Anti-inflammatory Natural Products Research Articles

Effects of some anti-ulcer and anti-inflammatory natural products on cyclooxygenase and lipoxygenase enzymes: insights from in silico analysis.

The online version contains supplementary material available at 10.1007/s40203-024-00269-2.

Recent Advances in Anti-Inflammatory Compounds from Marine Microorganisms.

Marine microbial secondary metabolites with diversified structures have been found as promising sources of anti-inflammatory lead compounds. This review summarizes the sources, chemical structures, and pharmacological properties of anti-inflammatory natural products reported from marine microorganisms in the past three years (2021-2023). Approximately 252 anti-inflammatory compounds, including 129 new ones, were predominantly obtained from marine fungi and they are structurally divided into polyketides (51.2%), terpenoids (21.0%), alkaloids (18.7%), amides or peptides (4.8%), and steroids (4.3%). This review will shed light on the development of marine microbial secondary metabolites as potential anti-inflammatory lead compounds with promising clinical applications in human health.

Magnolol-loaded polydopamine-chitosan coated pH-responsive nanoparticles for alleviation of ulcerative colitis

This study designed and developed a novel three-layer electrostatic, slow-releasing nanoparticle drug delivery system for the treatment of ulcerative colitis. The nanoparticles were composed of layers of zein-based polydopamine, chitosan and cellulose acetate phthalate to form a polyelectrolyte multilayer core−shell nanoparticle structure. The anti-inflammatory natural product magnolol was chosen to be the model drug for the study. The nanoparticles (260.50 ± 23.90 nm) were prepared with layer-by-layer coating and then assessed in vitro and in vivo using a mouse model of ulcerative colitis. The in vitro data confirmed the slow-releasing and pH-dependent characteristics of particles. Quantitative analysis of the in vivo distribution of Mag in mice showed significantly higher concentrations in colonic tissue than in the upper gastrointestinal tract (854.6 ng/g vs 291.5–351.1 ng/g, respectively). Histological and pro-inflammatory cytokine analysis indicated that the nanoparticles had a significant anti-inflammatory effect and were protective against DSS-induced structural damage of the colonic mucosal structure. These results confirm that this nano-delivery system could increase the levels of Mag reaching the colon, resulting in greater efficacy than free Mag in treating UC in this mouse model.

Synthesis and Biological Evaluation of Colchicine─Aryl/Alkyl Amine Hybrids as Potential Noncytotoxic Cholinesterase Inhibitors: Identification of SBN-284 as a Dual Inhibitor of Cholinesterases and NLRP3 Inflammasome.

Colchicine, one of the oldest anti-inflammatory natural products still used clinically, inhibits NF-κB signaling and NLRP3 inflammasome activation. Despite its cytotoxicity and narrow therapeutic range, colchicine continues to intrigue medicinal chemists exploring its anti-inflammatory potential. This study aimed to investigate the colchicine scaffold for its role in Alzheimer's disease by targeting neuroinflammation and cholinesterases. Molecular docking revealed that colchicine's hydrophobic trimethoxyphenyl framework can potentially bind to the peripheral anionic site of cholinesterases. Hybrid structures combining colchicine with aryl/alkyl amines were designed to bind both peripheral and catalytic sites of cholinesterases. We describe here the design, synthesis, and in vitro cytotoxicity evaluation of these colchicine-aryl/alkyl amine hybrids, along with their in silico interactions with the cholinesterase active site gorge. Nontoxic analogs demonstrating strong cholinesterase binding affinity were further evaluated for their anticholinesterase and antineuroinflammatory activities. The colchicine-donepezil hybrid, SBN-284 (3x), inhibited both acetylcholinesterase and butyrylcholinesterase as well as the NLRP3 inflammasome complex at low micromolar concentrations. It achieved this through noncompetitive inhibition, occupying the active site gorge and interacting with both peripheral and catalytic anionic sites of cholinesterases. Analog 3x was shown to cross the blood-brain barrier and exhibited no toxicity to neuronal cells, primary macrophages, or epithelial fR2 cells. These findings highlight the potential of this lead compound for further preclinical investigation as a promising anti-Alzheimer agent.

Potential of natural products in inflammation: biological activities, structure-activity relationships, and mechanistic targets.

A balance between the development and suppression of inflammation can always be found in the body. When this balance is disturbed, a strong inflammatory response can damage the body. It sometimes is necessary to use drugs with a significant anti-inflammatory effect, such as nonsteroidal anti-inflammatory drugs and steroid hormones, to control inflammation in the body. However, the existing anti-inflammatory drugs have many adverse effects, which can be deadly in severe cases, making research into new safer and more effective anti-inflammatory drugs necessary. Currently, numerous types of natural products with anti-inflammatory activity and distinct structural features are available, and these natural products have great potential for the development of novel anti-inflammatory drugs. This review summarizes 260 natural products and their derivatives with anti-inflammatory activities in the last two decades, classified by their active ingredients, and focuses on their structure-activity relationships in anti-inflammation to lay the foundation for subsequent new drug development. We also elucidate the mechanisms and pathways of natural products that exert anti-inflammatory effects via network pharmacology predictions, providing direction for identifying subsequent targets of anti-inflammatory natural products.

Treatment of Cachexia in Gastric Cancer: Exploring the Use of Anti-Inflammatory Natural Products and Their Derivatives.

(1) Background: Gastric cancer is a significant cause of cancer-related mortality worldwide. Weight loss and malnutrition associated with cancer are linked with increased mortality rates and reduced quality of life. Cancer cachexia, characterised by the loss of skeletal muscle, is associated with approximately 20% of cancer-related deaths and differs from malnutrition in that it cannot be fully reversed by nutritional support alone. It is now recognised that the primary pathophysiological process underlying cancer cachexia is chronic inflammation leading to increased calorie consumption. Current treatments that focus on nutritional supplementation, psychological counselling, appetite stimulation and reducing inflammation are lacking in efficacy. This review focuses on the evidence supporting the potential roles of natural anti-inflammatory products and their derivatives including fatty acids, probiotics, amino acids, curcumin, fucoidan, epigallocatechin-3-gallate, ginger, resveratrol and Boswellia serrata in the management of gastric cancer cachexia. (2) Results: While natural anti-inflammatory products show promise in a number of in vitro and in vivo studies, there are only a small number of human studies available. Where present, the evidence base is heterogeneous, with varying study methodologies and outcomes. (3) Conclusions: Natural anti-inflammatory products represent a potential adjunctive therapy for gastric cancer cachexia. Further research, particularly well-designed clinical trials, is needed to elucidate their optimal role, dosing and safety profiles in the management of gastric cancer cachexia.

Reduced Production of Pro-Inflammatory and Pro-Catabolic Factors by Human Serum Metabolites Derived from a Patented Saffron Extract Intake.

Safe and anti-inflammatory plant-based natural products present an increasing focus in the treatment of chronic inflammatory diseases such as osteoarthritis or inflammatory bowel diseases. Among them, saffron, a spice derived from the stigma of Crocus sativus, could have anti-inflammatory properties and would be therefore a promising therapeutic agent for the treatment of such conditions. However, the anti-inflammatory molecular mechanisms of saffron in humans are still understudied and unclear. In this study, combining human serum metabolites and cell cultures, we evaluated the effect of circulating metabolites from the consumption of a patented saffron extract (Safr'InsideTM) on the chondrocytes and colon epithelial cell responses to inflammatory stress. Parametric or non-parametric Analysis of Variance with post hoc tests was performed. We demonstrated that human serum containing metabolites from saffron intake attenuated IL-1β-stimulated production of PGE2 and MMP-13 in chondrocyte cells and limited the increase in ICAM-1, MCP-1, iNOS, and MMP-3 in human epithelial cells following combined IL-1β and TNF-α inflammatory stimulation. Altogether, these data provide new findings into the mechanisms underlying the beneficial effects of saffron on chondrocytes and enterocyte cells at the cellular level and in the context of chronic inflammatory disorders.

Anti-Inflammatory Effect of Extracts of Inonotus obliquus and Microalgae

Chaga mushroom (Inonotus obliquus) and marine microalgae are two emerging natural products with many potential physiological health benefits. The aim of this study was to investigate the anti-inflammatory effects of two extracts prepared from Chaga mushroom and microalgae using lipopolysaccharide-stimulated RAW 264.7 murine macrophage cell model. The Chaga mushroom extract dose-dependently reduced the production of proinflammatory biomarkers of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α). At a high concentration of 500 µg/L, Chaga mushroom extract significantly suppressed cyclooxygenase-2 levels. Similarly, the extract of microalgae suppressed the secretion of IL-6 and TNF-α by lipopolysaccharide-induced macrophages. Both extracts had no significant impact on the secretion of anti-inflammatory IL-4 production. These results suggest that extracts of Chaga mushroom and microalgae can be used in developing anti-inflammatory natural health products.

인간 기도 상피세포에서 IKK/IκBα/NF-κB p65 신호전달 경로를 경유한 호흡기 MUC5AC 뮤신 유전자의 발현에 미치는 올레아놀산의 영향

In the present study, we investigated whether oleanolic acid, an anti-inflammatory natural product, significantly affects the phorbol 12-myristate 13-acetate (PMA)-induced gene expression of airway MUC5AC mucin. Confluent NCIH292 cells were pretreated with oleanolic acid for 30 min and then stimulated with PMA for 24 h or the indicated periods. The MUC5AC mucin mRNA expression was measured by RT-PCR. Production of MUC5AC mucin protein was measured by ELISA. To elucidate the action mechanism of oleanolic acid, effect of oleanolic acid on PMA-induced NF-B signaling pathway was investigated by western blot analysis. The results were as follows: (1) Oleanolic acid significantly inhibited the production of MUC5AC mucin protein and down-regulated the expression of MUC5AC mucin mRNA; (2) Oleanolic acid inhibited PMA-induced activation (phosphorylation) of inhibitory kappa B kinase (IKK), and thus phosphorylation and degradation of inhibitory kappa Ba (IB); (3) Oleanolic acid inhibited PMA-induced nuclear translocation of nuclear factor kappa B (NF-B) p65, led to the down-regulation of MUC5AC mucin gene expression in NCI-H292 cells. These results suggest that oleanolic acid can regulate the gene expression of mucin by acting on airway epithelial cells through regulation of NF-B signaling pathway.

Design, synthesis, and anti-cancer evaluation of C-14 arylcarbamate derivatives of andrographolide

In this study, we explored a concise and mild synthetic route to produce novel C-14 arylcarbamate derivatives of andrographolide, a known anti-inflammatory and anticancer natural product. Upon assessing their anti-cancer efficacy against pancreatic ductal adenocarcinoma (PDAC) cells, some derivatives showed stronger cytotoxicity against PANC-1 cells than andrographolide. In addition, we demonstrated one derivative, compound 3m, effectively reduced the expression of oncogenic p53 mutant proteins (p53R273H and p53R248W), proliferation, and migration in PDAC lines, PANC-1 and MIA PaCa-2. Accordingly, the novel derivative holds promise as an anti-cancer agent against pancreatic cancer. In summary, our study broadens the derivative library of andrographolide and develops an arylcarbamate derivative of andrographolide with promising anticancer activity against PDAC.

Semisynthesis of Linariophyllenes A-C and Rumphellolide H, Structure Revisions and Proposed Biosynthesis Pathways.

The first semisynthetic routes toward terrestrial anti-inflammatory natural products linariophyllene A-C and the refined route toward marine natural product rumphellolide H are presented. Among the synthesized target compounds, the correct structure of linariophyllene A was determined to be the diastereomer of the originally proposed structure with an inverted stereocenter at the secondary alcohol. The proposed structures of linariophyllene B and rumphellolide H were confirmed. However, the correct structure of linariophyllene C was found to be the diastereomer of the originally proposed structure with an inverted stereocenter at the tertiary carbon of the epoxide moiety. The structures of linariophyllenes A-C and rumphellolide H were unequivocally confirmed by single-crystal X-ray diffractometry. The obtained results enabled the proposal of the biosynthetic origins of the aforementioned natural products and bolstered the diversity of available sesquiterpenoids. Linariophyllenes A-C and rumphellolide H were obtained in sufficient amounts to further expand their bioactivity profile and utility as reference standards in future studies of chemical constituents of terrestrial and marine organisms.

A Shear-Thinning, Self-Healing, Dual-Cross Linked Hydrogel based on Gelatin/Vanillin/Fe3+ /AGP-AgNPs: Synthesis, Antibacterial and Wound-Healing Assessment.

A shear-thinning and self-healing hydrogel based on a gelatin biopolymer was synthesized using vanillin and Fe3+ as dual crosslinking agents. Rheological studies indicate the formation of a strong gel found to be injectable and exhibit rapid self-healing (within 10 minutes). The hydrogels also exhibited a high degree of swelling, suggesting potential as wound dressings since the absorption of large amounts of wound exudate, and optimum moisture levels, lead to accelerated wound healing. Andrographolide, an anti-inflammatory natural product was used to fabricate silver nanoparticles, which were characterized, and composited with the fabricated hydrogels to imbue them with anti-microbial activity. The nanoparticle/hydrogel composites exhibit activity against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Burkholderia pseudomallei (B. pseudomallei), the pathogen that causes melioidosis, a serious but neglected disease affecting southeast Asia and northern Australia. Finally, the nanoparticle/hydrogel composites are shown to enhance wound closure in animal models compared to the hydrogel alone, confirming that these hydrogel composites hold great potential in the biomedical field. This article is protected by copyright. All rights reserved.

Design, synthesis, and evaluation of new anti-inflammatory natural products amide derivatives endowed with anti-blood cancer activity towards development of potential multifunctional agents against hematological cancers

New amide derivatives of the natural product 5,6,7-trimethoxyflavanone were designed as multifunctional antiproliferative molecules against blood cancer and the associated inflammatory conditions. The targeted compounds were synthesized efficiently in three linear steps employing known chalcone starting materials. Compounds 2h, 2i, 2l, 2t, 2v and 2x having bromo or nitro substituted-phenyl rings elicited potential inhibitory effects on macrophages production of nitric oxide, PGE2 and TNF-α which are proinflammatory mediators involved in tumorigenesis and progression of blood cancer. Additionally, evaluation of direct inhibitory effects on the growth of diverse blood cancers including leukemia, lymphoma, and myeloma cell lines unveiled compound 2v as the most potential molecules eliciting at least five-folds the potency of the standard imatinib drug over the used diverse blood cancers. Furthermore, compound 2v showed good selectivity to blood cancer cells rather than normal MRC5 cells. Moreover, compound 2v triggered death of HL60 leukemia cells via apoptosis induction. In conclusion, the natural product-derived compound 2v might serve as a multifunctional lead compound for further development of agents for treatment of blood cancers.

Pathogenesis of rheumatoid arthritis and its treatment with anti-inflammatory natural products.

Introduction Rheumatoid arthritis (RA) is a common autoimmune disease across the globe that is chronic and systemic as well. The disease is linked with autoantibodies and is inflammatory, eventually targeting several molecules along with certain modified self-epitopes. The disease majorly affects the joints of an individual. Rheumatoid arthritis is manifested clinically by polyarthritis linked with the dysfunction of the joints. This chiefly affects the synovial joint lining and is linked with progressive dysfunction, premature death, along with socioeconomic implications. The macrophage activation, along with the activation of certain defense cells, results in a response to self-epitopes that helps in providing a better understanding of the disease pathogenesis. Material and methodology For this review article, papers have been retrieved and reviewed from database including PubMed, Scopus and Web of science. Relevant papers were taken fulfilling the criteria for writing this review article. Results This has resulted in the establishment of several new therapeutic techniques that serve as potential inhibitors of such cells. Researchers have gained an interest in understanding this disease to provide strategies for treatment in the last two decades. This also includes recognition followed by the treatment of the disease at its early stages. Various allopathic treatment approaches often have chronic and toxic teratogenic effects. However, to avoid this issue of toxicity followed by side effects, certain medicinal plants have been used in treating RA. Conclusion Medicinal plants possess active phytoconstituents that entail antioxidants as well as anti-inflammatory properties, making them a helpful alternative to allopathic drugs that are often linked with highly toxic effects. This review paper entails a thorough discussion of the epidemiology, pathophysiology, diagnosis, and management of RA. The paper will also focus on the use of herbal plants in the treatment of the disease to avoid the side effects that generally occur in allopathic treatment.

Taurocholic Acid and Glycocholic Acid Inhibit Inflammation and Activate Farnesoid X Receptor Expression in LPS-Stimulated Zebrafish and Macrophages

A hyperactive immune response can be observed in patients with bacterial or viral infection, which may lead to the overproduction of proinflammatory cytokines, or "cytokine storm", and a poor clinical outcome. Extensive research efforts have been devoted to the discovery of effective immune modulators, yet the therapeutic options are still very limited. Here, we focused on the clinically indicated anti-inflammatory natural product Calculus bovis and its related patent drug Babaodan to investigate the major active molecules in the medicinal mixture. Combined with high-resolution mass spectrometry, transgenic zebrafish-based phenotypic screening, and mouse macrophage models, taurochiolic acid (TCA) and glycoholic acid (GCA) were identified as two naturally derived anti-inflammatory agents with high efficacy and safety. Both bile acids significantly inhibited the lipopolysaccharide-induced macrophage recruitment and the secretion of proinflammatory cytokines/chemokines in in vivo and in vitro models. Further studies identified strongly increased expression of the farnesoid X receptor at both the mRNA and protein levels upon the administration of TCA or GCA, which may be essential for mediating the anti-inflammatory effects of the two bile acids. In conclusion, we identified TCA and GCA as two major anti-inflammatory compounds in Calculus bovis and Babaodan, which could be important quality markers for the future development of Calculus bovis, as well as promising lead compounds in the treatment of overactive immune responses.

Anti-Neuroinflammatory Potential of Natural Products in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related chronic progressive neurodegenerative disease, which is the main cause of dementia in the elderly. Much evidence shows that the onset and late symptoms of AD are caused by multiple factors. Among them, aging is the main factor in the pathogenesis of AD, and the most important risk factor for AD is neuroinflammation. So far, there is no cure for AD, but the relationship between neuroinflammation and AD may provide a new strategy for the treatment of AD. We herein discussed the main etiology hypothesis of AD and the role of neuroinflammation in AD, as well as anti-inflammatory natural products with the potential to prevent and alleviate AD symptoms, including alkaloids, steroids, terpenoids, flavonoids and polyphenols, which are available with great potential for the development of anti-AD drugs.

Immobilization of the Amidohydrolase MxcM and Its Application for Biocatalytic Flow Synthesis of Pseudochelin A

The chemical synthesis of heterocycles typically requires elevated temperature and acid or base addition to form the desired product. Moreover, these reactions often involve hazardous reagents, which is why biocatalytic routes for heterocycle formation have gained increasing attention. In recent years, several enzymes belonging to the amidohydrolase superfamily have been identified to generate heterocycles via cyclocondensation reactions. Of particular interest is the amidohydrolase MxcM, which catalyzes the formation of an imidazoline moiety in the biosynthesis of the anti-inflammatory natural product pseudochelin A. In this study, we present a concept for the immobilization of this enzyme using a fused hexahistidine tag for fixation onto a solid, porous carrier. Notably, the immobilization improves the enzyme’s tolerance to organic solvents. The immobilized MxcM exhibits a residual activity of 169% in the polar solvent acetonitrile compared to the free enzyme, and the storage stability in the presence of 20 vol% acetonitrile was ameliorated. In addition, an immobilized enzyme reactor (IMER) was designed that can be operated under flow conditions. The MxcM-IMER retains its biocatalytic activity and mechanic stability over the tested operation time. These results provide important insights for the integration of heterocycle-forming amidohydrolases in chemical processes.

배양된 인간 기도 상피세포에서 포볼 에스터로 유발된 뮤신 유전자 발현과 세포 내 NF-κB 신호전달 경로에 대한 하이퍼로사이드의 작용

We investigated whether hyperoside, an anti-inflammatory natural product, significantly affects phorbol 12- myristate 13-acetate (PMA)-induced airway expression of MUC5AC encoded mucin. Confluent NCI-H292 cells were pretreated with hyperoside for 30 min, then stimulated with PMA for 24 h or the indicated periods. MUC5AC mucin mRNA expression was measured by RT-PCR. MUC5AC mucin protein expression was quantitated by ELISA. To elucidate the mechanism of hyperoside action, we investigated the effect of hyperoside on PMA-induced NF-κB signaling by western blot analysis. The results were as follows: (1) Hyperoside significantly inhibited MUC5AC mucin protein production and down-regulated MUC5AC mucin mRNA expression; (2) Hyperoside inhibited PMA-induced activation (phosphorylation) of inhibitory kappa B kinase (IKK), thereby inhibiting phosphorylation and degradation of inhibitory kappa Bα (IκBα); (3) Hyperoside inhibited PMA-induced nuclear translocation of nuclear factor kappa B (NF-κB) p65, thereby down-regulating MUC5AC mucin gene expression in NCI-H292 cells. These results suggest that hyperoside can regulate mucin gene expression by airway epithelial cells through regulation of the NF-κB signaling pathway.

Discovery of new cinnamic derivatives as anti-inflammatory agents for treating acute lung injury in mice.

The blockade of the overexpression of pro-inflammatory cytokines by anti-inflammatory natural products has been proven therapeutically beneficial in the treatment of acute lung injury (ALI). Given the fact that cinnamic acid has been proven to have significant anti-inflammatory activity, we selected it as a promising lead compound to develop more effective analogs in treating ALI. Learning from the symmetric structure of curcumin, 32 new symmetric cinnamic derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Among them, 6h not only displayed a remarkable inhibitory activity in vitro (85.9% and 65.7% forIL-6 and TNF-α, respectively) without cytotoxicity but also possessed chemical structure stability. Furthermore, an in vivo study in mice revealed that the administration of 6h significantly attenuated lipopolysaccharide-induced ALI, providing new lead structures for the development of anti-inflammatory drugs for the treatment of ALI.

Total Synthesis of Cryptoconcatone D via Construction of 1,3-Diol Units Using Chiral Horner-Wittig Reagents.

The modular synthesis of 1,3-polyols using a chiral phosphine oxide building block is reported. This versatile building block works in a repetitive way for the stereocontrolled synthesis of a tetraol key intermediate, which serves for the first total synthesis of the potentially anti-inflammatory natural product cryptoconcatone D. A new route toward the chiral building block is also presented: Starting from 2-deoxy-d-ribose, the optimized sequence now makes the use of the building block more attractive to practicing chemists again.