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Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal

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Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal. Aging Albany NY. Background: Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites in heroin addicts during withdrawal remain largely unknown. Methods: A total of 50 participants including 20 heroin addicts with acute abstinence stage, 15 with protracted abstinence stage and 15 healthy controls, were recruited. We performed metabolic profiling of plasma samples based on ultraperformance liquid chromatography coupled to tandem mass spectrometry to explore the potential biomarkers and mechanisms of heroin withdrawal. Results: Among the metabolites analyzed, omega-6 polyunsaturated fatty acids linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, n-6 docosapentaenoic acid , omega-3 polyunsaturated fatty acids docosahexaenoic acid, docosapentaenoic acid , aromatic amino acids phenylalanine, tyrosine, tryptophan , and intermediates of the tricarboxylic acid cycle oxoglutaric acid, isocitric acid were significantly reduced during acute heroin withdrawal. Although majority of the metabolite changes could recover after months of withdrawal, the levels of alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid do not recover. Conclusions: In conclusion, the plasma metabolites undergo tremendous changes during heroin withdrawal. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and withdrawal stages in heroin addicts. Heroin, an illegal, highly addictive drug, is extremely harmful to human physical and mental health \[ 1 , 2 \]. Heroin addiction is defined as a chronic obsessive-compulsive brain disease, which causes overwhelming desire, increased tolerance, and severe withdrawal symptoms \[ 3 \]. Major withdrawal symptoms include restlessness, insomnia, drug craving, diarrhea, muscle and bone pain, cold flashes with goose bumps, and leg movements \[ 4 \]. Usually, the withdrawal symptoms peak within 8 to 72 hours after the last heroin dose and last for 4 to 10 days \[ 4 , 5 \]. However, some people may experience withdrawal symptoms for months or even years \[ 6 \]. Compared with the healthy control group, their gray matter volume around the parieto-occipital sulcus was significantly reduced \[ 9 \]. The underlying mechanism of these dramatic changes after heroin withdrawal remains unclear. However, previous metabolic studies related to drug addiction have mainly used animal studies \[ 11 — 13 \] and human metabolism might be different from that of animal models. Understanding the status of the metabolic changes of heroin addicts is essential to address withdrawal symptoms. Increasing data indicate that the metabolic changes of fatty acids FAs are involved in a variety of neurodegenerative diseases and neuropsychiatric diseases \[ 14 — 17 \]. FAs are closely related to the neurogenesis of normal brain development, neuronal inflammation, and neurotransmitter production \[ 18 \]. The polyunsaturated FAs PUFAs in particular are very important, because they play a key role in the brain with regard to neuron survival, neurogenesis, neurodegeneration, and aging \[ 19 \]. Amino acids AAs have become another focus of metabolomic studies because of their fundamental role in physiology. Series of biomarkers of AA metabolites have been found in many diseases. The combination of glutamine, glycine, and ornithine may serve as a potential diagnostic biomarker for autism spectrum disorder \[ 22 \]. Single-voxel proton magnetic resonance spectroscopy has detected significant decreases in glutamate and glutamine within the medial frontal cortex in patients with major depression disorder compared with healthy controls \[ 23 \]. Research on rat models found that methamphetamine and cocaine can cause changes in energy metabolism \[ 11 — 13 \], suggesting that organic acids OAs play an important role in substance-related research. Taken together, the three types of metabolites FAs, AAs, and OAs may play important roles in neuropsychiatric diseases. However, there are few studies on human blood metabolism related to heroin addiction and withdrawal, and the related metabolic biomarkers have not been developed and utilized. The advances in metabolomics provide powerful tools for profiling global biochemical changes in disease and treatment, which simultaneously identify and quantify hundreds to thousands of metabolites, providing an excellent opportunity to profile the metabolic changes in a high-throughput manner. Although brain tissues or cerebrospinal fluid are ideal biological samples for research on neuropsychiatric disorders, they cannot be practically obtained because of ethical and safety concerns. In comparison, blood samples can be acquired at minimal risk and cost. Furthermore, because the concentration of peripheral blood metabolites is closely related to pharmacological or toxicological effects, and because it can reflect the current state of the organism, metabolites in the peripheral blood are increasingly used to discover disease biomarkers \[ 24 , 25 \]. In a cohort study of schizophrenia, myriad differential metabolites were found in the peripheral blood of patients; these metabolites have potential to develop diagnostic tool \[ 26 , 27 \]. This research will clarify the metabolic changes that occur in heroin addicts at different stages of withdrawal, which may generate valuable biomarkers of heroin withdrawal and change our view of acute heroin withdrawal. A total of 35 male heroin addicts including 20 with acute abstinence stage ABS and 15 with protracted abstinence stage PABS , as well as 15 healthy controls HCs , were recruited and analyzed in this work. The demographic characteristics of the participants are presented in Table 1. There were no significant differences in age, body mass index, education, smoking history, alcohol use, or tea drinking habits among the three groups of participants. The overall composition of the four types of metabolites from plasma samples of each group significantly differed Figure 1. Figure 1. Heroin withdrawal changes the overall composition of metabolites in plasma. A The relative abundance of the four types of metabolites in each group. B The relative abundance of the four types of metabolites in each sample. Multivariate statistical analysis was performed to compare the differences in plasma metabolic profiling among the three groups. As shown in the score plot of PLS-DA Figure 2A , a clear separation was observed among these three groups, suggesting that the overall metabolic pattern was altered in the plasma after heroin withdrawal and that the length of heroin withdrawal time may affect the metabolism. Furthermore, the variables were unit variance scaled, and cross-validation with 1,times permutation tests were used to identify the reliability of the models. Most of these differential metabolites were significantly lower in ABS, and they could be restored during the next few months. Figure 2. Obvious metabolic abnormalities during acute heroin withdrawal. E The heatmap of differential metabolites between the 3 groups. To obtain additional data about the differential metabolites of each group, we adopted univariate and multi-dimensional statistical methods and screened out the differential metabolites that met the double standard. These metabolites were the most reliable differential markers and may become potential biomarkers. Among these different metabolites, linoleic acid LA , dihomo-gamma-linolenic acid, arachidonic acid, and n-6 docosapentaenoic acid DPA belong to the omega-6 i. Although most differential metabolites returned to normal after an extended withdrawal time, four kinds of metabolites alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid did not have normal levels restored even during protracted withdrawal several months of withdrawal Figure 4I — 4L. Figure 3. Differential metabolites and pathway enrichment analysis between each two groups. A , B The heatmap and pathway impact analysis of differential metabolites between healthy controls and acute heroin withdrawal. C , D The heatmap and pathway impact analysis of differential metabolites between long-term heroin withdrawal and acute heroin withdrawal. E , F The heatmap and pathway impact analysis of differential metabolites between healthy controls and long-term heroin withdrawal. Note that pathway with P. Figure 4. Concentrations of plasma metabolites at 3 different stages. A — D omega-6 and omega-3 polyunsaturated fatty acids. E — H representative fatty acid, amino acids and organic acid. We developed a pathway analysis bubble plot based on different metabolite results obtained from comparison of two group each, combined with pathway enrichment analysis and pathway topology analysis to facilitate biological interpretation and thereby reveal the most relevant pathways involved in heroin withdrawal Figure 3B , 3D , 3F. The metabolites enriched in the pathway can be seen in Tables 2 — 4. This study aimed to identify potential biomarkers and elucidate the possible mechanism involving heroin withdrawal from a metabolic perspective. The clinical characteristics of depressive and anxiety symptoms are closely related to blood levels of PUFAs \[ 28 , 29 \]. In the study by Xie et al. In our study, the consistent result appeared in ABS. LA is considered essential, because it cannot be synthesized in humans. LA can be converted into dihomo-gamma-linolenic acid, and then into arachidonic acid, in the body \[ 29 \]. In cell membrane phospholipids, arachidonic acid is a substrate for the synthesis of many biologic compounds \[ 30 \]. Therefore, the membrane content of arachidonic acid is very important. Changes in arachidonic acid can affect signal pathways inside and outside the cell and affect gene expression and physiological metabolic reactions, which in turn ultimately affects health status \[ 29 \]. Although LA and arachidonic acid are the precursors of many effective pro-inflammatory mediators, such as prostaglandins and leukotrienes, they do not have pro-inflammatory effects. Instead, they have a wide range of physiological effects in a complex body \[ 29 , 31 — 33 \]. For example, supplementation of arachidonic acid normalize neurogenesis and behavior in depressed mice \[ 34 \]. During acute heroin withdrawal, the significant reduction of n-6 PUFAs may seriously interfere with the signaling pathways both inside and outside the cell, leading to changes in mental or physical behaviors that may be closely related to painful withdrawal symptoms. Emerging studies have shown that n-3 PUFAs support health and reduce the risk of chronic diseases \[ 35 , 36 \]. As a component of the cell membrane, n-3 PUFAs can affect the biosynthesis of eicosanoids by regulating the fluidity of the cell membrane or the complex assembly in lipid rafts, thereby affecting cell signal transduction and exerting immune regulation \[ 36 , 38 \]. In central nervous system, n-3 PUFAs are regulators of gene transcription, and they play a vital role in maintaining brain structure \[ 39 \]. In addition, Supplementation of n-3 PUFAs has a positive regulatory effect on neuropsychiatric diseases. For example, DHA supplementation in people with mild cognitive impairment could significantly improve cognitive function and slow the progression of hippocampal atrophy \[ 40 \]. Phe can be transformed into Tyr through phenylalanine hydroxylase, and Tyr could be metabolized further into neurotransmitters, such as dopamine, norepinephrine, epinephrine, and melanin, through the action of tyrosine hydroxylase. Trp could be metabolized through the kynurenine and serotonin pathways to produce biologically active compounds, such as serotonin, melatonin, and niacin. Heroin damages the reward system by affecting the activities of dopaminergic, gamma-aminobutyric acid GABA , serotonergic, and cholinergic neurotransmitters in the central nervous system \[ 41 , 42 \]. As the precursor AAs of catecholamines, Phe and Tyr have a wide range of physiological effects. Metabolic disorders in Phe and Tyr can lead to neurodystrophy and depression \[ 43 , 44 \]. Trp is involved in several physiological processes, including neuronal function, immunity, and gut homeostasis \[ 45 \]. Our results showed that the aromatic AAs are significantly reduced during acute heroin withdrawal. The reduction may have a great impact on the concentration of neurotransmitters in the central nervous system, especially some neurotransmitters that cannot directly pass through the blood-brain barrier, such as serotonin and dopamine. The TCA cycle is carried out in the mitochondrial matrix of the human body. It is the final metabolic pathway of the three main nutrients carbohydrates, lipids, and AAs and is the hub of energy metabolism. Our results suggest that, during acute heroin withdrawal, oxoglutaric acid and isocitric acid are significantly reduced. The two are important intermediate products of the TCA cycle. The synthesis of oxoglutaric acid from isocitric acid is an important rate-limiting step in the TCA cycle. The reduction of these metabolites indicates that the TCA cycle is largely affected, mitochondrial function is impaired, energy metabolism is weakened, and productivity is reduced during heroin withdrawal. This finding suggests that the TCA cycle is downregulated during acute heroin withdrawal. However, the results of animal experiments are contrary to this. Results from Zheng et al. Oxoglutaric acid helps stimulate collagen synthesis and can affect age-related processes, including stem cell proliferation, and it has emerged as master regulatory metabolite in aging biology \[ 52 , 53 \]. The decrease of oxoglutaric acid during the acute withdrawal also suggests that heroin may be related to aging. The human brain is a highly metabolized organ, and its energy requirements are almost entirely derived from the metabolism of glucose and pyruvic acid \[ 54 \]. In our research, we found that pyruvic acid metabolism is still disordered after several months of heroin withdrawal, suggesting that heroin may have chronic and lasting damage to the central nervous system. Pyruvic acid can be converted into lactic acid in the cytoplasm to provide energy, and it can be oxidized and decarboxylated into acetyl-CoA in the mitochondria; from there, it enters the TCA cycle to be oxidized to carbon dioxide and water \[ 55 \]. Recently, lactic acid has been considered a new type of signaling molecule involved in many key reactions, and it plays an indispensable role in learning and memory, which may be related to drug addiction \[ 56 , 57 \]. Lactate at physiological concentrations functions as a signaling molecule instead of an energy substrate \[ 57 \], and studies have shown that peripheral administration of lactic acid produces antidepressant-like effects in different animal models of depression \[ 58 \]. This finding suggests that the low lactate level may be closely related to acute withdrawal. Heroin has a lasting effect on the metabolism of the human body. Even after several months of heroin withdrawal, four metabolites alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid remain unrecovered. Alpha-aminobutyric acid is closely related to the metabolism of glutathione in the body \[ 59 \]. Glutathione deficiency leads to oxidative stress, which plays a key role in the pathogenesis of aging and many diseases \[ 60 \]. Under oxidative stress, the content of alpha-aminobutyric acid in cells will decrease, which suggests that alpha-aminobutyric acid may be related to aging or other diseases \[ 59 , 61 \]. For example, alpha-aminobutyric acid is closely related to depression symptoms in the elderly \[ 62 \]. Alloisoleucine is a stereoisomer of isoleucine; ketoleucine is produced by the incomplete breakdown of branched chain AAs. Both of them are related to the metabolism of branched chain AAs, and the reduction of branched chain AAs in the blood is one of the most consistent characteristics of aging \[ 61 \]. Such as autophagy, cell growth, apoptosis, cell senescence, stem cell and mitochondrial function \[ 65 \]. In addition, animal experiments showed that supplementation of branched chain amino acids has an important anti-aging effect \[ 66 \]. Our data indicate that heroin may accelerate the aging of the human body, and this effect still exists even after long-term heroin withdrawal. Oxalic acid is produced by the decomposition of ascorbic acid, which is a powerful antioxidant that can scavenge free radicals in different tissues including the central nervous system \[ 67 \]. The decrease of oxalic acid may indicate that the metabolism of ascorbic acid is affected, which aggravates oxidative stress in the body and promotes inflamm-aging \[ 68 \]. In addition, recent studies have shown that gut microbes play an important role in the metabolism of oxalic acid \[ 69 , 70 \]. Many microbiota, such as Oxalobacter formigenes, Lactobacilli, and Bifidobacteria, are involved in the degradation of oxalic acid. According to our previous research \[ 71 \], substance use disorders including heroin abuse can significantly change the gut microbiota. The persistent low level of oxalic acid during the heroin withdrawal may be related to and imbalance of gut microbes. Compared with other diseases, human metabolomics data in the field of drug addiction remain limited. Our data support the findings from previous animal studies and we found that metabolism of heroin addicts in the acute withdrawal period is significantly different from that in the late withdrawal period. In particular, the metabolism of essential FAs, neurotransmitter precursors and energy production pathways were obviously abnormal, and these insights might provide a strategy for intervention in heroin addicts during withdrawal. In this case-control study, a total of 35 men with heroin withdrawal were recruited from a joint program of drug detoxification and rehabilitation in the First Affiliated Hospital of Kunming Medical University and the Kunming Drug Rehabilitation Center from January to October , including 20 patients with acute abstinence stage ABS and 15 patients with protracted abstinence stage PABS. All patients had a clear history of heroin use that was confirmed by urine screening tests. Fifteen age-, sex-, and body mass index—matched non-heroin-use volunteers were enrolled as healthy controls HCs. All protocols and recruitment procedures described in this study were approved by the Research Ethics Committee of the First Affiliated Hospital of Kunming Medical University L , and the study was conducted according to the tenets of the Declaration of Helsinki. All participants provided written informed consent before enrollment. Blood samples were collected and stored in the First Affiliated Hospital of Kunming Medical University Biobank using standard procedures. Peripheral venous blood was collected from fasted participants with heroin withdrawal and from HCs between and AM using Vacutainer blood collection tubes with EDTA as an anticoagulant. The anticoagulant-treated blood samples were gently mixed by inverting the tube several times. The protocols for preparation and derivatization of plasma samples were based on a previously published method, with minor modifications. The sample was homogenized with zirconium oxide beads for 3 min and then was centrifuged at 18, g for 20 min. Serial dilutions of derivatized stock standards were added to the left well. We used the Wilcoxon test to analyze continuous variables and either the Fisher test or chi squared test to analyze categorical variables. Yiqun Kuang, Mei Zhu participated in the design of the study and supervised the project. All authors read and approved the final version of the manuscript. This corresponding author has a verified history of publications using a personal email address for correspondence. Juehua Yu juehuayu gmail. Kunhua Wang kunhuawang1 Impact Journals, LLC. Impact Journals is a member of the Society for Scholarly Publishing. Research Paper Volume 13, Issue 14 pp — Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal. Abstract Background: Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. Introduction Heroin, an illegal, highly addictive drug, is extremely harmful to human physical and mental health \[ 1 , 2 \]. Results Baseline characteristics A total of 35 male heroin addicts including 20 with acute abstinence stage ABS and 15 with protracted abstinence stage PABS , as well as 15 healthy controls HCs , were recruited and analyzed in this work. Table 1. Demographic features of drug withdrawal groups and HCs. Differences in metabolites between ABS and the other two groups Multivariate statistical analysis was performed to compare the differences in plasma metabolic profiling among the three groups. Effect of the heroin withdrawal on metabolite levels To obtain additional data about the differential metabolites of each group, we adopted univariate and multi-dimensional statistical methods and screened out the differential metabolites that met the double standard. Alterations in metabolic pathways We developed a pathway analysis bubble plot based on different metabolite results obtained from comparison of two group each, combined with pathway enrichment analysis and pathway topology analysis to facilitate biological interpretation and thereby reveal the most relevant pathways involved in heroin withdrawal Figure 3B , 3D , 3F. By enriching the different metabolites between groups, nine significantly altered pathways p Table 2. Pathways HC vs. Table 3. Pathways PABS vs. Table 4. Pathways HCs vs. Severe metabolic alterations of n-6 and n-3 PUFAs during acute heroin withdrawal The clinical characteristics of depressive and anxiety symptoms are closely related to blood levels of PUFAs \[ 28 , 29 \]. Significant changes in energy metabolism during acute heroin withdrawal The TCA cycle is carried out in the mitochondrial matrix of the human body. Effects of heroin on metabolites persist after prolonged withdrawal Heroin has a lasting effect on the metabolism of the human body. Conclusions Compared with other diseases, human metabolomics data in the field of drug addiction remain limited. Materials and Methods Patients In this case-control study, a total of 35 men with heroin withdrawal were recruited from a joint program of drug detoxification and rehabilitation in the First Affiliated Hospital of Kunming Medical University and the Kunming Drug Rehabilitation Center from January to October , including 20 patients with acute abstinence stage ABS and 15 patients with protracted abstinence stage PABS. A p value. Keywords heroin withdrawal metabolomics polyunsaturated fatty acids aromatic amino acids tricarboxylic acid cycle.

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