Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia

Heliobacter pylori(H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer.Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia(IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia(SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals.There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H.pylori infection.

Phytochemical Profile, Antioxidant, and Anti-Inflammatory Activities, Safety of Use and Spasmolytic Effects of Aqueous Decoction Extract of Diospyros mespiliformis Leaves Hochst. ex A. DC. (Ebenaceae) on the Isolated Duodenum of Rat

Diospyros mespiliformis Hochst. ex A. DC. (Ebenaceae) is a multi-use plant, including for therapeutic purposes. It is used in alternative medicine in Burkina Faso to treat conjunctivitis, menorrhagia, dysentery, and diarrhea. The aim of our study was to evaluate the chemical profile, antioxidant and anti-inflammatory activities, safety of use and spasmolytic effects of the aqueous decoction of Diospyros mespiliformis leaves. Phytochemical screening by HPTLC and assay of compounds of interest were carried out. Four methods were used to assess antioxidant activity. Inhibitory activity against 15-lipoxygenase and phospholipase A2 was assessed. Acute oral toxicity of the extract was tested on female mice (NMRI). Following these tests, the extract contained bioactive compounds of interest such as flavonoids, tannins, sterols, triterpenes, and saponosides. The total phenolic and flavonoid contents of the aqueous decoctate were 70.59 ± 3.20 mg EAT/g and 31.57 ± 0.78 mg EQ/g respectively. The extract was less active than Trolox with inhibitory concentrations of 50% (IC50) for the ABTS, DPPH, FRAP, and LPO tests of 7.53 ± 0.08 μg/mL, 29.47 ± 0.06 μg/mL, 1128.83 ± 4.82 mol EAA/g, and 32.30 ± 1.60 μg/mL respectively. The extract has an anti-inflammatory effect with inhibition of phospholipase A2 compared to betamethasone. In addition, the aqueous extract produced an antispasmodic effect with Emax of 70% and 80% respectively during contractions induced by BaCl2 and ACh. Finally, this study provided basic scientific data and could justify the use of D. mespiliformis leaves in the treatment of diarrhea.

Preventive and inhibitive effects of Yiwei Xiaoyu granules on the development and progression of spasmolytic polypeptideexpressing metaplasia lesions

BACKGROUND Spasmolytic polypeptide-expressing metaplasia(SPEM)is a potential preneoplastic lesion.AIM To elucidate the microRNA(miR)-7-mediated preventive and inhibitive effects of Yiwei Xiaoyu granules(YWXY)in SPEM lesions.METHODS Gastric mucosa biopsies were collected from chronic atrophic gastritis patients and healthy people with signed informed consent.YWXY was administered to the mice with induced SPEM by tamoxifen,and the gastric mucosa was harvested on the tenth day of the experiment.Then immunohistochemistry and immunofluorescence were performed to validate the SPEM,lesions and the potential mechanism was investigated.RNA transcripts were detected with reverse transcriptionquantitative polymerase chain reaction.RESULTS The expression of miR-7 was downregulated in the SPEM lesions,and expression of trefoil factor 2(TFF2)and clusterin was high in the human gastric mucosa.In vivo experiments showed that YWXY could inhibit the cell proliferation in the tamoxifen-induced SPEM lesions by regulating Ki67.Simultaneously,YWXY could restore the expression of miR-7 by regulating TFF2 by detection with immunofluorescence but not with reverse transcription-quantitative polymerase chain reaction,indicating its potential mechanism of targeting miR-7 by mediating TFF2.The expression of vascular endothelial growth factor-βand gastric intrinsic factor was restored within 3 d of YWXY administration for the SPEM lesions,speculating that the possible mechanism of YWXY is to inhibit the development and progression of SPEM by regulating vascular endothelial growth factor-βand gastric intrinsic factor.CONCLUSION miR-7 downregulation is an early event in SPEM through regulation of TFF2 in human gastric mucosa.YWXY is able to inhibit the cell proliferation and restore the expression of miR-7 by mediating TFF2 in the SPEM mouse model.

Anti-diarrheal and spasmolytic activities study of 3,4-Dihydro-2-(4-Morpholinylmethy)-1(2H)-Naphthalenone(CY)

Objective To investigate the spasmolytic and anti-diarrheal activities of 3,4-dihydro-2-(4-morpholinylmethy)-1(2H)-naphthalenone(CY),which was first synthesized by Welch,Willard M et al.in 1977.Methods The spasmolytic effects of CY were tested on isolated rabbit small intestine at the concentration of 0.01 to 3 mM;the diarrheal-index was evaluated on diarrhea mice to study the anti-diarrheal activities of CY.Results CY(0.1-1 mM)inhibited spontaneous motility of rabbit small intestine and at the concentration of 0.01 to 3 mM CY inhibited the contractile response of rabbit small intestine and colon induced by acetylcholine(10-2 mg·mL-1),high K+(60 mM)and BaCl2(1 mg·mL-1).When tested against calcium channel blocked in rabbit small intestine and colon,CY caused a rightward shift in the Ca2+ dose-response curves,similar to that produced by verapamil,a well-known calcium antagonist.CY could inhibit the diarrhea induced by castor oil,MgSO4 and liquid paraffin and LD50 of CY is 277.2 mg·kg-1.Conclusions CY may produce its spasmolytic and anti-diarrheal effects as a calcium antagonist.

Isolation and Spasmolytic Evaluation of New Alkaloids from Dichrostachys cinerea (L.) Wight et Arn. (Fabaceae)

Dichrostachys cinerea (L.) Wight et Arn. (Fabaceae) root bark is used in Ivorian Traditional Medicine to treat asthma, which is a respiratory disorder characterized by inflammation and the restriction of tracheal muscles obstructing the air circulation. The tracheal relaxant effect of a crude aqueous-alcoholic extract of the plant root bark was previously shown. For the present study, alkaloids were isolated from the same extract and investigated ex vivo in C57Bl/6j mice isolated trachea contracted with carbachol 1 μM, in comparison with a reference bronchodilatator, i.e. salbutamol. Two extraction procedures allowed isolating 2 Alkaloids that monodimensional and bi-dimensional nuclear magnetic resonance (NMR) and mass specters allowed identifying a pyrolidine structure type nucleus with a long bi-hydroxyled alkyl chain. Alkaloid 1, carrier of a sugar, is a glycoside of Alkaloid 2. Both alkaloids induced similar spasmolytic effects, but Alkaloid 1 was more effective than Alkaloid 2 at 9 × 10-6 M (p < 0.01), 3 × 10-5 M, and 9 × 10-5 M (p <0.001). Salbutamol induced its spasmolytic effect in a different way, and its maximal effect Emax (less than 30%) was obtained at 9 × 10-6 M, while Emax of both alkaloids (100%) was obtained at 3 × 10-4 M.

ISOLATION AND IDENTIFICATION OF PORCINE PANCREATIC POLYPEPTIDE AND PORCINE SPASMOLYTIC PEPTIDE

During the isolation of goose insulin, goose pancreatic polypeptide (GPP) was obtained and its primary structure was determined. Pancreatic polypeptide is a new hormone discovered not long ago, its biological function remains to be studied. In clinical studies, radioimmunoassay (RIA) of this hormone in blood has become increasingly important in order to know its changes in different pathological conditions. Because of the large difference between GPP and human pancreatic polypeptide (HPP),

Role of antispasmodics in the treatment of irritable bowel syndrome

Irritable bowel syndrome (IBS) is a long-lasting, relapsing disorder characterized by abdominal pain/discomfort and altered bowel habits. Intestinal motility impairment and visceral hypersensitivity are the key factors among its multifactorial pathogenesis, both of which require effective treatment. Voltage-gated calcium channels mediate smooth muscle contraction and endocrine secretion and play important roles in neuronal transmission. Antispasmodics are a group of drugs that have been used in the treatment of IBS for decades. Alverine citrate, a spasmolytic, decreases the sensitivity of smooth muscle contractile proteins to calcium, and it is a selective 5-HT1A receptor antagonist. Alverine, in combination with simethicone, has been demonstrated to effectively reduce abdominal pain and discomfort in a large placebo-controlled trial. Mebeverine is a musculotropic agent that potently blocks intestinal peristalsis. Non-placebo-controlled trials have shown positive effects of mebeverine in IBS regarding symptom control; nevertheless, in recent placebo-controlled studies, mebeverine did not exhibit superiority over placebo. Otilonium bromide is poorly absorbed from the GI tract, where it acts locally as an L-type calcium channel blocker, an antimuscarinic and a tachykinin NK2 receptor antagonist. Otilonium has effectively reduced pain and improved defecation alterations in placebo-controlled trials in IBS patients. Pinaverium bromide is also an L-type calcium channel blocker that acts locally in the GI tract. Pinaverium improves motility disorders and consequently reduces stool problems in IBS patients. Phloroglucinol and trimethylphloroglucinol are non-specific antispasmodics that reduced pain in IBS patients in a placebo-controlled trial. Antispasmodics have excellent safety profiles. T-type calcium channel blockers can abolish visceral hypersensitivity in animal models, which makes them potential candidates for the development of novel therapeutic agents in the treatment of IBS.

Otilonium bromide in irritable bowel syndrome:A dose-ranging randomized double-blind placebo-controlled trial

AIM: To examine the efficacy and safety of otilonium bromide (OB) in treatment-sensitive functional irritable bowel syndrome (IBS) clinical parameters.

Antidiarrheal properties of different extracts of Chinese herbal medicine formula Bao-Xie-Ning

OBJECTIVE： Bao-Xie-Ning （BXN）, a traditional Chinese herbal medicine （CHM） formula composed of Fructus Evodiae, Flos Caryophylli and Cortex Cinnamomi, and used for the treatment of infant diarrheal illness, was subject to systematic assessment for its putative multiple pharmacodynamic effects and pharmacological antidiarrheal mechanisms. METHODS： High-performance liquid chromatography-diode array detector-electrospray ionization- mass spectrometric/mass spectrometry was developed and validated for identification and quantification of the main constituents in different extracts of BXN. Male Kunming mice weighing 20 to 25 g were used for detecting the antidiarrheal activity of the extracts. Ethanolic extract （EE）, volatile oil extract （VOE）, and aqueous extract （AE） of BXN were respectively subjected to pharmacodynamic and pharmacological comparison in assessing antidiarrheal effects with senna-induced diarrhea, castor oil-induced diarrhea, acetic acid-induced writhing assay, and isolated duodenum test. RESULTS： The highest yields of three detected components of BXN, rutaecarpine, eugenol and cinnamaldehyde were observed in EE. EE showed the most remarkable antidiarrheal activity in dose-dependent and time-dependent manners in both senna- and castor oil-induced diarrhea models, and presented dose-dependent analgesic activity in acetic acid-induced algesthesia model. In addition, EE extract of BXN also exhibited strong antimobility action on the intestine and strongest depression on spontaneous contraction of isolated duodenum. CONCLUSION： Ethanol extraction is an efficient method to extract the active constituents of BXN. BXN extract demonstrated multiple pharmacological activities affecting the main mechanisms of diarrhea, which validated BXN＇s usage in the comprehensive clinical treatment of diarrhea.

Pharmacological basis for the medicinal use of Michelia champaca in gut, airways and cardiovascular disorders

Objective: To discover the mechanism behind ameliorative effects of Michelia champaca(M. champaca) in gastrointestinal, respiratory and cardiovascular disorders. Methods: Antispasmodic potential was evaluated by trying the M. champaca extract(aqueous:ethanolic) on rabbit aorta, trachea and jejunum in vitro. Isotonic and isometric transducers coupled with Power Lab data acquisition system was used to record the responses of isolated tissues. Results: M. champaca extract relaxed the spontaneous and high K^+(80 mmol/L)-induced contractions of isolated jejunum preparation of rabbit showing a Ca^(2+) channel blocking mechanism. Moreover, extract shifted calcium concentration response curves towards right like standard calcium channel blocker verapamil. In rabbit tracheal preparation, M. champaca relaxed both carbachol(1 μmol/L) and high K^+-induced contractions, likewise verapamil. In rabbit aorta preparation, M. champaca relaxed phenylephrine(1 μmol/L) and high K^+-induced contractions similar to verapamil. Conclusion: M. champaca possesses spasmolytic, airways relaxant and vasodilator actions mediated perhaps due to blocking of Ca^(2+) channels, hence validating its therapeutic usage in diarrhea, asthma and hypertension.

Ge-Gen Decoction attenuates oxytocin-induced uterine contraction and writhing response: potential application in primary dysmenorrhea therapy

The uterine tetanic contraction and uterine artery blood flow reduction are possible reasons for primary dysmenorrhea(PD). In the present study, we aimed to evaluate the uterine relaxant effect and the influence on uterine artery blood velocity of Ge-Gen Decoction(GGD), a well-known Chinese herbal formula. In female ICR mice, uterine contraction was induced by oxytocin exposure following estradiol benzoate pretreatment, and the uterine artery blood velocity was detected by Doppler ultrasound. Histopathological examination of the uterine tissue samples were performed by H&E staining. Ex vivo studies demonstrated that oxytocin, posterior pituitary, or acetylcholine induced contractions in isolated mouse uterus. GGD inhibited both spontaneous and stimulated contractions. In vivo study demonstrated that GGD significantly reduced oxytocin-induced writhing responses with a maximal inhibition of 87%. Further study demonstrated that GGD normalized oxytocin-induced abnormalities of prostaglandins F_2 alpha(PGF_(2α)) and Ca^(2+) in mice. In addition, injection of oxytocin induced a decrease in uterine artery blood flow velocity. Pretreatment with GGD reversed the oxytocin response on blood flow velocity. Histopathological examination showed pretreatment with GGD alleviated inflammation and edema in the uterus when compared with the model group. Both ex vivo and in vivo results indicated that GGD possessed a significant spasmolytic effect on uterine tetanic contraction as well as improvement on uterine artery blood velocity which may involve PGF_(2α) and Ca^(2+) signaling, suggesting that GGD may have a clinic potential in PD therapy.