Extracellular vesicles in the pathogenesis and treatment of acute lung injury.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common life-threatening lung diseases associated with acute and severe inflammation. Both have high mortality rates, and despite decades of research on clinical ALI/ARDS, there are no effective therapeutic strategies. Disruption of alveolar-capillary barrier integrity or activation of inflammatory responses leads to lung inflammation and injury. Recently, studies on the role of extracellular vesicles (EVs) in regulating normal and pathophysiologic cell activities, including inflammation and injury responses, have attracted attention. Injured and dysfunctional cells often secrete EVs into serum or bronchoalveolar lavage fluid with altered cargoes, which can be used to diagnose and predict the development of ALI/ARDS. EVs secreted by mesenchymal stem cells can also attenuate inflammatory reactions associated with cell dysfunction and injury to preserve or restore cell function, and thereby promote cell proliferation and tissue regeneration. This review focuses on the roles of EVs in the pathogenesis of pulmonary inflammation, particularly ALI/ARDS.

Zengye Decoction Attenuated Severe Acute Pancreatitis Complicated with Acute Kidney Injury by Modulating the Gut Microbiome and Serum Amino Acid Metabolome.

Objective: To explore the effect and underlying mechanism of Zengye decoction (ZYD), a traditional formula from China, on the severe acute pancreatitis (SAP) rat model with acute kidney injury (AKI). Methods: The SAP-AKI model was induced by 3.5% sodium taurocholate. Rats were treated with normal saline or ZYD twice and sacrificed at 36 h after modeling. Amylase, lipase, creatinine, blood urea nitrogen, kidney injury molecule 1(KIM-1), and multiple organs' pathological examinations were used to assess the protective effect of ZYD. Gut microbiome detected by 16S rRNA sequencing analysis and serum amino acid metabolome analyzed by liquid chromatography-mass spectrometry explained the underlying mechanism. The Spearman correlation analysis presented the relationship between microflora and metabolites. Results: ZYD significantly decreased KIM-1(P < 0.05) and the pathological score of the pancreas (P < 0.05), colon (P < 0.05), and kidney (P < 0.05). Meanwhile, ZYD shifted the overall gut microbial structure (ß-diversity, ANOSIM R = 0.14, P=0.025) and altered the microbial compositions. Notably, ZYD reduced the potentially pathogenic bacteria-Bacteroidetes, Clostridiales vadin BB60 group, and uncultured_Clostridiales_bacterium, but promoted the short-chain fatty acid (SCFA) producers-Erysipelotrichaceae, Bifidobacterium, Lactobacillus, and Moryella (all P < 0.05). Moreover, principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and hierarchical clustering analysis (HCA) presented a remarkable change in amino acid metabolome after SAP-AKI induction and an apparent regulation by ZYD treatment (R2Y 0.878, P=0.01; Q2 0.531, P=0.01). Spearman's correlation analysis suggested that gut bacteria likely influenced serum metabolites levels (absolute r > 0.4 and FDR P < 0.02). Conclusions: ZYD attenuated SAP-AKI by modulating the gut microbiome and serum amino acid metabolome, which may be a promising adjuvant treatment.

Acupuncture at the P6 Acupoint to Prevent Postoperative Pain after Craniotomy: A Randomized, Placebo-Controlled Study.

OBJECTIVE: Acute pain management after craniotomy can be challenging. Previous studies have shown inadequate pain control following the procedure. Oral medication can sometimes be delayed by postoperative nausea, and use of anesthetics may impair the assessment of brain function. We conducted this prospective study to evaluate the effect of acupuncture at the P6 acupoint on postoperative pain, nausea, and vomiting in patients undergoing craniotomy. METHODS: The authors conducted a randomized, placebo-controlled trial among 120 patients scheduled for craniotomy under general anesthesia. 120 patients were randomly assigned into an acupuncture group or a sham acupuncture group. All patients received standardized anesthesia and analgesia treatment. Acupuncture was executed in the recovery room after surgery. For the acupuncture group, the P6 points on each wrist were punctured perpendicularly to a depth of 20 mm. Needles were retained for 30 min and stimulated every 10 min to maintain the De-Qi sensation. For the sham acupuncture group, sham points on each wrist were punctured perpendicularly to a depth of 5 mm. Needles were retained for 30 min with no stimulation during the duration. The postoperative pain scores, PONV, and dose of tramadol were assessed 24 h, 48 h, and 72 h after surgery. RESULTS: A total of 117 patients completed the study. There was no statistically significant difference in baseline data between the two groups (P > 0.05). The VAS pain score of the acupuncture group was lower than that of the sham acupuncture group, and this difference was statistically significant (P=0.002). There was no difference in pain scores between the two groups during 0-24 h and 48-72 h (P > 0.05). The incidence of vomiting in the acupuncture group was lower than that in the sham acupuncture group during the 0-24 h period (13.8% vs. 28.8%, P=0.048). There was no difference in vomiting, however, during the 24-72 h period (P > 0.05). No significant differences were found in the degree of nausea and the dose of tramadol between the two groups at either time point in the acupuncture group and sham acupuncture group. CONCLUSION: The use of acupuncture at the P6 acupoint in neurosurgery patients did result in significantly lower pain scores and reduction in the incidence of vomiting after craniotomy. There were no significant side effects. Acupuncture at the P6 acupoint was well tolerated and safe in this patient population.

Effect of Sheng-Jiang Powder on Gut Microbiota in High-Fat Diet-Induced NAFLD.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is an alarming global health problem that is predicted to be the major cause of cirrhosis, hepatocellular carcinoma, and liver transplantation by next decade. Gut microbiota have been revealed playing an important role in the pathogenesis of NAFLD. Sheng-Jiang Powder (SJP), an empirical Chinese medicine formula to treat NAFLD, showed great hepatoprotective properties, but the impact on gut microbiota has never been identified. Therefore, we performed this study to investigate the effect of SJP on gut microbiota in NAFLD mice. METHODS: NAFLD was induced by 12 weeks' high-fat diet (HFD) feeding. Mice were treated with SJP/normal saline daily for 6 weeks. Blood samples were obtained for serum biochemical indices and inflammatory cytokines measurement. Liver tissues were obtained for pathological evaluation and oil red O staining. The expression of lipid metabolism-related genes was quantified by RT-PCR and Western blotting. Changes in gut microbiota composition were analyzed by the 16s rDNA sequencing technique. RESULTS: HFD feeding induced significant increase in bodyweight and serum levels of TG, TC, ALT, and AST. The pathological examination revealed obvious hepatic steatosis in HFD feeding mice. Coadministration of SJP effectively protected against bodyweight increase and lipid accumulation in blood and liver. Increased expression of PPARγ mRNA was observed in HFD feeding mice, but a steady elevation of PPARγ protein level was only found in SJP-treated mice. Meanwhile, the expression of FASN was much higher in HFD feeding mice. Microbiome analysis revealed obvious changes in gut microbiota composition among diverse groups. SJP treatment modulated the relative abundance of short-chain fatty acids (SCFAs) producing bacteria, including norank-f-Erysipelotrichaceae and Roseburia. CONCLUSIONS: SJP is efficient in attenuating HFD-induced NAFLD, and it might be partly attributed to the regulation of gut microbiota.

Effects of Yue-Bi-Tang on water metabolism in severe acute pancreatitis rats with acute lung-kidney injury.

BACKGROUND: The complications acute lung injury and acute kidney injury caused by severe inflammation are the main reasons of high mortality of severe acute pancreatitis (SAP). These two complications can both lead to water metabolism and acid-base balance disorders, which could act as additional critical factors affecting the disease trend. Aquaporins (AQPs), which can regulate the transmembrane water transport, have been proved to participate in the pathophysiological process of SAP and the associated complications, such as acute lung injury and acute kidney injury. Thus, exploring herbs that can effectively regulate the expression of AQP in SAP could benefit the prognosis of this disease. AIM: To determine whether Yue-Bi-Tang (YBT) can regulate the water metabolism in rats with severe acute pancreatitis via regulating the expression of aquaporins. METHODS: Sprague-Dawley rats were randomly divided into three groups, sham operation group (SOG), model group (MG), and treatment group (TG). SAP was induced with 3.5% sodium taurocholate in the MG and TG. Rats in the TG were administered with YBT while SOG and MG rats were given the same volume of saline. Blood and tissue samples were harvested to detect serum inflammatory cytokines, histopathological changes, malondialdehyde and superoxide dismutase in the lung, and protein and mRNA expression of kidney injury molecule-1, α-smooth muscle actin, and vimentin in the kidney, and AQP1 and 4 in the lung, pancreas, and kidney. RESULTS: The serum interleukin-10, tumor necrosis factor α, and creatinine levels were higher in the MG than in the SOG. Tumor necrosis factor α level in the TG was lower than that in the MG. Malondialdehyde level in lung tissues was higher than in the SOG. The pathological scores and edema scores of the pancreas, lung, and kidney tissues in the MG were all higher than those in the SOG and TG. The protein expression of AQP4 in lung tissues and AQP1 in kidney tissues in the MG were higher than those in the SOG and TG. The expression of vimentin was significantly higher in the MG than in the SOG. The expression of AQP1 mRNA in the lung and kidney, and AQP4 mRNA in the kidney was up-regulated in the MG compared to the SOG. CONCLUSION: YBT might regulate water metabolism to reduce lung and kidney edema of SAP rats via decreasing AQP expression, and alleviate the tissue inflammatory injury.

Optimal dosing time of Dachengqi decoction for protection of extrapancreatic organs in rats with experimental acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a pancreatic inflammatory disorder that is commonly complicated by extrapancreatic organ dysfunction. Dachengqi decoction (DCQD) has a potential role in protecting the extrapancreatic organs, but the optimal oral administration time remains unclear. AIM: To screen the appropriate oral administration time of DCQD for the protection of extrapancreatic organs based on the pharmacokinetics and pharmacodynamics of AP rats. METHODS: This study consisted of two parts. In the first part, 24 rats were divided into a sham-operated group and three model groups. The four groups were intragastrically administered with DCQD (10 g/kg) at 4 h, 4 h, 12 h, and 24 h postoperatively, respectively. Tail vein blood was taken at nine time points after administration, and then the rats were euthanized and the extrapancreatic organ tissues were immediately collected. Finally, the concentrations of the major DCQD components in all samples were detected. In the second part, 84 rats were divided into a sham-operated group, as well as 4 h, 12 h, and 24 h treatment groups and corresponding control groups (4 h, 12 h, and 24 h control groups). Rats in the treatment groups were intragastrically administered with DCQD (10 g/kg) at 4 h, 12 h, and 24 h postoperatively, respectively, and rats in the control groups were administered with normal saline at the same time points. Then, six rats from each group were euthanized at 4 h and 24 h after administration. Serum amylase and inflammatory mediators, and pathological scores of extrapancreatic organ tissues were evaluated. RESULTS: For part one, the pharmacokinetic parameters (C max, T max, T 1/2, and AUC 0 → t) of the major DCQD components and the tissue distribution of most DCQD components were better when administering DCQD at the later (12 h and 24 h) time points. For part two, delayed administration of DCQD resulted in lower IL-6 and amylase levels and relatively higher IL-10 levels, and pathological injury of extrapancreatic organ tissues was slightly less at 4 h after administration, while the results were similar between the treatment and corresponding control groups at 24 h after administration. CONCLUSION: Delayed administration of DCQD might reduce pancreatic exocrine secretions and ameliorate pathological injury in the extrapancreatic organs of AP rats, demonstrating that the late time is the optimal dosing time.

Effect of Different-Volume Fluid Resuscitation on Organ Functions in Severe Acute Pancreatitis and Therapeutic Effect of Poria cocos.

OBJECTIVE: To explore the effect of different-volume fluid resuscitation (FR) on organ functions in severe acute pancreatitis (SAP) and to elucidate the therapeutic effect and mechanism of Poria cocos on organ injuries caused by high-volume FR. METHODS: 1. Clinical study: retrospective analysis of thirty-one patients about the effect of titrated fluid resuscitation protocol (TFR) on the occurrence of acute kidney injury (AKI) secondary to SAP. 2. Experimental study: rats (N = 30) were randomly divided into five groups: sham, model, low-volume FR (1.5 ml/kg/h), high-volume FR (10 ml/kg/h), and Poria cocos combined with high-volume FR (10 ml/kg/h + intraintestinal administration Poria cocos 5 g/kg); serum or plasma indicators and histopathologic scores were compared to explore the effect and mechanism of different fluid volumes and Poria cocos on organ function in SAP. RESULTS: The occurrence of AKI, fluid volume, and fluid velocity in TFR group was lower than that in the control group. Logistic regression analysis showed that increased Marshall scores and fluid velocity were risk factors for predicting occurrence of AKI in SAP. Low-volume FR decreased the levels of blood urea nitrogen (BUN), serum creatinine (Cr), matrix metalloproteinase (MMP), and pathologic scores of the pancreas and kidney. High-volume FR increased ascites, MMPs, and kidney pathologic scores. Poria cocos decreased the levels of BUN, Cr, MMPs, and pathologic scores of the pancreas and kidney and increased the arterial oxygen saturation. CONCLUSION: TFR-associated lower fluid volume and velocity reduced the occurrence of AKI secondary to SAP. High volume might aggravate AKI via increased MMP release leading to endothelial glycocalyx damage and vascular endothelial dysfunction. Poria cocos reduced MMP release, relieved glycocalyx damage, and alleviated the pancreas and kidney injury aggravated by high fluid volume in SAP. Therefore, endothelial glycocalyx protection might be a new strategy in the treatment of SAP.

Effect of Sheng-jiang powder on multiple-organ inflammatory injury in acute pancreatitis in rats fed a high-fat diet.

BACKGROUND: Obesity worsens inflammatory organ injury in acute pancreatitis (AP), but there is no effective preventive strategy. Sheng-jiang powder (SJP) has been shown to alleviate multiple-organ inflammatory injury in rats with high-fat diet-induced obesity. Hence, SJP is supposed to have an effect on multiple-organ inflammatory injury in AP in rats fed a high-fat diet. AIM: To explore how obesity may contribute to aggravating inflammatory organ injury in AP in rats and observe the effect of SJP on multiple-organ inflammatory injury in AP in rats fed a high-fat diet. METHODS: Rats were randomly assigned to a control group (CG), an obese group (OG), and an SJP treatment group (SG), with eight rats per group. The rats in the OG and SG were fed a high-fat diet. From the third week, the rats in the SG were given oral doses of SJP (5 g/kg of body weight). After 12 wk, AP was induced in the three groups. Serum amylase level, body weight, Lee's index, serum biochemistry parameters, and serum inflammatory cytokine and tissue cytokine levels were assessed, and the tissue histopathological scores were evaluated and compared. RESULTS: Compared with the CG, serum triglyceride, total cholesterol, interleukin-6, and interleukin-10 levels were significantly higher in the OG, and serum high-density lipoprotein cholesterol level was significantly lower in the OG. Moreover, enhanced oxidative damage was observed in the pancreas, heart, spleen, lung, intestine, liver, and kidney. Evidence of an imbalanced antioxidant defense system, especially in the pancreas, spleen, and intestine, was observed in the obese AP rats. Compared with the OG, serum high-density lipoprotein cholesterol, interleukin-10, and superoxide dismutase expression levels in the pancreas, spleen, and intestine were increased in the SG. Additionally, SJP intervention led to a decrease in the following parameters: body weight; Lee's index; serum triglyceride levels; serum total cholesterol levels; malondialdehyde expression levels in the pancreas, heart, spleen, lung, and liver; myeloperoxidase expression levels in the lung; and pathological scores in the liver. CONCLUSION: Obesity may aggravate the inflammatory reaction and pathological multiple-organ injury in AP rats, and SJP may alleviate multiple-organ inflammatory injury in AP in rats fed a high-fat diet.

Sheng-Jiang Powder Ameliorates High Fat Diet Induced Nonalcoholic Fatty Liver Disease via Inhibiting Activation of Akt/mTOR/S6 Pathway in Rats.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is an alarming public health problem that directly contributes to increased prevalence of liver cirrhosis and hepatic cell cancer, but without any specific pharmacological option. Sheng-jiang powder (SJP), an empirical Chinese medicine formula to treat NAFLD, showed great efficacy but the specific mechanisms have never been reported. Therefore, we performed this study to explore the effect of SJP on NAFLD and the potential mechanism. METHODS: NAFLD was induced by high fat diet (HFD) feeding. Rats were treated with SJP/normal saline daily for 10 weeks and all rats were euthanized after 12 weeks' feeding. Liver tissue samples were obtained for biochemistry test and pathological evaluation. Additionally, oleic acid induced LO2 cells were employed to simulate a cell model of NAFLD. Cells were subjected to western blotting for Akt, mTOR, S6, SREBP1-c, and FASN detection after coincubated with SJP, LY294002 (a selective PI3K inhibitor), or the combination for 24h. RESULTS: HFD significantly induced hepatic steatosis. Plenty of lipid droplets were observed under transmission electron microscope. The ultrastructure of liver cells showed distinct changes with obvious endoplasmic reticulum expansion, mitochondrial contraction, and cell matrix solidification. Although no difference was detected in serum hepatic enzymes and tissue proinflammatory cytokines, the tissue level of SOD and GSH-px was much lower and the pathologic injuries were much severe in HFD feeding rats. However, SJP treatment significantly attenuated the ultrastructure changes and protected rat liver against inflammatory injury. Abundant of lipid droplets and high expression of pAkt, pmTOR, pS6, and FASN were observed in oleic acid treated LO2 cells, while these changes were restored by SJP treatment. CONCLUSIONS: SJP is efficient in attenuating HFD induced NAFLD in rats and this effect might be partly related to the inhibition of Akt/mTOR/S6 pathway.

Sheng-jiang powder ameliorates obesity-induced pancreatic inflammatory injury via stimulating activation of the AMPK signalling pathway in rats.

AIM: To investigate the mechanisms by which Sheng-jiang powder (SJP) ameliorates obesity-induced pancreatic inflammatory injury. METHODS: Sprague-Dawley rats were randomized into three groups: normal group (NG), obese group (HLG), or SJP treatment group (HSG). Obesity was induced by feeding a high-fat diet in the HLG and HSG, while the NG received standard chow. Rats were euthanized after 12 wk, and blood and pancreatic tissues were collected for histopathological analyses. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transforming growth factor beta (TGF-ß) expression, serum triglyceride and adiponectin levels, and apoptosis in pancreatic acinar cells were assessed. A high-fat AR42J acinar cell injury model was established using very low-density lipoprotein (VLDL). AR42J acinar cell culture supernatant, treated with different interventions, was applied to seven groups of pancreatic stellate cells (PSCs). The proliferation of PSCs and the expression of fibronectin and type I collagenase were assessed. RESULTS: Compared with the NG, we found higher pathological scores for pancreatic tissues, lower serum adiponectin levels, higher expression levels of NF-κB in pancreatic tissues and TGF-ß in pancreatic inflammatory cells, and increased apoptosis among pancreatic acinar cells for the HLG (P < 0.05). Compared with the HLG, we found reduced body weight, Lee's index scores, serum triglyceride levels, and pathological scores for pancreatic tissues; higher serum adiponectin levels; and lower expression levels of NF-κB, in pancreatic tissue and TGF-ß in pancreatic inflammatory cells for the HSG (P < 0.05). The in vitro studies showed enhanced PSC activation and increased expression levels of fibronectin and type I collagenase after SJP treatment. An adenosine 5'-monophosphate-activated protein kinase (AMPK) inhibitor inhibited PSC activation. CONCLUSION: SJP may ameliorate obesity-induced pancreatic inflammatory injury in rats by regulating key molecules of the adiponectin-AMPK signalling pathway.

[Administration of Electroacupuncture and Da-Cheng-Qi Decoction Has a Synergetic Effect in Relieving Injury of Pancreas, Lung and Large Intestine and Inflammatory Reactions in Rats with Acute Pancreatitis].

OBJECTIVE: To explore the effectiveness of electroacupuncture (EA) stimulation of Shu-and Mu-points of Lung and Large Intestine Meridians combined with administration of Da-Cheng-Qi Decoction (DCQD) in the treatment of inflammatory injury in rats with acute pancreatitis, so as to reveal their synergetic anti-inflammatory effect. METHODS: Forty male SD rats were randomly divided into five groups: normal control, model, DCQD, EA, EA+DCQD, with 8 rats in each group. All the rats except those in the normal group received a retrograde biliopancreatic duct injection of sodium Taurocholate (3.0%, 0.1 mL/100 g) to induce an acute pancreatitis model. Twenty-four hours after modeling, EA (4 Hz/50 Hz) was applied to bilateral Shu-points "Feishu" (BL 13) and "Dachangshu" (BL 25), and Mu-points "Zhongfu" (LU 1) and "Tianshu" (ST 25) for 20 min, once every 7 h, 3 times in total. Rats of the DCQD and EA+DCQD groups were given intra-gastric gavage of DCQD (1 mL/100 g) 24 h after modeling, and those of the other 3 groups were given intra-gastric gavage of same dosage of normal saline. The histopathological changes of the pancreas, lung and large intestine tissues were observed after H. E. staining and scored according to Schmidt's and colleagues' methods (the severity of edema, inflammation, hemorrhage, necrosis). The concentrations of interleukin-6 (IL-6) and IL-10 in the serum, and those of myeloperoxidase (MPO) and malonaldehyde (MDA) in the lung and large intestine tissues were detected by using double-antibody sandwich ELISA. RESULTS: After modeling, the histopathological scores of pancreas, lung and large intestine tissues, the concentrations of MPO and MDA in lung and large intestine, and the levels of IL-6 and IL-10 in serum were significantly increased in the model group compared with the normal control group (P<0.05). Following the treatment, the histopathological scores of pancreas, lung and large intestine tissues, the contents of MPO and MDA in the lung and large intestine, and serum IL-6 were considerably reduced in the EA, DCQD and EA+DCQD groups relevant to the model group (P<0.05), while serum IL-10 content was notably increased in the three treatment groups (P<0.05). The therapeutic effect of EA+DCQD was significantly superior to that of simple EA and simple DCQD in down-regulating the histopathological scores of lung and large intestine tissues, the contents of MPO and MDA in the lung and large intestine, and serum IL-6 level, and up-regulating serum IL-10 level (P<0.05). No significant differences were found between the EA and DCQD groups in the above-mentioned 9 indexes (P>0.05). CONCLUSION: EA and DCQD can relieve the inflammatory injury of the pancreas, lung and large intestine tissues in rats with acute pancreatitis, and EA combined with DCQD has a better synergetic effect in reducing oxidative stress level and inflammatory reaction.

Effect of Sheng-Jiang Powder on Obesity-Induced Multiple Organ Injuries in Rats.

BACKGROUND AND AIMS: Obesity has become the main public health issue nowadays with poor control and has been associated with increased risk of multiorgan disease, but the specific mechanism and effective medication are still to be addressed. Sheng-jiang powder (SJP) showed great potential in preventing obesity in Chinese researches but has no trace in English reports. This study was designed to investigate the effect of SJP on obesity and obesity-mediated multiorgan injuries. METHODS: Rats were randomized into normal group (NG), obese group (OG), and SJP treatment group (SG). Obesity was induced by high-fat diet feeding. Rats were gavaged with SJP/normal saline daily from the third week and all rats were sacrificed after 12 weeks' feeding. Tissues were obtained for cytokines tests. RESULTS: Firstly, high-fat diet feeding led to significant obesity. Compared to NG, the level of SOD in the liver, spleen, lung, and kidney was much lower in OG (p < 0.05), while the pathological scores of pancreas, liver, spleen, lung, and kidney were much higher. SJP significantly increased SOD level in the liver, spleen, and lung and reduced the pathological scores of pancreas, liver, spleen, lung, and kidney correspondingly (p < 0.05). CONCLUSIONS: SJP ameliorates inflammatory response and mitigates obesity-induced multiple organ injuries.

Optimal timing for the oral administration of Da-Cheng-Qi decoction based on the pharmacokinetic and pharmacodynamic targeting of the pancreas in rats with acute pancreatitis.

AIM: To identify the optimal oral dosing time of Da-Cheng-Qi decoction (DCQD) in rats with acute pancreatitis (AP) based on the pharmacokinetic and pharmacodynamic parameters. METHODS: First, 24 male Sprague-Dawley rats were divided into a sham-operated group [NG(a)] and three model groups [4hG(a), 12hG(a) and 24hG(a)]. The NG(a) and model groups were administered DCQD (10 g/kg.BW) intragastrically at 4 h, 4 h, 12 h and 24 h, respectively, after AP models induced by 3% sodium taurocholate. Plasma samples were collected from the tails at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after a single dosing with DCQD. Plasma and pancreatic tissue concentrations of the major components of DCQD were determined by high-performance liquid chromatography tandem mass spectroscopy. The pharmacokinetic parameters and serum amylase were detected and compared. Second, rats were divided into a sham-operated group [NG(b)] and three treatment groups [4hG(b), 12hG(b) and 24hG(b)] with three corresponding control groups [MG(b)s]. Blood and pancreatic tissues were collected 24 h after a single dosing with DCQD. Serum amylase, inflammatory cytokines and pathological scores of pancreatic tissues were detected and compared. RESULTS: The concentrations of emodin, naringin, honokiol, naringenin, aloe-emodin, chrysophanol and rheochrysidin in the 12hG(a) group were higher than those in the 4hG(a) group in the pancreatic tissues (P < 0.05). The area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration values (AUC0→t) for rhein, chrysophanol, magnolol and naringin in the 12hG(a) group were larger than those in the 4hG(a) or 24hG(a) groups. The 12hG(a) group had a higher Cmax than the other two model groups. The IL-10 levels in the 12hG(b) and 24hG(b) groups were higher than in the MG(b)s (96.55 ± 7.84 vs 77.46 ± 7.42, 251.22 ± 16.15 vs 99.72 ± 4.7 respectively, P < 0.05), while in the 24hG(b) group, the IL-10 level was higher than in the other two treatment groups (251.22 ± 16.15 vs 154.41 ± 12.09/96.55 ± 7.84, P < 0.05). The IL-6 levels displayed a decrease in the 4hG(b) and 12hG(b) groups compared to the MG(b)s (89.99 ± 4.61 vs 147.91 ± 4.36, 90.82 ± 5.34 vs 171.44 ± 13.43, P < 0.05). CONCLUSION: Late-time dosing may have higher concentrations of the most major components of DCQD, with better pharmacokinetics and pharmacodynamics of anti-inflammation than early-time dosing, which showed the late time to be the optimal dosing time of DCQD for AP.

Pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction in the liver of rats with severe acute pancreatitis.

AIM: To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction (DCQD) in the liver of rats with severe acute pancreatitis (SAP) based on an herbal recipe tissue pharmacology hypothesis. METHODS: Healthy male Sprague-Dawley rats were randomly divided into a sham operation group (SOG); a model group (MG); and low-, median- and high-dose treatment groups (LDG, MDG, and HDG, respectively). Different dosages (6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloe-emodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase (ALT) and aspartate transaminase (AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated. RESULTS: The major components of DCQD were detected in the liver, and their concentrations increased dose-dependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin (IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG (P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG (P < 0.05), while there was no statistical difference in the MG and HDG. CONCLUSION: DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.

Pharmacokinetics and pharmacodynamics of Shengjiang decoction in rats with acute pancreatitis for protecting against multiple organ injury.

AIM: To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction (SJD) in rats with acute pancreatitis (AP) for protecting against multiple organ injury. METHODS: An AP model was established by retrograde perfusion of 3.5% sodium taurocholate into the biliopancreatic duct, and a control group (CG) received 0.9% sodium chloride instead. Twelve male Sprague-Dawley rats were randomly divided into a CG treated with SJD (CG + SJD) and a model group treated with SJD (MG + SJD), both of which were orally administered with SJD (5 g/kg) 2 h after surgery. Blood samples were collected via the tail vein at 10, 20, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after a single dose of SJD to detect its main components using high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were compared. In the pharmacodynamic experiment, 18 male Sprague-Dawley rats were randomly divided into a CG, an AP model group (MG), and an SJD treated AP group (SJDG). Serum amylase, lipase, and inflammatory cytokines were measured, and heart, lung, liver, spleen, pancreas, kidney, and intestine tissues were collected for pathological examination. RESULTS: The MG + SJD displayed significantly shorter mean residence time (MRT) and higher clearance (CL) for emodin and aloe-emodin; significantly shorter time of maximum concentration and T1/2 and a lower area under curve (AUC) for aloe-emodin; a significantly higher AUC and lower CL for rhein; and longer MRT and lower CL for chrysophanol than the CG + SJD. In the pharmacodynamic experiment, the amylase, interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α levels in the MG were higher than those in the CG (P < 0.05). After the herbal decoction treatment, the SJDG had higher IL-10 and lower TNF-α levels than the MG (P < 0.05). The MG had the highest pathological scores, and the pathological scores of the lung, pancreas, kidney, and intestine in the SJDG were significantly lower than those in the MG (P < 0.05). CONCLUSION: AP may have varying effects on the pharmacokinetics of the major SJD components in rats. SJD might alleviate pathological injuries of the lung, pancreas, kidney, and intestine in rats with AP via regulating pro- and anti- inflammatory responses, which might guide the clinical application of SJD for AP treatment.

Effect of acute pancreatitis on the pharmacokinetics of Chinese herbal micron Liuhe Pill ointment in rats.

OBJECTIVE: To explore the effect of acute pancreatitis (AP) on the pharmacokinetics of herbal ointment micron Liuhe Pill, MLHP) components in anesthetized rats. METHODS: Rats were randomly divided into a AP model group (n=6) and a normal group as a control (n=6). The rat model of AP was induced by intraperitoneal injection of L-arginine in rats (15 mg/kg, twice, interval 1 h). Chinese herbal ointment MLHP was used externally on the belly after the 2nd injection for 48 h in both groups. Emodin, rhein, aloe emodin, physcion, chrysophanol from MLHP were detected and quantified in rat serum and pancreas (at 48 h) by high performance liquid chromatography-tandem mass spectrometry. RESULTS: Among the five components, only emodin, aloe emodin and physcion from MLHP were detected in all rat serum and most of the rats' pancreas. Rhein and chrysophanol were not detected in both serum and pancreas. T1/2α of emodin and physcion in MLHP were obviously shorter in the AP model group than those in the normal group (P<0.05), while there was no difference for T1/2α of aloe emodin. The peak concentration and area under curve of all three components were much higher in the AP group than those in the normal group with MLHP in external application for 48 h (P<0.05). Furthermore, the mean residence time (MRT) and maximum plasma concentration (Tmax) of emodin and aloe emodin were obviously longer in the AP model group than those in the normal control group (P<0.05). There was no significant difference for Ka of all components between the two groups. Emodin could be detected in all rats' pancreas at 48 h in both groups, while its mean pancreatic concentration was higher in the AP model group than in the normal group (0.61±0.54 ng/mL, 0.42±0.37 ng/mL, respectively,P<0.05). Aloe emodin could be detected in all rats' pancreas at 48 h in both groups and their mean pancreatic concentration were similar (0.31±0.24 ng/mL, 0.33±0.17 ng/mL, respectively,P>0.05). Physcion could be detected in pancreas of most rats in the AP model while only two rats in the normal group. CONCLUSION: AP could significantly affect the pharmacokinetics of absorbed components of Chinese herbal MLHP ointment in rats.

Metabolomic profiles illuminate the efficacy of Chinese herbal Da-Cheng-Qi decoction on acute pancreatitis in rats.

BACKGROUND AND OBJECTIVES: Chinese herbal drug Da-Cheng-Qi decoction (DCQD) has been widely used for decades to treat acute pancreatitis (AP). Previous trials are mostly designed to state the potential mechanisms of the therapeutic effects rather than to detect its whole effect on metabolism. This study aimed to investigate the efficacy of DCQD on metabolism in AP. METHODS: Twenty-two male adult Sprague-Dawley rats were randomized into three groups. AP was induced by retrograde ductal infusion of 3.5% sodium taurocholate solution in DCQD and AP group, while 0.9% saline solution was used in sham operation (SO) group. Blood samples were obtained 12 h after drug administration and a 600 MHz superconducting Nuclear Magnetic Resonance (NMR) spectrometer was used to detected plasma metabolites. Principal Components Analysis (PCA) and Partial Least Squares-Discriminant Analysis after Orthogonal Signal Correction (OSC-PLS-DA) were applied to analyze the Longitudinal Eddy-delay (LED) and Carr-Purcell-Meiboom-Gill (CPMG) spectra. RESULTS: Differences in concentrations of metabolites among the three groups were detected by OSC-PLS-DA of 1HNMR spectra (both LED and CPMG). Compared with SO group, DCQD group had higher levels of plasma glycerol, glutamic acid, low density lipoprotein (LDL), saturated fatty acid (FA) and lower levels of alanine and glutamine, while the metabolic changes were reversed in the AP group. CONCLUSIONS: Our results demonstrated that DCQD was capable of altering the changed concentrations of metabolites in rats with AP and 1HNMR-based metabolomic approach provided a new methodological cue for systematically investigating the efficacies and mechanisms of DCQD in treating AP.

Classification and Management of Pancreatic Pseudocysts.

This article aims to elucidate the classification of and optimal treatment for pancreatic pseudocysts. Various approaches, including endoscopic drainage, percutaneous drainage, and open surgery, have been employed for the management of pancreatic pseudocysts. However, no scientific classification of pancreatic pseudocysts has been devised, which could assist in the selection of optimal therapy. We evaluated the treatment modalities used in 893 patients diagnosed with pancreatic pseudocysts according to the revision of the Atlanta classification in our department between 2001 and 2010. All the pancreatic pseudocysts have course of disease >4 weeks and have mature cysts wall detected by computed tomography or transabdominal ultrasonography. Endoscopic drainage, percutaneous drainage, or open surgery was selected on the basis of the pseudocyst characteristics. Clinical data and patient outcomes were reviewed. Among the 893 patients, 13 (1.5%) had percutaneous drainage. Eighty-three (9%) had type I pancreatic pseudocysts and were treated with observation. Ten patients (1%) had type II pseudocysts and underwent the Whipple procedure or resection of the pancreatic body and tail. Forty-six patients (5.2%) had type III pseudocysts: 44 (4.9%) underwent surgical internal drainage and 2 (0.2%) underwent endoscopic drainage. Five hundred six patients (56.7%) had type IV pseudocysts: 297 (33.3%) underwent surgical internal drainage and 209 (23.4%) underwent endoscopic drainage. Finally, 235 patients (26.3%) had type V pseudocysts: 36 (4%) underwent distal pancreatectomy or splenectomy and 199 (22.3%) underwent endoscopic drainage. A new classification system was devised, based on the size, anatomical location, and clinical manifestations of the pancreatic pseudocyst along with the relationship between the pseudocyst and the pancreatic duct. Different therapeutic strategies could be considered based on this classification. When clinically feasible, endoscopic drainage should be considered the optimal management strategy for pancreatic pseudocysts.