Antinociceptive activities of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol, and its possible mechanisms of action in mice.

A novel synthetic compound from the 2-benzoyl-6-benzylidenecyclohexanone analogue, namely 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC), showed pronounced nitric oxide inhibition in IFN-γ/LPS-induced RAW 264.7 cells. Based on this previous finding, our present study aimed to investigate the antinociceptive effects of BBHC via chemical and thermal stimuli in vivo. The investigation of the antinociceptive activity of BBHC (0.1, 0.3, 1.0 and 3.0 mg/kg, i.p.) was initiated with 3 preliminary screening tests, then BBHC was subjected to investigate its possible involvement with excitatory neurotransmitters and opioid receptors. The potential acute toxicity of BBHC administration was also studied. Administration of BBHC significantly inhibited acetic acid-induced abdominal constrictions, formalin-induced paw licking activity and developed notable increment in the latency time. BBHC's ability to suppress capsaicin- and glutamate-induced paw licking activities, as well as to antagonise the effect of naloxone, had indicated the possible involvement of its antinociception with TRPV1, glutamate and opioid receptors, respectively. The antinociceptive activities of BBHC was not related to any sedative action and no evidence of acute toxic effect was detected. The present study showed that BBHC possessed significant peripheral and central antinociceptive activities via chemical- and thermal-induced nociceptive murine models without any locomotor alteration and acute toxicity.

Moscatilin, a bibenzyl derivative from the orchid Dendrobium loddigesii, induces apoptosis in melanoma cells.

The use of orchids in herbal medicine has a very long history. Dendrobium species are known to produce a variety of secondary metabolites such as phenanthrens, bibenzyls, fluorenones and sesquiterpenes, and alkaloids and are responsible for their wide variety of medicinal properties. For decades, bibenzyls, which are the main bioactive components derived from Dendrobium species, have been subjected to extensive investigation as likely candidates for cancer treatment. The present study was undertaken to investigate the effect of moscatilin, a bibenzyl derivative from the orchid Dendrobium loddigesii on human melanoma cells. In A375 cells compound moscatilin showed a clear dose-response relationship in the range of 6.25-50 µM concentrations. In addition, we demonstrated an apoptotic response after treatment of cancer cells with this bibenzyl compound at 6.25 and 12.5 µM concentrations that probably involves PTEN activity, inhibition of Hsp70 expression and reactive oxygen species production. Alternatively, the inhibition of the caspase cascade at higher concentrations, 25 and 50 µM, correlated with additional reactive oxygen species increase, probably switched the mode of moscatilin-induced cell death from apoptosis to necrosis.

Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis.

BACKGROUND: Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE. METHODS: Minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells. RESULTS: Siponimod administration (0.45 µg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission. CONCLUSIONS: Altogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.

Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents.

In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6h at a dosage of 4.0mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.

Acupuncture for functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) has been a worldwide complaint. More effective therapies are needed with fewer adverse effects than are seen with conventional medications. Acupuncture, as a traditional therapeutic method, has been widely used for functional gastrointestinal disorders in the East. Manual acupuncture and electroacupuncture have been recognized treatments for FD, but to date, no robust evidence has been found for the effectiveness and safety of these interventions in the treatment of this condition. OBJECTIVES: This review was conducted to assess the efficacy and safety of manual acupuncture and electroacupuncture in the treatment of FD. SEARCH METHODS: Trials meeting the inclusion criteria were identified through electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Allied and Complementary Medicine Database (AMED), Chinese Biology Medicine Disc (CBMdisc), China National Knowledge Infrastructure (CNKI), the Wanfang Database, the VIP Database, and six trial registries. Handsearching was done to screen the reference sections of potential trials and reviews. SELECTION CRITERIA: Randomized controlled trials (RCTs) were included if investigators reported efficacy and safety of manual acupuncture or electroacupuncture for patients with FD diagnosed by Rome II or Rome III criteria, compared with medications, blank control, or sham acupuncture. DATA COLLECTION AND ANALYSIS: Data were extracted by independent review authors. Study limitations were assessed by using the tool of The Cochrane Collabration for assessing risk of bias. For dichotomous data, risk ratios (RRs) and 95% confidence intervals (95% CIs) would be applied, and for continuous data, mean differences (MDs) and 95% CIs. A fixed-effect model was applied in the meta-analysis, or a descriptive analysis was performed. The quality of evidence for the outcome measure was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: Seven studies were included in the review, involving 542 participants with FD (212 males and 330 females). These studies generally had an unclear risk of bias based on inadequate descriptions of allocation concealment and a high risk of bias based on lack of blinding. None of the studies reported on outcomes of the Functional Digestive Disorder Quality of Life questionnaire (FDDQL), the Satisfaction With Dyspepsia Related Health scale (SODA), the Digestive Health Status Instrument (DHSI), or effective/inefficient rate and symptom recurrence six months from completion of acupuncture treatment.Four RCTs of acupuncture versus medications (cisapride, domperidone, and itopride) were included in the review. No statistically significant difference was noted in the reduction in FD symptom scores and the frequency of FD attack by manual acupuncture, manual-electroacupuncture, or electroacupuncture compared with medications. In three trials of acupuncture versus sham acupuncture, all descriptive or quantitative analysis results implied that acupuncture could improve FD symptom scores and scores on the Neck Disability Index (NDI), the 36-Item Short Form Health Survey (SF-36), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) more or as significantly as sham acupuncture. With regard to adverse effects, acupuncture was superior to cisapride treatment (one study; all minor events), but no statistically significant difference was reported between acupuncture and sham acupuncture. No adverse effects data were reported in studies examining manual acupuncture versus domperidone, manual-electroacupuncture versus domperidone, or electroacupuncture versus itopride.Nevertheless, all evidence was of low or very low quality. The body of evidence identified cannot yet permit a robust conclusion regarding the efficacy and safety of acupuncture for FD. AUTHORS' CONCLUSIONS: It remains unknown whether manual acupuncture or electroacupuncture is more effective or safer than other treatments for patients with FD.

Amiloride and SN-6 suppress audiogenic seizure susceptibility in genetically epilepsy-prone rats.

AIMS: We have recently reported that amiloride, a potent and nonselective blocker of acid-sensing ion channels, prevents the development of pilocarpine-induced seizures and status epilepticus. Amiloride is also known to suppress the activity of Na(+) /Ca(2+) and Na(+) /H(+) exchangers that have been implicated in the pathophysiology of seizures. Here, we evaluated the effects of amiloride, SN-6 (a potent blocker of Na(+) /Ca(2+) exchangers) and zoniporide (a potent blocker of Na(+) /H(+) exchangers) on acoustically evoked seizures (audiogenic seizures, AGS) in genetically epilepsy-prone rats (GEPR-3s), a model of inherited generalized epilepsy. METHODS: Male, six-week-old GEPR-3s were used. The GEPR-3s were tested for AGS susceptibility before and after treatment with various doses of amiloride, SN-6, and zoniporide (1, 3, 10, and 30 mg/kg; per os). RESULTS: We found that pretreatment with amiloride and SN-6 markedly reduced the incidence and severity of AGS in the GEPR-3s. In contrast, administration of zoniporide only minimally reduced the incidence and severity of AGS in the GEPR-3s. A combination of noneffective doses of SN-6 and zoniporide also suppressed AGS susceptibility in the GEPR-3s. CONCLUSIONS: These findings suggest acid-sensing ion channels and the Na(+) /Ca(2+) exchanger may play an important role in the pathophysiology of inherited AGS susceptibility in the GEPR-3s.

Cytoprotective effect of benzyl N'-(5-chloro-indol-3-yl-methylidene)-hydrazinecarbodithioate against ethanol-induced gastric mucosal injury in rats.

Indolic compounds have attracted a lot of attention due to their interesting biological properties. The present study was performed to evaluate the subacute toxicity and anti-ulcer activity of BClHC against ethanol-induced gastric ulcers. Experimental animal groups were orally pre-treated with different doses of BClHC (50, 100, 200 and 400 mg/kg) in 10% Tween 20 solution (vehicle). Blank and ulcer control groups were pre-treated with vehicle. The positive group was orally pretreated with 20 mg/kg omeprazole. After one hour, all groups received absolute ethanol (5 mL/kg) to generate gastric mucosal injury except the blank control group which was administered the vehicle solution. After an additional hour, all rats were sacrificed, and the ulcer areas of the gastric walls determined. Grossly, the ulcer control group exhibited severe mucosal injury, whereas pre-treatment with either derivative or omeprazole resulted in significant protection of gastric mucosal injury. Flattening of gastric mucosal folds was also observed in rats pretreated with BClHC. Histological studies of the gastric wall of ulcer control group revealed severe damage of gastric mucosa, along with edema and leucocytes infiltration of the submucosal layer compared to rats pre-treated with either BClHC or omeprazole where there were marked gastric protection along with reduction or absence of edema and leucocytes infiltration of the submucosal layer. Subacute toxicity study with a higher dose of derivative (5 g/kg) did not manifest any toxicological signs in rats. In conclusions, the present finding suggests that benzyl N'-(5-chloroindol-3-ylmethylidene)hydrazinecarbodithioate promotes ulcer protection as ascertained by the comparative decreases in ulcer areas, reduction of edema and leucocytes infiltration of the submucosal layer.

Aurones: interesting natural and synthetic compounds with emerging biological potential.

Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only for their physiological properties and effects on Nature, but also for their therapeutic potential. Aurones are recently attracting the interest of an increasing number of research groups, and, since the last review, some interesting advances have been made in understanding the aurones. In this review, we report the recent advances made on the synthetic routes towards aurones. We also highlight their activity in different biological areas, as well as applied genetic plant modifications to produce these colored compounds. Their synthesis, structure-activity relationships and the importance of the substitution pattern will also be mentioned. Finally, some aspects regarding the possible development of aurones will be discussed briefly.

New bibenzyl glycosides from leaves of Camellia oleifera Abel. with cytotoxic activities.

Studies on the chemical constituents of leaves of Camellia oleifera Abel. led to the isolation of 3 new bibenzyl glycosides. Their structures have been elucidated as 1-(3',5'-dihydroxy)phenyl-2-(4″-O-ß-D-glucopyranosyl)phenylethane (1), 1-(3',5'-dimethoxy)phenyl-2-(4″-O-ß-D-glucopyranosyl)phenylethane (2) and 1-(3',5'-dimethoxy)phenyl-2-[4″-O-ß-D-glucopyranosyl(6→1)-O-α-L-rhamnopyranosyl]phenylethane (3) through spectral studies including HR-ESI-MS, ((1))H NMR, ((13))C NMR and 2D NMR experiments. All the above 3 bibenzyl glycosides showed cytotoxic activities to Hela and hep2 cell lines.

Inhibition of CD44 N- and O-linked glycosylation decreases endometrial cell lines attachment to peritoneal mesothelial cells.

The attachment of endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs) to peritoneal mesothelial cells (PMCs) with and without inhibition of N- and O-linked glycosylation, the viability of EECs and ESCs, and the expression of CD44 surface density were evaluated. Inhibition of CD44 N- and O-linked glycosylation by using tunicamycin and/or B-GalNAc statistically significantly inhibited endometrial cell attachment to peritoneal mesothelial cells, suggesting a role in establishment of early endometriotic lesions.

A critical review of the therapeutic potential of dibenzyl trisulphide isolated from Petiveria alliacea L (guinea hen weed, anamu).

The data compiled in the present review on dibenzyl trisulphide (DTS) isolated from Petiveria alliacea L (the guinea hen weed or anamu) revealed that the compound and its derivatives could be of tremendous pharmaceutical interest. The mode of action elucidated for DTS revealed that it is a mitogen activated protein extracellular regulated kinases 1 and 2 (MAPKinases erk1 and erk 2) signal transduction molecule. Dibenzyl trisulphide caused hyper-phosphorylation of growth factor induced MAPKinases (erk 1 and erk 2) phosphorylation, a process critical for the improvement of long term memory, and is implicated in neuronal growth. Dibenzyl trisulphide and its derivatives exhibited potent anti-proliferation/cytotoxic activity on a wide range of cancer cell lines. The cytotoxic activity of DTS was increased by 70-1000 fold when bound to albumin in vitro. Dibenzyl trisulphide seems to have a cytokine switching mechanism in which it down regulates cytokines from the Type I helper cells (Th -1 cell) pathway which contained several pro-inflammatory cytokines and up-regulates those on the Type 2 helper cells (Th-2) pathway. The trisulphide up-regulates some reticuloendothelial system parameters eg granulocyte counts and increased thymic and Peyer's patches masses via cell proliferation processes which are known to be regulated via the MAPKinase signal transduction pathway. When the zygotes ofAsternia pectinifera (Starfish) were exposed to DTS at concentration of 10 mM, a dose lethal to all cancer cells tested, it was observed that the sensitive process of protein biosynthesis was not affected Similarly, the proliferation of the HOFA human fibroblast, a noncancerous cell line, was not severely affected by DTS at 8.9 microM over seven days, a concentration also lethal to most cancer cell lines tested The implications of the findings will be highlighted in the present review.

A critical review of the therapeutic potential of dibenzyl trisulphide isolated from Petiveria alliacea L (guinea hen weed, anamu) / Un estudio crítico del potencial terapéutico del trisulfuro de dibencilo aislado a partir de petiveria alliacea l (yerba de guinea, anamú)

The data compiled in the present review on dibenzyl trisulphide (DTS) isolated from Petiveria alliacea L (the guinea hen weed or anamu) revealed that the compound and its derivatives could be of tremendous pharmaceutical interest. The mode of action elucidated for DTS revealed that it is a mitogen activated protein extracellular regulated kinases 1 and 2 (MAPKinases erk1 and erk 2) signal transduction molecule. Dibenzyl trisulphide caused hyper-phosphorylation of growth factor induced MAPKinases (erk 1 and erk 2) phosphorylation, a process critical for the improvement of long term memory, and is implicated in neuronal growth. Dibenzyl trisulphide and its derivatives exhibited potent anti-proliferation/cytotoxic activity on a wide range of cancer cell lines. The cytotoxic activity of DTS was increased by 70-1000 fold when bound to albumin in vitro. Dibenzyl trisulphide seems to have a cytokine switching mechanism in which it down regulates cytokines from the Type I helper cells (Th -1 cell) pathway which contained several pro-inflammatory cytokines and up-regulates those on the Type 2 helper cells (Th-2) pathway. The trisulphide up-regulates some reticuloendothelial system parameters eg granulocyte counts and increased thymic and Peyer's patches masses via cell proliferation processes which are known to be regulated via the MAPKinase signal transduction pathway. When the zygotes ofAsternia pectinifera (Starfish) were exposed to DTS at concentration of 10 mM, a dose lethal to all cancer cells tested, it was observed that the sensitive process of protein biosynthesis was not affected Similarly, the proliferation of the HOFA human fibroblast, a noncancerous cell line, was not severely affected by DTS at 8.9 microM over seven days, a concentration also lethal to most cancer cell lines tested The implications of the findings will be highlighted in the present review.

Los datos compilados en el presente estudio sobre el trisulfuro de dibencilo (TSD) aislado a partir de Petiveria alliacea L (yerba de Guinea, ó anamú) revelaron que el compuesto y sus derivados podrían tener extraordinario interés farmacéutico. El modo de acción esclarecido en el TSD, reveló que se trata de una molécula de transducción de señales de proteínas kinasas 1 y 2 (MAP quinasas ERk 1 y 2) reguladas extracelularmente y activadas por mitógenos. El trisulfuro de dibencilo causó hiperfosforilación de la fosforilación de las quinasas MAP (Erk 1 y 2) inducidas mediante factor de crecimiento, un proceso crítico para el mejoramiento de la memoria a largo plazo, y que está implicado en el crecimiento neuronal. El trisulfuro de dibencilo y sus derivados mostraron una poderosa actividad citotóxica y antiproliferativa en una amplia gama de líneas celulares de cáncer. La actividad citotóxica del TSD se incrementaba de 70 á 1000 veces, cuando se vinculaba a la albúmin in vitro. El trisulfuro de dibencilo parece poseer un mecanismo conmutador citoquínico que regula por decremento las citoquinas provenientes de la vía de las células auxiliares de tipo 1 (células Th-1), que contiene varias citoquinas pro-inflamatorias y regula por incremento las de la vía de las células auxiliares de tipo 2 (Th-2). El trisulfuro regula por incremento los parámetros del sistema reticuloendotelial, p.ej. los conteos de granulocitos y el aumento tanto de las masas tímicas como de las masas de placas de Peyer, a través de los procesos de proliferación celular, de los cuales se sabe que son regulados mediante la vía de la transducción de señales de la quinasa MAP. Cuando los cigotos de Asternia pectinifera (estrella de mar) fueron expuestos al TSD a una concentración de 10 mM ­ una dosis letal para todas las células cancerosas sometidas a prueba ­ se observó que el proceso sensible de biosíntesis de la proteína no era afectado. De modo similar, la proliferación del fibroblasto humano HOFA ­ una línea celular no cancerosa ­ no fue afectada severamente por el TSD a 8.9 µM en siete días ­ una concentración letal para la mayoría de las líneas celulares cancerosas sometidas a prueba. Las implicaciones de los hallazgos se pondrán de relieve en el presente estudio

Two new benzylbenzoate glucosides from Curculigo orchioides.

An extract from in vitro cultures of Curculigo orchioides grown as bulbils in shake flasks, afforded two new glucosides of substituted benzylbenzoate - curculigoside C (3) and curculigoside D (4) - together with two known compounds - curculigoside A (1) and curculigoside B (2). Their structures were elucidated on the basis of spectral evidence, in particular by using 2D NMR methods. Their vasoactive properties were assessed in isolated rat aortic rings.

Hepatoprotective effect of myristicin from nutmeg (Myristica fragrans) on lipopolysaccharide/d-galactosamine-induced liver injury.

To evaluate the hepatoprotective activity of spices, 21 different spices were fed to rats with liver damage caused by lipopolysaccharide (LPS) plus d-galactosamine (D-GalN). As assessed by plasma aminotranferase activities, nutmeg showed the most potent hepatoprotective activity. Bioassay-guided isolation of the active compound from nutmeg was carried out in mice by a single oral administration of the respective fractions. Myristicin, one of the major essential oils of nutmeg, was found to possess extraordinarily potent hepatoprotective activity. Myristicin markedly suppressed LPS/D-GalN-induced enhancement of serum TNF-alpha concentrations and hepatic DNA fragmentation in mice. These findings suggest that the hepatoprotective activity of myristicin might be, at least in part, due to the inhibition of TNF-alpha release from macrophages. However, further studies are needed to elucidate the hepatoprotective mechanism(s) of myristicin.

Fedotozine reversal of peritoneal-irritation-induced ileus in rats: possible peripheral action on sensory afferents.

Two kappa agonists, fedotozine and trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolydinyl)-cyclohexyl ]- benzeneacetamide methanesulfonate [(+/-)U-50,488H] were used to reverse the gastrointestinal transit inhibition induced by either peritoneal irritation (PI) or intracisternal (i.c.) administration of corticotropin releasing factor (CRF). PI was induced by acetic acid given i.p. Gastric emptying and intestinal transit were estimated with a 51Cr-labeled test meal. PI inhibited both gastric emptying (-50.9%) and intestinal transit (-48.8%). These inhibitions were prevented in a dose-dependent manner by the CRF antagonist, alpha-helical-CRF9-41 at doses (1-10 nmol/rat i.c.) that had no effect in control animals. CRF (300 pmol/rat i.c.) reproduced the gastrointestinal transit inhibitions seen under PI. The CRF effects were blocked by alpha-helical-CRF9-41 (10 nmol/rat) given i.c. but not i.v. Fedotozine (1-10 mg/kg s.c. but not 300 micrograms/rat i.c.v. or intrathecally) and (+/-)U-50,488H (0.3-3 mg/kg s.c. but not 100 micrograms/kg i.c.v.) reversed PI- but not CRF-induced ileus. Neither PI-induced ileus nor the fedotozine response was affected by perivagal capsaicin treatment. It was concluded that the PI-induced ileus depends on central CRF receptors. This result is consistent with the activation of an extrinsic inhibitory reflex. The reversal by kappa agonists of PI- but not CRF-induced ileus suggests that kappa agonists do not act after but before the CRF receptors. A possible peripheral action on nonvagal sensory afferents is suggested.

[The periodontally prophylactic effect of the dentifrice "Silka". 1. The effect of the dentifrice "Silka" on the periodontium compared to other dentifrices from the DDR production]. / Der parodontalprophylaktische Effekt der Zahnpaste "Silka" 1. Mitteilung: Die Wirkung der Paste "Silka" auf das parodontium im Vergleich zu anderen Pasten aus der DDR-Produktion.

As compared to a toothpaste without periodontal-prophylactic adjuncts, the commercially available silka toothpaste exerted a statistically significant beneficial effect on the chronically inflamed gingivae. Thus, a periodontal-prophylactic efficiency may be attributed to the Silka toothpaste.