Methamphetamine: Mechanism of Action and Chinese Herbal Medicine Treatment for Its Addiction / 中国结合医学杂志

With the proliferation of synthetic drugs, research on the mechanism of action of addictive drugs and treatment methods is of great significance. Among them, methamphetamine (METH) is the most representative amphetamine synthetic drug, and the treatment of METH addiction has become an urgent medical and social problem. In recent years, the therapeutic effects of Chinese herbal medicines on METH addiction have gained widespread attention because of their non-addictiveness, multiple targets, low side effects, low cost, and other characteristics. Previous studies have identified a variety of Chinese herbal medicines with effects on METH addiction. Based on the research on METH in recent years, this article summarizes the mechanism of action of METH as the starting point and briefly reviews the Chinese herbal medicine-based treatment of METH.

Inhibition of macrophage migration inhibitory factor prevents thyroid dysfunction in pregnant rats with acute pancreatitis.

Acute pancreatitis during pregnancy (APIP) rarely occurs but may lead to preterm delivery and be associated with high fetal mortality. Macrophage migration inhibitory factor (MIF) participates in various inflammatory diseases as a pro-inflammatory cytokine. In this study, we aimed to explore the effects of (S, R)-3-(4-hydroxyphenyl)-4, 5dihydro-5-isoxazole acetic methyl ester (ISO-1), an inhibitor of MIF, on maternal thyroid injury associated with APIP and its potential mechanisms in a pregnant rat model. APIP model was induced by retrograde injection of sodium taurocholate. ISO-1 was injected intraperitoneally 30 min before model establishment. The severity of pancreatitis was assessed by levels of tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL-6 of maternal serum as well as histopathological score. Thyroid injury was determined by free triiodothyronine (FT3), free tetraiodothyronine (FT4) and thyroid histopathological score. Levels of MIF in maternal serum and the expression of MIF, CD68, CD3 and intercellular cell adhesion molecule-1 (ICAM-1) as well as oxidative stress status in maternal thyroid tissues were detected. Ultrastructure of maternal thyroid tissues was observed by transmission electron microscope. Thyroid injuries occurred in APIP and the lesions were attenuated with the pretreatment of ISO-1. Moreover, ISO-1 reduced the expression of MIF, attenuated the activations of CD68, CD3, ICAM-1 while improved oxidative stress status in maternal thyroid. Our research suggested a protective role of ISO-1 on thyroid injury and endocrine disorder during APIP, which may be associated with the inhibition of biological functions of MIF.

High-Fat Diet Aggravates Acute Pancreatitis via TLR4-Mediated Necroptosis and Inflammation in Rats.

High-fat diet (HFD) often increases oxidative stress and enhances inflammatory status in the body. Toll-like receptor 4 (TLR4) is widely expressed in the pancreatic tissues and plays an important role in pancreatitis. This study is aimed at investigating the effect of HFD on acute pancreatitis (AP) and the role of TLR4-mediated necroptosis and inflammation in this disease. Weight-matched rats were allocated for an 8-week feeding on the standard chow diet (SCD) or HFD, and then, the AP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at an indicated time point after modeling. Additionally, inhibition of TLR4 signaling by TAK-242 in HFD rats with AP was conducted in vivo. The results showed that the levels of serum free fatty acid (FFA) in HFD rats were higher than those in SCD rats. Moreover, HFD rats were more vulnerable to AP injury than SCD rats, as indicated by more serious pathological damage and much higher pancreatic malondialdehyde (MDA) and lipid peroxidation (LPO) levels as well as lower pancreatic superoxide dismutase (SOD) activities and reduced glutathione (GSH) contents and more intense infiltration of MPO-positive neutrophils and CD68-positive macrophages. In addition, HFD markedly increased the expressions of TLR4 and necroptosis marker (RIP3) and aggravated the activation of NF-κB p65 and the expression of TNF-α in the pancreas of AP rats at indicated time points. However, TLR4 inhibition significantly attenuated the structural and functional damage of the pancreas induced by AP in HFD rats, as indicated by improvement of the above indexes. Taken together, these findings suggest that HFD exacerbated the extent and severity of AP via oxidative stress, inflammatory response, and necroptosis. Inhibition of TLR4 signaling by TAK-242 alleviated oxidative stress and decreased inflammatory reaction and necroptosis, exerting a protective effect during AP in HFD rats.

4-Phenylbutyric Acid Attenuates Endoplasmic Reticulum Stress-Mediated Intestinal Epithelial Cell Apoptosis in Rats with Severe Acute Pancreatitis.

OBJECTIVES: The present study aimed to determine whether intestinal epithelial cell (IECs) apoptosis could be induced by endoplasmic reticulum stress (ERS) in severe acute pancreatitis (SAP), and the role of chemical chaperone 4-phenylbutyric acid (4-PBA) in SAP-associated intestinal barrier injury. METHODS: Twenty-four male Sprague Dawley rats were randomly divided into three groups: the sham operation group, the SAP group, and the SAP model plus 4-PBA treatment group (4-PBA group). A rat model of SAP was induced by retrograde injection of 5% sodium taurocholate (STC) into the biliopancreatic duct; in the 4-PBA group, 4-PBA was injected intraperitoneally at a dose of 50 mg/kg body weight for 3 days before modeling. RESULTS: The results indicated that 4-PBA attenuated the following: (1) pancreas and intestinal pathological injuries, (2) serum TNF-α, IL-1ß, and IL-6, (3) serum DAO level, serum endotoxin level, (4) the apoptosis of IECs, (5) ER stress markers (caspase-12, CHOP, GRP78, PERK, IRE1α, ATF6) and caspase-3 expression in intestinal. However, the serum AMY, LIPA levels, and the expression of caspase-9, caspase-8 were just slightly decreased. CONCLUSIONS: ERS may be considered a predominant pathway, which is involved in the apoptosis of IECs during SAP. Furthermore, 4-PBA protects IECs against apoptosis in STC-induced SAP by attenuating the severity of ERS.

Inhibition of macrophage migration inhibitory factor attenuates inflammation and fetal kidney injury in a rat model of acute pancreatitis in pregnancy.

Acute pancreatitis in pregnancy (APIP) is a severe disease during pregnancy that mostly occurs during the third trimester. It can lead to additional complications including preterm delivery and high fetal mortality. In this study, we investigated the protective effects of (S, R)-3-(4-hydroxyphenyl)-4, 5dihydro-5-isoxazole acetic methyl ester (ISO-1), an inhibitor of macrophage migration inhibitory factor (MIF), on fetal kidney injury associated with the maternal acute necrotizing pancreatitis (ANP) and its potential mechanisms in a rat model. The APIP rat model was induced by retrograde infusion of sodium taurocholate saline solution into biliopancreatic duct. ISO-1 was given by intraperitoneally injection 30 min before the model was induced. The levels of maternal serum amylase, lipase, tumor necrosis factor-α (TNF-α) and interleukins (IL)-1ß were measured. Maternal pancreas and fetal kidney injury were evaluated, and the expressions of MIF, phospho-p38MAPK (p-p38), nuclear factor-κB (NF-κB), TNF-α, IL-1ß in fetal kidneys were detected. The results showed that fetal rats exhibited obvious acute kidney injury during APIP, and pregnant rats pretreated with ISO-1 notably attenuated the lesions. ISO-1 also significantly reduced the expression of MIF and the activations of p38MAPK, NF-κB, as well as the levels of TNF-α and IL-1ß. These results indicated that ISO-1 could attenuate fetal kidney injury in pregnant rats with ANP by inhibiting MIF mediated p38MAPK/NF-κB signal pathways to reduce inflammatory response.

High-Fat Diet Aggravates the Intestinal Barrier Injury via TLR4-RIP3 Pathway in a Rat Model of Severe Acute Pancreatitis.

OBJECTIVE: For patients with severe acute pancreatitis (SAP), a high body mass index (BMI) increases the possibility of infection derived from the intestine. In this study, we evaluate whether TAK242 can alleviate severe acute pancreatitis-associated injury of intestinal barrier in high-fat diet-fed rats. METHODS: A SAP model was established by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Thirty Sprague-Dawley (SD) adult rats were randomly divided into five groups: standard rat chow (SRC) normal (SN), SRC SAP (SAP), high-fat diet normal (HN), HFD SAP (HSAP), and TLR4 inhibitor pretreatment HFD SAP (HAPT) groups. Intraperitoneal injection of 3 mg/kg TAK242 was administered 30 minutes before SAP model establishment in the HAPT group. Rats were sacrificed 12 hours after SAP modeling, followed by blood and pancreatic and distal ileum tissue collection for further analyses. Changes in the pathology responses of the rats in each group were assessed. RESULT: Analyses of serum amylase, lipase, cholesterol, triglyceride, IL-1ß, IL-6, DAO, and serum endotoxin as well as tight junction protein expression including zonula occluden-1 and occludin indicated that high-fat diet aggravated SAP-induced intestinal barrier injury via increasing inflammatory response. In addition, the level of necroptosis was significantly higher in the SAP group compared with the SN group while the HSAP group exhibited more necroptosis compared with the SAP group, indicating the important role of necroptosis in pancreatitis-associated gut injury and illustrating that high-fat diet aggravated necroptosis of the ileum. Pretreatment with TLR4 inhibitor significantly alleviated inflammatory response and reduced necroptosis and level of oxidative stress while improving intestinal barrier function. CONCLUSION: High-fat diet aggravated SAP-induced intestinal barrier injury via inflammatory reactions, necroptosis, and oxidative stress. Inhibition of TLR4 by TAK242 reduced inflammation, alleviated necroptosis, and lowered the level of oxidative stress and then protected the intestinal barrier dysfunction from SAP in high-fat diet-fed rats.

Corrigendum to "4-Phenylbutyric Acid Attenuates Pancreatic Beta-Cell Injury in Rats with Experimental Severe Acute Pancreatitis".

[This corrects the article DOI: 10.1155/2016/4592346.].

Serum thyroid hormones levels are significantly decreased in pregnant rats with acute pancreatitis.

Acute pancreatitis in pregnancy (APIP), which was thought to be a rare but severe disease, with a high perinatal mortality among maternal-fetuses. Our research aimed to study and assess thyroid injury in a rat model of APIP and its possible mechanisms. The APIP model was established by retrograde injection with sodium taurocholate. Sham-operated (SO) and APIP groups were performed at 3 time-points. Histological changes in the maternal thyroid and pancreas were assessed. The activities of serum amylase, lipase and levels of FT3, FT4, MDA, TNF-α and IL-1ß were detected in maternal rats, and the expression of MIF, ICAM-1 and CD68 in the maternal thyroids were determined. In this study, maternal thyroid injury as well as pancreas injury occurred in a time-dependent manner. The activities of serum amylase, lipase and levels of MDA, TNF-α and IL-1ß were markedly increased in acute pancreatitis rats, the levels of serum FT3 and FT4 were obviously decreased in APIP groups, and the expressions of MIF, ICAM-1 and CD68 were significantly increased in the thyroid of the APIP group. Ultrastructural thyroid injuries were observed in the APIP group. Our research suggests that thyroid injury is involved in the rat experimental model of APIP. The degree of thyroid dysfunction is associated with APIP, which may affect the prognosis of acute pancreatitis.

Inhibition of endoplasmic reticulum stress by 4-phenylbutyric acid prevents vital organ injury in rat acute pancreatitis.

This study was conducted to investigate the effect of 4-phenylbutyric acid (4-PBA) on vital organ injury following sodium taurocholate-induced acute pancreatitis (AP) in rats and the pertinent mechanism. The serum biochemical indicators and key inflammatory cytokines, histopathological damage and apoptosis of vital organs in rat AP, were evaluated in the presence or absence of 4-PBA. Moreover, mRNA and protein levels of endoplasmic reticulum stress (ERS) markers were assessed. 4-PBA significantly attenuated the structural and functional damage of vital organs, including serum pancreatic enzymes, hepatic enzymes, creatinine, and urea. The morphological changes and infiltration of neutrophils and macrophages were reduced as well. These effects were accompanied by decreased serum levels of proinflammatory TNF-α and IL-1ß. Furthermore, 4-PBA diminished the expression of ERS markers (glucose-regulated protein 78, CCAAT/enhancer-binding protein homologous protein, protein kinase R-like ER kinase, activated transcription factor 6, and type-1 inositol requiring enzyme) in vital organs of AP rats. 4-PBA also reduced AP-induced apoptosis in lung, liver, and kidney tissues as shown by TUNEL assay. The present study demonstrated that 4-PBA protected pancreas, lung, liver, and kidney from injury in rat AP by regulating ERS and mitigating inflammatory response to restrain cell death and further suggested that 4-PBA may have potential therapeutic implications in the disease. NEW & NOTEWORTHY In this study, we suggest that endoplasmic reticulum stress (ERS) is an important player in the development of acute pancreatitis-induced multiorgan injury, providing additional evidence for the proinflammatory role of ERS. Because 4-phenylbutyric acid has been suggested to inhibit ERS in many pathological conditions, it is possible that this effect can be involved in alleviating inflammatory response and cell death to ameliorate vital organ damage following acute pancreatitis induced by sodium taurocholate in rats.

ß cells can be generated from cytokeratin 5-positive cells after cerulein-induced pancreatitis in adult mice.

Clinical studies have revealed that some patients will develop glucose tolerance dysfunction after recovering from acute pancreatitis (AP), which indicated the importance of investigating the potential therapies for restoration of islet ß cell function. Cytokeratin 5 (Krt5)-positive cells are considered to function as stem or progenitor cells in the regeneration of lung and salivary gland following injury. In the present study, AP was induced by six hourly intraperitoneal injections of 100 µg/kg cerulein for 4 consecutive days in adult mice, in order to determine the role of Krt5-positive cells in pancreatic regeneration, especially in the restoration of ß cell function and the underlying mechanisms. Results showed that glucose homeostasis were deteriorated partly during the recovery process after AP. Furthermore, clusters of Krt5-positive cells were significantly increased in the damaged pancreas marked by inflammatory cells infiltration and acinar cell eradication. In addition, cells co-labelling insulin and Krt5 were found in the injured region after cerulein administration, part of these cells were immunopositive for GLUT2. Taken together, our data demonstrated that Krt5-expressing cells could be involved in the natural pancreas self-healing process and the renewal of ß cells after AP in adult mice. It is promising that promoting conversion of Krt5-expressing cells into functional ß cells may be a novel method to mitigate the development of diabetes mellitus after AP in vivo.

Fetal liver injury ameliorated by migration inhibitory factor inhibition in a rat model of acute pancreatitis in pregnancy.

AIM: This study was designed to investigate and assess fetal liver injury in a rat model of acute pancreatitis in pregnancy (APIP) as well as its possible mechanisms and potential therapeutic targets. METHODS: The APIP model was induced by sodium taurocholate in Sprague-Dawley rats during the third trimester. ISO-1, a macrophage migration inhibitory factor (MIF) antagonist, was given before the induction of APIP. In addition, sham-operated rats at later gestation were set as controls. Histological changes in the fetal liver and maternal pancreas were assessed. Amylase and lipase activity as well as the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß were examined. The expression of MIF in fetal liver was determined by immunochemistry and the expression of NF-κB, IκBα, high mobility group box-1 protein (HMGB1), TNF-α, and IL-1ß in fetal liver was determined by Western blot analysis. Ultrastructures of hepatic cells in fetal rats were observed under transmission electron microscopy. RESULTS: ISO-1 ameliorated the following: (i) pathological injuries in maternal pancreas and fetal liver; (ii) levels of TNF-α and IL-1ß in maternal serum; and (iii) levels of MIF, myeloperoxidase, NF-κB, HMGB1, TNF-α, and IL-1ß in fetal liver. CONCLUSION: Pathological damage and an inflammatory response in fetal liver were induced by APIP, and MIF inhibition ameliorated fetal liver injury by inhibiting the inflammatory cascade.

A preliminary study on fetal lung injury in a rat model of acute pancreatitis in pregnancy.

Acute pancreatitis in pregnancy (APIP), which was thought to be rare, is becoming more frequent. In addition, high perinatal mortality among fetuses has been reported. Our research aimed to investigate and assess fetal lung injury in a rat model of APIP and its possible mechanisms. The APIP model was induced by sodium taurocholate in Sprague-Dawley rats during the third trimester. Sham-operated (SO) rats in late gestation were used as controls, and dynamic observation and detection in the SO and acute pancreatitis (AP) groups were performed at 3 time-points. Histological changes in the fetal lungs, as well as the maternal pancreas and placenta were assessed. The levels of serum amylase, lipase, TNF-α and IL-1ß were detected in maternal rats, and the expression of surfactant proteins A, B, C and D as well as their mRNA were determined. In this study, fetal lung injury as well as maternal pancreas and placenta injuries occurred in a time-dependent manner. The levels of serum amylase, lipase and TNF-α were markedly increased in maternal rats, and the levels of surfactant proteins A, B, C and D in fetal lungs were significantly decreased in the fetal lungs of the AP group. Ultrastructure injuries and the dysregulated synthesis and secretion of pulmonary surfactant proteins were observed in the AP group. Our research suggests that fetal lung injury is involved in the rat model of APIP and that the dysregulated synthesis and secretion of pulmonary surfactant proteins play a critical role in fetal lung injury during APIP.

Effects of Castanospermine on Inflammatory Response in a Rat Model of Experimental Severe Acute Pancreatitis.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is an acute inflammatory disorder characterized by autodigestion of pancreatic tissue resulting in local pancreatic injury or systemic inflammatory response. Castanospermine (CAST) is an alkaloid from the Castanospermum australe, known as an anti-inflammatory agent and immunosuppressant in animal experiments. However, whether CAST can attenuate AP remains unclear. This study investigated the effects of CAST on sodium taurocholate (STC)-induced severe acute pancreatitis (SAP) in rats and the pertinent mechanism. METHODS: SAP was induced in rats by a retrograde infusion of 5% STC (1 mL/kg) into the biliopancreatic duct. CAST (10, 50, 100, 200 and 500 mg/kg body weight) was then administered via intraperitoneal injection. Measurement of serum amylase, lipase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen and pancreas pathological grading was used to estimate the severity of pancreatitis. Serum levels of interleukin (IL) -1ß, IL-6 and IL-10 were studied by enzyme-linked immunosorbent assay (ELISA). Nuclear factor (NF) -κB, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression in pancreas was evaluated by immunohistochemistry. RESULTS: Administration of CAST following SAP was found to ameliorate the acute pancreatic tissue injury and exhibit a more appropriately protective effect at the dose of 200 mg/kg body weight. In addition, it decreased the interleukin production in serum and NF-κB activation, TNF-α, ICAM-1 and VCAM-1 up-regulation in pancreatic tissue. CONCLUSIONS: Our study demonstrated that CAST exerts a protective effect on SAP in rats.

4-Phenylbutyric Acid Attenuates Pancreatic Beta-Cell Injury in Rats with Experimental Severe Acute Pancreatitis.

Endoplasmic reticulum (ER) stress is a particular process with an imbalance of homeostasis, which plays an important role in pancreatitis, but little is known about how ER stress is implicated in severe acute pancreatitis (SAP) induced pancreatic beta-cell injury. To investigate the effect of 4-phenylbutyric acid (4-PBA) on the beta-cell injury following SAP and the underlying mechanism, twenty-four Sprague-Dawley rats were randomly divided into sham-operation (SO) group, SAP model group, and 4-PBA treatment group. SAP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. 4-PBA or normal saline was injected intraperitoneally for 3 days in respective group before successful modeling. Results showed that 4-PBA attenuated the following: (1) pancreas and islet pathological injuries, (2) serum TNF-α and IL-1ß, (3) serum insulin and glucose, (4) beta-cell ultrastructural changes, (5) ER stress markers (BiP, ORP150, and CHOP), Caspase-3, and insulin expression in islet. These results suggested that 4-PBA mitigates pancreatic beta-cell injury and endocrine disorder in SAP, presumably because of its role in inhibiting excessive endoplasmic reticulum stress. This may serve as a new therapeutic target for reducing pancreatic beta-cell injury and endocrine disorder in SAP upon 4-PBA treatment.