Supplementation of syringic acid-rich Phrynium pubinerve leaves imparts protection against allergic inflammatory responses by downregulating iNOS, COX-2, and NF-κB expressions.

Background: The present study was designed to characterize the role of ethanolic leaf extract of Phrynium pubinerve Blume (EPP) supplement in attenuating allergic inflammation, encouraged by the presence of syringic acid in it, as this phenolic acid is reportedly promising in suppressing serum immunoglobulin E (IgE) and inflammatory cytokine levels. Materials and methods: HPLC-DAD dereplication analysis was performed to determine the presence of the vital polyphenolic metabolites. The efficacy of EPP against lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 cells was evaluated by measuring its inhibitory effects on NO and ROS/RNS production. The expressions of major inflammation-associated molecules (iNOS, COX-2, NF-κB, IL-6, and TNF-α) in RAW 264.7 cells were assessed through Western blot. Physiological and behavioral changes, BMI, and different biochemical parameters in mice blood serum were investigated in the toxicological assays. Formaldehyde-induced paw edema test in mice was conducted using established animal model. TDI-induced allergic model in mice was carried out to determine different allergy-like symptoms, and differential white blood cell (WBC) counts in blood and bronchoalveolar lavage (BAL) fluid. The intermolecular interaction analysis of the identified major metabolite of EPP with H1R and iNOS was studied by molecular docking. Results: HPLC-DAD analysis showed the presence of syringic acid (89.19 mg/100 g EPP) and a few other compounds. LPS-induced NO generation was reduced by EPP in a concentration-dependent manner, showing IC50 of 28.20 ± 0.27 µg/mL. EPP exhibited a similar inhibitory effect on ROS/RNS production with IC50 of 29.47 ± 2.19 µg/mL. Western blotting revealed that EPP significantly downregulated the expressions of iNOS, COX-2, NF-κB, IL-6, and TNF-α in RAW 264.7 cells when challenged with LPS. The toxicological assays confirmed the dosage and organ-specific safety of EPP. In the formaldehyde-induced paw edema test, EPP caused a 66.41% reduction in mice paw volume at 500 mg/kg dose. It ameliorated TDI-induced allergy-like symptoms and decreased different inflammatory WBCs in mice's blood and BAL fluid in a dose-dependent manner. Finally, syringic acid demonstrated mentionable intermolecular binding affinity towards H1R (-6.6 Kcal/moL) and iNOS (-6.7 Kcal/moL). Conclusions: Collectively, considerable scientific reasoning was obtained in favor of the suppressive potential of EPP against allergic inflammatory responses that are proposed to be exerted via the downregulation of iNOS, COX-2, and NF-κB expressions, H1R antagonism and suppression of cytokines, such as IL-6, and TNF-α.

Identification of Potential Diuretic and Laxative Drug Candidates from Avicennia officinalis L. Bark through In Vivo Mice Model Studies and In Vitro Gas Chromatography-Mass Spectrometry and Molecular Docking Analysis.

Background: Avicennia officinalis is a medicinal plant that has traditionally been used as a diuretic, anti-infective, and antiasthmatic. Our investigation was designed to explore the diuretic and laxative potentials of different fractions of this plant's bark extract as well as the identification of possible drug candidates for the activity. Methods: Collected bark was extracted in ethanol and fractionated in different polar and nonpolar solvents, i.e., water, chloroform, ethyl acetate, and n-hexane. Phytoconstituents were identified following the published protocols and gas chromatography-mass spectrometry (GC-MS). In the diuretic test, Na+ and K+ ions were measured using a flame photometer whereas the Cl- ion content was measured by titrimetric method against AgNO3. In the laxative test, feces amount and consistency were also measured. Molecular docking analysis was conducted using the "Vina Wizard" program in PyRx-Python Prescription 0.8. Results: Phytochemical analysis indicated that alkaloids, tannins, flavonoids, saponins, glycosides, and terpenoids were detected in the most bioactive crude extracts, whereas alkaloids, terpenoids, saponins, and gums were found in bioactive n-hexane fraction and steroids, glycosides, and terpenoids were found positive in chloroform fraction. Almost all the fractions demonstrated a dose-dependent increment of stool production with a soft consistency; however, the chloroform fraction was found to be the most active (p < 0.001). The crude extract and n-hexane fractions significantly increased (p < 0.01) the urinary output at the dose of 200 and 400 mg/kg. The concentrations of Na+, K+, and Cl- in collected urine were found to be more compared with the control group. The GC-MS analysis identified seven compounds in bioactive n-hexane fraction (phenolic and ester-type mainly) whereas seven other compounds (acidic and ester-type mainly) were identified in chloroform fraction. In molecular docking, two drug candidates of this extract (2,4-bis(2-phenylpropan-2-yl)phenol and 2-[4-[2-(dimethylamino)-2-oxo-1,1-diphenylethyl]phenyl]-2-phenylacetic acid) showed excellent binding affinity with the receptor compared with furosemide. Conclusion: A. officinalis bark might be a potential source of bioactive compounds for treating hypertension, edema, and constipation.

A systematic review on the neuroprotective perspectives of beta-caryophyllene.

Beta (ß)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect. This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords "beta (ß)-caryophyllene" and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action. A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer's disease. Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.

Toxicogenetic study of omeprazole and the modulatory effects of retinol palmitate and ascorbic acid on Allium cepa.

Omeprazole (OME) is a proton pump inhibitor used for the treatment of various gastric and intestinal disease; however, studies on its effects on the genetic materials are still restricted. The present study aimed to evaluate possible toxicogenic effects of OME in Allium cepa meristems with the application of cytogenetic biomarkers for DNA damage, mutagenic, toxic and cytotoxic effects. Additionally, retinol palmitate (RP) and ascorbic acid (AA) were also co-treated with OME to evaluate possible modulatory effects of OME-induced cytogenetic damages. OME was tested at 10, 20 and 40 µg/mL, while RP and AA at 55 µg/mL and 352.2 µg/mL, respectively. Copper sulphate (0.6 µg/mL) and dechlorinated water were used as positive control and negative control, respectively. The results suggest that OME induced genotoxicity and mutagenicity in A. cepa at all tested concentrations. It was noted that cotreatment of OME with the antioxidant vitamins RP and/or AA significantly (p < 0.05) inhibited and/or modulated all toxicogenic damages induced by OME. These observations demonstrate their antigenotoxic, antimutagenic, antitoxic and anticitotoxic effects in A. cepa. This study indicates that application of antioxidants may be useful tools to overcome OME-induced toxic effects.

Safety and Effectiveness of Short-Course AmBisome in the Treatment of Post-Kala-Azar Dermal Leishmaniasis: A Prospective Cohort Study in Bangladesh.

Background: A safe and effective short-course treatment regimen for post-kala-azar dermal leishmaniasis (PKDL) is considered essential for achieving and sustaining elimination of visceral leishmaniasis (VL) in the Indian subcontinent [1, 2]. Here, single-dose liposomal amphotericin B (AmBisome) has been adopted as a first-line regimen for VL; however the effectiveness and safety of AmBisome for PKDL has not been formally evaluated. Methods: The safety and effectiveness of AmBisome 15 mg/kg, given over 15 days in 5 biweekly infusions of 3 mg/kg on an outpatient basis, was evaluated between April and November 2014 in patients with clinically diagnosed PKDL, aged ≥12 years and residing in a highly VL-endemic area in Bangladesh. This was a prospective cohort observational study, with the objective to assess final cure 12 months after treatment. Clinical response was monitored at 1, 3, 6, and 12 months, and safety during treatment and up to 1 month after treatment. Results: Of the 280 patients meeting the inclusion criteria, 273 were assessed at 12 months. A complete or major improvement of lesions was seen in 245 patients (89.7%); 213 (78.0%) were considered completely cured. Lesions did not improve in 28 (10.3%) and new lesions appeared in 13 (4.8%). All patients completed treatment without severe or serious adverse events. Conclusions: A short-course 15-mg/kg AmBisome regimen proved safe and effective in the treatment of clinically diagnosed PKDL in Bangladesh, and should be considered a treatment option for routine programmatic use in the VL elimination effort in the Indian subcontinent.

Andrographolide, a diterpene lactone from Andrographis paniculata and its therapeutic promises in cancer.

The diterpene lactone andrographolide, isolated from Andrographis paniculata, has been proven to possess several important protective biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiseptic, antimicrobial, cytotoxic, hypolipidemic, cardioprotective, hepatoprotective, and neuroprotective effects. In addition, it has been reported to play a therapeutic role in the treatment of major human diseases, such as Parkinson's disease, rheumatoid arthritis, and colitis. This systematic review aims to highlight andrographolide as a promising agent in cancer treatment. To this purpose, a number of databases were used to search for the cytotoxic/anticancer effects of andrographolide in pre-clinical and clinical studies. Among 1703 identified literature articles, 139 were included in this review; 109 were investigated as non-clinical, whereas 24, 3, and 3 were pre-clinical, clinical, and non-pre-clinical trials, respectively. Among the model systems, cultured cell lines appeared as the most frequently (79.14%) used, followed by in vivo models using rodents, among others. Furthermore, andrographolide was found to exert cytotoxic/anticancer effects on almost all types of cell lines with the underlying mechanisms involving oxidative stress, cell cycle arrest, anti-inflammatory and immune system mediated effects, apoptosis, necrosis, autophagy, inhibition of cell adhesion, proliferation, migration, invasion, anti-angiogenic activity, and other miscellaneous actions. After careful consideration of the relevant evidence, we suggest that andrographolide can be one of the potential agents in the treatment of cancer in the near future.

In Vivo and In Vitro Evaluation of Pharmacological Potentials of Secondary Bioactive Metabolites of Dalbergia candenatensis Leaves.

Background. Dalbergia species has wide range of secondary metabolites and is traditionally used in treatment of painful micturition, swelling, and leprosy and as blood tonic. The study evaluates membrane stabilizing, anticoagulant, analgesic, cytotoxic, subacute anti-inflammatory, and depression potentials of D. candenatensis leaves metabolites. Methods. Membrane stabilizing activity was evaluated by hypotonic induced hemolysis assay, whereas anticoagulant activity is done through extrinsic pathway by measuring prothrombin time. Analgesic action, cytotoxic effect, and subacute anti-inflammatory activity were determined by acetic acid induced writhing model, brine shrimp lethality bioassay, and formaldehyde induced model, respectively. Depression activity was measured by the Open Field, Hole Cross, Hole Board, and thiopentone induced sleeping time measuring methods. Results. D. candenatensis contains phenolic, flavonoid, and tannin, quantified as 416.25 mg, 330.00 mg, and 432.22 mg Gallic Acid Equivalent/100 g of dry extract, respectively. Extract showed maximum inhibition of writhe, hemolysis, and edema, approximate to 57.14%, 36.62%, and 34.1%, respectively. LC50 value for nauplii was 151.499 µg/ml. Mean prothrombin time was approximate to 31.0 ± 2.31 seconds at 1.0 mg/ml. Extract showed depression activity, and maximum sleeping time was noted to be about 141 minutes. Conclusion. D. candenatensis leaves show dose dependent membrane stabilizing, anticoagulant, depression, analgesic, moderate cytotoxic, and subacute anti-inflammatory activities.

The isolation and synthesis of a novel benzofuran compound from Tephrosia purpurea, and the synthesis of several related derivatives, which suppress histamine H1 receptor gene expression.

A novel naturally occurring compound with a benzofuran skeleton was isolated from a plant, Tephrosia purpurea collected in Bangladesh. The chemical synthesis of this compound confirmed its structure, and preliminary biological results showed its suppressive activity towards histamine H1 gene expression. One isomer and four derivatives were also synthesized, and their suppression activity was investigated. Although only small quantities of this compound can be isolated from its natural source, a 10 g scale synthesis was demonstrated by the newly developed method.

Clinical Evaluation of Neurosensory Changes in the Infraorbital Nerve Following Surgical Management of Zygomatico-Maxillary Complex Fractures.

INTRODUCTION: Zygomatico-orbital fractures are the second most common facial injuries. Trauma to mid-facial region can lead to an alteration or loss of sensation in the facial region which sometimes requires early surgical intervention to aid in an early recovery. AIM: To evaluate the different neurosensory changes in the infraorbital nerve function following common treatment modalities used in the management of zygomatico-maxillary complex fractures. MATERIALS AND METHODS: Thirteen patients selected for the study had unilateral zygomatic complex fracture with altered sensation in the region of distribution of the infraorbital nerve. The fractures were managed either by reduction followed by internal fixation with mini-plates (Group A), reduction alone (Group B) or conservatively (Group C). Infraorbital nerve function tests were done by mechanical, heat and pain threshold detection. Evaluation was done on 1(st), 3(rd), 7(th) day, one month, three months and six months interval in a manner similar to that done at the beginning of the study (Day0). RESULTS: A male predominance with male:female ratio of 5.5:1 and an age range of 21 to 50 years was found with the right side mostly affected. Road traffic accident was the most common aetiology. Most common clinical presentations were sub-conjunctival haemorrhage (84.61%), flattening of the malar prominence (69.23%) with deficit in neurosensory function of infra orbital nerve. Recovery in the infraorbital nerve function was relatively complete in 76.92% cases with partial recovery in 23.07% of the patients. CONCLUSION: Marked improvement in the neurosensory function of the infraorbital nerve was found when some form of treatment either in the form of Open Reduction and Internal Fixation (ORIF) or approach through Gillie's temporal or Keen's intraoral approach were applied as compared to when conservative treatment was provided. In zygomatic complex fractures, any form of treatment employed brought about decompression of the infraorbital nerve which aided in the recovery of the nerve within a span of 1-6 months, except when no treatment was applied.

Involvement of protein kinase Cdelta/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 (PARP-1) signaling pathway in histamine-induced up-regulation of histamine H1 receptor gene expression in HeLa cells.

The histamine H(1) receptor (H1R) gene is up-regulated in patients with allergic rhinitis. However, the mechanism and reason underlying this up-regulation are still unknown. Recently, we reported that the H1R expression level is strongly correlated with the severity of allergic symptoms. Therefore, understanding the mechanism of this up-regulation will help to develop new anti-allergic drugs targeted for H1R gene expression. Here we studied the molecular mechanism of H1R up-regulation in HeLa cells that express H1R endogenously in response to histamine and phorbol 12-myristate 13-acetate (PMA). In HeLa cells, histamine stimulation caused up-regulation of H1R gene expression. Rottlerin, a PKCδ-selective inhibitor, inhibited up-regulation of H1R gene expression, but Go6976, an inhibitor of Ca(2+)-dependent PKCs, did not. Histamine or PMA stimulation resulted in PKCδ phosphorylation at Tyr(311) and Thr(505). Activation of PKCδ by H(2)O(2) resulted in H1R mRNA up-regulation. Overexpression of PKCδ enhanced up-regulation of H1R gene expression, and knockdown of the PKCδ gene suppressed this up-regulation. Histamine or PMA caused translocation PKCδ from the cytosol to the Golgi. U0126, an MEK inhibitor, and DPQ, a poly(ADP-ribose) polymerase-1 inhibitor, suppressed PMA-induced up-regulation of H1R gene expression. These results were confirmed by a luciferase assay using the H1R promoter. Phosphorylation of ERK and Raf-1 in response to PMA was also observed. However, real-time PCR analysis showed no inhibition of H1R mRNA up-regulation by a Raf-1 inhibitor. These results suggest the involvement of the PKCδ/ERK/poly(ADP-ribose) polymerase-1 signaling pathway in histamine- or PMA-induced up-regulation of H1R gene expression in HeLa cells.

Transcriptional microarray analysis reveals suppression of histamine signaling by Kujin alleviates allergic symptoms through down-regulation of FAT10 expression.

Previously, we have shown that hot water extract from Kujin, the dried roots of Sophora flavescens alleviates allergic symptoms by suppressing histamine signaling at the transcription level in toluene 2,4-diisocyanate (TDI)-sensitized rats. To know more insights into the mechanism of the anti-allergic action of Kujin, we carried out the microarray analysis to explore genes that were up-regulated by treatment with TDI and also were suppressed these up-regulated gene expression by Kujin. Microarray analysis revealed the substantial up-regulation of FAT10 (also called UbD) mRNA due to TDI sensitization and Kujin extract significantly suppressed this up-regulation. FAT10 is an ubiquitin like protein having an active role in the immune system and is induced by proinflammatory cytokines. Activation of NF-κB by FAT10 also has been reported. However, the role of FAT10 in allergic pathogenesis remains unknown. Here we investigated the correlation of FAT10-NF-κB signaling with histamine signaling in TDI-sensitized rats. Real time RT-PCR analysis confirmed that treatment with TDI up-regulated FAT10 mRNA expression in the nasal mucosa of TDI-sensitized rats and Kujin extract suppressed this elevation. Treatment with H(1)-antihistamines suppressed the TDI-induced up-regulation of FAT10 mRNA expression in TDI-sensitized rats. Direct administration of histamine into the nasal cavity of non-TDI-treated normal rats up-regulated the expression of FAT10 mRNA. Our data suggest that Kujin might alleviate allergic symptoms by inhibition of NF-κB activation through suppression of histamine-induced up-regulation of FAT10 mRNA expression.

Antinociceptive and anti-hyperglycemic activity of methanol leaf extract of Cyperus scariosus.

The objective of the present study was to investigate the antinociceptive and anti-hyperglycemic activity of methanolic leaf extract of Cyperus scariosus. Antinociceptive activity was determined using a model of acetic acid-induced gastric pain in mice and anti-hyperglycemic activity through glucose tolerance test using glucose loaded mice. In writhing assays induced by acetic acid, the methanolic leaf extract showed dose dependent significant pain inhibition compared to control. The maximum writhing inhibition (46.62%) was found at a dose of 200 mg/kg body weight which was less than that of the positive control, aspirin (56.74%), when used at the same dose. Anti-hyperglycemic activity of the extract was also found to be significant in mice loaded with glucose at doses of 200 and 400 mg/kg body weight. Maximum tolerance (42.86%) was showed at 400 mg extract/kg body weight, which compared favorably with that of glibenclamide at 10 mg/kg body weight (57.62%). In summary, the methanol extract of C. scariosus leaves has had beneficial effects as a pain reliever and also in reducing the elevated blood glucose level of hyperglycemic mice.

Effect of Delonix regia leaf extract on glucose tolerance in glucose-induced hyperglycemic mice.

Delonix regia (Fabaceae) leaf is used in folk medicine of Bangladesh for the treatment of diabetes, but so far no scientific study has been done which may support its use in traditional medicine. The present study was carried out to evaluate the possible glucose tolerance efficacy of methanolic extract of Delonix regia leaf using glucose-induced hyperglycemic mice. The extract at different doses was administered one hr prior to glucose administration and blood glucose level was measured after two hrs of glucose administration (p.o.) using glucose oxidase method. The statistical data indicated significant oral hypoglycemic activity on glucose-loaded mice at every dose. Maximum anti-hyperglycemic activity was showed at 400 mg/kg which was comparable to that of a standard drug, glibenclamide (10 mg/kg). The methanolic extract of leaf of Delonix regia had beneficial effects in reducing the elevated blood glucose level of hyperglycemic mice.

Sho-seiryu-to suppresses histamine signaling at the transcriptional level in TDI-sensitized nasal allergy model rats.

BACKGROUND: The therapeutic use of Kampo medicine, Sho-seiryu-to (SST) in allergic disorders is well known. As histamine plays a central role in allergic diseases, it is possible that SST affects the allergy-related histamine signaling. In this study, we investigated the effect of SST on allergy-related histamine signaling in the nasal mucosa of toluene 2, 4-diisocyanate (TDI)-sensitized nasal allergy model rats. METHODS: Six-week-old male, Brown Norway rats were sensitized for 2 weeks with 10 microl of 10% TDI, and after a 1 week interval, provocation was initiated with the same amount of TDI. SST (0.6g/rat) was given orally 1 hour before TDI treatment began for a period of 3 weeks. Nasal symptoms were scored for 10 minutes immediately after TDI-provocation. The genes expression in nasal mucosa was determined using real-time quantitative RT-PCR. RESULTS: SST significantly suppressed TDI-induced nasal allergy-like symptoms. TDI provocation showed a significant up-regulation of histamine H(1) receptor (H1R) and histidine decarboxylase (HDC) gene expressions. Prolonged pre-treatment of SST significantly suppressed the mRNA levels of H1R and HDC that was up-regulated by TDI. SST also suppressed TDI-induced interleukin (IL)-4 and IL-5 mRNA elevation. However, SST showed no significant effect for TDI-induced mRNA elevation of IL-13. CONCLUSIONS: These results demonstrate that SST alleviates nasal symptoms by the inhibition of histamine signaling through suppression of TDI-induced H1R and HDC gene up-regulation. SST also suppresses cytokine signaling through suppression of IL-4 and IL-5 gene expression. Suppression of histamine signaling may be a novel mechanism of SST in preventing allergic diseases.

Heterologous up-regulation of the histamine H1 receptor by M3 muscarinic receptor-mediated activation of H1-receptor gene transcription.

Histamine H(1) receptor (H1R) level varies under various pathological conditions, and these changes may be responsible for some pathogenesis, such as allergic rhinitis. Previously, we showed that H1R was heterologously down-regulated (through degradation of H1R) by prolonged stimulation with muscarinic M(3) receptor (M3R) in Chinese hamster ovary (CHO) cells stably expressing H1R and M3R. However, this cell was inadequate for studying the effects on H1R gene regulation, because the cell expresses H1R, which is under the control of the SV40 promoter. Therefore, in this study, we have investigated the possible role of M3R stimulation in the H1R gene transcription and H1R mRNA stability by using U373 astrocytoma cells that express endogenous H1R and transfected M3R. Stimulation of M3R significantly increased H1R promoter activity and H1R mRNA level without alteration in H1R mRNA stability. The H1R level was also up-regulated by M3R activation (150% of control by treatment with carbachol for 24 h). These M3R-mediated events were almost completely blocked by the protein kinase C (PKC) inhibitor, Ro 31-8220, suggesting the involvement of PKC. These results indicated that M3R was involved in the up-regulation of H1R by activating H1R gene transcription through a PKC-dependent process.

Recent advances in molecular pharmacology of the histamine systems: regulation of histamine H1 receptor signaling by changing its expression level.

Histamine H1 receptor (H1R) signaling is regulated by changing its expression level. Two mechanisms are involved in this regulation. One is down-regulation through receptor desensitization. Receptor phosphorylation seemed crucial because stimulation of the mutant H1R lacking five putative phosphorylation sites did not show down-regulation. The phosphorylation level of the mutant receptor was much smaller than that of the wild type ones by several protein kinases. The other is up-regulation through activation of receptor gene expression. Protein kinase C (PKC) signaling was suggested to be involved in this up-regulation. Regulation of H1R expression level was mediated not only through H1R but also autonomic nerve receptors. Stimulation of M3 muscarinic receptors (M3R) induced both down-regulation and up-regulation of H1R. Down-regulation of M3R-mediated H1R seemed not to be mediated by PKC activation, although PKC activation induced H1R phosphorylation. Elevation of H1R expression was induced by the stimulation of M3Rs. PKC was suggested to be involved in this up-regulation. Stimulation of beta2-adrenergic receptors induced H1R down-regulation through several mechanisms. One of them is enhanced receptor degradation after desensitization and another is suppression of receptor synthesis that includes the suppression of receptor gene expression and enhanced degradation of the receptor mRNA. Protein kinase A was suggested to be involved in enhanced degradation and the activation of the receptor gene expression. Elevation of both H1R expression and its mRNA was observed in nasal mucosa of nasal hypersensitivity allergy model rat after toluene diisocyanate provocation. These results suggest that activation of H1R gene expression plays an important patho-physiological role in allergy. Elevation of the mRNA was partially but significantly suppressed by antihistamines.