Abstract
Objective
This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying mechanism.
Methods
A total of 156 adult men were included, comprising active smokers and nonsmokers. In addition to demographic information and body mass index (BMI), plasma levels of ApoA1 and ApoB, high-density lipoprotein, low-density lipoprotein, cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase in the participants were measured. Moreover, the metabolic hormones adiponectin, fibroblast growth factor 21 (FGF21), ghrelin, leptin, and orexin A, as well as the trace elements iron and zinc in CSF, were assessed.
Results
Compared to nonsmokers, active smokers showed higher BMI, and elevated CSF levels of FGF21, Zn, and Fe, but decreased levels of metabolic hormones adiponectin, ghrelin, leptin, and orexin A. Negative correlations existed between CSF FGF21 and ghrelin, between CSF Zn and ghrelin, as well as between CSF Fe and orexin A in active smokers. Furthermore, elevated CSF FGF21 and Zn predicted ghrelin level decrease in the smokers.
Conclusion
These data relate smoking-induced weight gain to its neurotoxic effect on the neurons that synthesize metabolic hormones such as adiponectin, ghrelin, leptin, or orexin A in the brain, by disrupting mitochondrial function and causing oxidative stress in the neurons.
Introduction
Epidemiological studies have concluded that cigarette smoking is associated with various chronic diseases including cardiovascular disease (1), chronic obstructive pulmonary disease (2), cancers (3), neurodegenerative diseases (4), as well as obesity (5). Clinical studies reveal that active cigarette smoking is associated with detectable abnormalities in brain morphology, blood flow, biochemistry, micro-structural integrity, and multiple neurocognitive domains of brain function. Specifically, MRI applied to human brains revealed smaller total brain volume (6) and gray matter volume (7), reduced white matter volume and fractional anisotropy (FA), as well as T2 hyperintensity signal in some white matter structures (8). Moreover, a history of cigarette smoking in cognitively normal elders was associated with an elevated invivo cortical amyloid deposition and decreased cortical glucose metabolism (9).
Cigarette smoke contains more than 4000 chemical constituents, including nitric oxide and potent oxidants, in addition to nicotine and metals (10). The oxidants react with oxygen, increasing the generation of free radicals in intracellular redox cycling reactions, thus causing oxidative stress (OS) (11). Consequently, the intracellular antioxidant system may be depleted, followed by the oxidation of lipids and proteins (12, 13). Because of its high metabolism and the susceptibility of membrane phospholipids to radical attack, the brain is highly susceptible to oxidative damage (14, 15), particularly the hippocampus (16). Meanwhile, cerebral OS triggers inflammation changes in the brain by promoting proinflammatory cytokine release (17). Significantly, some biomarkers of cigarette smoking-induced neural damage, neuroinflammation, and oxidation can be detected in the cerebrospinal fluid (CSF), exemplified by a recent study demonstrating that a history of cigarette smoking in cognitively normal elders was associated with elevated CSF level of F2-isoprostane, which is an established biomarker of radical-induced OS (18).
Unlike the blood and urine-based OS biomarkers which mainly reflect radical-mediated peroxidation of peripheral organ systems and plasma lipids, CSF OS biomarkers are believed to characterize lipid peroxidation of brain tissue more accurately (19). Indeed, one of our previous studies has demonstrated that a high CSF Aβ42 level is strongly associated with Alzheimer’s disease (AD) and mild cognitive impairment in AD patients (20). In another study, higher levels of CSF Aβ42 and tumor necrosis factor alpha (TNFα), along with lower brain-derived neurotrophic factor and total superoxide dismutase, were found in active smokers (AS) compared to nonsmokers (NS), in addition to increased BMI (21). Moreover, a negative association was found between CSF TNFα level and sleep quality in AS. The cigarette smoking-induced sleep disturbance was accompanied by higher dopamine levels but lower dopamine transporter levels in the CSF of AS (22).
In the present study, we compared AS and NS in levels of adiponectin, ghrelin, leptin, and orexin A in their CSF, in addition to demographic data and BMI of the two groups. All these hormones are involved in energy balance in humans. We also measured levels of fibroblast growth factor 21 (FGF21), zinc, Cu, and iron in CSF. FGF21 is a metabolic cytokine involved in a plethora of tissue-specific effects (23, 24, 25, 26). Intracellular Zn2+ plays an important role in mitochondrial function under physiological and pathological conditions (27). Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including AD and Parkinson’s disease (PD) (28). Copper is an important trace element required for essential enzymes. Both copper deficiency and excess may seriously affect brain functions (29). This study aimed to examine the effects of cigarette smoking on levels of the aforementioned metabolic hormones in CSF and to correlate any changes (if any) with the BMI of the smokers. We thought that changes in CSF Fe, Cu, and Zn may be regarded as biomarkers of damage to the brain neurons involved in the synthesis of the metabolic hormones, if any.
Materials and methods
Participants
This study included a total of 156 male participants who were registered for anterior cruciate ligament reconstruction surgery at the Affiliated Hospital of Inner Mongolia Medical University, China, between September 2014 and January 2016. They were assigned to AS or NS groups. Nonsmokers had no history of cigarette smoking or any substance use disorder. Active smokers were defined as those who consumed at least ten cigarettes per day for more than 1 year. All participants had no other psychiatric disorders according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). The research protocol and procedures were conducted in accordance with the Helsinki Declaration and International Ethical Guidelines for Biomedical Research Involving Human Subjects and were approved by the Human Ethics Committee of Inner Mongolian Medical University, China. Each participant provided written consent after being informed of the research purpose and procedures, as well as their rights and interests in this research.
Demographic information and measures of plasma glucose–lipid metabolism
The demographic information, including age and education, of all participants was collected. Information relevant to substance use and dependence was obtained from each participant and confirmed by his family members. The BMI of each participant was calculated based on body weight and height. Smoking-related information was collected from the AS, including age at smoking onset, years of smoking, the average daily amount of cigarette smoking, and the maximum daily amount of smoking.
Data on plasma ApoA1 and ApoB, high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol (CHO), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) were resulted from a physical examination done for a participant in the same year.
Measurements of metabolic hormones and trace elements in CSF
All participants in this study underwent lumbar puncture as part of the preoperative procedure for anterior cruciate ligament reconstructive surgery. The procedure was performed by licensed anesthetists. A 5 mL CSF sample was obtained from each participant via intrathecal collection. Within 2 h, the CSF samples were centrifuged at 1800 g for 10 min at 4°C to remove cell components, and the supernatant was aliquoted into vials of 0.5 mL and stored at −80°C until further analysis.
Levels of orexin A in CSF were measured using a commercially available ELISA kit (Cloud-clone Corp., Katy, TX, USA) following the manual provided by the vendor. Levels of leptin, adiponectin, and FGF21 in CSF were detected using radioimmunoassay kits purchased from Phoenix Pharmaceuticals, Inc. (Burlingame, CA, USA), while ghrelin was assessed using a radioimmunoassay kit from DIAsource ImmunoAssays (Louvain-la-Neuve, Belgium). Levels of iron, copper, and zinc in CSF were evaluated by means of an electron multiplier using inductively coupled mass spectrometry (NexION 300D; PerkinElmer).
Statistical analyses
Data were presented as mean ± s.d. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 20.0 (IBM). Non-continuous data of the two groups were compared using the Wilcoxon rank-sum test, whereas continuous data were compared by analysis of variance followed by Student–Newman–Keuls test. Correlation coefficient between smoking-related changes was calculated. Multiple linear regression analysis was done for correlation analysis. The level of statistical significance was set at 0.05.
Results
Cigarette smoking increases BMI, but not plasma measures of glucose and lipid metabolism
The demographic information, along with clinical characteristics, including BMI and plasma measures of glucose and lipid metabolism of all participants, are shown in Table 1. The AS and NS groups were significantly different in terms of participants’ age, education, and BMI. Specifically, the participants in the AS group were older and had received education for fewer years than those in the NS group. Moreover, cigarette smoking significantly increases BMI. However, no difference was found between the two groups in plasma measures of glucose and lipid metabolism.
Participants’ demographic data and plasma glucose and lipid metabolism measurements. Data are expressed as means (s.d .).
| Variables | NS (n = 97) | AS (n = 59) | P |
|---|---|---|---|
| Age (years) | 29.2 (9.3) | 34.2 (10.8) | 0.003 |
| Education (years) | 12.9 (3.1) | 10.8 (4.3) | 0.002 |
| BMI (kg/m2) | 25.0 (4.1) | 26.4 (3.4) | 0.032 |
| Plasma parameters | |||
| ALT (U/L) | 30.5 (23.2) | 35.1 (24.4) | 0.239 |
| AST (U/L) | 21.7 (9.6) | 21.4 (7.8) | 0.866 |
| GGT (U/L) | 41.1 (31.2) | 49.5 (39.8) | 0.169 |
| APO A1 (g/L) | 1.5 (0.5) | 1.4 (0.2) | 0.300 |
| Apo B (g/L) | 1.0 (0.3) | 0.9 (0.2) | 0.592 |
| CHO (mg/dL) | 4.7 (1.0) | 4.8 (0.8) | 0.386 |
| HDL (mg/dL) | 1.3 (0.3) | 1.2 (0.3) | 0.397 |
| LDL (mg/dL) | 2.6 (0.7) | 2.7 (0.6) | 0.585 |
| TG (mg/dL) | 1.9 (1.1) | 1.8 (1.2) | 0.701 |
ALT, alanine aminotransferase; Apo, apolipoprotein; APO A1, apolipoprotein A1; AS, active smokers; AST, aspartate aminotransferase; BMI, body mass index; CHO, cholesterol; GGT, γ-glutamyl transferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglycerides.
Changes in CSF levels of metabolic hormones, Fe, and Zn in active smokers
We measured CSF levels of adiponectin, FGF21, ghrelin, leptin, and orexin A, as well as the trace elements Fe, Cu, and Zn for all participants. Compared to NS, AS showed significantly higher CSF levels of FGF21, Fe, and Zn, but decreased levels of adiponectin, ghrelin, leptin, and orexin A. No difference was found between the two groups in CSF levels of Cu (Table 2). In the absence of changes in plasma measures, the above changes in CSF measures indicate that these measures in CSF are more sensitive to metabolic disorders.
CSF measurements of metabolic hormones, iron, and zinc in participants.
| CSF parameters | Nonsmokers (n = 97) | Active smokers (n = 59) | P |
|---|---|---|---|
| Adiponectin (ng/mL) | 9.8 (1.8) | 8.3 (1.0) | <0.001 |
| FGF21 (pg/mL) | 129.1 (37.3) | 202.1 (28.6) | <0.001 |
| Ghrelin (pg/mL) | 1564.0 (147.1) | 1198.0 (136.5) | <0.001 |
| Leptin (pg/mL) | 8.2 (1.5) | 6.8 (0.9) | <0.001 |
| Orexin A (pg/mL) | 183.3 (35.8) | 168.7 (32.0) | 0.011 |
| Cu (mg/L) | 0.7 (0.1) | 0.7 (0.1) | 0.903 |
| Fe (µM/L) | 11.4 (1.7) | 14.6 (1.2) | <0.001 |
| Zn (µM/L) | 11.1 (1.3) | 13.2 (1.5) | <0.001 |
Data are expressed as mean (s.d.).
CSF, cerebrospinal fluid; FGF, fibroblast growth factor.
Correlations between the cigarette smoking-induced changes
We wondered if a linear correlation existed between BMI and any CSF measure or between any two CSF measures. No significant correlation was found between cigarette smoking-induced BMI increase and any single CSF measure. However, significant negative correlations were found between CSF FGF21 and ghrelin (r = −0.409; Fig. 1A), between CSF zinc and ghrelin (r = −0.341; Fig. 1B), as well as between CSF iron and orexin A (r = −0.344; Fig. 1C).
The correlations between smoking-induced changes in CSF FGF21, ghrelin, orexin A, Fe, and Zn. Negative correlations were found between CSF FGF21 and ghrelin levels (A), between Zn and ghrelin levels (B), as well as between Fe and orexin A levels (C) in active smokers.
Citation: Endocrine Connections 13, 6; 10.1530/EC-24-0016
Increased CSF FGF21 and zinc predict CSF ghrelin decrease in active smokers
We performed multiple linear regression analysis on the CSF measures of FGF21, ghrelin, orexin A, Fe, and Zn, with ghrelin as the dependent variable and the others as independent variables. As shown in Table 3, all three models indicate significant associations between CSF levels of FGF21 and ghrelin, and between Zn and ghrelin. Model 1 was unadjusted. Model 2 was adjusted with age and education duration. Model 3 was adjusted with age, education, and BMI. Significance tests rejected the H1 hypothesis for the correlation between orexin A and Fe but confirmed the significant correlation between CSF levels of FGF21 and ghrelin, as well as the significant correlation between CSF levels of Zn and ghrelin in cigarette smokers.
Multiple linear regression analysis with ghrelin as the dependent variable.
| Independent variables | Model 1 (R2 = 0.285) | Model 2 (R2 = 0.275) | Model 3 (R2 = 0.279) | |||
|---|---|---|---|---|---|---|
| R2 | β coefficient (95% CI) | R2 | β coefficient (95% CI) | R2 | β coefficient (95% CI) | |
| FGF21 (pg/mL) | 0.15 | −1.96 (−3.11, −0.79)b | 0.145 | −1.96 (−3.18, −0.75)a | 0.14 | −1.94 (−3.16, −0.72)a |
| Fe (μM/L) | −0.017 | −1.75 (−32.00, 28.51) | −0.017 | −2.41 (−33.31, 28.50) | −0.021 | −1.57 (−32.60, 29.46) |
| Zn (μM/L) | 0.101 | −30.47 (−52.78, −8.17)a | 0.102 | −30.48 (−53.01, −7.96)a | 0.10 | −30.35 (−52.92, −7.78)a |
| Orexin A (pg/mL) | −0.014 | 0.26 (−0.87, 1.39) | −0.011 | 0.33 (−0.8, 1.46) | −0.011 | 0.41 (−0.74, 1.55) |
Model 1: unadjusted; model 2: adjusted for age and education; model 3: adjusted for age, education, and BMI.
aP < 0.05; bP < 0.01.
Discussion
As far as we know, this is the first case–control study reporting changes in CSF levels of metabolic hormones and trace elements in AS who showed no change in plasma measures of glucose and lipid metabolism. Along with these changes, AS had higher BMI compared to NS. These results indicate that the above metabolic hormones in CSF are sensitive biomarkers to the smoking-induced weight gain. And higher levels of CSF FGF21, Fe, and Zn constitute evidence of mitochondrial damage in brain neurons involved in the regulation of glucose and lipid metabolism in humans.
Cigarette smoking decreased CSF levels of adiponectin, ghrelin, leptin, and orexin A (Table 2). The decreased CSF adiponectin is in line with previous studies showing that smoking status is associated with lower levels of adiponectin in Korean men (30) and that plasma adiponectin is significantly lower in current smokers as compared to NS in China (31) and Japan (32). Taken together, the data from the present study and the foregoing previous studies suggest that cigarette smoking inhibits the production of adiponectin, instead of increasing the permeability of the blood–brain barrier (BBB) to this metabolic hormone in AS. In support of this suggestion, cigarette smoking was shown to mediate adiponectin levels in part through its direct inhibiting effect on adiponectin expression in adipocytes (33). Moreover, adiponectin decrease co-exists with BMI increase in AS in the present study, adding evidence for the involvement of this hormone in smoking-induced obesity. Indeed, a previous study reported that hypoadiponectinemia is associated with impaired glucose tolerance and coronary artery disease in non-diabetic men (34).
Leptin is an adipose-derived metabolic and neuroendocrine hormone with the functions of reducing food intake and increasing energy expenditure, thereby regulating body weight homeostasis. However, previous studies showed heterogeneity in the impact of smoking on leptin levels in humans. For example, early human studies reported lower plasma leptin levels in male smokers relative to NS (35, 36), whereas another study showed higher leptin levels in smokers relative to people who had never smoked before (37). The third study reported no difference in leptin levels between smokers and NS in a multiethnic population (38). These inconsistent results suggest that plasma leptin is not a reliable index for human research on smoking-related metabolic disorders. Although few studies measured CSF leptin levels in humans, CSF and circulating peripheral levels of leptin were positively correlated in previous studies (39, 40). Furthermore, a strong linear relation between CSF and plasma leptin levels in the morning and afternoon was revealed in fasting humans, as evidenced by concurrent decreases in CSF and plasma leptin concentrations during a 12- to 20-h period of fasting (41). In the context of these previous studies, CSF leptin decrease seen in AS in the present study adds further evidence that smoking decreases plasma leptin in humans.
Orexins refer to orexin A and orexin B, cleaved from a single propeptide. In mammals, the majority of central nervous system orexins are synthesized in neurons in the lateral hypothalamus and perifornical area (42). One primary function of orexins is to drive energy expenditure and inhibit obesity, as demonstrated in an animal model of mice with postnatal loss of orexin neurons. These mice exhibited hypophagia and lower levels of spontaneous physical activity and developed spontaneous-onset obesity when fed a regular diet (43, 44). However, the impact of orexin A on human energy balance is complex, involving its interactions with other energy homeostasis-related hormones such as leptin and ghrelin. Nonetheless, the overall impact of obesity resistance can be inferred from patients with narcolepsy. The patients are characterized by significantly reduced or absent orexin along with significantly increased body mass (45, 46, 47). In line with this, the AS in the present study showed higher BMI but lower CSF orexin A, adding further evidence for the overall impact of obesity resistance of this neuropeptide.
Ghrelin is a gut peptide synthesized and secreted primarily in the stomach (48), while low levels of ghrelin expression are found in the bowel, pancreas, kidney, ovary, and brain (49). Due to its appetite-stimulating effect, ghrelin induces weight gain and adiposity (50, 51). It has been reported that circulating ghrelin levels increase during fasting and before meals but decreased postprandially (52, 53, 54, 55). Additionally, ghrelin promotes adipose tissue deposition, reduces energy expenditure, and enhances the efficient storage of lipids (56, 57). Moreover, a recent study reported that obese people have low ghrelin levels (58), while patients with anorexia have high plasma ghrelin levels compared with healthy, normal weight subjects (59). This negative correlation has been considered a compensatory response (60, 61) as weight loss is accompanied by an increased ghrelin level (62), whereas weight gain is accompanied by a decreased ghrelin level (60, 63). The coexistence of increased BMI and decreased CSF ghrelin in AS in the present study adds further evidence for the above compensatory theory.
FGF21 is a peptide hormone produced by several tissues such as the liver, muscle, adipocytes, pancreas, and brain (64, 65). It targets these tissues and improves glucose and/or lipid homeostasis (65, 66). Circulating FGF21 levels are elevated in various metabolic diseases, such as obesity, insulin resistance, and type 2 diabetes mellitus (67, 68). In addition, serum concentrations of FGF21, soluble α-klotho, and interleukin 6 are significantly higher in male smokers compared with NS (69, 70). Moreover, this peptide hormone is activated and released under various conditions such as energy stress, mitochondrial dysfunction, and cold stress (71, 72). Relevantly, a history of cigarette smoking in cognitively normal elders was associated with elevated CSF biomarkers of OS in a previous study (15). Consistent with these previous studies, AS show higher levels of CSF FGF21, along with higher levels of CSF Fe and Zn relative to NS in the present study, suggesting that CSF FGF21 could serve as one of the biomarkers of smoking-induced OS in humans (discussed below).
Although the effects of cigarette smoking on serum mineral status, including Zn and Fe, are inconsistent (73, 74, 75), there is increasing evidence suggesting that high intracellular free Zn promotes neuronal death by inhibiting cellular energy production. Consequences of cellular Zn overload include increased production of cellular reactive oxygen species (ROS), loss of mitochondrial membrane potential, and decreased cellular ATP levels (76). Therefore, the excess CSF Zn may be a clue to mitochondrial damage in the brain cells of AS. In support of this point of view, high levels of Zn promoted ROS production in the mitochondria, disrupted activities of metabolic enzymes, and activated apoptotic processes in a previous study (77). Release of zinc from metallothionein 3 after injury induced ROS (78), followed by OS and ensuing secondary injuries such as mitochondrial disruption and inflammation (79). Consistent with these previous studies, AS in the present study showed higher levels of CSF Zn relative to NS, adding further evidence for mitochondrial damage in the brain cells of AS. Further evidence for the smoking-induced mitochondrial damage and OS in human brain is the elevated CSF Fe in AS relative to NS, given that free Fe can cause free radical formation and oxidative brain damage. Indeed, Fe is considered to accelerate cognitive impairment by inducing OS, ferroptosis, or inflammatory responses (80). Interestingly, no difference was found between the two groups in the CSF level of Cu. This finding seems to be different from a recent study with heterozygous LPP rats reporting that brain mitochondria present with exceptional copper sensitivity (81). In an earlier animal study with rats, copper levels were greatly reduced in the brains of developing rats fed with a low copper diet during gestation and lactation (82). Human studies, however, reported CSF copper increase in PD patients (83). The inconsistent results from the previous animal and human studies may be accounted for by species differences. The CSF copper increase in PD patients and no change in AS indicate the difference between PD patients and AS in brain neuropathology. This interpretation is consistent with the tight regulation of cellular uptake, storage, as well as export of copper in the brain so as to guarantee sufficient copper supply for the synthesis of copper-containing enzymes (29). Taken together, higher CSF levels of Fe, Zn, and FGF21 in AS in the present study constitute a group of evidence for mitochondrial damage in brain cells, although no change was found in CSF Cu.
No significant correlation was found between cigarette smoking-induced BMI increase and any single CSF measurement, indicating that a complex neuroendocrine network, rather than any single component, regulates human glucose and lipid metabolism and energy homeostasis. Alternatively, it may be due to the relatively small sample size in this study. Future study should be done with a larger sample registered in multiple hospitals. However, the interactions between individual components of this network can be inferred from the correlations among them, as seen in the present study. Specifically, a negative correlation exists between CSF FGF21 and ghrelin, indicating a compensatory response of AS to smoking-induced weight gain. This interpretation is in line with a previous study that reported higher FGF21 levels in people with obesity, supporting the hypothesis that obesity may represent a FGF21-resistant state (84). Also, negative correlations exist between CSF Zn and ghrelin, as well as between CSF Fe and orexin A, indicating that the decreased hormones in CSF may be attributed to mitochondrial damage in brain neurons that synthesize these metabolic hormones, as interpreted above, based on the data from previous studies and the present one. In line with this inference, our recent studies reported higher levels of CSF Fe, Zn, lead, magnesium, and aluminum in AS. These changes are associated with cognitive impairment and/or depression (22, 85).
We are aware of the limitations of this study. First, all the participants in this study are male cigarette smokers registered for anterior cruciate ligament reconstruction surgery in one hospital. Relevant to these limitations, the sample of this study is relatively small, which did not allow us to analyze correlations between smoking duration and changes in CSF measures in AS. Future studies should be done with a larger sample of smokers consisting of both males and females registered in multiple hospitals. Last but not least, we were unable to assess the structural and functional integrity of BBB in the subjects of this study. Therefore, we are not excluding the damaging effects of cigarette smoking on BBB, although the cigarette smoking-induced decreases in CSF levels of the metabolic hormones adiponectin, ghrelin, leptin, and orexin A do not indicate damage to the structure or integrity of BBB in AS in this study. Indeed, previous data have shown that chronic smokers have a higher incidence of small vessel ischemic disease, a pathological condition characterized by leaky brain microvessels and loss of BBB integrity (86). Recent studies have suggested that tobacco smoke can trigger a loss of BBB function and integrity (87, 88). A tentative interpretation may suggest that cigarette smoking damages brain parenchyma before disrupting BBB, in other words, BBB must not be the first line of defense in cigarette smokers.
Conclusion
Cigarette smoking-induced decreases in CSF levels of the metabolic hormones of adiponectin, ghrelin, leptin, and orexin A indicate a damaged neuroendocrine network in AS responsible for the weight-gain effect of smoking in humans. Concurrent increases in CSF FGF21, Zn, and Fe point to the existence of mitochondrial dysfunction in the neurons that synthesize the above metabolic hormones in AS.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This work was supported by grant 2017E0267 from the Technology Support Project of Xinjiang; grants 2018D01C228 and 2018D01C239 from the Natural Science Foundation of Xinjiang Uyghur Autonomous Region; grant 2017Q007 from the Tianshan Youth Project – Outstanding Youth Science and Technology Talents of Xinjiang; grants 81560229 and 81760252 from the Natural Science Foundation of China; grant 7152074 from the Beijing Natural Science Foundation; and the Opening Project of Zhejiang Provincial Top Key Discipline of Pharmaceutical Sciences.
Author contribution statement
ZP and FW: conceptualization, data curation, formal analysis, and writing original draft; HL: methodology and investigation; HC, ML, and HM: methodology and data analysis; JH, LC, and YL: supervision, project administration, and review; HX: conceptualization, results interpretation, and writing – review and editing. All the authors gave final approval and agreed to be responsible for all aspects of the work, ensuring accuracy and precision.
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