Promising Anti-inflammatory Activity Research Articles

Phytochemistry and pharmacology of the genus Entandrophragma over the 50years from 1967 to 2018: a 'golden' overview.

For centuries, the genus Entandrophragma (Meliaceae), endemic to Africa, has been used in traditional medicine for the treatment of several illnesses. This review deals with large range of phytochemicals from the genus Entandrophragma and their pharmacological potentials covering the period from 1967 to 2018. Phytochemical investigations of the genus Entandrophragma led to the report of about 166 secondary metabolites which have been thoroughly summarized herein including some of their semisynthetic derivatives obtained from chemical transformations as well as their biological activities in the medicinal and agricultural domains. The limonoids or meliacins and their precursor called protolimonoids (protomeliacins) reported so far represent almost 69.28% of the total secondary metabolites obtained from the genus, and they display the most potent biological activities. Collectively, both classes of metabolites constitute the markers of Entandrophragma. However, squalene-type triterpenoids and sesquiterpenoids were reported only from the species E.cylindricum and therefore could be its chemotaxonomic markers. The pharmacological investigations of the extracts of some species exhibited interesting results which support the traditional uses of these Entandrophragma plants in folk medicine. Some compounds revealed promising antiplasmodial and anti-inflammatory activities and deserve therefore further attention for new drug discovery.

Design, Synthesis, Characterization, QSAR, Docking, Anti-inflammatory and Analgesic Evaluation of Some New Phthalazinediones.

phthalazine derivatives were reported to possess anticonvulsant , cardiotonic , antibacterial, analgesic , anti-inflammatory, and anti-microbial activity. In the current study, we applied the QSAR for prediction of newly phthalazinediones incorporating thioamide moiety aiming to reach a more potent anti-inflammatory and Analgesic agent. Phthalazinediones 10-15 have been synthesized through condensation of dibenzobarallene 3 with thiosemicarbazides 4-8. One equation was predicted using quantitative structure activity relationship (QSAR) and regression analysis for the anti-inflammatory activity with a regression correlation (R) close to unity. The docking studies were performed to investigate the biological trends of the organic compounds (thiol form) against cyclooxygenas- 2 enzyme, which is a responsible inflammation mediator by using Molgro Virtual Docker (MVD) software. The anti-inflammatory activity and analgesic effect of the thioamides 10-15 were determined by collagen II-adjuvant induced paw edema test in rats. Compounds 10, 11, 12, and 14, exhibited promising anti-inflammatory activity. Furthermore, in the pain scoring, compounds 10, 11 and 12 were found to be more effective than piroxicam and the order of the analgesic effect of the investigated compounds is as followed 14 >12 > 10 > 11 > 15. It is clear from the foregoing that the compound 14 is a promising compound if future pharmacological detailed studies. This is consistent with what has been predictable equation 1 in this study.

Bioassay-guided isolation and UHPLC-DAD-ESI-MS/MS quantification of potential anti-inflammatory phenolic compounds from flowers of Inula montana L

Ethnopharmacological relevanceFlowers of Inula montana L. (Asteraceae), commonly known as “Arnica de Provence”, are used in the traditional medicine of Provence in France with the same indication as Arnica montana, for the relief of bruises, as an anti-inflammatory agent. Aims of the studyThe aim of our study is to evaluate its anti-inflammatory properties and to justify its traditional uses. Its potential valorization is evaluated in order to propose Inula montana as an alternative to Arnica montana. Materials and methodsBio-guided fractionation of ethanolic extract allowed the isolation of compounds responsible of the inhibition of NO production. The fractionation was realized using chromatographic techniques and structure elucidation was conducted by ESI-MS and NMR spectral data. Anti-inflammatory effect of ethanolic extract, different fractions and isolated pure compounds was studied in vitro on immortalized mouse macrophages RAW 264.7. An analytical UHPLC-DAD-ESI-MS/MS method was developed for the identification of these compounds in the herbal drug. This UHPLC-DAD method was validated and was used to compare the phenolic profile and content in plant material from the two collection sites: Bonnieux and Merindol. ResultsEleven compounds were identified by UHPLC-MS. Chlorogenic acid (1), Luteolin (2), Nepetin (3), 3,5-O-Dicaffeoylquinic acid (4), 1,5-O-Dicaffeoylquinic acid (5), Nepitrin (6), Hispiduloside (7) and Jaceosid (8) were isolated and identified by NMR. Compounds 9, 10 and 11 were confirmed to be 6-Hydroxykaempferol 3,7-dimethyl ether, Hispidulin and Chrysosplenol C, respectively by comparing retention times and MS/MS data with those of the authentic substances. Six compounds: 1 and 4–8 are reported for the first time in Inula montana L. Compounds 2–8 showed promising anti-inflammatory activity with the release of NO with IC50 value < 7 µM. The UHPLC-DAD method of quantification of three major bioactive compounds (1, 3 and 5) was validated. ConclusionFlowers extracts and isolated compounds present promising anti-inflammatory activity which provides a scientific basis for the traditional use of Inula montana and may be proposed in the same indications as Arnica montana. The developed and validated simple, accurate and rapid UHPLC method can be used for the quality control of the herbal drug.

Cardioprotective effects of nanoceria in a murine model of cardiac remodeling

Isoproterenol (ISO), a synthetic β1 adrenergic agonist is a well-known agent to be associated with severe cardiotoxicity manifested as marked myocardial necrosis and fibrosis. Oxidative stress plays a crucial role in mediating ISO induced cardiotoxicity. In present study, we have investigated the possible protective effect of nanoceria (NC) in ISO induced cardiac injury. We have given long duration exposure (a total of 10 days) of low dose ISO (20 mg/kg/day) to investigate the protective effects of NC in chronic cardiac injury model. ISO (20 mg/kg/day for 10 days) produced cardiac injury as evident by increased plasma LDH and CK-MB, AST, ALT, cardiac hypertrophy, severe myocardial fibrosis (MF) and significantly higher levels of cytokines, IL-6, TGF-β and TNF-α. Interestingly, the treatment with NC (0.2 and 2 mg/kg) abrogated cardiotoxicity symptoms and provided protection from ISO induced cardiac injury. The results from present study demonstrated strong evidences of cardioprotective effects of NC as shown by reduction in the levels of LDH (p < 0.05 at 2 mg/kg) and CK-MB (p < 0.05 at 2 mg/kg). In addition, NC reduced oxidative stress parameters MDA (p < 0.05 at 2 mg/kg) and enhanced GSH levels which is physiological antioxidant (p < 0.01 at both doses). Further, NC exhibited promising anti-inflammatory activity and curbed the levels of cytokines (p < 0.05 at 0.2 mg/kg and p < 0.001 for IL-1β and p < 0.001 at both doses for IL-6). In addition, NC also reduced the levels of pro-fibrotic cytokine, TGF-β (p < 0.05 at 2 mg/kg) and helped in reduction of collagen deposition in heart thereby, preventing the myocardial remodeling. Our results strongly suggested that NC might be of potential use as a cardioprotective agent.

Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-\u03baB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT)

BackgroundHistamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells.MethodsInterleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways.ResultsHistamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 ± 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC50) value of 4.91 ± 2.50 μM and median lethal concentration (LC50) value of 28.82 ± 7.56 μM. In gene expression level, we found that MS65 inhibits NF-κB and MAPK pathways through suppression of IKK/IκB/NFκB and c-Raf/MEK/ERK inflammatory cascades.ConclusionTaken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases.

Syzygium aqueum: A Polyphenol- Rich Leaf Extract Exhibits Antioxidant, Hepatoprotective, Pain-Killing and Anti-inflammatory Activities in Animal Models.

Syzygium aqueum is widely used in folk medicine. A polyphenol-rich extract from its leaves demonstrated a plethora of substantial pharmacological properties. The extract showed solid antioxidant properties in vitro and protected human keratinocytes (HaCaT cells) against UVA damage. The extract also reduced the elevated levels of ALT, AST, total bilirubin (TB), total cholesterol (TC) and triglycerides (TG) in rats with acute CCl4 intoxication. In addition to reducing the high MDA level, the extract noticeably restored GSH and SOD to the normal control levels in liver tissue homogenates and counteracted the deleterious histopathologic changes in liver after CCl4 injection. Additionally, the extract exhibited promising anti-inflammatory activities in vitro where it inhibited LOX, COX-1, and COX-2 with a higher COX-2 selectivity than that of indomethacin and diclofenac and reduced the extent of lysis of erythrocytes upon incubation with hypotonic buffer solution. S. aqueum extract also markedly reduced leukocyte numbers with similar activities to diclofenac in rats challenged with carrageenan. Additionally, administration of the extract abolished writhes induced by acetic acid in mice and prolonged the response latency in hot plate test. Meanwhile, the identified polyphenolics from the extract showed a certain affinity for the active pockets of 5-lipoxygenase (5-LOX), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) explaining the observed anti-inflammatory activities. Finally, 87 secondary metabolites (mostly phenolics) were tentatively identified in the extract based on LC-MS/MS analyses. Syzygium aqueum displays good protection against oxidative stress, free radicals, and could be a good candidate for treating oxidative stress related diseases.

One-pot solvent-free synthesis of triaryl- and triheteroarylmethanes by Bi(OTf)3-catalyzed Friedel-Crafts reaction of arenes/heteroarenes with trialkyl orthoformates

A convenient, practical and highly efficient one-pot method has been developed for the synthesis of triaryl- and triheteroarylmethane derivatives by Bi(OTf)3-catalyzed Friedel-Crafts alkylation of trialkyl orthoformates in combination with a wide variety of arenes/heteroarenes at room temperature under solvent-free conditions and in an air atmosphere. The methodology offers an operational simplicity, high atom economy and environmentally benign procedure. Furthermore, selected compound 3k showed promising anti-inflammatory activity with inhibition nitric oxide and did not exhibit significant cytotoxic effects on macrophage cells.

4β‐hydroxywithanolide E inhibits tumor necrosis factor α‐induced tissue factor expression and tumor‐associated coagulation in non‐small cell lung cancers

The relation between cancer and inflammation has been widely discussed, and the onset of inflammation in tumor microenvironment promotes the progression of cancer is generally recognized. Tumor necrosis factor (TNF) α, a major inflammatory cytokine, which exists in tumor microenvironment and is constitutively produced by both stromal cells and malignant cells. The implication of TNFα in tumor growth and metastasis has been reported in several literatures. In addition, TNFα causes tissue factor (TF) upregulation in several cell types, including monocyte, endothelial cells, and cancer cells that may contribute to tumor‐associated coagulopathy and cancer metastasis. 4β‐hydroxywithanolide E (4HW) is a natural compound isolated from an edible plant, Physalis peruviana. 4HW has been reported to exhibit promising anti‐cancer and anti‐inflammatory activities. In the present study, we examined the effect of 4HW on TNFα‐induced TF expression and procoagulant activity in two non‐small cell lung cancer cell lines, A549 and H1299. At the non‐cytotoxic concentrations, 4HW potently prevented TF expression caused by TNFα in both cell lines. The procoagulant activity of TNFα‐induced TF was further studied by using plasma clotting assay. The plasma clotting time in the presence of TNFα‐treated cancer cells was obviously shorter than control group, and this phenomenon was successfully reversed by pretreating with either 4HW or anti‐TF antibody. Our results suggest that 4HW might have the potential to treat tumor‐associated thrombosis and inflammation.Support or Funding InformationThis research was supported by Ministry of Science and Technology (MOST 106‐2320‐B‐037‐003‐MYB) and Kaohsiung Medical University (KMU‐TP105H03)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A new para-quinone-type flavan from the leaves of Ilex centrochinensis and its anti-inflammatory activities

A new para-quinone-type flavan, (2S)-7-methoxy-3′,4′-dihydroxy-5,8-quinoflavan (1), together with three known compounds, were isolated from the leaves of Ilex centrochinensis. Their structures were elucidated by detailed spectroscopic analyses for new structure and in comparison with published data for known compounds. Moreover, the new compound was evaluated its cytotoxic and anti-inflammatory activities in vitro on LPS induced RAW 264.7 cells and the results showed that 1 has promising anti-inflammatory activities.

Synthesis of some novel orcinol based coumarin triazole hybrids with capabilities to inhibit RANKL-induced osteoclastogenesis through NF-κB signaling pathway

A total of twenty-two novel coumarin triazole hybrids (4a-4k and 6a-6k) were synthesized from orcinol in good to excellent yields of 70–94%. The structures of all the synthesized compounds were elucidated by spectroscopic techniques such as 1H NMR, 13C NMR, and HRMS. The anti-inflammatory potential of synthesized compounds was investigated against the proinflammatory cytokine, TNF-α on U937 cell line and compounds 4d, 4j, and 6j were found to exhibit promising anti-inflammatory activity. These three compounds were further screened against TNF-α on LPS-stimulated RAW 264.7 cells, which confirm their anti-inflammatory potential. Furthermore, the above said active compounds were tested for their inhibitory effect on RANKL-induced osteoclastogenesis in RAW 264.7 cells by using tartrate resistant acid phosphatase (TRAP) staining assay at 10 µM. Molecular mechanism studies demonstrated that compound 4d exhibited dose dependent inhibition of RANKL-induced osteoclastogenesis by suppression of the NF-kB pathway. Thus, compound 4d is a promising candidate for further optimization to develop as a potent anti-osteoporotic agent.

Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile

Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO2Me or/and SO2NH2) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED50 = 15.06, 42.51 and 50.43 μmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 μmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72–3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.

Anti-proliferative and anti-inflammatory activities of the sea cucumber Holothuria polii aqueous extract.

Objective:Sea cucumbers are considered among the most important functional foods. Following bioassay guided fractionation, we assessed the anti-proliferative and anti-inflammatory activities of Holothuria polii (H. polii) extracts.Methods:Sea cucumber ethanolic extract and the partially purified aqueous fractions were assessed for their anti-proliferative activities. These latter bioactivities were evaluated in the highly invasive MDA-MB-231 human breast cancer cells in two-dimensional and three-dimensional cultures using trypan blue exclusion assay. The tumor-suppressive effects of sea cucumber ethanolic extract and aqueous fractions were assayed by measuring the trans-well invasion of MDA-MB-231 cells and the expression of some epithelial mesenchymal transition markers using quantitative reverse-transcription polymerase chain reaction and western blot analysis. The anti-inflammatory activity of the aqueous fraction was tested by measuring the secreted levels of interleukin-6, nitric oxide, and matrix metalloproteinase 9 in endotoxin-induced mammary epithelial SCp2 cells and interleukin-1β in phorbol-12-myristate-13-acetate-activated human monocytic THP-1 cells.Results:Sea cucumber ethanolic extract and the aqueous fraction significantly decreased the proliferation of MDA-MB-231 cells by more than 50% at similar and noncytotoxic concentrations and caused an arrest in the S-phase of the cell cycle of treated cells. In contrast, petroleum ether, chloroform, ethyl acetate, and n-butanol organic fractions did not show any significant activity. Furthermore, sea cucumber ethanolic extract and aqueous fraction reduced the proliferation of MDA-MB-231 cells in three-dimensional cultures by more than 60% at noncytotoxic concentrations. In addition, treatment with these concentrations resulted in the loss of stellate outgrowths in favor of spherical aggregates and a 30% decrease in invasive properties. Both sea cucumber ethanolic extract and aqueous decreased the transcription of vimentin and the protein expression levels of vimentin and N-cadherin in three-dimensional cultures. The aqueous fraction decreased the levels of inflammatory markers interleukin-6, nitric oxide, and matrix metalloproteinase 9 in the mouse mammary SCp2 cells, and the level of interleukin-1β produced by phorbol-12-myristate-13-acetate-activated THP-1 human monocytic cells.Conclusion:The data reveal for the first time promising anti-proliferative and anti-inflammatory activities in H. polii water extract in two-dimensional and three-dimensional culture models.

Murrayanine-Chalcone Transformed into Novel Pyrimidine Compounds Demonstrated promising Anti-Inflammatory Activity

A new series of murrayanine based pyrimidine derivatives were synthesized from the previously reported starting material, known as murrayanine-chalcone and urea as the reagent in alkaline-ethanolic media. The in vivo anti-inflammatory activity of the fabricated compounds was performed by the carrageenan-induced paw edema standard method. The produced molecules were characterized using modern sophisticated analytical techniques such as IR, 1H-NMR, and mass spectral data, spectroscopic data revealed the possible structures of the synthesized compounds and characterization data were found to be in full agreement with that of the structures. The compound 6-(4-fluorophenyl)-4-(1-methoxy-9H-carbazol-3-yl)-1, 6-dihydropyrimidin-2-ol (3b), having para-fluorine substituent exhibited the highest anti-inflammatory activity with 58.33% reduction after 3 hrs. The anti-inflammatory activity was observed to be reasonably analogous with that of indomethacin, the standard drug. A very clear structure-activity relationship was not established due to mixed results. It was detected that fluorine substituted compound exhibited the best activity, followed by bromine, and iodine substituent. It was also seen that while substituting the chlorine along with fluorine in the derivative, the activity fallen drastically. The introduction of bulky group did not show an impressive activity as compared to the single electron-withdrawing group. On increasing the number of substituent to double, it was found that the activity reduces severely. This research will undoubtedly encourage scientists across the globe in the rational designing and synthesis of molecules with distinct pharmacological action(s).

Anti-inflammatory effects of 4-o-methyl-benzenesulfonyl benzoxazolone (MBB) in vivo and in vitro as a novel NSAIDs lead compound.

Great attention has been paid to the development of novel anti-inflammatory drugs to overcome the adverse reactions of traditional drugs. Recently, a new compound 4-o-methyl-benzenesulfonyl benzoxazolone (MBB) we have prepared attracted our attention for its promising anti-inflammatory activity and low toxicity. The present study aimed to further investigate the anti-inflammatory effects of MBB both in vivo and in vitro in order to determine its potential as a novel NSAIDs lead compound. The anti-inflammatory effects in vivo were evaluated using acetic acid-induced mice writhing, xylene-induced mice ear edema and collagen-induced rat arthritis. NO, TNF-α, IL-6, IL-1β and iNOS productions by LPS-stimulated RAW264.7 cells were determined to investigate the basis of anti-inflammatory effects. Finally, the COX inhibition effect was tested in vitro using COX inhibitor screening assay kit. MBB could significantly decrease the writhing and ear swelling in a dose-dependent manner, and it also had a moderate anti-arthritic potential associated with an attenuation of arthritis index score, arthritis swelling, and inhibition of TNF-α and IL-1β. MBB could inhibit the activity of NO, TNF-α, IL-6, IL-1β and iNOS to perform its activity in vitro, but it had no effect against COX-1 and COX-2. The anti-inflammation effect may be mediated via the inhibition of iNOS to reduce the production of inflammatory mediators which should be further confirmed. The compound MBB displayed anti-inflammatory and anti-arthritic effect, and it could be considered as a new NSAIDs lead compound for the further structure modification to develop novel anti-inflammatory drugs.

Synthesis and Structure Activity Relationship of Some Indole Derivatives as Potential Anti-inflammatory Agents.

A series of fused pyrroles were synthesized and tested for their in vivo anti-inflammatory activity. Among 14 examined derivatives, 5 derivatives (1b-e, g and 5b), showed a promising anti-inflammatory activity equivalent to reference anti-inflammatory drugs (indomethacin and ibuprofen). A molecular docking study was conducted to interpret the biological activities of the tested compounds. The docking results were complementary with the phase of the biological survey and confirmed the biological effects.

Facile synthesis of some pyrazoline-based compounds with promising anti-inflammatory activity.

Search for new anti-inflammatory agents with higher efficacy and lower toxicity is an urgent demand in drug discovery era. Different pyrazoline derivatives 4a,b, 5a,b, 6a-h and 7a-f were prepared from the condensation reactions of 1,5-bis(5-methylfuran/thiophen-2-yl)penta-1,4-dien-3-ones 3a,b with different hydrazine derivatives. All compounds were screened for their anti-inflammatory activity using the carrageenan-induced paw edema method in rats and TNF-α inhibition assay. Many compounds revealed promising anti-inflammatory activity relative to indomethacin especially compounds 4a, 5a, 5b, 6b, 6d, 6f and 7b. They were safe to the gastric mucosa and did not cause toxicity up to tenfolds the anti-inflammatory dose, in addition, all compounds inhibited TNF-α with IC50 values of 1.7-100nM.

Chalcone Derivatives: Anti-inflammatory Potential and Molecular Targets Perspectives.

Chalcone or (E)-1,3-diphenyl-2-propene-1-one scaffold has gained considerable scientific interest in medicinal chemistry owing to its simple chemistry, ease in synthesizing a variety of derivatives and exhibiting a broad range of promising pharmacological activities by modulating several molecular targets. A number of natural and (semi-) synthetic chalcone derivatives have demonstrated admirable anti-inflammatory activity due to their inhibitory potential against various therapeutic targets like Cyclooxygenase (COX), Lipooxygenase (LOX), Interleukins (IL), Prostaglandins (PGs), Nitric Oxide Synthase (NOS), Leukotriene D4 (LTD4), Nuclear Factor-κB (NF- κB), Intracellular Cell Adhesion Molecule-1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and TLR4/MD-2, etc. The chalcone scaffold with hydroxyl, methoxyl, carboxyl, prenyl group and/or heterocyclic ring substitution like thiophene/furan/indole showed promising anti-inflammatory activity. In this review, a comprehensive study (from the year 1991 to 2016) on multi-targets of inflammatory interest, related inflammation reactions and their treatment by chalcone-based inhibitors acting on various molecular targets entailed in inflammation, Structure-Activity Relationships (SARs), Mechanism of Actions (MOAs), and patents are highlighted.

Pharmacokinetics, pharmacodynamics and safety profiling of IS01957, a preclinical candidate possessing dual activity against inflammation and nociception

In spite of unprecedented advances in modern systems of medicine, there is necessity for exploration of traditional plant based secondary metabolites or their semisynthetic derivatives which may results in better therapeutic activity, low toxicity and favourable pharmacokinetics. In this context, computational model based predictions aid medicinal chemists in rational development of new chemical entity having unfavourable pharmacokinetic properties which is a major hurdle for its further development as a drug molecule. Para-coumaric acid (p-CA) and its derivatives found to be have promising antiinflammatory and analgesic activity. IS01957, a p-CA derivative has been identified as dual acting molecule against inflammation and nociception. Therefore, objective of the present study was to investigate pharmacokinetics, efficacy and safety profile based on in-silico, in-vitro and in-vivo model to assess drug likeliness. In the present study, it has excellent pharmacological action in different animal models for inflammation and nociception. Virtual pharmacokinetics related properties of IS01957 have resemblance between envision and experimentation with a few deviations. It has also acceptable safety pharmacological profile in various animal models for central nervous system (CNS), gastro intestinal tract (GIT)/digestive system and cardiovascular system (CVS). Finally, further development of IS01957 is required based on its attractive preclinical profiles.

Effect of Solanum nigrum Linn on Acute and Sub-Acute Models of Inflammation

Objective: The aim of the study was to see the effect of ethanolic extract of Solanum nigrum Linn on Acute and Sub-acute inflammation. Method: Wistar rats weighing 150-200gms were used, divided into four groups Group 1 was control group, two groups Group 2 and 3 treated with the plant extracts at 100 & 200 mg/kg b.w and Group 4 treated with indomethacin, 10 mg/kg b.w. Acute inflammation was induced by injecting 0.1 mL of 1% homogenized carrageenan suspension in normal saline to the right hind paw of the rats prior to which drug treatment was given and paw volume was measured using a digital plethysmometer. Sub-acute anti-inflammatory studies were carried out as described by winter and Porter and hematological parameters were estimated. The granuloma tissue formed during the proliferative process was isolated and wet and dry exudates formation was estimated in various treatment groups. The effect of extract and indomethacin on vital organs like liver, kidney, stomach was also studied by performing histological studies. Results: Study shows that the hydroalcoholic extract of whole plant of Solanum nigrum L. is effective only at higher dose effectively suppressing carrageenan induced inflammation suggesting the inhibition of release of prostaglandin, bradykinin, leukotrienes and polymorphonuclear cells. The histological studies further confirm the anti-inflammatory property of the extract while simultaneously maintaining normal cellular architecture of vital organs than as compared to indomethacin treated group. Conclusion: The ethanolic extract of whole plant of Solanum nigrum Linn shows promising anti-inflammatory activity on both acute and sub-acute stages of inflammation. Key words: Acute Inflammation, Sub-acute Inflammation, Anti-inflammatory activity, Solanum nigrum , Hematological parameters, Histological studies.

Oligomeric proanthocyanidins attenuate airway inflammation in asthma by inhibiting dendritic cells maturation

To date, although a promising anti-inflammatory activity of oligomeric proanthocyanidins (OPCs) has been observed in asthma, the mechanism responsible for these immunomodulatory properties remains obscure. Dendritic cells (DCs) that reside in the airway have been widely perceived as an important contributor to asthma. Our study was to demonstrate OPCs’ effects on maturation and immunoregulation of pulmonary CD11c+ dendritic cells (DCs). BALB/c mice were exposed to ovalbumin (OVA) to induce murine model of asthma. In addition, pulmonary DCs and bone marrow-derived DCs (BMDCs) cultures were used to evaluate impacts of OPCs on DCs function. The results obtained here indicated that OPCs treatment dramatically reduced airway inflammation, such as the infiltration of inflammatory cells and the levels of allergen-specific serum IgE and Th2 cytokines. The expression of co-stimulatory molecules especially CD86 distributed on pulmonary DCs and bone marrow-derived DCs (BMDCs) also markedly declined. The phosphorylation of cAMP responsive element-binding protein (CREB) was significantly inhibited while no changes were observed in the expression of cAMP responsive element modulator (CREM). By transferring BMDCs into the airways of naïve mice, we found that OPCs-treated DCs (DC+OVA+OPC) were much less potent in promoting CD4+ T cells proliferation than OVA-pulsed DCs (DC+OVA), followed by the ameliorated eosinophilic inflammation in airway. Our findings tailor a novel profile of OPCs in the regulation of DCs function, shedding new light on the therapeutic potential of OPCs in asthma management.