miR-191 is involved in renal dysfunction in arsenic-exposed populations by regulating inflammatory response caused by arsenic from burning arsenic-contaminated coal

Abstract

Chronic exposure to arsenic may result in the manifestation of damage in multiple organs or systems of the body. Arsenic-induced renal dysfunction has been determined, but their pathogenesis has not been fully examined. In this study, we measured the expression levels of miR-191 in plasma, the contents of pro-inflammatory (interleukin (IL)-6 and tumor necrosis factor alpha) and anti-inflammatory (IL-2 and transforming growth factor beta) cytokines, and renal dysfunction indicators (blood urea nitrogen, blood creatinine, uric acid, and cystatin C) in serum from control and arsenic poisoning populations and analyzed the relationship between the miR-191, cytokines, and renal dysfunction indicators. The results clearly show the alteration of miR-191 expression was significantly associated with arsenic-induced renal dysfunction. Overall, the association of miR-191, inflammatory response and renal dysfunction, is clearly supported by the current findings. In other words, miR-191 is involved in renal dysfunction in exposed populations by regulating inflammatory response caused by coal-burning arsenic. The study provides a scientific basis for further studies of the causes of the arsenic-induced renal dysfunction, the biological role of miR-191, and targeted prevention strategies.

Keywords

Arsenic miR-191 renal dysfunction immune inflammation coal

Introduction

Arsenic is ubiquitous in nature and is a well-known environmental pollutant.¹ Chronic arsenic poisoning in the general population has been widely reported in many areas of the world and occurs through drinking water contaminated with high arsenic.^1

–9 However, exposure through arsenic-contaminated air and food caused by the burning of coal in unventilated indoor stoves remains a major environmental public health concern in the Guizhou Province of China.¹⁰ Chronic exposure to arsenic may result in the manifestation of toxicity in practically all systems of the body.¹ It is well-known that the kidney is the main organ of the urinary system that is primarily responsible for arsenic excretion; as such, its structure and function are vulnerable to damage. Renal dysfunction caused by arsenic has been demonstrated with epidemiologic investigations^11,12 as well as in animal studies,^13,14 mainly affecting the function of proximal convoluted tubules and glomeruli. Recent studies^9,15 in Taiwan have also revealed the relationship between arsenic exposure and chronic arsenic disease. However, the mechanism involved in arsenic-induced renal dysfunction remains limited.

MicroRNAs (miRNAs) play important roles in biological processes, such as cell development, differentiation, apoptosis, proliferation, and carcinogenesis.^16,17 The results of chip array assays and small sample (n = 50) verification results show that the levels of miR-191 were most prominently increased in the arsenic-exposed population caused by burning coal.¹⁸ Further large sample (n = 456) logistic regression analysis confirmed the relationship between miR-191 and arsenic-induced renal dysfunction and that the miR-191 expression changes can increase the risk of arsenic-induced renal dysfunction by 3.65-fold.¹⁹ A study on dogs²⁰ found that urinary exosome-derived miR-191 significantly increased with renal dysfunction. This is also a good proof of the relationship between miR-191 and renal dysfunction. However, the mechanism by which miR-191 is involved in arsenic-induced renal dysfunction remains a scientific problem to be solved.

According to current research,^21
–23 the potential mechanisms of arsenic-induced renal dysfunction include inflammation, oxidative stress, cell death and altered glucose uptake, and so on. Under physiological conditions, anti-inflammatory cytokines maintain a certain balance with pro-inflammatory cytokines to restrict a sustained or over-inflammatory response.²⁴ An imbalance in the regulation of inflammation can decrease the body’s ability to resist infection, thus inducing repeated infections. Accumulating lines of evidence^25

–28 indicate that arsenic may alter the expression of anti-inflammatory (interleukin-2 (IL-2) and transforming growth factor beta (TGF-β)) and pro-inflammatory (IL-6 and tumor necrosis factor alpha (TNF-α)) cytokines and induce abnormal inflammatory responses. However, the relationship between miR-191 and inflammatory response in arsenic-induced renal dysfunction is poorly understood.

In this study, we measured the expression levels of plasma miR-191, renal dysfunction indicators (blood creatinine (CREA), cystatin C (CYSC), uric acid (UA), and blood urea nitrogen (UREA)), anti-inflammatory (IL-2 and TGF-β) and pro-inflammatory (IL-6 and TNF-α) cytokines from control and arsenic-exposed populations and analyzed the relationship between the three types of indicators. The aim was to study the role of miR-191 in arsenic-induced renal dysfunction.

Materials and methods

Study sites

An endemic area noted for arsenic poisoning that arises from burning of arsenic-contaminated coal²⁹ (Jiaole village, Xingren County, Guizhou Province, China, the arsenic content of coal in the region reached 397.20 mg/kg in 1998) was selected as the test site, while an arsenic-free area in the suburbs of Daguoduo village (located approximately 13 km from Jiaole) was chosen as the control site. The eating habits, economic status, and nutritional status of the control area were similar to the arsenic exposure area.

Study population

The proposal for this population-based study was reviewed and approved by the Ethics Committee of Guizhou Medical University. Written informed consent was obtained from all participants. We worked with the 44th Hospital of the Chinese People’s Liberation Army, Xingren Center for Disease Control and Prevention, and Yuzhang Town Central Health Center to mobilize candidates. A total of 246 villagers were selected by a cluster sampling method. Table S1 shows the characteristics of this study participants. All participants were required to be permanent residents of the local area (Jiaole and Daguoduo villages) and were matched for age and sex. Exclusion criteria included pregnant women, kidney trauma and kidney transplant residents, and a recent history of consuming seafood and drugs, which could affect the urinary excretion of arsenic. Based on the history of exposure to high arsenic, the participants were divided into control (45 cases) and arsenic-exposed (201 cases) groups. According to the Standard of Diagnosis for Endemic Arsenism (WS/T 211-2015, Ministry of Health of the People’s Republic of China), 246 villagers were stratified as follows: control (45 cases), suspected (19 cases), mild (60 cases), moderate (59 cases), and severe (63 cases) arsenic-poisoned groups. The American Conference of Governmental Industrial Hygienists (ACGIH) biological exposure index is 35 μg/L for arsenic. In the survey area, the mean urinary creatinine (UCr) was 1.7 mg/L in the normal population. After normalizing to the mean creatinine (1.7 mg/L), the biological exposure index was about 20 μg As/g creatinine for arsenic. Based on the reference values of arsenic in urine, with double geometric spacing, urinary arsenic (UAs) was divided into control (<20 μg As/gCr, 73 cases), low (20–40 μg As/gCr, 115 cases), and high (>40 μg As/gCr, 58 cases) levels.

Interviews and sample collection

A structured questionnaire was used to record information about demographic factors, lifestyle, and residential history of participants. After giving informed consent, fasting venous blood and morning urine samples were collected. All participants were instructed on how to avoid contamination. Anticoagulated (collected with ethylenediaminetetraacetic acid) and non-anticoagulated (collected with separate hose) blood samples were centrifuged at 3000 × g for 10 min at 4°C. The plasma fractions were separated and stored at −80°C for the determination of miR-191, and the sera were separated for the determination of cytokines and renal dysfunction indicators.

UAs and creatinine determination

UAs was determined by ICP-MS (Thermo Fisher, USA). The concentration of UCr was determined by the Jaffe reaction method.³⁰ All urinary parameters were normalized to the concentration of creatinine in urine.

RNA extraction and miR-191 determination

RNA extraction, primer sequences of Has-miR-191, and miR-191 determination were described previously.¹⁸ The thawed plasma samples were centrifuged at 14,000 × g for 10 min, and the supernatants were extracted. Total RNA was isolated from plasma using mirVana PARIS Kits (Thermo Fisher/Life Technologies, New York, USA; final elution volume: 60 μL), according to the manufacturer’s instructions. miR-39 snRNA was used as the control. Total cellular RNA was isolated using Trizol (Thermo Fisher/Invitrogen, New York, USA) according to the manufacturer’s directions. To detect miRNAs, 1 μg of total RNA was transcribed into cDNA using RevertAid First Strand cDNA Synthesis Kits (Thermo Fisher, USA) according to the manufacturer’s protocol. After RNA was transcribed into cDNA, quantitative polymerase chain reaction (q-PCR) was performed using the Power SYBR Green Master Mix (TaKaRa, Japan) and a Bio-Rad CFX96 real-time PCR detection system (RT-PCR). The primers of RT-PCR and q-PCR were specific stem-loop primers synthesized by RiboBio (Guangzhou, China). Fold changes in the expression of miR-191 were calculated by a comparative threshold cycle (Ct) method using the formula 2^−(ΔΔCt).³¹ And the absolute expression in each subject was calculated with a standard curve, and the mean value of the control group was determined. The relative values between each sample and the mean values of the control group were calculated. The primer sequence of Has-miR-191 is as follows: forward primer 5′-ACACTCCAGCTGGGCAACGGAATCCCAAAAG-3′ and reverse primer 5′-TGGTGTCGTGGAGTCG-3′.^18,19

Renal function determination

Various renal function indicators (CREA, CYSC, UA, and UREA) were calibrated and controlled by an Olympus calibrator and quality control solution (Olympus, Japan). After calibration and quality control, the serum CREA, CYSC, UA, and UREA levels were determined by Olympus AU400 automatic biochemical analyzer (Olympus, Japan). The reagents of the above indicators were purchased from BioSino Bio-Technology & Science, Inc. (BioSino, China).

Pro-inflammatory and anti-inflammatory cytokines determination

The concentration of IL-2, TGF-β, IL-6, and TNF-α in serum was determined by enzyme-linked immunosorbent assay method. These biomarkers were determined using kits from the CUSABIO in China. Each sample was analyzed twice.

Statistical analysis

SPSS version 22.0 software was used for the frequency calculations, t-test, nonparametric test, and correlation analysis. For quantitative data, such as CREA, CYSC, UA, UREA, IL-2, TGF-β, IL-6, and TNF-α, independent sample t-tests were used to compare differences between the control and arsenic-exposed groups, and a one-way analysis of variance was used for comparison of more than two groups. The above data were expressed as the mean ± standard deviation. The median test was used to compare the expression of miR-191 between various groups, and the results were expressed as median and interquartile range. The relationship between miR-191, cytokines (IL-2, TGF-β, IL-6, and TNF-α), and renal dysfunction indicators (CREA, CYSC, UA, and UREA) was determined using Pearson correlations. The criterion for a significant difference between means was p < 0.05.

Results

Coal-burning arsenic can cause renal dysfunction by upregulating miR-191

To study the role of coal arsenic exposure in renal dysfunction, sensitive indicators that clinically reflect renal function were analyzed. Figure 1(a) shows the differences in the contents of renal function indicators in the serum of different groups. The content of CYSC in the arsenic exposure group was significantly increased compared with the control group (t = −6.60, p < 0.01). However, there was no significant difference in the contents of UREA, CREA, and UA in the two groups (t = 0.46, −0.92, −0.97; p = 0.66, 0.36, 0.34). No significant differences were seen in the contents of UREA, CREA, UA, and CYSC in the various UAs exposure groups (F = 0.02, 0. 83, 0.42, 0.15; p = 0.98, 0.44, 0.66, 0.87). Subsequently, the differences in the contents of renal function indicators of different condition groups were analyzed. The content of UREA in the moderate arsenic poisoning group was higher than the control and suspicious groups (t = −3.12, −2.50; p = <0.01, 0.01). Compared with the control group, the contents of CYSC in the mild, moderate, and severe arsenic poisoning groups were significantly increased (t = −3.90, −6.46, −8.97; p all <0.01). The contents of CYSC in the moderate and severe arsenic poisoning groups were higher than the suspicious (t = −3.14, −4.93; p all <0.01) and mild arsenic poisoning groups (t = −2.80, −5.48; p = 0.01, <0.01). And the content of CYSC in the severe arsenic poisoning group was increased compared with the moderate arsenic poisoning group (t = 2.61, p = 0.01). No significant differences were seen among the contents of CYSC in the other groups.

Figure 1.

Coal-burning arsenic can cause renal dysfunction by upregulating miR-191. (a) and (b) The differences in the contents of renal function indicators in serum and the expression levels of miR191 in plasma of different groups. (c) To study the association of miR-191 with arsenic-induced renal dysfunction, the correlation between miR-191 and indicators of renal function was analyzed. From the graph, we can see that the renal dysfunction indicator and miR-191significantly increased caused by exposure to coal-burning arsenic. And the UA and CYSC show a significant correlation with miR-191. But all the indicators did not find significant differences in various urinary arsenic groups. CYSC: cystatin C; UA: uric acid.

Based on the previous results of chip array assays, the expression levels of miR-191 in plasma were measured to confirm the role of arsenic exposure on the changes of miR-191 expression. Figure 1(b) depicts the median and range of miR-191 for each group. As shown in Figure 1(b), the levels of miR-191 in the exposed group were significantly increased compared with the control group (Z = 5.80, p = 0.02). However, there was no significant difference in the levels of miR-191 in the various UAs exposure groups (Z = 0.51, p = 0.78). Moreover, the levels of miR-191 in the mild (Z = 4.58, 4.25; p = 0.03, 0.03), moderate (Z = 11.32, 6.92; p = <0.01, 0.01), and severe arsenic poisoning (Z = 32.04, 13.56; p all <0.01) groups were increased compared with the control, suspected, and mild arsenic-poisoned groups. And the levels of miR-191 in the moderate (Z = 33.81, p < 0.01) and severe (Z = 9.33, p < 0.01) arsenic poisoning groups were higher than the mild arsenic poisoning group. No significant differences were seen in the levels of miR-191 in the other groups.

To study the association of miR-191 with arsenic-induced renal dysfunction, the correlation between miR-191 and indicators of renal function was investigated. The results of the correlational analysis are shown in Figure 1(c). From the graph, it could be seen that UA and CYSC showed a significant correlation with miR-191. No significant differences were observed between the miR-191 and other indicators of renal function.

Inflammatory response is involved in miR-191-mediated renal dysfunction in coal-burning arsenic-exposed population

To further study the mechanism of miR-191-mediated renal dysfunction in coal-burning arsenic-exposed population, sensitive cytokines that reflect inflammation and anti-inflammation from previous studies were determined. Figure 2(a) clearly shows that the content of IL-2 in the arsenic-exposed group was decreased compared with the control group (t = 7.32, p < 0.01). In contrast, the contents of IL-6 and TGF-β in the arsenic-exposed group were higher than the control group (t = −4.08, −11.17; p all <0.01). No significant differences were seen in the TNF-α between the control and arsenic-exposed groups (t = −0.45, p = 0.66). For different UAs groups, only the content of the TGF-β in high UAs group was increased compared with the control group (t = −3.05, p = 0.03). No significant differences were seen among the other pro-inflammatory and anti-inflammatory cytokines of various UAs groups. Subsequently, the differences in the contents of pro-inflammatory and anti-inflammatory cytokines of different condition groups were analyzed. Compared with the control group, the content of IL-2 in the moderate and severe arsenic-poisoned groups was significantly decreased (t = 3.45, 4.08; p = 0.01, <0.01). The content of IL-6 in the severe arsenic-poisoned group was higher than the control and suspected groups (t = −3.08, −2.58; p = <0.01, 0.01). However, there was a significant difference in the contents of TGF-β only in the severe arsenic-poisoned group compared with control (t = −3.98, p < 0.01). No significant differences were observed among the pro-inflammatory and anti-inflammatory cytokines in the other groups.

Figure 2.

Inflammatory response is involved in miR-191-mediated renal dysfunction in coal-burning arsenic exposure population. To further study the reason of miR-191-mediated renal dysfunction in coal-burning arsenic exposure population, sensitive cytokines that previous study reflect inflammation and anti-inflammation were analyzed. (a) The differences in the contents of inflammatory response indicators of different groups. It clearly shows that arsenic can significantly reduce the contents of IL-2 and increase the IL-6 and TGF-β levels, causing the pro-inflammatory and anti-inflammatory imbalance. (b) and (c) Further studies show that the inflammatory response (pro-inflammatory and anti-inflammatory imbalance) caused by arsenic exposure is closely related to miR-191-mediated arsenic-induced renal dysfunction. IL: interleukin; TGF-β: transforming growth factor beta.

To study the association of miR-191 with the inflammatory response, correlation between miR-191 and the pro-inflammatory and anti-inflammatory cytokines was carried out. The results of the correlational analysis are shown in Figure 1(b). From the graph, it could be seen that IL-2, IL-6, and TGF-β showed a significant correlation with miR-191. No significant correlation was observed between the miR-191 and TNF-α.

Subsequently, the correlation between inflammatory response and renal dysfunction indicators was carried out. Figure 2(c) shows that there was a significant correlation between IL-2, IL-6, TGF-β and UA, CYSC. No correlation was observed between the other inflammatory response and renal function indicators.

Discussion

Arsenic poisoning caused by the burning of coal in unventilated indoor stoves is unique to China. Previous study¹¹ indicated that chronic arsenic exposure had a significant adverse impact on renal function of residents, including proximal convoluted tubules and glomeruli. Our results also demonstrated that arsenic exposure through burning of coal could cause renal dysfunction. Several studies^15,32,33 have observed the importance of the glomerular filtration rate in the kidney damage caused by arsenic. Serum CYSC is a sensitive indicator for evaluating glomerular filtration rate. Our result shows that the content of CYSC in the arsenic-exposed group was higher than the control group, and as the condition gradually worsens, its content continues to increase. This finding is consistent with that of drinking water type of arsenic poisoning¹² and occupational arsenic poisoning,³⁴ which can cause glomerular damage. Both UREA and CREA are common indicators in clinical examination that reflect renal function. However, there was no significant difference in the contents of UREA and CREA between the control and arsenic-exposed groups. A possible explanation for this might be that the sensitivity of the above clinical indicators in reflecting renal dysfunction caused by arsenic is less sensitive than CYSC. However, the arsenic-exposed grouping results are a good proof. Kidney damage is one of the main causes of high UA, in this study, there was no significant difference in the contents of UA between the arsenic-exposed groups and the control groups. However, the UA that tends to increase gradually has been observed in these groups. It suggests that as kidney damage progresses, that UA could increase significantly cannot be ruled out, and this could lead to hyperuricemia. Therefore, the observation of hyperuricemia should be considered in population health monitoring in areas exposed to arsenic, to better understand the arsenic-induced renal dysfunction. Nordberg et al.³⁵ and Hong et al.¹¹ assessed levels of urinary β2-microglobulin, N-acetyl-β-d-glucosaminidase, and albumin as markers of renal dysfunction, which was increased in response to arsenic exposure. Our results indicate that serum CYSC could be a potential biological marker of arsenic-induced renal dysfunction, but more studies are needed to confirm this.

The previous chip array assays and small sample verification results show that the levels of miR-191 were most prominently increased in the arsenic-poisoned population caused by burning of coal.¹⁸ Our results are in agreement with that of Sun et al.,¹⁸ suggesting that miR-191 is involved in the pathogenesis of arsenic toxicity. Consistent with this was the observation of a good correlation between miR-191 and arsenic-induced renal dysfunction indices in a recently concluded study in our laboratory.¹⁹ An experimental study of dogs also found that miR-191 increased significantly with renal dysfunction.²⁰ In the present study, there was a good correlation between miR-191 and UA and CYSC. This further supports our proposition that arsenic poisoning from burning of coal can cause renal dysfunction by upregulating miR-191.

Inflammation, one of the potential mechanisms of arsenic-induced renal dysfunction, has been confirmed by some studies.^21
–23 Inflammatory vasculature and leukocyte responses are achieved through the action of a series of chemical factors called inflammatory mediators. Cytokines, as one of the common inflammatory mediators, are mainly produced by activated lymphocytes and monocytes and play an important role in mediating inflammatory responses. IL-2 is a type of immunoregulatory factor mainly produced by T lymphocytes, it can stimulate activated T-lymphocytes to synthesize more cytokines, including IL-2 and interferon.³⁶ Population-based study²⁵ showed that the IL-2 mRNA levels in the peripheral blood mononuclear cells of the arsenic-poisoned groups were significantly lower than those in the control group and exposed group and correlated with the severity of the disease. This is in accordance with the observations in this study, which showed that arsenic exposure from coal burning can decrease the content of IL-2 in serum. The decline in IL-2 can affect the delayed allergic T lymphocytes, and cytotoxic T lymphocytes contribute an immune effect³⁶ and reduce the body’s ability to fight infection, thereby inducing inflammation. IL-6 is a common pro-inflammatory cytokine. When the body develops an inflammatory response, serum IL-6 levels are significantly increased. In this study, the content of IL-6 in the arsenic exposure group was increased compared with the control group, and the IL-6 content in severe arsenic poisoning group was higher than the control and suspicious groups. The results of this study are similar to those observed in in vitro study.²⁶ It demonstrated that inflammation is one of the possible mechanisms of arsenic poisoning. TGF-β is a cytokine with pleiotropic functions in hematopoiesis, angiogenesis, cell proliferation, differentiation, migration, and apoptosis.³⁷ The results showed that the content of TGF-β in the arsenic-exposed group was increased compared with the control group, and the TGF-β content in the severe arsenic-exposed group and the high UAs group was higher than the control group. Human kidney 2 epithelial cells were used to evaluate the effects of long-term arsenic exposure, similar results were found that chronic arsenic exposure can cause the upregulation of TGF-β.²⁷ Given that TGF-β is an important anti-inflammatory cytokine, one possible explanation is that after inflammation occurs, the body is self-protected, causing an increase in TGF-β reactivity. Fibrosis is the pathological outcome of most inflammatory diseases, and TGF-β is an important fibrotic factor.³⁸ Therefore, another possible cause is that chronic long-term arsenic exposure induces chronic inflammation of the kidney, which in turn causes fibrosis of the kidney. This needs to be confirmed in future crowds and animal experiments. TNF-α is a pro-inflammatory cytokine produced primarily by macrophages and monocytes and is involved in inflammatory and immune responses.³⁹ Our results did not reveal significant differences in TNF-α between the different groups. This is contrary to the results observed in animal experiment.²⁸ Whether the reason is related to species difference, exposure type (drinking water and coal burning) needs to be further explored.

Changes in miR-191 and inflammatory mediators were observed in this study. However, the relationship between miR-191 and inflammatory response in arsenic-induced renal dysfunction is poorly understood. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses show that miR-191 can inhibit the target genes of pathways related to immune inflammation.¹⁸ Another study has found that circulating miR-191 may be regulators of inflammation.⁴⁰ Our results showed that IL-2, IL-6, and TGF-β all had significant correlation with miR-191. Furthermore, there was a good correlation between IL-2, IL-6, TGF-β and UA, CYSC. These results indicate that miR-191 is involved in renal dysfunction in exposed populations by regulating inflammatory response caused by coal-burning arsenic. Although in vitro studies have confirmed that miR-191 is involved in arsenic-induced epithelial–mesenchymal transition,⁴¹ angiogenesis, and metastasis.⁴² Our study is the first to delineate the role of miR-191 in arsenic-induced inflammatory responses in vivo. Our results thus provide a scientific basis for further studies on mechanisms of arsenic-induced renal dysfunction, the biological role of miR-191, and targeted prevention strategies.

Moreover, another important finding was that other indicators were not significant differences in various urinary arsenic groups except TGF-β, but after stratification by exposure or condition, some of these indicators showed significant statistical differences in different groups. These results suggest that urinary arsenic is not a good exposure biomarker of health monitoring for chronic arsenic poisoning in a population.

Conclusions

Overall, the association between miR-191, inflammatory response and renal dysfunction, is clearly supported by the current findings. Our findings suggest that the modulation of inflammatory responses by miR-191 might be a possible mechanism underlying renal dysfunction in exposed populations occasioned by exposure to arsenic through burning of coal (Figure 3). However, being limited to population-based study data, this study lacks validation of this hypothesis. Next, we will confirm the regulation of cytokines by miR-191 and their role in arsenic-induced renal dysfunction by in vitro studies.

Figure 3.

miR-191 is involved in renal dysfunction in exposed populations by regulating inflammatory response caused by coal-burning arsenic. Overall, the association of miR-191, inflammatory response and renal dysfunction, is clearly supported by the current findings that miR-191 is involved in renal dysfunction in exposed populations by regulating inflammatory response caused by coal-burning arsenic.

Supplemental material

Supplemental Material, Supplementary_Table_abstract - miR-191 is involved in renal dysfunction in arsenic-exposed populations by regulating inflammatory response caused by arsenic from burning arsenic-contaminated coal

Supplemental Material, Supplementary_Table_abstract for miR-191 is involved in renal dysfunction in arsenic-exposed populations by regulating inflammatory response caused by arsenic from burning arsenic-contaminated coal by Y Xu, Z Zou, Y Liu, Q Wang, B Sun, Q Zeng, Q Liu and A Zhang in Human & Experimental Toxicology

Footnotes

Authors’ contribution

XY, ZZ, and LY contributed equally to this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Natural Science Foundations of China (81430077, 81730089 and U1812403).

ORCID iD

A Zhang

Supplemental material

Supplemental material for this article is available online.

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