Lafutidine, a Protective H2 Receptor Antagonist, Enhances Mucosal Defense in Rat Esophagus

Luminal acid or CO2 induces a hyperemic response in the esophagus, via activation of acid sensors on capsaicin-sensitive afferent nerves (CSAN). Since disruption of the hyperemic response to luminal CO2 acidifies the interstitium of the esophageal mucosa, the hyperemic response may maintain interstitial pH (pHint). We hypothesized that acid-related hyperemia maintains pHint, preventing acid-induced injury in the esophageal mucosa. We examined the effects of capsaicin (Cap) or lafutidine (Laf), a mucosal protective H2 antagonist, on the regulation of pHint and blood flow in rat esophagus using ratiometric microimaging and laser-Doppler measurements of the lower esophageal mucosa of living rats. The esophagus was topically superfused with pH 7.0 buffer, or a pH 1.0 or pH 1.0 + pepsin (1 mg/ml) solution with or without Laf. Cap (30 or 100 µM) or Laf (0.1 or 1 mM) dose-dependently increased blood flow, accompanied by increased pHint. The pH 1.0 solution increased blood flow without pHint change, whereas Laf (1 mM) increased blood flow and pHint during acid exposure. The effects of Laf were abolished by ablation of CSAN. Perfusion of the acidified pepsin solution gradually decreased pHint, inhibited by Laf perfusion. Activation of CSAN by Laf with or without acid, accompanied by hyperemia, increased pHint, preventing acidified pepsin-induced interstitial acidification. Stimulation of the capsaicin pathway with compounds such as Laf enhances mucosal protection from acid-related injury in the upper gastrointestinal tract

Afferent signalling from the acid-challenged rat stomach is inhibited and gastric acid elimination is enhanced by lafutidine

<p>Abstract</p> <p>Background</p> <p>Lafutidine is a histamine H₂receptor antagonist, the gastroprotective effect of which is related to its antisecretory activity and its ability to activate a sensory neuron-dependent mechanism of defence. The present study investigated whether intragastric administration of lafutidine (10 and 30 mg/kg) modifies vagal afferent signalling, mucosal injury, intragastric acidity and gastric emptying after gastric acid challenge.</p> <p>Methods</p> <p>Adult rats were treated with vehicle, lafutidine (10 – 30 mg/kg) or cimetidine (10 mg/kg), and 30 min later their stomachs were exposed to exogenous HCl (0.25 M). During the period of 2 h post-HCl, intragastric pH, gastric volume, gastric acidity and extent of macroscopic gastric mucosal injury were determined and the activation of neurons in the brainstem was visualized by c-Fos immunocytochemistry.</p> <p>Results</p> <p>Gastric acid challenge enhanced the expression of c-Fos in the nucleus tractus solitarii but caused only minimal damage to the gastric mucosa. Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl. Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity. The H₂receptor antagonist cimetidine had similar but weaker effects.</p> <p>Conclusion</p> <p>These observations indicate that lafutidine inhibits the vagal afferent signalling of a gastric acid insult, which may reflect an inhibitory action on acid-induced gastric pain. The ability of lafutidine to decrease intragastric acidity following exposure to excess HCl cannot be explained by its antisecretory activity but appears to reflect dilution and/or emptying of the acid load into the duodenum. This profile of actions emphasizes the notion that H₂receptor antagonists can protect the gastric mucosa from acid injury independently of their ability to suppress gastric acid secretion.</p

Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa−/− and Csb−/− CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa−/− and Xpc−/− XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa−/−, Csb−/−) or highly sporadic (Xpa−/−, Xpc−/−) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa−/− and Csb−/− TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival

Anti-tumor effect of Liqi, a traditional Chinese medicine prescription, in tumor bearing mice

<p>Abstract</p> <p>Background</p> <p><it>Liqi</it>, an herbal preparation used in traditional Chinese medicine, has been used to treat cancer in China for centuries. We investigated the anti-tumor effects of liqi and their mechanisms in mice that had been xenografted with tumors.</p> <p>Methods</p> <p>Sarcoma 180 tumor, Lewis lung carcinoma, and SGC-7901 cells were implanted in BALB/c mice, C57BL/6 mice, and BALB/c nude mice, respectively. Liqi was administered to subgroups of these mice. The tumor weight and size were measured. Cell cycle analysis and T lymphocyte subsets were determined by flow cytometry. The activity of NK cells and TNF was tested using cytotoxicity assay on YAC-1 cells and L929 cells, respectively, and the activity of IL-2 was tested with an IL-2-dependent CTLL-2 cell proliferation assay. Platelet aggregation was monitored by measuring electric impedance, and the levels of thromboxane A2 (TXA₂) and prostacyclin (PGI₂) in blood were measured by ¹²⁵I-TXB₂and ¹²⁵I-Keto-PGF_1αradioimmunoassay.</p> <p>Results</p> <p>The results showed that liqi inhibited tumor growth in tumor-implanted mice and arrested the cell proliferation in the G0/G1 phase and reduced the portion of cells in S and G2/M phase for SGC-7901 cells. Liqi increased the activity of NK cells and TNF-α, stimulated IL-2 production and activity, and regulated T lymphocyte subpopulations. Liqi inhibited the Lewis lung carcinoma metastasis by inhibiting platelet aggregation and normalizing the balance between TXA₂and PGI₂.</p> <p>Conclusion</p> <p>All these findings demonstrated that liqi has an anti-tumor effect in vivo. The mechanism may be related to immune regulation and anticoagulation effects.</p

FORMATION OF THE (γ/α) - INTERPHASE BOUNDARIES IN FeCrNi ALLOYS BY A DIFFUSION BONDING METHOD

Characteristics of the interphase boundary in two-phase (γ/α)-stainless steel couples produced by a solid-solid diffusion method, starting from Fe-30%Cr (α-phase) and Fe-15%Cr-15%Ni (γ-phase) alloys, have been described. Interphase boundaries between a parent (γ-phase and a transformed (α-phase have been found to be essentially planar and no special structual defects have been detected, excepting a so-called "diffusion-induced twins" grown often in the (γ-phase, similar to those found in the diffusion couples of α/β-brass bicrystals by one of the authors and his colleagues / 1 /. It is found that the transformed α(αn)-phase inherits the crystallographic orientation of the original α(α0)-phase in a similar manner to GRAIN GROWTH. However, if the bonding orientation relation is set to be a near Kurjumov- Sachs relation, NUCLEATION of the phase transformation occurs and the resulting orientation relations become closer to the preferencial one. The present results suggest that the critical condition for the occurrence of the nucleation is attributable to the interfacial energy criterion on the (γ/α)-interface and the grain boundary between the α0 and αn-phases