Promising Anti-inflammatory Activity Research Articles

Discovery of Coixol Derivatives as Potent Anti-inflammatory Agents.

Coixol, a derivative of 2-benzoxazolinone extracted from coix (Coix lachryma-jobi L. var. ma-yuen Stapf), has demonstrated promising anti-inflammatory activity and low cytotoxicity. In this study, 26 coixol derivatives were designed and synthesized by hybridization with cinnamic acid to identify new anti-inflammatory agents. The anti-inflammatory activities of the derivatives were screened using LPS-induced overexpression of nitric oxide (NO) in RAW264.7 macrophages. On the basis of the screening results, compounds containing furan (9c) or nitrofuran (9j) moieties displayed more pronounced activity than coixol and celecoxib. Mechanistic investigations revealed that 9c and 9j suppressed the expression of induced nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β, which was associated with the inhibition of the nuclear factor (NF)-κB signaling pathway. In vivo studies confirmed the anti-inflammatory activity of 9c and 9j in a xylene-induced mice auricles edema model. The preliminary in vitro and in vivo research findings suggest that 9c and 9j have the potential to be developed as anti-inflammatory agents.

Chemistry and Antifungal Activity of Homoisoflavonoids

This review deals with the antifungal profile of a subclass of natural products known as homoisoflavonoids. These molecules belong to the larger flavonoids class, yet they are less common for presenting an extra carbon in their basic chemical structures. Homoisoflavonoids are important bioactive molecules because they exhibit promising antimutagenic, antiproliferative, antioxidant, anti-inflammatory, and antimicrobial activity. This review lists the principal experimental studies addressing homoisoflavonoid antifungal activity with the aim of discussing the role of these molecules in obtaining new antifungal agents. The vast majority of research consists of antimicrobial screenings. It was noted that sappanin-type homoisoflavonoids commonly exhibit antifungal activity, but their overall antifungal profile is still very little known. Studies evaluating mechanisms of action are needed to better understand the antifungal potential of homoisoflavonoids.

Phytochemical screening and evaluation of antioxidant, anti-inflammatory, antimicrobial, and membrane-stabilizing activities of different fractional extracts of Grewia nervosa (Lour.) Panigrahi

BackgroundGrewia nervosa (Lour.) Panigrahi, a medicinal herb native to the steep forested region of Bangladesh, is utilized as a treatment for a variety of diseases or conditions, including dysmenorrhea, paratyphoid, bone fractures, jaundice, kidney stones, dyspepsia, heat stroke, cold, fever, diarrhea, hepatitis B, ingestion, and anthelmintic medication. This research aims to investigate the phyto-pharmacological qualities of this herb. MethodsThe herb was extracted using absolute ethanol followed by fractionation with n-hexane and chloroform. Following an initial investigation of phytochemicals, antioxidant, anti-inflammatory, antimicrobial, and membrane stabilization activities were assessed using the DPPH, egg albumin model, disc diffusion method, and erythrocyte hemolysis model, respectively. ResultsA preliminary phytochemical report suggests that G. nervosa contains reducing sugars, gums, amides, alkaloids, glycosides, flavonoids, steroids, tannins, flavonoids, and saponins. In a concentration-dependent approach, its fractional extracts displayed promising antioxidant, anti-inflammatory, antimicrobial, and membrane-stabilizing activity. It was seen that all fractions had a statistically significant capacity to prevent RBCs from hemolyzing, which suggests a potent membrane stabilizing function in-vitro. ConclusionTaken together, G. nervosa possesses important secondary metabolites and exhibits in-vitro antioxidant, anti-inflammatory, antimicrobial, and membrane stabilizing capacities. This endorses the conventional usage of G. nervosa, although additional study is needed on this potentially beneficial plant.

Datura stramonium Flowers as a Potential Natural Resource of Bioactive Molecules: Identification of Anti-Inflammatory Agents and Molecular Docking Analysis.

The present study investigated the antioxidant, antibacterial, antiviral and anti-inflammatory activities of different aerial parts (flowers, leaves and seeds) of Datura stramonium. The plant material was extracted with 80% methanol for about 24 h. The sensitivity to microorganisms analysis was performed by the microdilution technique. Antioxidant tests were performed by scavenging the DPPH and ABTS radicals, and by FRAP assay. Anti-inflammatory activity was evaluated through the inhibition of nitric oxide production in activated macrophage RAW 264.7 cells. Cell viability was assessed with an MTT assay. Results show that the flower extract revealed a powerful antimicrobial capacity against Gram-positive bacteria and strong antioxidant and anti-inflammatory activities. No significant cytotoxicity to activated macrophages was recorded. High resolution electrospray ionization mass spectrometry and nuclear magnetic resonance analysis identified two molecules with important anti-inflammatory effects: 12α-hydroxydaturametelin B and daturametelin B. Molecular docking analysis with both pro-inflammatory agents tumor necrosis factor alpha and interleukin-6 revealed that both compounds showed good binding features with the selected target proteins. Our results suggest that D. stramonium flower is a promising source of compounds with potential antioxidant, antibacterial, and anti-inflammatory activities. Isolated withanolide steroidal lactones from D. stramonium flower extract with promising anti-inflammatory activity have therapeutic potential against inflammatory disorders.

Electrospun/3D-Printed Bicomponent Scaffold Co-Loaded with a Prodrug and a Drug with Antibacterial and Immunomodulatory Properties.

This work reports the construction of a bicomponent scaffold co-loaded with both a prodrug and a drug (BiFp@Ht) as an efficient platform for wound dressing, by combining the electrospinning and 3D-printing technologies. The outer component consisted of a chitosan/polyethylene oxide-electrospun membrane loaded with the indomethacin-polyethylene glycol-indomethacin prodrug (Fp) and served as a support for printing the inner component, a gelatin methacryloyl/sodium alginate hydrogel loaded with tetracycline hydrochloride (Ht). The different architectural characteristics of the electrospun and 3D-printed layers were very well highlighted in a morphological analysis performed by Scanning Electron Microscopy (SEM). In vitro release profile studies demonstrated that both Fp and Ht layers were capable to release the loaded therapeutics in a controlled and sustained manner. According to a quantitative in vitro biological assessment, the bicomponent BiFp@Ht scaffold showed a good biocompatibility and no cytotoxic effect on HeLa cell cultures, while the highest proliferation level was noted in the case of HeLa cells seeded onto an Fp nanofibrous membrane. Furthermore, the BiFp@Ht scaffold presented an excellent antimicrobial activity against the E. coli and S. aureus bacterial strains, along with promising anti-inflammatory and proangiogenic activities, proving its potential to be used for wound dressing.

The potential beneficial role of Ginkgetin in doxorubicin-induced hepatotoxicity: Elucidating the underlying claim

Doxorubicin (DOX) is a widely used chemotherapeutic agent for various tumors treatment; apart from its chemotherapeutic activity, the traditional usage of DOX has been limited by its adverse effects on multiple organs, mainly hepatotoxicity. The molecular mechanisms underlying DOX hepatotoxicity are mainly due to the production of reactive oxygen species (ROS) inducing oxidative stress, diminishing antioxidant enzymes, apoptosis, inflammation, and mitochondrial dysfunction. Thus, there is an urgent need to develop a therapy that minimizes DOX hepatotoxicity and widens its use in various types of cancers without fear of its serious hepatotoxicity. Ginkgetin (GINK), a natural biflavonoid, exhibits diverse actions, including promising free radical scavenging, antioxidant, and anti-inflammatory activities. So, this study's objectives were to determine whether GINK could mitigate DOX's hepatotoxic effects and look into a putative hepatoprotective molecular pathway. Mice were divided into five groups: Normal control, control GINK 100, Untreated DOX group, and DOX groups treated with GINK (50 and 100 mg/kg) intraperitoneally daily for four days before DOX administration and an additional three days afterward. GINK 100 pretreatment showed marked protection from DOX hepatotoxicity and also attenuation of histopathological structural alterations. These outcomes were corroborated biochemically by a considerable decrease in alanine aminotransferases, aspartate aminotransferase, and alkaline phosphatase levels. GINK significantly augmented silent information regulator 1 and nuclear translocation of NF-E2-related factor 2 and repressed the expression and protein levels of forkhead box protein O1, inducible nitric oxide synthase, and P53 relative to DOX group. GINK alleviated oxidative stress and induced significant anti-inflammatory effects via suppression of interleukin-6, nuclear factor Kabba B, and iNOS respectively. This study is the first to investigate GINK's potentially beneficial effects in acute DOX hepatotoxicity, possibly exhibiting antioxidant, anti-inflammatory, and anti-apoptotic effects by modulation of Sirt1/FOXO-1/NF-κB Signal.

Synthesis of (E)-N'-(Pyridine-2-ylmethylene) Picolino Hydrazide with Promising Antimicrobial and Anti-inflammatory Activities Along with their In-silico Studies

In recent years, there has been a significant amount of interest in hydrazide-hydrazone compounds as a result of their extensive use in the pharmaceutical industry. In this study, the new compound (E)-N'-(pyridin-2-ylmethylene) picolino hydrazide, with the formula C20H19N3O2, was synthesised and confirmed using different spectroscopic techniques. The newly synthesised compound was tested for anti-inflammatory and antibacterial properties in vitro. The results of an in vitro anti-inflammatory activity test using the denaturation of bovine serum albumin as the measurement kit revealed a highly effective inhibitory effect. In addition, the results of the antimicrobial test showed that the compound demonstrated a maximum zone of inhibition (18.2 mm) against the Staphylococcus aureus strain at a higher concentration (32 μg/ml) of the tested sample (32 g/ml), which is greater than the standard drug (ciprofloxacin: 17.5 mm). The antifungal activity of (E)-N'-(pyridin-2-ylmethylene) picolinohydrazide indicated a maximum inhibition zone of 9.2 mm at a higher concentration (32 μg/ml) of the tested sample, which is comparable to that of the standard drug (ketoconazole: 9.0 mm). The anti-inflammatory activity performed by the carrageenan-induced paw edema method also gave a promising result. Molecular docking analysis revealed that the active compounds had a higher docking score and interacted effectively with the target protein. In silico molecular docking, results revealed the COX-5 and LL-37 (residues 17–29) proteins mainly depends on H-bonds between the pyridine groups of the synthesized ligand and the catalytic residues of the binding site, π-cation/anion interactions, (iii) π-alkyl interactions, and formation of carbon-hydrogen bond, π- π bond that stabilizes the interaction with the active site. Among the analogs of the hydrazine hydride class, the newly synthesized compound: (E)-N'-(pyridin-2-ylmethylene) picolino hydrazide proved to be a vital bioactive molecule.

Cinchonain Ia Shows Promising Antitumor Effects in Combination with L-Asparaginase-Loaded Nanoliposomes.

Cancer is among the leading causes of death worldwide, with no effective and safe treatment to date. This study is the first to co-conjugate the natural compound cinchonain Ia, which has promising anti-inflammatory activity, and L-asparaginase (ASNase), which has anticancer potential, to manufacture nanoliposomal particles (CALs). The CAL nanoliposomal complex had a mean size of approximately 118.7 nm, a zeta potential of -47.00 mV, and a polydispersity index (PDI) of 0.120. ASNase and cinchonain Ia were encapsulated into liposomes with approximately 93.75% and 98.53% efficiency, respectively. The CAL complex presented strong synergistic anticancer potency, with a combination index (CI) < 0.32 in two-dimensional culture and 0.44 in a three-dimensional model, as tested on NTERA-2 cancer stem cells. Importantly, the CAL nanoparticles demonstrated outstanding antiproliferative efficiency on cell growth in NTERA-2 cell spheroids, with greater than 30- and 2.5-fold increases in cytotoxic activity compared to either cinchonain Ia or ASNase liposomes, respectively. CALs also presented extremely enhanced antitumor effects, reaching approximately 62.49% tumor growth inhibition. Tumorized mice under CALs treatment showed a survival rate of 100%, compared to 31.2% in the untreated control group (p < 0.01), after 28 days of the experiment. Thus, CALs may represent an effective material for anticancer drug development.

Hydrocortisone-Loaded Lipid-Polymer Hybrid Nanoparticles for Controlled Topical Delivery: Formulation Design Optimization and In Vitro and In Vivo Appraisal.

The barrier functionalities of the skin offer a major but not insuperable hindrance for fabrication of skin delivery effective systems. This work aimed to develop an optimized lipid polymer hybrid nanoparticle and assess the skin delivery effectiveness of hydrocortisone (9.872 ± 0.361 × 10-3 cm2/h) of a drug through the skin from an optimized formulation when compared with a drug solution. Meanwhile, histological examination after topical application of the optimized formulation showed a safe increase in epidermal thickness. In vivo, the optimized formulation showed promising anti-inflammatory activity in a croton oil-induced ear rosacea model. As an excellent anti-inflammatory agent, these findings propose that the use of lipomers could be a promising strategy to improve the topical effectiveness of hydrocortisone acetate (HCA) against inflammatory diseases. Collectively, these results support our view that lipid polymer hybrid nanoparticles can proficiently deliver hydrocortisone to the skin in treating skin inflammatory conditions.

Promising biotherapeutic prospects of different probiotics and their derived postbiotic metabolites: in-vitro and histopathological investigation

BackgroundProbiotics and their derived postbiotics, as cell-free supernatants (CFS), are gaining a solid reputation owing to their prodigious health-promoting effects. Probiotics play a valuable role in the alleviation of various diseases among which are infectious diseases and inflammatory disorders. In this study, three probiotic strains, Lactiplantibacillus plantarum, Lacticaseibacillus rhamnosus, and Pediococcus acidilactici, were isolated from marketed dietary supplements. The antimicrobial activity of the isolated probiotic strains as well as their CFS was investigated. The neutralized CFS of the isolated probiotics were tested for their antibiofilm potential. The anti-inflammatory activity of the isolated Lactobacillus spp., together with their CFS, was studied in the carrageenan-induced rat paw edema model in male Wistar rats. To the best of our knowledge, such a model was not previously experimented to evaluate the anti-inflammatory activity of the CFS of probiotics. The histopathological investigation was implemented to assess the anti-inflammatory prospect of the isolated L. plantarum and L. rhamnosus strains as well as their CFS.ResultsThe whole viable probiotics and their CFS showed variable growth inhibition of the tested indicator strains using the agar overlay method and the microtiter plate assay, respectively. When tested for virulence factors, the probiotic strains were non-hemolytic lacking both deoxyribonuclease and gelatinase enzymes. However, five antibiotic resistance genes, blaZ, ermB, aac(6’)- aph(2”), aph(3’’)-III, and vanX, were detected in all isolates. The neutralized CFS of the isolated probiotics exhibited an antibiofilm effect as assessed by the crystal violet assay. This effect was manifested by hindering the biofilm formation of the tested Staphylococcus aureus and Pseudomonas aeruginosa clinical isolates in addition to P. aeruginosa PAO1 strain. Generally, the cell cultures of the two tested probiotics moderately suppressed the acute inflammation induced by carrageenan compared to indomethacin. Additionally, the studied CFS relatively reduced the inflammatory changes compared to the inflammation control group but less than that observed in the case of the probiotic cultures treated groups.ConclusionsThe tested probiotics, along with their CFS, showed promising antimicrobial and anti-inflammatory activities. Thus, their safety and their potential use as biotherapeutics for bacterial infections and inflammatory conditions are worthy of further investigation.

Anti-Atherogenic Protection by Oligomeric Proanthocyanidins via Regulating Collagen Crosslinking Against CC Diet-Induced Atherosclerosis in Rats.

The synthesis of collagen and its turnover remained as critical determinants for the progression of atherosclerosis. During this condition, proteases secreted by SMCs and foam cells in the necrotic core degrade collagen. Growing evidences demonstrated that consumption of antioxidant rich diet is highly associated with a reduced risk of atherosclerosis. Oligomeric proanthocyanidins (OPC) have been proved to possess promising antioxidant, anti-inflammatory and cardioprotective activity, based on our previous studies. The present study aims to investigate the efficacy of OPC isolated from Crataegus oxyacantha berries as a natural collagen crosslinker and anti-atherogenic agent. Spectral studies like FTIR, ultraviolet and circular dichroism analysis confirmed the in vitro crosslinking ability of OPC with rat tail collagen when compared to the standard epigallocatechin gallate. The administration of cholesterol:cholic acid (CC) diet induces proteases-mediated collagen degradation that could result in plaque instability. Further, the CC diet fed rats showed significantly increased levels of total cholesterol and triacylglycerols which, in turn, increases the activities of collagen degrading proteases-MMPs (MMP 1, 2 and 9) and Cathepsin S and D. Upon OPC treatment, marked reduction in the lipid content, activation of proteases with concomitant increase in the mRNA levels of collagen Type I and Type III as similar to atorvastatin treatment were observed .Thus, OPC supplementation may contribute to the prevention of atherosclerotic plaque instability by acting as a natural crosslinker of collagen.

Antidepressant and Anxiolytic Potentials of the Chewing Stick, Salvadora persica.

Salvadora persica stem bark was extracted with two different solvents, i.e., ethyl acetate and water, and preliminary phytochemical screening was performed. Two behavioral models were used: an elevated plus maze test (EPM) and the light and dark model test for anxiolytic parameters, and a forced swim test (FST) for antidepressant effects. Healthy mice weighing 18-40 gms were treated orally in four groups (n = 6), i.e., negative control treated with normal saline and positive control with 1 mg/kg diazepam (EPM) and 30 mg/kg fluoxetine (FST), and the test groups were treated with 500 mg/kg of aqueous and ethyl acetate Sp extract. The number of entries and duration spent in the open arm for 5 minutes were the parameters for evaluating the anxiolytic activity (EPM). Duration of immobility was measured for 5 min in the FST model. In EPM, both the Sp extracts significantly (p < 0.005) increased the number of entries and the time spent in the open arms and was much similar to those of diazepam. Similarly, these extracts and fluoxetine significantly (p < 0.005) decreased the immobility time in FST. The results suggest the therapeutic potential of Salvadora persica an alternative in the management of comorbid anxiety and depression.

Design, synthesis and evaluation of novel pyrrole-hydroxybutenolide hybrids as promising antiplasmodial and anti-inflammatory agents

In the pursuance of novel scaffolds with promising antiplasmodial and anti-inflammatory activity, a series of twenty-one compounds embraced with most promising penta-substituted pyrrole and biodynamic hydroxybutenolide in single skeleton was designed and synthesized. These pyrrole-hydroxybutenolide hybrids were evaluated against Plasmodium falciparum parasite. Four hybrids 5b, 5d, 5t and 5u exhibited good activity with IC50 of 0.60, 0.88, 0.97 and 0.96 μM for chloroquine sensitive (Pf3D7) strain and 3.92, 4.31, 4.21 and 1.67 μM for chloroquine resistant (PfK1) strain, respectively. In vivo efficacy of 5b, 5d, 5t and 5u was studied against the P. yoelii nigeriensis N67 (a chloroquine-resistant) parasite in Swiss mice at a dose of 100 mg/kg/day for 4 days via oral route. 5u was found to show maximum 100% parasite inhibition with considerably increased mean survival time. Simultaneously, the series of compounds was screened for anti-inflammatory potential. In preliminary assays, nine compounds showed more than 85% inhibition in hu-TNFα cytokine levels in LPS stimulated THP-1 monocytes and seven compounds showed more than 40% decrease in fold induction in reporter gene activity analyzed via Luciferase assay. 5p and 5t were found to be most promising amongst the series, thus were taken up for further in vivo studies. Wherein, mice pre-treated with them showed a dose dependent inhibition in carrageenan induced paw swelling. Moreover, the results of in vitro and in vivo pharmacokinetic parameters indicated that the synthesized pyrrole-hydroxybutenolide conjugates abide by the required criteria for the development of orally active drug and thus this scaffold can be used as pharmacologically active framework that should be considered for the development of potential antiplasmodial and anti-inflammatory agents.

Thiamethoxam evoked neural oxido-inflammatory stress in male rats through modulation of Nrf2/NF-kB/iNOS signaling and inflammatory cytokines: Neuroprotective effect of Silymarin

Thiamethoxam (TMX), a neonicotinoid insecticide, is a widely used insecticide with neurotoxic potential. Silymarin (SM), a milk thistle-derived flavonoid, is known with its promising biological activities. This study explored the neuroprotective effects of SM against TMX-triggered cortical injury in male rats. Animals were divided into four groups and treated daily either with SM (150 mg/kg), TMX (78.15 mg/kg), or both at the aforementioned doses for 28 days. Our results revealed marked declines in cortical SOD and CAT activities with elevations in MDA, IL-1b and TNF-α levels in TMX-treated rats. Further, TMX induced down-regulation in the gene expressions of Sod, Cat, Gpx, and Nrf-2, with up-regulation in the gene expressions of IL-1b, IL-6, iNOS, TNF-α and NF-kB. Interestingly, pre-treatment with SM provided a notable neuroprotective action against TMX-mediated cortical damage that indicates its promising antioxidant and anti-inflammatory activities. This effect may be mediated by Nrf2/NF-kB/iNOS signalling and suppression of excess free radicals and production of inflammatory cytokines. In brief, SM could be a promising therapeutic agent against TMX-mediated neural complication via its antioxidant and anti-inflammatory properties. Practical applicationsThe using of neonicotinoids as thiamethoxam is recently increased and is associated with brain damage. TMX induced excessive oxidative and inflammatory damage. Therefore, new therapeutic approaches are needed to counteract its adverse effects on the nervous system. SM, a flavonoid, is extracted from the seeds and fruits of milk thistle. Due to its potent antioxidative activity, SM have been applied to mitigate the oxidative stress as well as inflammatory disorders. Herein, we examined the potential therapeutic role of SM against TMX-induced brain oxidative stress and inflammation in rats through evaluating oxidative markers, inflammatory response, and histopathological changes in the brain cortical tissue.

Green Synthesis of Novel Pyridines via One-Pot Multicomponent Reaction and Their Anti-Inflammatory Evaluation.

A functional and environmentally green procedure for the design of novel pyridine 5a-h and 7a-d derivatives through two pathways is presented. The first pathway is via a one-pot, four-component reaction of p-formylphenyl-4-toluenesulfonate (1), ethyl cyanoacetate (2), acetophenone derivatives 3a-h or acetyl derivatives 6a-d, and ammonium acetate (4) under microwave irradiation in ethanol. The advantages of this method are an excellent yield (82%-94%), pure products, a short reaction time (2-7 min), and low-cost processing. The second pathway was obtained by the traditional method with treatment of the same mixture under refluxing in ethanol, which afforded the same products, 5a-h and 7a-d, in less yield (71%-88%) and over a longer reaction time (6-9 h). The constructions of the novel compounds were articulated via spectral and elemental analysis. Overall, the compounds have been designed, synthesized, and studied for their in vitro anti-inflammatory activity using diclofenac as a reference drug (5 mg/kg). The most potent four compounds, 5a, 5f, 5g, and 5h, showed promising anti-inflammatory activity.

Untargeted metabolites profiling of volatile and non-volatile components of Egyptian lotus (Nelumbo nucifera Gaertn.) using UHPLC/PDA/ESI-MS and solid-phase microextraction (SPME) GC/MS in relation to its antiaging and anti-inflammatory effects

Nelumbo nucifera Gaertn. is a unique member of the family Nymphaeaceae, and one of the most important industrial crops with a cultural and medicinal value, especially in the traditional herbal medicines. The beautiful scent of its pink flowers had been used in many cosmetic preparations, but rarely investigated. The goal of this study was to characterize N. nucifera flower aroma profile using solid-phase microextraction coupled with GC/MS. A total of 33 volatile compounds belonging to several classes were identified with cineole reported for the first time and likely to contribute to its aroma. Untargeted metabolites profiling of non-volatile components in leaves, flowers, and seeds was attempted using high-resolution ultra-performance liquid chromatography-mass spectrometry analysis. UPLC-MS. MS-based profiling provided an annotation of more than 60 secondary metabolites with two newly reported glycoalkaloids alongside with floral anthocyanins. Principal component analysis of the UPLC-MS dataset revealed that flowers exhibited a distinct metabolome compared to seeds and leaves. Ultimately, flower extract exhibited a promising anti-aging and anti-inflammatory activities providing a new insight into lotus flower incorporation in the industrial cosmetic formulations.

Diastereoselective Synthesis of trans-anti-Hydrophenanthrenes via Ti-mediated Radical Cyclization and Total Synthesis of Kamebanin.

Ent-kaurenes consist of an ABC-ring based on a trans-anti-hydrophenanthrene skeleton and a D ring with an exomethylene. Highly oxygen-functionalized ent-kauren-15-ones have promising antiinflammatory pharmacological activity. In this study, we developed a novel diastereoselective synthesis of trans-anti-hydrophenanthrenes via a Ti-mediated reductive radical cyclization. We also demonstrated the applicability of this method by developing the first total synthesis of (±)-kamebanin (longest linear sequence; 17 steps, overall yield; 6.5 %). Furthermore, this synthesis provided a formal semi-pinacol rearrangement for the construction of the quaternary carbon at C8 and a novel Thorpe-Ziegler-type reaction for the construction of the D-ring.

The antimicrobial peptide LK2(6)A(L) exhibits anti-inflammatory activity by binding to the myeloid differentiation 2 domain and protects against LPS-induced acute lung injury in mice

Acute lung injury (ALI) is a life-threatening disease that is generally attributable to an uncontrolled inflammatory response in the lung, but there is a lack of effective treatments. At present, regulating the inflammatory response has become an important strategy for treating ALI. In the present study, LK2(6)A(L), a peptide derived from the natural antimicrobial peptide temporin-1CEa, inhibited lipopolysaccharide (LPS)-induced expression of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and NO in RAW264.7 cells. Herein, the anti-inflammatory mechanism of LK2(6)A(L) was investigated. The RNA-sequencing (RNA-seq) results showed that LK2(6)A(L) significantly inhibited the TLR4-mediated NF-κB and MAPK signaling pathways in LPS-induced RAW264.7 cells. The results of co-immunoprecipitation (Co-IP), pull-down experiment, confocal laser scanning microscopy, and surface plasmon resonance (SPR) suggested that MD2 was the direct target of LK2(6)A(L). Chemical inhibition of MD2 and its knockdown abolished the anti-inflammatory effect of LK2(6)A(L). Molecular dynamic simulation indicated that LK2(6)A(L) could bind to the active domain of the MD2 hydrophobic pocket via six hydrogen bonds. The truncated peptides were designed based on analysis of the molecular docking of LK2(6)A(L) to MD2. The truncated peptide IS-7 showed strong affinity to MD2 and a remarkable inhibitory effect on pro-inflammatory factors that was comparable to the effect of LK2(6)A(L). Finally, LK2(6)A(L) and IS-7 relieved inflammatory symptoms and lung tissue destruction in the ALI mouse model. Overall, our study suggested that LK2(6)A(L) showed promising anti-inflammatory activity by targeting MD2, and the amino acid domain 7–13 was an important area that binds with MD2 and also an anti-inflammatory active region. LK2(6)A(L) and IS-7 may be potential new treatments for ALI and other acute inflammatory diseases.

Therapeutic Potential of Catechin as an IKK-β Inhibitor for the Management of Arthritis: In vitro and In vivo Approach.

Rheumatoid arthritis (RA) is associated with increased levels of cytokines, for instance, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and interleukin-1 (IL-1), which exhibit potent pro-inflammatory effects and are contributing factors to disease progression. A range of cytokines, cell adhesion molecules, and enzymes that are implicated in the debilitating effects of RA are transcribed by nuclear factor kappa. The purpose of this research was to characterize the efficacy of "catechin" as an IkappaB kinase-beta (IKK-β) inhibitor in collagen-induced arthritis (CIA) model in mice, as IKK-β is crucial in the transmission of signal-inducible NF-κβ activation. Arthritis was brought on in Bagg and Albino, but it is written BALB/c (BALB/c) male mice through subcutaneous immunization with bovine type II collagen on days 0 and 21. Catechin is given orally every day after the onset of the disease. Clinical evaluation of the prevalence and severity of the condition was done throughout the trial, and biochemical testing was done at the end (day 42). In vitro findings of the study demonstrated catechin as a potent inhibitor of IKK-β with Half maximal Inhibitory Concentration (IC50) values of 2.90 μM and 4.358 μM in IKK-β and NF-κβ transactivation activity assay, respectively. Furthermore, catechin (dose range of 10-100 mg/kg, p.o.) was effective in reducing disease incidence and clinical signs in a dose-dependent manner, with an Effective Dose for 50% of the population (ED50) value of 79.579 mg/kg. The findings of this study demonstrate dose-dependent efficacy in terms of both disease severity (clinical scoring) and inflammatory markers (biochemical evaluation of the serum and joints). IKK inhibitors are a prospective target for the creation of new therapeutics for arthritis and other inflammatory diseases because it has been suggested that this enzyme is crucial in the pathophysiology of RA. The finding of this study suggests that "catechin" represents a novel inhibitor of IKK-β with promising anti-inflammatory activity.

Neuroprotective efficacy of the bacterial metabolite, prodigiosin, against aluminium chloride-induced neurochemical alternations associated with Alzheimer's disease murine model: Involvement of Nrf2/HO-1/NF-κB signaling.

Prodigiosin (PDG) is a bacterial metabolite with numerous biological and pharmaceutical properties. Exposure to aluminium is considered a root etiological factor in the pathological progress of Alzheimer's disease (AD). Here, in this investigation, we explored the neuroprotective potential of PDG against aluminium chloride (AlCl3 )-mediated AD-like neurological alterations in rats. For this purpose, rats were gavaged either AlCl3 (100 mg/kg), PDG (300 mg/kg), or both for 42 days. As a result of the analyzes performed on the hippocampal tissue, it was observed that AlCl3 induced biochemical, molecular, and histopathological changes like those related to AD. PDG pre-treatment significantly decreased acetylcholinesterase activity and restored the levels of brain-derived neurotrophic factor, monoamines (dopamine, norepinephrine, and serotonin), and transmembrane protein (Na+ /K+ -ATPase). Furthermore, PDG boosted the hippocampal antioxidant capacity, as shown by the increased superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione contents. These findings were accompanied by decreases in malondialdehyde and nitric oxide levels. The antioxidant effect may promote the upregulation of the expression of antioxidant genes (Nrf2 and HO-1). Moreover, PDG exerted notable anti-inflammatory effects via the lessening of interleukin-1 beta, tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor kappa B, and decreases in the gene expression of inducible nitric oxide synthase. In addition, noteworthy decreases in pro-apoptotic (Bax and caspase-3) levels and increases in anti-apoptotic (Bcl-2) biomarkers suggested an anti-apoptotic effect of PDG. In support, the hippocampal histological examination validated the aforementioned changes. To summarize, the promising neuromodulatory, antioxidative, anti-inflammatory, and anti-apoptotic activities of PDG establish it as a potent therapeutic option for AD.