Potent Anti-inflammatory Compound Research Articles

Alginate/chitosan/diallyl disulfide nanoparticles: Synthesis, characterization and their anti-inflammatory efficacy on TPA-induced acute mouse ear inflammation

Diallyl disulfide (DADS) is a garlic (Allium sativum) derived potent anti-inflammatory compound. Due to poor bioavailability, its biological application has limitations. Nanoencapsulation of therapeutic drugs is a promising approach to increase their bioavailability, specificity, and efficacy. In our approach, DADS was coated with the natural polymers alginate and chitosan into a polyelectrolytic nano-formulation. Characterization of the nanoparticles showed monodispersed nanosized particles and a release study at pH 5.5 revealed sustained release of the drug. To investigate the anti-inflammatory efficacy of the DADS nanoparticle (DADS-NP), a comparative study with the free drug was conducted on a mouse model of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced ear edema. The results indicated that DADS-NP significantly alleviated TPA-induced ear edema more effectively than the free drug of the same concentration. Further, mechanistic studies indicated that DADS-NP more efficiently downregulated the phosphorylation of p38 mitogen activated protein kinase which subsequently restricted the activation and nuclear translocation of downstream transcription factor nuclear factor- кB (NF-кB). This downregulated the expression of pro-inflammatory proteins cyclooxygenase-2 (COX-2) and inducible-nitric oxide synthase (i-NOS) thus mitigating ear edema. Cellular internalization of the DADS-NP was observed. Collectively, our studies indicate enhanced anti-inflammatory efficiency of DADS-NP when compared to free DADS suggesting enhanced stability and bioavailability.

Chemical composition and biological activities of the extracts of Peperomia pellucida fractions

Background: Peperomia pellucida is a medicinal and vegetable plant used worldwide, representing a multi-purpose vegetable with applications in the pharmaceutical, food and cosmetic industries. Objective: This study evaluated the antioxidant, antibacterial, antifungal, anti-inflammatory, and antidiabetic potential of fractional extracts from P. pellucida plant derived from Can Tho City, Vietnam. Methods: Four fractional extracts were prepared using different polarity solvents (hexane, dichloromethane, ethyl acetate) and used to determine the best extract for each biological property. The fractions’ total alkaloid, phenolic, and flavonoid content were observed. The four extracts were evaluated for their potential bioactivities: antioxidant, antibacterial, antifungal, anti-inflammatory, and antidiabetic. Results: Correspond with the hexane, dichloromethane, ethyl acetate, and aqueous fractions, the total content of alkaloids was determined to be 255 ± 23.8; 157 ± 14.0; 219 ± 6.55; 221 ± 6.23 (mg AE/g extract), the total phenolic content was 112 ± 3.34; 141 ± 1.77; 234 ± 29.5; 123 ± 5.04 (mg GAE/g extract), whereas the total content of flavonoids was 423 ± 22.6; 169 ± 6.30; 1839 ± 18.8; 173 ± 22.6 (mg QE/g extract), respectively. The ethyl acetate fraction gave the best efficiency in DPPH, ABTS, iron reduction, and TAC methods (IC50 = 334 ± 2.10 µg/mL; 51.4 ± 0.41 µg/mL; 79.1 ± 0.40 µg/mL; and 83.0 ± 0.17 µg/mL, respectively). Antibacterial activity was investigated on 5 strains of Bacillus cereus, Escherichia coli, Staphylococcus aureus, Salmonella typhimunum, Pseudomonas aeruginosa; the results showed that the extracts were resistant to 5 strains of bacteria, especially best resistant in 2 fractions of ethyl acetate and aqueous. The minimum inhibitory concentration (MIC) value ranged from 0.5 to 32 mg/mL, while the minimum bactericidal concentration (MBC) value ranged from 16 to 64 mg/mL. The best anti-inflammatory activity was ethyl acetate with an IC50 value of 216.7 ± 7.2 µg/mL, close to that of Diclofenac at 205.4 ± 0.5. The antidiabetic activity was investigated based on the ability to inhibit α-amylase and α-glucosidase enzymes. The results showed that the best α-amylase inhibitors were hexane and dichloromethane (IC50 = 208.83 ± 2.41 and 191.60 ± 1.27 µg/mL, respectively), roughly equal to the acarbose (155.68 ± 2.59 µg/mL). The best α-glucosidase inhibitory fraction was ethyl acetate (IC50 of 157.04 ± 0.23 µg/mL), close to that of acarbose (116.45 ± 0.21 µg/mL). Conclusion: Fractional extracts from P. pellucida distributed in gardens of Can Tho City, Vietnam, contain potential antioxidant, antibacterial, antifungal, anti-inflammatory, and antidiabetic bioactive compounds.

A novel imidazo[1,2-a]pyridine derivative and its co-administration with curcumin exert anti-inflammatory effects by modulating the STAT3/NF-κB/iNOS/COX-2 signaling pathway in breast and ovarian cancer cell lines.

Imidazo[1,2-a]pyridine derivatives with diverse pharmacological properties and curcumin, as a potential natural anti-inflammatory compound, are promising compounds for cancer treatment. This study aimed to synthesize a novel imidazo[1,2-a]pyridine derivative, (MIA), and evaluate its anti-inflammatory activity and effects on nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways, and their target genes, alone and in combination with curcumin, in MDA-MB-231 and SKOV3 cell lines. We evaluated the interaction between imidazo[1,2-a]pyridine ligand, curcumin, and NF-κB p50 protein, using molecular docking studies. MTT assay was used to investigate the impacts of compounds on cell viability. To evaluate the NF-κB DNA binding activity and the level of inflammatory cytokines in response to the compounds, ELISA-based methods were performed. In addition, quantitative polymerase chain reaction (qPCR) and western blotting were carried out to analyze the expression of genes and investigate NF-κB and STAT3 signaling pathways. Molecular docking studies showed that MIA docked into the NF-κB p50 subunit, and curcumin augmented its binding. The MTT assay results indicated that MIA and its combination with curcumin reduced cell viability. According to the results of the ELISA-based methods, MIA lowered the levels of inflammatory cytokines and suppressed NF-κB activity. In addition, real-time PCR and Griess test results showed that the expression of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) genes, and nitrite production were reduced by MIA. Furthermore, the western blotting analysis demonstrated that MIA increased the expression of inhibitory κB (IκBα) and B-cell lymphoma 2 (Bcl-2)-associated X proteins (BAX), and suppressed the STAT3 phosphorylation, and Bcl-2 expression. Our findings revealed that curcumin had a potentiating role and enhanced all the anti-inflammatory effects of MIA. This study indicated that the anti-inflammatory activity of MIA is exerted by suppressing the NF-κB and STAT3 signaling pathways in MDA-MB-231 and SKOV3 cancer cell lines.

Identification, Heterologous Expression, and Characterization of the Tolypodiol Biosynthetic Gene Cluster through an Integrated Approach.

Cyanobacteria are tremendous producers of biologically active natural products, including the potent anti-inflammatory compound tolypodiol. However, linking biosynthetic gene clusters with compound production in cyanobacteria has lagged behind that in other bacterial genera. Tolypodiol is a meroterpenoid originally isolated from the cyanobacterium HT-58-2. Here we describe the identification of the tolypodiol biosynthetic gene cluster through heterologous expression in Anabaena and in vitro protein assays of a methyltransferase found in the tolypodiol biosynthetic gene cluster. We have also identified similar biosynthetic gene clusters in cyanobacterial and actinobacterial genomes, suggesting that meroterpenoids with structural similarity to the tolypodiols may be synthesized by other microbes. We also report the identification of two new analogs of tolypodiol that we have identified in both the original and heterologous producer. This work further illustrates the usefulness of Anabaena as a heterologous expression host for cyanobacterial compounds and how integrated approaches can help to link natural product compounds with their producing biosynthetic gene clusters.

The Analgesic and Anti-inflammatory Effects of Partially Purified Polysaccharide Fractions of Cell-free Medium and Biomass of Spirulina platensis PCST5.

Spirulina is a cyanobacteria species containing various bioactive compounds. Spirulina is a known source of nutrients in some traditional diets. Different activities have been reported for various extracts of S. platensis. In this study, the polysaccharide content of culture media and biomass extract of one species of Spirulina was partially purified, and its analgesic and anti-inflammatory effects were evaluated. Spirulina platensis PCST5 was cultured in a sterile Zarouk medium at 27°C and 16/8h of light/ dark exposure cycle for 25 days. Then, the polysaccharide content of biomass and cell-free culture medium samples (BPSs and CFPSs, respectively) was partially purified. The analgesic and anti-inflammatory effects were evaluated using animal models. 16S rRNA gene analysis confirmed that the organism was genetically similar to Spirulina platensis. The CFPSs (30 and 100 mg/kg) and BPSs (30 mg/kg) significantly reduced pain-related behaviors in rats. Similarly, all samples could significantly reduce carrageenan-induced paw inflammation volume compared with the control group. Our results suggest Spirulina's polysaccharide fractions (CFPSs and BPSs) had significant analgesic and anti-inflammatory effects. Since Spirulina is a readily available source of bioactive compounds, finding such potent anti-inflammatory and anti-nociceptive compounds can provide promising leads for novel drug development.

Melatonin protected against kidney impairment induced by 5-fluorouracil in mice.

The utility of 5-fluorouracil (5-FU) as a successful chemotherapeutic drug for several cancers is limited by the induction of kidney injury and dysfunction due to redox imbalance, inflammation, and apoptosis. Meanwhile, melatonin (MLT) is a potent antioxidant and anti-inflammatory natural compound with a wide safety range. The current study aimed to investigate MLT's protective effect against 5-FU-induced kidney impairment. Male mice were given multiple doses of 5-FU at 25 and 100 mg/kg, as well as MLT at 20 mg/kg. MLT treatment alleviated the toxic effect of 5-FU by normalizing blood urea and creatinine levels and preserving the histological structure, indicating MLT's nephroprotective ability. This is accompanied by body weight maintenance, an increase in survival percentage, and preserved hematological parameters in comparison to the 5-FU-treated mice. MLT's renoprotective effect was explained by improvements in C-reactive protein, IL-6, and caspase-3 in kidney tissue, indicating MLT's anti-inflammatory and antiapoptotic ability. Furthermore, MLT inhibited 5-FU-induced lipid peroxidation by maintaining the activity of superoxide dismutase and catalase, as well as glutathione levels in kidney tissue from mice treated with both doses of 5-FU. The current findings show that MLT has a novel protective effect against 5-FU-induced renal injury and renal impairment.

Acetyl-11-Keto-Beta-Boswellic Acid Has Therapeutic Benefits for NAFLD Rat Models That Were Given a High Fructose Diet by Ameliorating Hepatic Inflammation and Lipid Metabolism.

Acetyl-11-keto-beta-boswellic acid (AKBA), a potent anti-inflammatory compound purified from Boswellia species, was investigated in a preclinical study for its potential in preventing and treating non-alcoholic fatty liver disease (NAFLD), the most common chronic inflammatory liver disorder. The study involved thirty-six male Wistar rats, equally divided into prevention and treatment groups. In the prevention group, rats were given a high fructose diet (HFrD) and treated with AKBA for 6weeks, while in the treatment group, rats were fed HFrD for 6weeks and then given a normal diet with AKBA for 2weeks. At the end of the study, various parameters were analyzed including liver tissues and serum levels of insulin, leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-β), interferon gamma (INF-ϒ), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). Additionally, the expression levels of genes related to the inflammasome complex and peroxisome proliferator-activated receptor gamma (PPAR-ϒ), as well as the levels of phosphorylated and non-phosphorylated AMP-activated protein kinase alpha-1 (AMPK-α1) protein, were measured. The results showed that AKBA improved NAFLD-related serum parameters and inflammatory markers and suppressed PPAR-ϒ and inflammasome complex-related genes involved in hepatic steatosis in both groups. Additionally, AKBA prevented the reduction of the active and inactive forms of AMPK-α1 in the prevention group, which is a cellular energy regulator that helps suppress NAFLD progression. In conclusion, AKBA has a beneficial effect on preventing and avoiding the progression of NAFLD by preserving lipid metabolism, improving hepatic steatosis, and suppressing liver inflammation.

Suppressing Inflammation for the Treatment of Diabetic Retinopathy and Age-Related Macular Degeneration: Dazdotuftide as a Potential New Multitarget Therapeutic Candidate.

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are major causes of blindness globally. The primary treatment option for DME and neovascular AMD (nAMD) is anti-vascular endothelial growth factor (VEGF) compounds, but this treatment modality often yields insufficient results, and monthly injections can place a burden on the health system and patients. Although various inflammatory pathways and mediators have been recognized as key players in the development of DR and AMD, there are limited treatment options targeting these pathways. Molecular pathways that are interlinked, or triggers of multiple inflammatory pathways, could be promising targets for drug development. This review focuses on the role of inflammation in the pathogenesis of DME and AMD and presents current anti-inflammatory compounds, as well as a potential multitarget anti-inflammatory compound (dazdotuftide) that could be a candidate treatment option for the management of DME and AMD.

Dietary fatty acids differentially affect secretion of pro-inflammatory cytokines in human THP-1 monocytes

Monocytes are a major population of circulating immune cells that play a crucial role in producing pro-inflammatory cytokines in the body. The actions of monocytes are known to be influenced by the combinations and concentrations of certain fatty acids (FAs) in blood and dietary fats. However, systemic comparisons of the effects of FAs on cytokine secretion by monocytes have not be performed. In this study, we compared how six saturated FAs (SFAs), two monounsaturated FAs (MUFAs), and seven polyunsaturated FAs (PUFAs) modulate human THP-1 monocyte secretion of TNF, IL-1β, and IL-6 in the absence or presence of lipopolysaccharide. SFAs generally stimulated resting THP-1 cells to secrete pro-inflammatory cytokines, with stearic acid being the most potent species. In contrast, MUFAs and PUFAs inhibited lipopolysaccharide-induced secretion of pro-inflammatory cytokines. Interestingly, the inhibitory potentials of MUFAs and PUFAs followed U-shaped (TNF and IL-1β) or inverted U-shaped (IL-6) dose–response curves. Among the MUFAs and PUFAs that were analyzed, docosahexaenoic acid (C22:6 n-3) exhibited the largest number of double bonds and was found to be the most potent anti-inflammatory compound. Together, our findings reveal that the chemical compositions and concentrations of dietary FAs are key factors in the intricate regulation of monocyte-mediated inflammation.

Development of an online UPLC-PDA-ESI-Q-TOF-MS-LOX-FLD system for rapid screening of anti-inflammatory compounds in Polygala tenuifolia Willd

In this study, the first ultra-high performance liquid chromatography-photo-diode array-electrospray ionization-quadrupole-time-of-flight-mass spectrometry-lipoxygenase-fluorescence detector (UPLC-PDA-ESI-Q-TOF-MS-LOX-FLD) online system was developed for the identification and evaluation of anti-inflammatory active ingredients in Polygala tenuifolia Willd. Using this system, the UPLC fingerprints, mass fragments and LOX-binding peak profiles in the samples were rapidly and simultaneously obtained. A total of 101 compounds were isolated and identified and 38 compounds (11 oligosaccharide esters, nine xanthones, 17 saponins, and one glycosyloxyflavone) showed strong LOX-binding activity. Six compounds were selected to study their LOX-binding ability, and the results indicated that the content of the six compounds had a good linear relationship with the LOX-binding ability, and it was found that the substitution position, the type of substituent and the number of glycosyl groups all had a certain influence on the LOX-binding ability of the compounds. The LOX-binding activities of 10 compounds were verified by the surface plasmon resonance (SPR) technique and the activity results were consistent with the online system. After validation, we identified 7 active compounds that combined with LOX to exert anti-inflammatory effects for the first time. All the results fully demonstrate the efficiency, stability and reliability of the online system and this work provides an exemplary and useful method for the rapid screening of potential anti-inflammatory active compounds in P. tenuifolia and other traditional Chinese medicines. At the same time, it provides a new direction for screening small molecule inhibitors of enzymes like LOX.

Fast and efficient identification of hyaluronidase specific inhibitors from Chrysanthemum morifolium Ramat. using UF-LC-MS technique and their anti-inflammation effect in macrophages

The purpose of the study was to establish a rapid analytical strategy to screen potential anti-inflammatory compounds from Flos Chrysanthemum flower. The enzyme assay was conducted to prescreen botanical extracts, in which Chrysanthemum morifolium aqueous extract (CME) displayed hyaluronidase (HAase) inhibitory activity in a dose-dependent manner with the values of 8.31, 24.25, and 66.51% at concentrations of 1.00, 2.00, and 4 0.00 mg/mL, respectively. Eight potential compounds targeting HAase (compounds 9, 10, 11, 13, 15, 17, 20 and 21) from CME were screened using ultrafiltration affinity liquid chromatography coupled with mass spectrometry (UF-LC-MS) technology. The well-known inhibitor, dipotassium glycyrrhizinate (DG), was used as a positive control and competitive ligand to eliminate false positives. Then, four of these potential components (compounds 9, 10, 17, and 21), namely eriodictyol-7-O-glucoside, luteoloside, apigenin-7-O-glucoside and diosmetin-7-O-glucoside, were distinguished as potent HAase specific inhibitor candidates with high BD and CBD values. The enzyme inhibitory activities of candidate compounds were verified using enzyme inhibition assay. At a concentration of 1000 μM, compounds 9, 10, 17, and 21 showed 40.15, 44.85, 18.04, and 24.15% inhibition of HAase, respectively. Furthermore, all the four compounds significantly decreased the production of nitric oxide (NO) and IL-6, and significantly suppressed the mRNA expression of inducible NO synthase (iNOS) and IL-1β in both murine and human macrophages.

Luteolin-rich fraction from Perilla frutescens seed meal inhibits spike glycoprotein S1 of SARS-CoV-2-induced NLRP3 inflammasome lung cell inflammation via regulation of JAK1/STAT3 pathway: A potential anti-inflammatory compound against inflammation-induced long-COVID.

The multi-systemic inflammation as a result of COVID-19 can persevere long after the initial symptoms of the illness have subsided. These effects are referred to as Long-COVID. Our research focused on the contribution of the Spike protein S1 subunit of SARS-CoV-2 (Spike S1) on the lung inflammation mediated by NLRP3 inflammasome machinery and the cytokine releases, interleukin 6 (IL-6), IL-1beta, and IL-18, in lung epithelial cells. This study has attempted to identify the naturally- occurring agents that act against inflammation-related long-COVID. The seed meal of Perilla frutescens (P. frutescens), which contains two major dietary polyphenols (rosmarinic acid and luteolin), has been reported to exhibit anti-inflammation activities. Therefore, we have established the ethyl acetate fraction of P. frutescens seed meal (PFEA) and determined its anti-inflammatory effects on Spike S1 exposure in A549 lung cells. PFEA was established using solvent-partitioned extraction. Rosmarinic acid (Ra) and luteolin (Lu) in PFEA were identified using the HPLC technique. The inhibitory effects of PFEA and its active compounds against Spike S1-induced inflammatory response in A549 cells were determined by RT-PCR and ELISA. The mechanistic study of anti-inflammatory properties of PFEA and Lu were determined using western blot technique. PFEA was found to contain Ra (388.70 ± 11.12 mg/g extract) and Lu (248.82 ± 12.34 mg/g extract) as its major polyphenols. Accordingly, A549 lung cells were pre-treated with PFEA (12.5-100 μg/mL) and its two major compounds (2.5-20 μg/mL) prior to the Spike S1 exposure at 100 ng/mL. PFEA dose-dependently exhibited anti-inflammatory properties upon Spike S1-exposed A549 cells through IL-6, IL-1β, IL-18, and NLRP3 gene suppressions, as well as IL-6, IL-1β, and IL-18 cytokine releases with statistical significance (p < 0.05). Importantly, Lu possesses superior anti-inflammatory properties when compared with Ra (p < 0.01). Mechanistically, PFEA and Lu effectively attenuated a Spike S1-induced inflammatory response through downregulation of the JAK1/STAT3-inflammasome-dependent inflammatory pathway as evidenced by the downregulation of NLRP3, ASC, and cleaved-caspase-1 of the NLRP3 inflammasome components and by modulating the phosphorylation of JAK1 and STAT3 proteins (p < 0.05). The findings suggested that luteolin and PFEA can modulate the signaling cascades that regulate Spike S1-induced lung inflammation during the incidence of Long-COVID. Consequently, luteolin and P. frutescens may be introduced as potential candidates in the preventive therapeutic strategy for inflammation-related post-acute sequelae of COVID-19.

Cinnamic aldehyde, an anti-inflammatory component in Du-Huo-Ji-Sheng-Tang, ameliorates arthritis in II collagenase and monosodium iodoacetate induced osteoarthritis rat models.

Du-Huo-Ji-Sheng-Tang (DHJST) is a Chinese herbal formula used for arthralgia and arthritis treatment clinically. This study aims to evaluate the joint-protecting efficacy of DHJST and to identify the active constituents as the evaluation marker. DHJST can be categorized into three recipes: Blood-tonifying-herbs Si-Wu-Tang (SWT), Wind-dampness-dispelling-herbs (WDH) and Qi-tonifying-herbs (TH). All formulas were used to explore the joint-protecting efficacies. s: Firstly, DHJST could decrease the arthritis progression in the monosodium-iodoacetate-induced rat and cure arthritis in the type II collagenase-induced rat. Further, in lipopolysaccharide-stimulated RAW 264.7cells, DHJST, TH and Cinnamomum cassia (CC), an ingredient in TH, were the most potent nitric oxide (NO) and prostaglandin E2 (PGE2) inhibitors. The major components, cinnamic aldehyde, showed the strongest NO and PGE2 inhibition. Up-regulated inducible NO synthase (iNOS) and cyclooxygenase-2 were inhibited by DHJST, TH, CC, and cinnamic aldehyde. In interleukin-1β-stimulated primary chondrocytes, upregulated iNOS was inhibited by DHJST, TH, Cinnamomum cassia, and cinnamic aldehyde. Upregulated matrix metalloprotease-13 was only inhibited by DHJST and TH and Eucommia ulmoides (EU) extract. Results suggest that DHJST presented joint-protective and cure arthritis effects. TH presented equal joint-protective effects as DHJST. The major anti-inflammatory ingredient in TH was Cinnamomum cassia in TH. And cinnamic aldehyde was the potent anti-inflammatory active compound in Cinnamomum cassia. Therefore, this study may facilitate the modern use of DHJST with TH as a simplified version but equally effective anti-osteoarthritic agents with cinnamic aldehyde as a quality control marker of DHJST and TH in osteoarthritis prevention or treatment.

Licochalcone A protects against LPS-induced inflammation and acute lung injury by directly binding with myeloid differentiation factor 2 (MD2).

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a challenging clinical syndrome that leads to various respiratory sequelae and even high mortality in patients with severe disease. The novel pharmacological strategies and therapeutic drugs are urgently needed. Natural products have played a fundamental role and provided an abundant pool in drug discovery. A compound library containing 160 natural products was used to screen potential anti-inflammatory compounds. Mice with LPS-induced ALI was then used to verify the preventive and therapeutic effects of the selected compounds. Licochalcone A was discovered from the anti-inflammatory screening of natural products in macrophages. A qPCR array validated the inflammation-regulatory effects of licochalcone A and indicated that the potential targets of licochalcone A may be the upstream proteins in LPS pro-inflammatory signalling. Further studies showed that licochalcone A directly binds to myeloid differentiation factor 2 (MD2), an assistant protein of toll-like receptor 4 (TLR4), to block both LPS-induced TRIF- and MYD88-dependent pathways. LEU61 and PHE151 in MD2 protein are the two key residues that contribute to the binding of MD2 to licochalcone A. In vivo, licochalcone A treatment alleviated ALI in LPS-challenged mice through significantly reducing immunocyte infiltration, suppressing activation of TLR4 pathway and inflammatory cytokine induction. In summary, our study identified MD2 as a direct target of licochalcone A for its anti-inflammatory activity and suggested that licochalcone A might serve as a novel MD2 inhibitor and a potential drug for developing ALI/ARDS therapy.

Exploring molecular docking with MM-GBSA and molecular dynamics simulation to predict potent inhibitors of cyclooxygenase (COX-2) enzyme from terpenoid-based active principles of Zingiber species

Cyclooxygenase 2 (COX-2), the key enzyme involved in prostaglandin (PGs) production, is known to take part in inflammatory and immune responses. Though COX-2 inhibitors are therapeutically effective anti-inflammatory drugs, they deficit anti-thrombotic activity thus leading to increased cardiovascular diseases. Therefore, COX-2 inhibitors with improved therapeutic efficacy and tolerance are still needed. In recent years, traditional medicine systems have paid attention to the essential oil of genus Zingiber, particularly for the treatment of various inflammatory illnesses, with lesser side effects. Thus, the present study aims to explore the anti-inflammatory activity of Zingiber essential oil through computational-biology approaches. In this regard, virtual screening, molecular docking, and simulations were carried out on 53 compounds derived from the essential oil of Zingiber species in order to provide mechanistic insights into COX-2 inhibition and identify the most actively potent anti-inflammatory compounds. Among all the docked ligands, epi-cubenol, δ-cadinene, γ-eudesmol, cubenol, and α-terpineol were found to be powerful bioactive compounds with an increased binding affinity towards COX-2 along with favorable physiochemical properties. Additionally, MD simulation in DPPC lipid bilayers was studied to examine the intrinsic dynamics and adaptability of the chosen ligands and COX-2-complexes. The findings showed that the selected five components interacted steadily with the COX-2 active site residues throughout the simulation via different bondings. The integrative-computational approach showed that the identified natural compounds may be taken into further consideration for potential in vitro and in vivo evaluation as COX-2 inhibitors, which would lead to the development of more potent and efficient anti-inflammatory drugs. Communicated by Ramaswamy H. Sarma

Synthesis, molecular docking, bio-evaluation and quantitative structure activity relationship of new chalcone derivatives as antioxidants

The therapeutic suppression of oxidative stress represents an attractive therapeutic target across an array of inflammatory disease setting. The nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative regulator Kelch-like ECH-associated protein1 (Keap1) are principal components in the homeostatic regulatory responses to oxidative and electrophilic stress and as such, reflect promising therapeutic targets. Flavonoids are a structurally diverse class of compounds possessing a wide range of pharmacological properties that have been postulated to suppress inflammation through their suppression of the Nrf2 pathway. The present study describes the synthesis of new 2-Hydroxy-5-nitro chalcones in the flavonoid family by the condensation of acetophenone and benzaldehydes. The structures of these compounds (3a-3e) were elucidated by spectroscopic studies including FTIR, 1H NMR and 13C NMR. Antioxidant potential of the compounds was determined by DPPH and iron chelating assays. Molecular docking analysis revealed that all the compounds had a marked affinity for Keap1 and computational studies revealed that all compounds possessed antioxidant potential. The compounds 3a>3b>3c>3e>3d showed an increasing order in IC50 for iron chelation, but were poor DPPH scavengers. Anti-inflammatory and analgesic activities were determined by carrageenan induced paw edema and acetic acid induced writhing test respectively in Sprague–Dawley rats. Of the compounds studied, both 3a and 3b demonstrated significant anti-inflammatory properties while 3c possessed analgesic effects. These studies suggest that these new 2-Hydroxy-5-nitro chalcones are potential anti-oxidant and anti-inflammatory compounds through their interaction with the Nrf2-Keap1 pathway. Further study of these compounds at the molecular level is now required to validate the presence of Nrf2 dependent anti-inflammatory pathway.

Phenethyl Ester of Gallic Acid Ameliorates Experimental Autoimmune Encephalomyelitis.

Gallic acid is a phenolic acid present in various plants, nuts, and fruits. It is well known for its anti-oxidative and anti-inflammatory properties. The phenethyl ester of gallic acid (PEGA) was synthesized with the aim of increasing the bioavailability of gallic acid, and thus its pharmacological potential. Here, the effects of PEGA on encephalitogenic cells were examined, and PEGA was found to modulate the inflammatory activities of T cells and macrophages/microglia. Specifically, PEGA reduced the release of interleukin (IL)-17 and interferon (IFN)-γ from T cells, as well as NO, and IL-6 from macrophages/microglia. Importantly, PEGA ameliorated experimental autoimmune encephalomyelitis, an animal model of chronic inflammatory disease of the central nervous system (CNS)-multiple sclerosis. Thus, PEGA is a potent anti-inflammatory compound with a perspective to be further explored in the context of CNS autoimmunity and other chronic inflammatory disorders.

Computer-aided analysis for identification of novel analogues of ketoprofen based on molecular docking, ADMET, drug-likeness and DFT studies for the treatment of inflammation

Computer-based drug design is increasingly used in strategies for discovering new molecules for therapeutic purposes. The targeted drug is ketoprofen (KTP), which belongs to the family of non-steroidal anti-inflammatory drugs, which are widely used for the treatment of pain, fever, inflammation and certain types of cancers. In an attempt to rationalize the search for 72 new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines molecular docking towards COX-2 receptor (5F1A), ADMET pharmacokinetic parameters, drug-likeness rules and molecular electrostatic potential (MEP). It was found that six of the compounds analyzed satisfy with the associated values to physico-chemical properties as key evaluation parameters for the drug-likeness and demonstrate a hydrophobic character which makes their solubility in aqueous media difficult and easy in lipids. All the compounds presented good ADMET profile and they showed an interaction with the amino acids responsible for anti-inflammatory activity of the COX-2 isoenzyme. The calculation of the MEP of the six analogues reveals new preferential sites involving the formation of new bonds. Consequently, this result allowed us to understand the origin of the potential increase in the anti-inflammatory activity of the candidates. Finally, it was obtained that six compounds have a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug ketoprofen, suggesting that these compounds could become a powerful candidate in the inhibition of the COX-2 enzyme. Communicated by Ramaswamy H. Sarma

Identification of anti-inflammatory components in Dioscorea nipponica Makino based on HPLC-MS/MS, quantitative analysis of multiple components by single marker and chemometric methods

The rhizome of Dioscorea nipponica Makino (RDN) is a widely used herbal medicine, which has significant anti-inflammatory activities on various inflammatory diseases. However, the bioactive compositions responsible for the anti-inflammatory activity of RDN are still unknown. This study aimed to identify the anti-inflammatory bioactive compounds in RDN using high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-Q/TOF-MS), quantitative analysis of multiple components by single marker (QAMS) and chemometric methods. Firstly, an HPLC-Q/TOF-MS method was employed for identification of bioactive steroidal saponins in RND, and a total of twelve steroid saponins were identified. Then, QAMS method was employed to determine the contents of seven bioactive steroidal saponins, including protodioscin, protogracillin, methyl protodioscin, pseudoprotodioscin, pseudoprogracillin, dioscin and gracillin in RND samples using dioscin as the reference analyte. The anti-inflammatory effects of RDN samples were then evaluated by inhibition of NO production in LPS-induced RAW264.7 cells. Furthermore, chemometric methods, including Pearson correlation analysis and partial least squares regression (PLSR) were employed to investigate the correlations between chemical components and anti-inflammatory activities, and explore the potential anti-inflammatory bioactive compounds of RDN. The results indicated that protodioscin, dioscin and gracillin were selected as the major anti-inflammatory compounds in RND. The further verification experiments showed that protodioscin, dioscin and gracillin exhibited great inhibition on NO production with IC50 values (the half maximal inhibitory concentration) of 0.712 μM, 0.469 μM and 0.815 μM, respectively. They also significantly reduced the levels of TNF-α, IL-1β, and IL-6 in LPS-induced RAW264.7 cells. The present study provided evidences for the anti-inflammatory activity of RND and identification of the anti-inflammatory components in RDN.

Assessing the Anti-inflammatory Effects of Bacopa-Derived Bioactive Compounds Using Network Pharmacology and In Vitro Studies.

Bacopa monnieri is reported as a potent Indian medicinal plant that possesses numerous pharmacological activities due to the presence of various bioactive compounds. These pharmacological activities were used in the ancient medicine system to cure inflammatory conditions. Bacopa has the ability to reduce acute pain and inflammation by inhibiting the enzyme cyclo-oxygenase-2 (COX-2) and reducing COX-2-arbitrated prostanoid mediators. Moreover, the anti-inflammatory property may also be associated with the neuroprotective activity of Bacopa. Considering this importance, the current pilot study focused on the anti-inflammatory potential of various phytocompounds of bacopa and their interaction with inflammation responsible genes such as COX2, iNOS, LOX, STAT3, CCR1, and MMP9 through pharmacology analysis of its systems. Docking results revealed that, quercetin (QR) showed significant binding energies with inflammatory genes. Hence, we selected QR as a potential phytocompound for further in vitro experiments. This existing study aimed to evaluate the efficacy of QR as a potent anti-inflammatory compound against lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The in vitro analysis concludes that QR effectively reduces the production of nitric oxide (NO) in LPS-induced RAW264.7 cells and downregulates the expression of COX-2 and iNOS genes due to the inhibitory potential of QR on LPS-stimulated NO production.