• Biomolecules & Therapeutics
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• v.15 no.3
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• pp.150-155
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• 2007

In the present study, we have tested the effect of dioleoyl phosphatidic acid (PA) on intracellular $Ca_{2+}$ concentration ($[Ca^{2+}]_{i}$) in two human colon cancer cell lines (HCT116 and HT29). PA and lysophosphatidic acid (LPA), a bioactive lysolipid, increased $[Ca^{2+}]_{i}$ in both HCT116 and HT29 cell lines. Increases of $[Ca^{2+}]_{i}$ by PA and LPA were more robust in HCT116 cells than in HT29 cells. A specific inhibitor of phospholipase C (U73122), however, was not inhibitory to the cell responses. Pertussis toxin, a specific inhibitor of $G_{i/o}$ type G proteins, however, had an inhibitory effect on the responses except for an LPA-induced one in HT29 cells. Ruthenium red, an inhibitor of the ryanodine receptor, was not inhibitory on the responses, however, 2-APB, a specific inhibitor of inositol 1,4,5-trisphosphate receptor, completely inhibited both lipid-induced $Ca^{2+}$ increases in both cell types. Furthermore, by using Ki16425 and VPC32183, two structurally dissimilar specific antagonists for $LPA_{1}/LPA_{3}$ receptors, an involvement of endogenous LPA receptors in the $Ca^{2+}$ responses was observed. Ki16425 completely inhibited the responses but the susceptibility to VPC32183 was different to PA and LPA in the two cell types. Expression levels of five LPA receptors in the HCT116 and HT29 cells were also assessed. Our data support the notion that PA could increase $[Ca^{2+}]_{i}$ in human colon cancer cells, probably via endogenous LPA receptors, G proteins and $IP_{3}$ receptors, thereby suggesting a role of PA as an intercellular lipid mediator.

• BMB Reports
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• v.38 no.2
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• pp.238-242
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• 2005

5-HT2A is one of major serotonin receptor that is involved in the action of serotonin-targeting drugs. Previous clinical studies have shown an unexpected association between lower cholesterol level and psychiatric diseases, in which T102C polymorphism of HTR2A, gene of 5-HT2A serotonin receptor, might be involved. Therefore, we hypothesized a potential association between lower cholesterol level and T102C polymorphism. The effect of the T102C polymorphism on the serum lipid profiles of 646 subjects without specific psychiatric disease was investigated. Genotype was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. There were significantly lower levels of total cholesterol ($193.6{\pm}35.0$ versus $202.1{\pm}45.5\;mg/dl$, p = 0.016) and HDL-cholesterol ($42.7{\pm}11.6$ versus $46.3{\pm}12.7\;mg/dl$, p = 0.004) in CC genotype than non-CC genotypes. Moreover, multivariate analysis showed that the CC genotype is a strong predictor of a lower HDL-cholesterol level (p < 0.001). In conclusion, this study shows that the CC genotype of the HTR2A gene is related to lower HDL-cholesterol level in Koreans. This is the first demonstration showing the potential genetic relationship between the serotonin receptor gene polymorphism and the HDL-cholesterol level.

• Journal of Ginseng Research
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• v.29 no.2
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• pp.94-99
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• 2005

In the previous study, we reported that the in viかo inhibitory effect of ginsenosides, active ingredient of Panax ginseng, on $5-HT_{3A}$ receptor channel activity is coupled to in vivo anti-vomiting and anti-nausea effect. In the present study, we further investigated that the inhibitory effect of ginsenosides, active ingredient of Panax ginseng, on 5-HT3A receptor channel activity is also coupled to attenuation of irritable bowel syndrome (IBS), which is induced by colorectal distention (CRD) and $0.6\%$ acetic acid treatment. The CRD-induced visceral pains induced by CRD and acetic acid treatment are measured by frequency of contractions of the external oblique muscle in conscious rats. Treatment of GTS significantly inhibited CRD-induced visceral pain with dose-dependent manner. The $EC_{50}$ was $5.5{\pm}4.7$ mg/kg ($95\%$ confidence intervals: 1.2-15.7) and the antinociceptive effect of GTS on visceral pain was persistent for 4 h. We also compared the effects of protopanaxadiol (PD) ginsenosides and protopanaxatriol (PT) ginsenosides with saline on acetic acid-and CRD-induced visceral pain, and found that protopanaxatriol (PT) ginsenosides was much more potent than PD ginsenosides in attenuating CRD-induced visceral pain. These results indicate that U ginsenosides of Panax ginseng are components far attenuation of experimentally CRD-induced visceral pains.

• The Korean Journal of Pharmacology
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• v.28 no.2
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• pp.137-146
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• 1992

The central tryptaminergic system has been shown to play an important role in the regulation of renal function: $5-HT_1$ receptor mediate diuresis and natriuresis, whereas both $5-HT_2$ and $5-HT_3$ mediate antidiuresis and antinatriuresis. Recently, $5-HT_1$ receptors are further subdivided into many subtypes, and central $5-HT_{1A}$ subtype was shown to mediate diuretic and natriuretic effects. The present study was undertaken to delineate the role of $5-HT_{1B}$ subtype. Trifluoromethylphenylpiperazine (TFMPP), a selective $5-HT_{1B}$ agonist in doses ranging from 8 to $750\;{\mu}g/kg$ icv elicited diuresis, natriuresis and kaliuresis in dose-dependent fashion, with the fractional excretion of filtered Na reaching 5.44% with $250\;{\mu}g/kg$ icv. The natriuresis outlasted the transient increases in renal hemodynamics, suggesting humoral mediation in the decreased tubular Na reabsorption. Plasma concentration of atrial natriuretic peptide increased along with the natriuresis. Systemic blood pressure transiently increased. When given intravenously, no diuresis and natriuresis was elicited, indicating the central mechanism. The icv TFMPP effects were not significantly affected by icv methysergide, a nonselective $5-HT_1$ blocker. Both ketanserin and MDL 72222, selective $5-HT_2$ and $5-HT_3$ antagonists, resp., did not abolish the TFMPP effects. Nor did NAN-190, $5-HT_{1A}$ blocker, affect the TFMPP effects. These observations suggest that central $5-HT_{1B}$ receptors may play a role in the central regulation of renal function by exerting diuretic and natriuretic influences, mainly through natriuretic factors.

• Journal of Acupuncture Research
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• v.22 no.2
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• pp.19-32
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• 2005

Objectives : to evaluate the analgesic effect of bee venom acupuncture on Choksamni (ST36) in the collagen-induced arthritis rats and investigate the role played by serotonergic receptor subtypes (5-HT1a, 5-HT2a) in the antinociceptive effect of bee venom acupuncture in a thermal hyperalgesia test Methods : Experiments were performed on 5 week-aged 60 male Sprague-Dawley rats according to National Institute of Health guidelines and the ethical guidelines of the International Association for the Study of Pain (IASP). Arthritis was induced with arthrogenic collagen emulsion (Bovine type II collagen ${\mu}g$ with incomplete Freund's adjuvant $100\;{\mu}g$). The onset of arthritis was considered to be present when erythema and swelling were detected in at least one joint. The thermal hyperalgesia was evaluated weekly with tail flick test in the rats of severity grade 3 without any injury at tail and foot (including inflammation, ulceration, snap). In the fourth week after first immunization, the analgesic effect of bee venom acupuncture (Choksamni, ST36) was measured with consecutive tail flick latency after intraperitoneal injection of spiroxatrine (1mg/kg) and spiperone (1mg/kg). Results : Chronic inflammatory pain was induced as time elapsed after the immunization of arthrogenic collagen and the maximum value was reached from third to fifth week. Chronic inflammatory pain induced by CIA was inhibited by bee venom acupuncture on the left ST36. The analgesic effect of bee venom acupuncture was inhibited by intraperitoneal injection of 5-HT1a antagonist spiroxatrine and 5-HT2a antagonist spiperone. Conclusions : Therefore, a conclusion. that the analgesic effect of bee venom acupuncture in the chronic inflammatory pain is partially mediated by 5-HT1a and 5-HT2a receptors can be made.

• Proceedings of the Ginseng society Conference
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• 2006.05a
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• pp.77-77
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• 2006

• Toxicological Research
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• v.17 no.2
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• pp.159-161
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• 2001

The anti-emetic effect of a 5-HT$_3$ receptor antagonist, Ondaron, was compared with that of the approved ondansetron agent, Zofran$\circledR$ in the ferrets. Emesis was induced by single intraperitoneal injection of cisplatin 10 mg/kg, and Ondaron or Zofran$\circledR$ was injected intraperitoneally in a dose of 1.0 mg/kg, respectively. Ondaron and Zofran$\circledR$ effectively antagonised the emetic response for 4 hours after injection. They significantly reduced the number of vomiting and retching, and prolonged the latency to the first episode. The anti-emetic effect of Ondaron was almost the equal to that of Zofran$\circledR$. These results suggest that Ondaron is an effective anti-emetic agent against cisplatin-induced emesis, and its anti-emetic potency is similar to that of 5-$HT_3$ receptor abtagonist, Zofran$\circledR$.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.23
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• pp.10045-10051
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• 2015

Chemotherapy is a major therapeutic approach for malignant neoplasms; however, due to the most common adverse events of nausea and vomiting, scheduled chemotherapeutic programs may be impeded or even interrupted, which severely impairs the efficacy. Aprepitants, 5-HT3 antagonists and dexamethasone are primary drugs used to prevent chemotherapy-induced nausea and vomiting (CINV). These drugs have excellent efficacy for control of acute vomiting but are relatively ineffective for delayed vomiting. Aprepitant may remedy this deficiency. Substance P was discovered in the 1930s and its association with vomiting was confirmed in the 1950s. This was followed by a period of non-peptide neurokinin-1 (NK-1) receptor antagonist synthesis and investigation in preclinical studies and clinical trials (phases I, II and III). The FDA granted permission for the clinical chemotherapeutic use of aprepitant in 2003. At present, the combined use of aprepitant, 5-HT3 antagonists and dexamethasone satisfactorily controls vomiting but not nausea. Therefore, new therapeutic approaches and drugs are still needed.

• Proceedings of the Ginseng society Conference
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• 2005.11a
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• pp.32-40
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• 2005

The last two decades have shown a marked expansion in publications of diverse effects of Panax ginseng. Ginsenosides, as active ingredients of Panax ginseng, are saponins found in only ginseng. Recently, a line of evidences shows that ginsenosides regulate various types of ion channel activity such as Ca$^{2+}$, K$^+$, Na$^+$, Cl$^-$, or ligand gated ion channels (i.e. 5-HT$_3$, nicotinic acetylcholine, or NMDA receptor) in neuronal, non-neuronal cells, and heterologously expressed cells. Ginsenosides inhibit voltage-dependent Ca$^{2+}$, K$^+$, and Na$^+$ channels, whereas ginsenosides activate Ca$^{2+}$-activated Cl$^-$ and Ca$^{2+}$-activated K$^+$ channels. Ginsenosides also inhibit excitatory ligand-gated ion channels such as 5-HT$_3$. nicotinic acetylcholine, and NMDA receptors. This presentation will introduce recent findings on the ginsenoside-induced differential regulations of ion channel activities as a ligand as other drugs do.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.5
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• pp.2637-2641
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• 2016

Tumor necrosis factor ($TNF-{\alpha}$), an inflammatory cytokine that plays an important role in the control of cell proliferation, differentiation, and apoptosis, has previously been used in anti-cancer therapy. However, the therapeutic applications of $TNF-{\alpha}$ are largely limited due to its general toxicity and anti-apoptotic influence. To overcome this problem, the present study focused on the effect of active constituents isolated from a medicinal plant on $TNF-{\alpha}$-induced apoptosis in human colon adenocarcinoma (HT-29) cells. Nimbolide from Azadirachta indica was evaluated for cytotoxicity by methyl tetrazolium 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay and phase contrast microscopy. Effects on apoptotic signaling proteins were investigated using Western blot analysis. Nimbolide showed cytotoxicity against HT-29 cells that was significantly different from the control group (p<0.01), a concentration of $10{\mu}M$ significantly inducing cell death (p<0.01). In combination with $TNF-{\alpha}$, nimbolide significantly enhanced-induced cell death. In apoptotic pathway, nimbolide activated c-Jun N-terminal kinase (JNK) phosphorylation, BH3 interacting-domain death agonist (Bid) and up-regulated the death receptor 5 (DR5) level. In the combination group, nimbolide markedly sensitized $TNF-{\alpha}$-induced JNK, Bid, caspase-3 activation and the up-regulation of DR5. Our findings overall indicate that nimbolide may enhance $TNF-{\alpha}$-mediated cellular proliferation inhibition through increasing cell apoptosis of HT-29 cells by up-reglation of DR5 expression via the JNK pathway.