Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry最新文献

Background: Macrophages are the main players involved in inflammation. Intercellular adhesion molecule-1 (ICAM-1) facilitates macrophage polarization prior to extravasation into inflamed tissue. Piperine, a natural product derived from black pepper, possesses useful biological and pharmacological activities. In the current study, the possible anti-inflammatory effect of piperine on the expression of ICAM-1 on J774.1 murine macrophage cell line was investigated.

Methods: Lipopolysaccharide (LPS)-stimulated J774.1 cells were cultured in the presence of different concentrations of piperine to examine the changes in ICAM-1 expression by real-time PCR and flow cytometry.

Results: We found that piperine decreased ICAM-1 gene expression level from 2.4 ± 0.25 RFC (relative fold change) in LPS-only treated cells to 0.85 ± 0.525 RFC at 1µg/ml (p<0.05), 0.43 ± 0.27 RFC at 10µg/ml (p<0.01), and 0.26 ± 0.25 RFC at 20µg/ml (p<0.01). In flow cytometry, piperine at all concentrations significantly decreased ICAM-1 surface expressions (P<0.05). The geometric mean fluorescence intensity (g-MFI) in LPS-only treated cells (792 ± 57.3) decreased to 482±70 g-MFI at 20 μg/ml piperine.

Conclusion: According to the results of this study, by decreasing the expression of ICAM-1, piperine has been suggested to reduce inflammation and have the potential to provide therapeutic benefits for immune-mediated diseases.

Background: Hydrocephalus is a complex neurologic disorder that has a widespread impact on the central nervous system and a multifactor disease which affects the CSF dynamics and causes severe neurological impairments in children. The pathophysiology of hydrocephalus is not fully understood. However, increasing evidence suggests that oxidative stress may be an important factor in the pathogenesis of hydrocephalus.

Objective: The purpose of this study is to investigate the relationship of the KEAP-1/NRF-2/HO-1 pathway, one of the main regulators of the antioxidant system in the hydrocephalus pathology, on oxidative stress and tau protein level.

Methods: The study included 32 patients with hydrocephalus and 32 healthy controls. KEAP-1, NRF-2, HO-1, TAU, and MPO levels are measured using ELISA method TAS, TOS, and Total THIOL colorimetric method.

Results: KEAP-1, TAS, and Total THIOL levels were found significantly lowerer in the hydrocephalus group than in the control group. Nevertheless, it was identified that in the hydrocephalus group that the NRF-2, HO-1, TAU, MPO, TOS, and OSI levels were significantly elevated.

Conclusion: In conclusion, although the KEAP-1/NRF-2/HO-1 pathway is activated in patients with hydrocephalus, it is identified that the antioxidant defense system is insufficient and ultimately leads to elevated oxidative stress. The elevation in the tau level may be an indicator of oxidative stress induced neurodegenerative damage.

Background: Chronic Spontaneous Urticaria (CSU) is a disease presenting typical wheals characterized by itching, angioedema or both. Although CU is, by appearance, a relatively "simple" disease, yet it has a devastating effect on those suffering due to its immense social implications.

Aims: The aim of the present study was to investigate the effect of omalizumab in the treatment of CSU. In particular, gender, co-administration of drugs and comorbidities were taken into account.

Materials and methods: 108 patients (25 Males/83 Females) admitted to our department were diagnosed with CSU and were treated for 30 months. CSU was estimated on a score basis, which was used in order to define disease severity. The mean total CSU score and the mean CSU score of the first trimester, as well as the first semester, were calculated. Patients were treated with omalizumab, and in several cases, with co-administration of dapsone, cyclosporine and anti-histamines.

Results: Females manifested significantly higher scores as compared to males. Further on, patients who relapsed manifested significantly higher scores during the whole time course, as well as at the end of the first semester.

Conclusion: Females are more prone to CSU. Although CSU scores in patients with remission, relapse and poor response manifested no significant difference at diagnosis, relapsed patients manifested higher CSU scores in the first semester. Therefore, the first semester of treatment is probably critical for the final patient outcome. Further studies are necessary in order to understand the mechanisms of CSU for better treatment and prognosis.

Background: Due to the presence of both five-membered heterocyclics like pyrrole and thiophene in one molecule considerable attention was made for their enormous pharmacological activities out of which include anti-inflammatory and anti-ulcer activities.

Objective: Chalcones with toluenesulfonylmethyl isocyanide (TosMIC) undergo synthesis to form some new aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives. Molecular docking of synthesized compounds with protein receptors of anti-inflammatory COX-1(3N8Y), COX-2 (1PXX) along with anti-ulcer H+/K+ATPase enzyme (2XZB) followed with drug-likeness, and in silico ADMET properties.

Materials and methods: The multicomponent reaction was carried out by the intermediate formation of α, β-unsaturated ketone from carbonyl compounds which on sequential addition undergoes [3+2] cycloaddition reaction in same medium affords aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives by addition of TosMIC in basic medium had resulted in series of compounds PY1 to PY12. All the new synthesized compounds were screened for their in-vitro anti-inflammatory activity by bovine serum albumin method followe with COX assay, and in-vivo by using carrageenan-induced rat paw edema method of the selected compounds PY1, PY5 and PY12 which is also screened for anti-ulcer activity by pylorus ligation method, respectively. Molecular docking was performed using autodock tools, drug-likeness by OSIRIS property explorer and admetSAR properties.

Results and discussion: From the synthesized compounds of aryl (4-aryl-1H-pyrrol-3-yl) (thiophen- 2-yl) methanone derivatives PY5 showed decent in-vitro and in-vivo anti-inflammatory along selectivity index of 6.2 for COX-1 with IC50(μM) value of 9.54 over diclofenac with 8.74 and PY1 showed decent in-vivo anti-ulcer activities along with drug-likeness and in silico ADMET predictions revealed that all the synthesized compounds have minimal toxic effects with good absorption as well as solubility characteristics. The selected compounds may serve as potential lead compounds for developing new anti-inflammatory and anti-ulcer drugs.

Conclusion: From the newly synthesized molecules PY5 was found to be effective for anti-inflammatory and PY1 was found to be effective for anti-ulcer activities further derivitization and designed of modification to achieve more compounds with potent anti-inflammatory and anti-ulcer activities.

Background and aims: Following a fat-rich diet, alterations in gut microbiota contribute to enhanced gut permeability, metabolic endotoxemia, and low grade inflammation-associated metabolic disorders. To better understand whether commensal bifidobacteria influence the expression of key metaflammation-related biomarkers (chemerin, MCP-1, PEDF) and modulate the pro-inflammatory bacteria- and lipid-coupled intracellular signaling pathways, we aimed at i) investigating the influence of the establishment of microbial signaling molecules-based cell-cell contacts on the involved intercellular communication between enterocytes, immune cells, and adipocytes, and ii) assessing their inflammatory mediators' expression profiles within an inflamed adipose tissue model.

Material and methods: Bifidobacterium animalis R101-8 and Escherichia coli TG1, respectively, were added to the apical side of a triple co-culture model consisting of intestinal epithelial HT-29/B6 cell line, human monocyte-derived macrophage cells, and adipose-derived stem cell line in the absence or presence of LPS or palmitic acid. mRNA expression levels of key lipid metabolism genes HILPDA, MCP-1/CCL2, RARRES2, SCD, SFRP2 and TLR4 were determined using TaqMan qRT-PCR. Protein expression levels of cytokines (IL-1β, IL-6, and TNF-α), key metaflammation-related biomarkers including adipokines (chemerin and PEDF), chemokine (MCP- 1) as well as cellular triglycerides were assessed by cell-based ELISA, while those of p-ERK, p-JNK, p-p38, NF-κB, p-IκBα, pc-Fos, pc-Jun, and TLR4 were assessed by Western blotting.

Results: B. animalis R101-8 inhibited LPS- and palmitic acid-induced protein expression of inflammatory cytokines IL-1β, IL-6, TNF-α concomitant with decreases in chemerin, MCP-1, PEDF, and cellular triglycerides, and blocked NF-kB and AP-1 activation pathway through inhibition of p- IκBα, pc-Jun, and pc-Fos phosphorylation. B. animalis R101-8 downregulated mRNA and protein levels of HILPDA, MCP-1/CCL2, RARRES2, SCD and SFRP2 and TLR4 following exposure to LPS and palmitic acid.

Conclusion: B. animalis R101-8 improves biomarkers of metaflammation through at least two molecular/signaling mechanisms triggered by pro-inflammatory bacteria/lipids. First, B. animalis R101-8 modulates the coupled intracellular signaling pathways via metabolizing saturated fatty acids and reducing available bioactive palmitic acid. Second, it inhibits NF-kB's and AP-1's transcriptional activities, resulting in the reduction of pro-inflammatory markers. Thus, the molecular basis may be formed by which commensal bifidobacteria improve intrinsic cellular tolerance against excess pro-inflammatory lipids and participate in homeostatic regulation of metabolic processes in vivo.

Background: (Quinazoline-4-ylidene)hydrazides are valued intermediates in modern organic chemistry, as they are commonly used for the synthesis of substituted [1,2,4]triazolo[1,5-c]quinazolines.

Objective: Unknown N-acyl-2-([1,2,4]triazolo[1,5-c]quinazoline-2-yl)-alkyl-(alkaryl-, aryl-) amines were synthesized and evaluated for anti-inflammatory potential.

Methods: The peculiarities of the synthesized compounds structures were studied by IR-, NMR spectroscopy and chromatography-mass spectrometry and were discussed in detail. Probable molecular mechanisms of activity (inhibition of COX-1 and COX-2) were predicted due to molecular docking. Anti-inflammatory activity of synthesized compounds was determined by their ability to reduce the formalin-induced paw edema in rats. Diclofenac sodium was used as reference drug.

Results: In this study, the synthesis of N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5-c]quinazolinе- 2-yl)alkyl-(aralkyl-, aryl-)amines, using (3H-quinazoline-4-ylidene)hydrazides of Nprotected amino acids or 4-hydrazinoquinazoline and N-prorotected amino acids as starting compounds was developed. It was established that the reaction of (3H-quinazoline-4- ylidene)hydrazides of Boc-amino acids occurred with the formation of N-acetyl-substituted triazoloquinazolines. High anti-inflammatory activity was detected for unknown (3Hquinazoline- 4-ylidene)hydrazides Boc-amino acids (1.13-1.15) and N-acetyl-(benzoyl)-2- ([1,2,4]triazolo[1,5-c]quinazoline-2-yl-)aralkyl-(aryl-)amines (3.2, 3.3, 3.11, 3.12), using the experimental formalin test.

Conclusion: The conducted SAR-analysis allowed to detect critical fragments. Namely, the Boc-aminoaralkyl-(aryl-)acid residue in (3H-quinazoline-4-ylidene)hydrazides (1.13- 1.15), benzyl and phenyl linker groups in N-acetyl-(benzoyl)-2-([1,2,4]triazolo[1,5- c]quinazoline-2-yl-)aralkyl-(aryl-) amines (3.2, 3.3, 3.11, 3.12) are believed to be substantial for anti-inflammatory activity.