Berberine reduces gut-vascular barrier permeability via modulation of ApoM/S1P pathway in a model of polymicrobial sepsis.

AIMS: The hyperpermeability of gut-vascular barrier (GVB) plays a role in gut-derived sepsis. The goal of this study was to evaluate if berberine might improve hepatic apolipoprotein M (ApoM) generation and raise plasma ApoM level to protect the compromised GVB. MATERIALS AND METHODS: The compromised GVB was induced by sepsis. Hepatic ApoM mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA and plasma ApoM level were assayed by qRT-PCR and ELISA, respectively. The permeability of intestinal capillary in vivo and of rat intestinal microvascular endothelial cells (RIMECs) in vitro was assayed by FITC-dextran. The blood glucose was detected by a glucometer. Plasma insulin, TNF-α and IL-1ß were assayed by ELISA. The plasmalemma vesicle-associated protein-1 (PV1), ß-catenin and occludin in RIMECs were assayed by Western blot. KEY FINDINGS: Sepsis decreased hepatic ApoM mRNA and plasma ApoM level, but raised hepatic PEPCK mRNA and plasma glucose, insulin, TNF-α, and IL-1ß levels. The increased vascular endothelial permeability was abrogated by recombinant rat ApoM in vivo or ApoM-bound S1P in vitro. ApoM-bound S1P decreased PV1 but increased occludin and ß-catenin expression in LPS-treated RIMECs. Berberine in a dose-dependent manner raised hepatic ApoM mRNA and plasma ApoM level, but decreased septic hyperglycemia, insulin resistance and plasma TNF-α and IL-1ß levels. Berberine reduced sepsis-induced PEPCK and TLR4 mRNA overexpression in the liver. SIGNIFICANCE: This study demonstrated berberine inhibited TLR4-mediated hyperglycemia, insulin resistance and proinflammatory molecule production, thereby increasing ApoM gene expression and plasma ApoM. Berberine protected the damaged GVB via modulation of ApoM/S1P pathway.

Timing of postexercise carbohydrate-protein supplementation: roles of gastrointestinal blood flow and mucosal cell damage on gastric emptying in humans.

It is well known that protein ingestion immediately after exercise greatly stimulates muscle protein synthesis during the postexercise recovery phase. However, immediately after strenuous exercise, the gastrointestinal (GI) mucosa is frequently injured by hypoperfusion in the organ/tissue, possibly resulting in impaired GI function (e.g., gastric emptying; GE). The aim of this study was to examine the effect of GI blood flow on the GE rate. Eight healthy young subjects performed an intermittent supramaximal cycling exercise for 30 min, which consisted of a 120% V̇o2peak for 20 s, followed by 20 W for 40 s. The subjects ingested 300 ml of a nutrient drink containing carbohydrate-protein at either 5 min postexercise in one trial (PE-5) or 30 min postexercise in another trial (PE-30). In the control trial (Con), the subjects ingested the same drink without exercise. The celiac artery blood flow (CABF) and superior mesenteric artery blood flow (SMABF) and GE rate were assessed by ultrasonography. Before drink ingestion in PE-5, CABF significantly decreased from baseline, whereas in PE-30, it returned to baseline. Following drink ingestion in PE-5, CABF did not change from baseline, but it significantly increased in PE-30 and Con. SMABF increased significantly later in PE-5 than in PE-30 and Con. The GE rate was consistently slower in PE-5 than in PE-30 and Con. In conclusion, the CABF response after exercise seems to modulate the subsequent GE rate and SMABF response.NEW & NOTEWORTHY A carbohydrate-protein drink was ingested at either 5 min (i.e., profoundly decreased celiac artery blood flow; CABF) or 30 min (i.e., already recovered CABF) postexercise. In the 5-min postexercise trial, the gastric emptying (GE) rate and superior mesenteric artery blood flow (SMABF) response were slower than those in the 30-min postexercise trial. The GE rate and SMABF response may be altered depending on the postexercise CABF response.

Notes from the field: Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement--Connecticut, 2014.

In October 2014, a hospital in Connecticut notified CDC and the Connecticut Department of Public Health of a fatal case of gastrointestinal mucormycosis in a preterm infant. The infant, born at 29 weeks' gestation and weighing 1,400 grams (about 3 pounds), had developed signs and symptoms initially consistent with necrotizing enterocolitis approximately 1 week after birth. Exploratory laparotomy revealed complete ischemia of the gastrointestinal tract from the esophagus to the rectum; a portion of necrotic cecum was sent for microscopic examination. Following surgery, the infant developed multiple areas of vascular occlusion, including a large clot in the aorta, findings not usually associated with necrotizing enterocolitis. The infant died soon after. Histopathology results from the resected cecum revealed an angioinvasive fungal infection consistent with mucormycosis. Gastrointestinal mucormycosis is an extremely rare fungal infection caused by mold in the order Mucorales. It occurs predominantly in low birth weight infants, patients with diarrhea and malnutrition, and those receiving peritoneal dialysis; mortality is 85%. Local investigation revealed that the infant had received a dietary supplement, ABC Dophilus Powder, for 7 days, beginning on day 1 of life.

Anti-angiogenic therapy, a new player in the field of sarcoma treatment.

Sarcomas encompass a heterogeneous family of mesenchymal malignancies. In metastatic disease improvement in outcome has been limited and there is a clear need for the development of new therapies. One potential target is angiogenesis, already an accepted target for treatment of more prevalent cancers. Multiple (pre)clinical studies focused on the role of angiogenesis and anti-angiogenic treatment in sarcomas. However, getting significant results is complicated due to the relatively small number of patients and the broad range of sarcoma subtypes. Recently, pazopanib has been approved for the treatment of advanced soft tissue sarcoma patients, which is an important step forward and paves the way for the introduction of anti-angiogenic treatment in sarcomas. However, more studies are needed to understand the biological mechanisms by which patients respond to angiogenic inhibitors and to detect markers of response. This review covers the knowledge that has been gained on the role of angiogenesis and anti-angiogenic therapy in sarcomas.

Prophylactic effect of egualen sodium, a stable azulene derivative, on gastrointestinal damage induced by ischemia/reperfusion, double antiplatelet therapy and loxoprofen in rats.

We examined the effect of egualen, a stable azulene derivative, against gastric damage induced by ischemia/reperfusion (I/R), gastric bleeding induced by double antiplatelet therapy with aspirin (ASA) plus clopidogrel, and small intestinal damage generated by loxoprofen, and investigated the possible mechanisms involved in its protective action. Male C57BL/6 mice or SD rats were used under urethane anesthesia (gastric lesions) or in a conscious (intestinal lesions) state. I/R-induced gastric injury was produced in mice by clamping the celiac artery for 30 min, followed by reperfusion for 60 min. Gastric bleeding was induced in rats by luminal perfusion with 25 mM ASA+50 mM HCl for 2 hours in the presence of clopidogrel (30 mg/kg). To produce small intestinal lesions the rats were given loxoprofen (60 mg/kg) p.o. and killed 24 hours later. Egualen was given i.d. 60 min before I/R or ASA perfusion, while given p.o. twice 30 min before and 6 hours after loxoprofen. Egualen significantly prevented the I/R-induced gastric damage, and the effect was equivalent to that of seratrodast (TXA2 antagonist). This agent also significantly suppressed gastric bleeding induced by ASA plus clopidogrel, similar to PGE2. Likewise, egualen significantly prevented loxoprofen-induced damage in the small intestine, accompanied by an increase in the secretion of mucus and suppression of bacterial invasion as well as iNOS expression. These results suggest that egualen has a prophylactic effect against various lesions in the gastrointestinal mucosa, probably through its characteristic pharmacological properties, such as TXA2 antagonistic action, local mucosal protection, and stimulation of mucus secretion.

[Effects of electro-acupuncture at Zusanli point on gastric and intestinal blood flow in rats with acute necrotizing pancreatitis].

OBJECTIVE: To investigate the effects of electro-acupuncture (EA) at Zusanli point on gastric and intestinal blood flow and serum endothelin-1(ET-1), nitricoxide(NO), thromboxaneB2 (TXB2), 6-keto-prostaglandin F1alpha (6-K-PGF1alpha) in rats with acute necrotizing pancreatitis (ANP). METHODS: Thirty-six male Sprague Dawley (SD) rats were randomly divided into sham operation (sham), ANP and EA groups (n = 12). ANP model was induced by retrograde injection of 5% sodium taurocholate into pancreaticobiliary. EA was applied to Zusanli for 30 min at 2 h and 6 h after the operation in EA group. Gastric and intestinal mucosal blood flow was measured by laser doppler flowmetry (LDF) at 12 h and 24 h after operation, while the levels of serum ET-1, NO, TXB2 and 6-K-PGF1alpha were detected. RESULTS: The gastric and intestinal blood flow in ANP rats were significantly lower than those in the sham group (P < 0.05), but those of EA groups were higher than those in ANP groups (P < 0.05). The serum ET-1, NO and ET-1/NO levels in ANP group were increased when compared with SO group (P < 0.05). After the electro-acupuncture treatment at Zusanli point, the levels of ET-1, NO and ET-1/N were decreased, and there were significant differences of ET-1 (at 12 h, 24 h), NO (at 12 h) and ET-1/NO (at 24 h) between EA and ANP group (P < 0.05). The levels of serum TXB2, 6-K-PGF1alpha and TXB2/6-K-PGF1alpha in ANP group were also increased (P < 0.05), but those in EA group were decreased, and there were significant differences of TXB2 (at 12 h, 24 h), 6-K-PGF1alpha (at 12 h) and TXB2/6-K-PGF1alpha (at 24 h) compared with ANP groups (P < 0.05). CONCLUSION: Electro-acupuncture at Zusanli point can significantly improve the gastric and intestinal mucosa blood flow in ANP rats, which may be related to the regulation of serum ET-1, NO, TXB2, 6-K-PGF1alpha.

[The use of ozone and low-intensive laser irradiation in complex treatment of complicated duodenal ulcer].

The study is based on the examination of 12 patients with perforative duodenal ulcer and 24 patients operated on recurrent bleeding duodenal ulcer. Some component of the immune system, such as T- and B-lymphocytes rates, immunoglobulin rate and macrophagal activity, were decreased prior the beginning of the complex treatment. Normalisation of humoral and cell immunity was registered on 10-12 days after the beginning of the ozone and low-intensive laser irradiation.

Role of enteral nutrition and pharmaconutrients in conditions of splanchnic hypoperfusion.

In critically ill patients there is consistent evidence that significant benefits are achieved if nutrients are delivered within the gut compared with the parenteral route. However, in conditions related to gut hypoflux, enteral nutrition may play a double role in counterbalancing the installed low-flow state. On the one hand, enteral-induced postprandial hyperemia may preserve the mucosal barrier and ameliorate immune competence; on the other hand, feeding by the gut may pose a theoretical risk of intestinal ischemia. Despite limited investigation, a strategic temporary minimal enteral nutrition with hypocaloric content has been recommended recently aiming to avoid the overfeeding syndrome and the menace of gut hypoperfusion. Under these conditions, the early luminal delivery of key nutrients such as arginine, glutamine dipeptides, antioxidants, and butyrate are an attractive option for this subset of patients. Arginine may prevent intestinal injury due to hypoperfusion but may harm the gut if ischemia is established. In contrast, glutamine may promote benefits in both conditions. Further investigations by randomized trials in this field are necessary.

Mucosal strengthening activity of central and peripheral melatonin in the mechanism of gastric defense.

This review summarizes the involvement of centrally and peripherally applied melatonin, a major hormone of pineal gland, in the mechanism of gastric mucosal integrity, gastroprotection and ulcer healing. Melatonin was originally shown to attenuate gastric mucosal lesions but the controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole or rather that locally generated from L-tryptophan within gastric mucosa, plays predominant role in the mechanism of gastrointestinal integrity. Both, intragastric (i.g.) and intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan to rats without or with removed pineal gland by pinealectomy attenuates in the dose-dependent manner the formation of on gastric lesions induced by topical irritants and water immersion restraint stress (WRS). Melatonin accelerated the gastric ulcer healing and this was accompanied by the rise in gastric blood flow (GBF), the plasma melatonin and gastrin levels, the mucosal generation of PGE(2) and luminal NO content. Pinealectomy, which suppresses the plasma melatonin levels, markedly aggravated the gastric lesions induced by WRS. Concurrent supplementation of pinealectomized animals with melatonin or L-tryptophan, the melatonin precursor, attenuated the lesions induced by WRS. Treatment with luzindole, an antagonist of Mel(2) receptors, or with L-NNA, the NO-synthase inhibitor, significantly attenuated melatonin- and L-tryptophan-induced protection and the acceleration of ulcer healing and the accompanying increase in the GBF and luminal content of NO. We conclude that 1) exogenous melatonin and that released from the L-tryptophan attenuate lesions induced by topical irritant such as ethanol and WRS via interaction with MT(2) receptors and due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from cNOS, iNOS and COX-2 overexpression and activity, and 2) the pineal gland plays an important role in the limitation of WRS-induced gastric lesions and acceleration of ulcer healing via releasing melatonin predominately at night time, that exerts gastroprotective and ulcer healing actions.

Effect of shenfu injection on gastrointestinal microcirculation in rabbits after myocardial ischemia-reperfusion injury.

AIM: To investigate the effect of shenfu injection on gastrointestinal microcirculation after myocardial ischemic-reperfusion (IR) injury in rabbits and probe into the mechanism. METHODS: Forty healthy flap-eared white rabbits were randomly divided into 4 groups: IR injury control group (group I), shenfu injection 5 mL/kg per h group (group II), shenfu injection 10 mL/kg per h group (group III) and shenfu injection 20 mL/kg per h group (group IV). The four groups were treated with Lactated Ringer's solution, shenfu injection 5, 10, and 20 mL/ kg per h were infused intravenously 30 min before experiment respectively. The values of hemodynamics [mean arterial pressure (MAP), heart rate (HR), gastric intramucosal partial pressure of carbon dioxide (PCO2), blood gas analysis and pH] were measured and compared with those before myocardial ischemia, 60 min after myocardial ischemia and 60, 90, and 180 min after reperfusion. RESULTS: The MAP, HR and gastric intramucosal pH were (70.50 +/- 4.50) kPa, (165 +/- 14) beats per min, 7.032 +/- 0.024 in group I 60 min after myocardial ischemia, which were significantly decreased compared with those before myocardial ischemia (88.50 +/- 9.75 kPa, 217 +/- 18 beats per min, 7.112 +/- 0.035, P < 0.05). The MAP, HR and gastric intramucosal pH were significantly decreased in group I 60, 90, and 180 min after reperfusion (61.50 +/- 5.25 kPa, 133 +/- 31 beats per min, 6.997 +/- 0.025) compared with those before reperfusion respectively (P < 0.05), whereas the values were insignificantly different in groups II, III or IV after reperfusion, compared with those before reperfusion, and there were no significant differences between groups II, III, and IV after reperfusion. CONCLUSION: Pre-infusion of shenfu injection has a protective effect on gastrointestinal microcirculation after myocardial IR injury in rabbits, in a dose independent manner.