Y. Zhang, and Y. Sun, “Plasma level of miR-93 is associated with higher risk to develop type 2 diabetic retinopathy,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 255, no. 6, pp. 1159–1166, 2017.
View at: Publisher Site | Google Scholar
T. Curtis, T. Gardiner, and A. Stitt, “Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?” Eye, vol. 23, no. 7, pp. 1496–1508, 2009.
View at: Publisher Site | Google Scholar
Q. Wang, S. N. Bozack, Y. Yan, M. E. Boulton, M. B. Grant, and J. V. Busik, “Regulation of retinal inflammation by rhythmic expression of MiR-146a in diabetic retina,” Investigative Ophthalmology & Visual Science, vol. 55, no. 6, pp. 3986–3994, 2014.
View at: Publisher Site | Google Scholar
Q. Gong, J.'. Xie, Y. Li, Y. Liu, and G. Su, “Enhanced ROBO4 is mediated by up-regulation of HIF-1α/SP1 or reduction in miR-125b-5p/miR-146a-5p in diabetic retinopathy,” Journal of Cellular and Molecular Medicine, vol. 23, no. 7, pp. 4723–4737, 2019.
View at: Publisher Site | Google Scholar
S. A. Rasoulinejad, A. Akbari, and K. Nasiri, “Interaction of miR-146a-5p with oxidative stress and inflammation in complications of type 2 diabetes mellitus in male rats: anti-oxidant and anti-inflammatory protection strategies in type 2 diabetic retinopathy,” Iranian Journal of Basic Medical Sciences, vol. 24, no. 8, pp. 1078–1086, 2021.
View at: Publisher Site | Google Scholar
P.-M. Lledo and M. Valley, “Adult olfactory bulb neurogenesis,” Cold Spring Harbor Perspectives in Biology, vol. 8, no. 8, article a018945, 2016.
View at: Publisher Site | Google Scholar
A. Jiménez, D. Organista-Juárez, A. Torres-Castro, M. A. Guzmán-Ruíz, E. Estudillo, and R. Guevara-Guzmán, “Olfactory dysfunction in diabetic rats is associated with miR-146a overexpression and inflammation,” Neurochemical Research, vol. 45, no. 8, pp. 1781–1790, 2020.
View at: Publisher Site | Google Scholar
O. G. Shaker, O. O. Abdelaleem, R. H. Mahmoud et al., “Diagnostic and prognostic role of serum miR-20b, miR-17-3p, HOTAIR, and MALAT1 in diabetic retinopathy,” IUBMB Life, vol. 71, no. 3, pp. 310–320, 2019.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2023 Mahyar Ghaffari et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1271

Downloads

683

Citations