A Review on Anti-Inflammatory Agents obtained from Natural Sources

Abstract

Inflammation is a complex, biological response accompanying most of the chronic disorders, such as arthritis, cardiovascular diseases, diabetes, and neurodegenerative conditions. Due to the adverse effects associated with long-term use of synthetic anti-inflammatory drugs, increasing attention has shifted toward natural resources as safer and multi-targeted therapeutic alternatives. Many plants, animals, and microorganisms provide bioactive compounds, including curcumin, gingerols, boswellic acids, resveratrol, omega-3 fatty acids, and microbial peptides, which modulate key inflammatory pathways such as NF-?B, COX/LOX enzymes, cytokine production, and oxidative stress. These natural agents have great pharmacological potential, as supported by traditional uses and an ever-growing body of modern evidence, but their clinical application is still hindered by problems such as poor bioavailability, variability in the composition, and lack of standardization. Recent advances in nanotechnology, molecular screening, and formulation techniques are improving their therapeutic efficacy and opening their way for future drug development. Overall, natural anti-inflammatory agents continue to be an important source of novel therapeutics with promising applications in integrative and evidence-based medicine.

Keywords

Introduction

NATURAL ANTI-INFLAMMATORY AGENTS

Plant Derived Anti-Inflammatory Agents

1. Turmeric (Curcuma longa) — Curcumin

Curcumin inhibits NF-κB, COX-2 and reduces TNF-α, IL-6. ^[15]

2. Ginger (Zingiber officinale) — Gingerols, Shogaols

Ginger Suppresses NO, PGE?, and inflammatory cytokines. ^[16]

3. Boswellia (Boswellia serrata) — Boswellic acids

Boswellia Strong 5-LOX inhibitor; useful in arthritis and chronic inflammation. ^[17]

4. Willow Bark (Salix alba) — Salicin

Willow Bark Natural precursor to salicylic acid; reduces pain and inflammation. ^[18]

5. Green Tea (Camellia sinensis) — EGCG

Green Tea Suppresses NF-κB and oxidative stress-driven inflammation. ^[19]

6. Garlic (Allium sativum) — Allicin

Garlic Shows immunomodulatory and anti-inflammatory effects. ^[16]

7. Cinnamon (Cinnamomum zeylanicum) — Cinnamaldehyde

Cinnamon Reduces IL-1β, TNF-α, and NF-κB activation. ^[16]

8. Neem (Azadirachta indica) – Limonoids, Azadirachtin

Neem Demonstrates inhibition of inflammatory enzymes and cytokines. ^[17]

9. Licorice (Glycyrrhiza glabra) — Glycyrrhizin

Licorice Reduces COX-2, ROS, and inflammatory cytokine release. ^[18]

10. Clove (Syzygium aromaticum) — Eugenol

Clove Decreases prostaglandins and leukotrienes. ^[16]

11. Black Pepper (Piper nigrum) — Piperine

Black Pepper gives Anti-inflammatory action also enhances the bioavailability of other phytochemicals. ^[19]

12. Aloe vera — Aloin, Aloesin

Aloe vera Reduces inflammation in skin and gastrointestinal tissues. ^[18]

13. Tulsi (Ocimum sanctum) — Eugenol, Rosmarinic acid

Tulsi Exhibits antioxidant and anti-inflammatory activities. ^[17]

14. Grape / Red Wine (Vitis vinifera) — Resveratrol

Grape / Red WineSuppresses COX-2, iNOS and cytokines. ^[15]

15. Andrographis (Andrographis paniculata) — Andrographolide

Andrographis is a Potent inhibitor of NF-κB and multiple inflammatory mediators. ^[19]

Marine Derived Anti-Inflammatory Agents

1. Fucoidan (Brown seaweeds)

It is a sulfated polysaccharide that inhibits NF-κB, COX-2, TNF-α and reduces leukocyte adhesion. ^[20,21]

2. Phlorotannins (Brown algae)

Marine polyphenols that suppress NO, iNOS, COX-2 and MAPK inflammatory pathways. ^[20,21]

3. Astaxanthin (Microalgae & Crustaceans)

It is Potent antioxidant carotenoid, lowers TNF-α, IL-1β, and NF-κB activation. ^[20,22]

4. EPA & DHA (Fish oil omega-3 fatty acids)

It lowers the pathways of COX/LOX, reduce TNF-α, IL-6, and promote anti-inflammatory lipid mediators. ^[21,22]

5. Carrageenan (Red algae)

Sulfated galactans exhibiting immunomodulatory activity and suppression of inflammatory mediators. ^[20]

6. Pseudopterosins (Soft coral)

The diterpene glycosides inhibit leukocyte activation and production of eicosanoids. ^[20]

7. Manoalide (Marine sponge)

Irreversible PLA? inhibitor, decreasing the formation of prostaglandins and leukotrienes. ^[20]

8. Spongian diterpenes (Marine sponges)

Inhibit NO, prostaglandins, and cytokine release; act on PLA? and COX pathways. ^[20,21]

9. Bryostatins (Bryozoans)

PKC modulators with anti-inflammatory and immunoregulatory actions. ^[20]

10. Triterpene glycosides of sea cucumbers (Holothurians)

Inhibit NF-κB, cytokines, and oxidative inflammatory responses. ^[21]

Animal Derived Anti-Inflammatory Agents

1. Chondroitin Sulfate (from Animal Cartilage)

Found in bovine/tracheal cartilage; reduces joint inflammation by inhibiting NF-κB and preventing cartilage degradation. ^[23]

2. Glucosamine (from Crustacean Shells)

Extracted from crab/shrimp shells; reduces inflammatory mediators in osteoarthritis and promotes cartilage repair. ^[23]

3. Omega-3 Fatty Acids (Fish Oil – EPA & DHA)

From cold-water fish (salmon, tuna); reduce IL-1β, TNF-α and leukotriene synthesis; widely used in arthritis and cardiovascular inflammation. ^[24]

4. Chitin & Chitosan (from Crustacean Exoskeletons)

Biopolymers showing inhibition of pro-inflammatory cytokines and NO release in macrophages. ^[25]

5. Collagen Peptides (Bovine or Marine Sources)

Anti-inflammatory through suppression of TNF-α and MMPs; promotes joint and connective-tissue healing. ^[23]

6. Honeybee Products – Propolis, Royal Jelly

Contain flavonoids and peptides with strong anti-inflammatory effects, which reduce COX-2 and oxidative stress. ^[25]

7. Snake Venom Peptides (e.g., Captopril precursor from Bothrops jararaca)

Certain venom peptides have anti-inflammatory and immunomodulatory activities by modulating the bradykinin pathway. ^[24]

8. Shark Cartilage Extracts

Used experimentally for anti-inflammatory and anti-angiogenic effects; modulates cytokines. ^[23]

PHARMACOLOGICAL EVALUATION

The pharmacological evaluation of natural anti-inflammatory agents involves a thorough phytochemical profiling using HPTLC, HPLC, LC-MS/MS, and NMR to define bioactive classes, apart from ensuring extract standardization ^[26,28]. Bioassay-guided fractionation is an approach in which chromatographic separation and iterative screening enable tracing of activity down to specific fractions and molecules ^[26,28].

In vitro evaluation includes enzyme assays like COX-1/COX-2 and 5-LOX inhibition, supplemented by cell-based assays in LPS-stimulated macrophage models assessing NO, iNOS, TNF-α, IL-6, and IL-1β, and reporter systems for NF-κB and AP-1 ^[26,27]. Mechanistic studies using western blotting, qPCR, ELISA, and sometimes proteomics/metabolomics help define actions on MAPK signalling, NF-κB translocation, Nrf2 activation, and inflammasome regulation ^[26,27,28].

In vivo validation is performed with acute models, such as carrageenan paw edema, the formalin test, and the writhing test, and chronic models, including adjuvant arthritis, colitis, and granuloma formation, which are supported by decreases in cytokines, oxidative stress, and histopathological damages ^[26,28]. Further evaluation involves pharmacokinetics, particularly for low orally bioavailable compounds, and safety studies like acute/subchronic toxicity and CYP inhibition profiling ^[26,28]. Isolated single molecules undergo SAR studies in order to enhance potency, stability, and COX-2 selectivity ^[26,27].

Single-constituent botanical extracts require strict standardization to marker compounds and validated potency assays, while multiconstituent extracts require the same to ensure consistent therapeutic performance ^[26,27]. Overall, natural anti-inflammatory agents have NF-κB and MAPK suppression, COX/LOX inhibition, Nrf2-ARE activation, JAK/STAT modulation, and inflammasome inhibition as common pathways that support their potential for development into optimized derivatives, standardized botanicals, and safe nutraceuticals through proper pharmacological and regulatory evaluation ^[26,27,28].

MECHANISM OF ACTION:

Plant-derived anti-inflammatory agents work through many molecular pathways, thus giving them a broader therapeutic effect compared to synthetic drugs with single targets. A major mechanism involves the inhibition of the NF-κB pathway, where phytochemicals such as curcumin, quercetin, resveratrol, and berberine prevent NF-κB nuclear translocation and thereby reduce the transcription of inflammatory mediators including COX-2, iNOS, and pro-inflammatory cytokines ^[29].

These agents also modulate the MAPK pathway (ERK, JNK, p38), generally suppressing kinase phosphorylation and interrupting inflammatory signal transmission. Another important mechanism is the activation of the Nrf2-Keap1 antioxidant pathway, which increases the expression of cytoprotective genes such as HO-1 and NQO1 and reduces oxidative stress-driven inflammation.

Many phytochemicals also suppress the activity of important inflammatory enzymes like COX-2, 5-LOX, PLA2, as well as mast-cell degranulation, T-cell proliferation, macrophage activation, and neutrophil migration. They also decrease nitric oxide levels by suppression of iNOS and stabilize lysosomal membranes to prevent the release of proteases responsible for tissue damage.

Safety assessment is imperative, and acute/sub-chronic toxicity studies performed according to OECD guidelines review LD??, histology of organs, and biochemical markers. While a large number of extracts possess extensive margins of safety, high-dose administration of certain constituents results in hepato-, nephro-, or cytotoxicity. Pharmacokinetic-ADME assessment aids in ascertaining the bioavailability, and nanotechnology-based formulations, including nanoparticles, liposomes, and phytosomes, are being used to enhance the therapeutic delivery. In summary, MoA and pharmacology understanding forms the scientific basis for translating natural anti-inflammatory agents into validated therapeutic products ^[29].

LIMITATIONS OF NATURAL ANTI-INFLAMMATORY AGENTS

1. Poor Bioavailability

Poor absorption, rapid metabolism, and limited systemic availability of bioactive phytochemicals (for example, curcumin, resveratrol) are common.^[30]

2. Chemical Composition Variability

Natural products can vary due to soil, climate, method of harvesting, extraction techniques, and maturity of the plant, producing variable potency.^[31]

3. Lack of Standardization

Many herbal preparations are not standardized in their dosage, and therefore, pharmacological activity is often unpredictable and cannot be reliably reproduced.^[31]

4. Slow Onset of Action

In general, natural agents exert mild-to-moderate effects compared to synthetic NSAIDs and must be taken continuously over an extended period to achieve clinical benefits.^[32]

5. Possible Contamination or Adulteration

Botanical and animal-derived products may contain pesticides, heavy metals, microbial contamination, or adulterants.^[31]

6. Limited Large-Scale Clinical Evidence

Whereas most of the studies are in vitro or animal-based, high-quality randomized clinical trials are still limited for many natural compounds.^[32]

7. Potential Drug–Herb Interactions

Compounds such as St. John’s wort, garlic, and ginkgo may interfere with anticoagulants, antidiabetics, or cardiovascular drugs.^[30]

FUTURE PROSPECTS OF NATURAL ANTI-INFLAMMATORY AGENTS

1. Development of New Drug Formulations

Advancing nanotechnology will highly increase the bioavailability of nano-curcumin, nano-resveratrol, liposomes, phytosomes, enhance stability, and assure targeted delivery. ^[33]

2. Discovery of New Bioactive Molecules

New anti-inflammatory phytochemicals, peptides, and microbial metabolites will be identified with the help of modern techniques such as metabolomics, proteomics, and high-throughput screening. ^[34]

3. Standardization and Quality Control

Future research will be directed at developing reproducible extraction, processing, and standardization protocols that can help to ensure consistent potency and safety. ^[35]

4. Integration with Conventional Medicine

The role of natural agents in integrative therapy will be increasingly employed, combining herbal formulations with synthetic drugs to reduce side effects and enhance the therapeutic outcome. ^[34]

5. Personalized / Precision Herbal Medicine

Genomics and pharmacogenomics will allow for the tailoring of natural anti-inflammatory therapies to individual metabolic profiles and disease patterns. ^[33]

6. Additional Clinical Trials and Regulatory Approval

High-quality clinical trials will be driven by increasing global interest and will help more natural products achieve not only regulatory acceptance but also global market expansion. ^[35]

CONCLUSION

Natural anti-inflammatory agents, sourced from plants, animals, and microorganisms, may offer a safer alternative to conventional synthetic drugs due to their multitarget mechanisms, antioxidant properties, and generally lower incidence of adverse effects. The ability of a wide array of bioactive compounds, including curcumin, gingerols, boswellic acids, omega-3 fatty acids, and microbial-derived metabolites, to modulate key inflammatory pathways, such as NF-κB, COX/LOX enzymes, cytokine release, and oxidative stress, is quite significant. However, despite their therapeutic potential, several challenges remain, including poor bioavailability, variability in composition, lack of standardization, and limited large-scale clinical evidence. Advances in formulation technology, natural product screening, molecular pharmacology, and integrative medicine are expected to enhance the efficacy, safety, and clinical acceptance of these agents. Overall, natural anti-inflammatory compounds remain a vital source for drug discovery and possess strong potential for future development into safe, effective, and evidence-based therapeutic options.

REFERENCES

1. Medzhitov R. Inflammation 2010: New Adventures of an Old Flame. Cell (2010) 140:771–6. 10.1016/j.cell.2010.03.006
2. Jabbour H N Sales K J Catalano R D Norman JE. Inflammatory Pathways in Female Reproductive Health and Disease. Reprod (2009) 138:903–19. 10.1530/rep-09-0247
3. Kaminska B. MAPK Signalling Pathways as Molecular Targets for Anti-inflammatory Therapy-From Molecular Mechanisms to Therapeutic Benefits. Biochim Biophys Acta (Bba) - Proteins Proteomics (2005) 1754:253–62. 10.1016/j.bbapap.2005.08.017
4. Hannoodee S, Nasuruddin DN. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 8, 2024. Acute Inflammatory Response.
5. Ferrero-Miliani LNielsen OHAndersen PSGirardin SE. Chronic Inflammation: Importance of NOD2 and NALP3 in Interleukin-1beta Generation. Clin Exp Immunol (2007) 147:227–35. 10.1111/j.1365-2249.2006.03261.x
6. Nathan CDing A. Nonresolving Inflammation. Cell (2010) 140:871–82. 10.1016/j.cell.2010.02.029
7. Zhou Y Hong Y Huang H. Triptolide Attenuates Inflammatory Response in Membranous Glomerulo-Nephritis Rat via Downregulation of NF-Κb Signaling Pathway. Kidney Blood Press Res (2016) 41:901–10. 10.1159/000452591
8. Chen L Deng H Cui H Fang J Zuo Z Deng Jet al Inflammatory Responses and Inflammation-Associated Diseases in Organs. Oncotarget (2018) 9:7204–18. 10.18632/oncotarget.23208
9. Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW, Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Effros RB, Lucia A, Kleinstreuer N, Slavich GM. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019 Dec;25(12):1822-1832.
10. Sproston NR, Ashworth JJ. Role of C-Reactive Protein at Sites of Inflammation and Infection. Front Immunol. 2018;9:754.
11. Bagad A. S., Joseph J. A., Bhaskaran N., Agarwal A. Comparative evaluation of anti-inflammatory activity of curcuminoids, turmerones, and aqueous extract of Curcuma longa . Advances in Pharmacological Sciences. 2013;2013:7. Doi: 10.1155/2013/805756.805756
12. Ghasemian M., Owlia M. B. A different look at pulsed glucocorticoid protocols; is high dose oral prednisolone really necessary just after initiation of pulse therapy Journal of Case Reports in Practice. 2015;3(1):1–3.
13. Locatelli, C.; Nardi, G.M.; Anuário, A.d.F.; Freire, C.G.; Megiolaro, F.; Schneider, K.; Perazzoli, M.R.A.;Nascimento, S.R.D.; Gon, A.C.; Mariano, L.N.B.; et al. Anti-in?ammatory activity of berry fruits in micemodel of in?ammation is based on oxidative stress modulation. Pharmacogn. Res.2016,8, S42–S49.
14. Virshette, S.J.; Patil, M.K.; Somkuwar, A.P. A review on medicinal plants used as anti in?ammatory agents.J. Pharmacogn. Phytochem. 2019,8, 1641–1646
15. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin. Int J Biochem Cell Biol. 2009;41(1):40-59.
16. Mashhadi NS, Ghiasvand R, Askari G, Hariri M, Darvishi L, Mofid MR. Anti-inflammatory effects of ginger, garlic, cinnamon, and clove: a review. Int J Prev Med. 2013;4(Suppl 1):S1-S9.
17. Siddiqui MZ. Boswellia serrata and other natural sources as anti-inflammatory agents. Indian J Pharm Sci. 2011;73(3):255-261.
18. Fiore C, Eisenhut M, Krausse R, Ragazzi E, Pellati D, Armanini D, Bielenberg J. Anti-inflammatory plant constituents including salicin and glycyrrhizin. Phytother Res. 2008;22(10):1419-1424.
19. Singh BN, Shankar S, Srivastava RK. Green tea polyphenol EGCG, piperine, and andrographolide as natural anti-inflammatory molecules. J Nutr Biochem. 2011;22(9): 845-852.
20. Blunt JW, Carroll AR, Copp BR, Davis RA, Keyzers RA, Prinsep MR. Marine natural products. Nat Prod Rep. 2012;29(2):144–222.
21. Li YX, Wijesekara I, Li Y, Kim SK. Phlorotannins and other marine-derived bioactive compounds with anti-inflammatory properties. Food Chem. 2011;120(3): 713–720.
22. Calder PC. Omega-3 fatty acids and inflammatory processes. Proc Nutr Soc. 2010;69(3):273–278.
23. Henrotin Y, Mathy M, Sanchez C, Lambert C. Chondroitin sulfate in osteoarthritis: anti-inflammatory and structural effects. J Biosci. 2010;35(4): 603–611.
24. Calder PC. Omega-3 fatty acids and inflammation: mechanisms and clinical applications. Br J Nutr. 2012;107(S2):S1–S23.
25. Sforcin JM. Biological properties and anti-inflammatory effects of bee products. J Apicult Res. 2007;46(2):57–67.
26. Wu, Z., Zhang, T., Ma, X., Guo, S., Zhou, Q., Zahoor, A., & Deng, G. (2023). Recent advances in anti-inflammatory active components and action mechanisms of natural medicines. Inflammopharmacology, 31, 2901–2937.
27. Habtemariam, S. (2023). Anti-inflammatory therapeutic mechanisms of natural products: Insight from rosemary diterpenes, carnosic acid and carnosol. Biomedicines, 11(2), 545.
28. Deng, W., Du, H., Liu, D., & Ma, Z. (2022). Editorial: The role of natural products in chronic inflammation. Frontiers in Pharmacology, 13, 901538.
29. Calixto, J. B. Phytomedicine – “Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (including natural anti-inflammatory agents)” – 2000 – Vol. 6, pp. 89–95.
30. Pan MH, Lai CS, Ho CT. Anti-inflammatory natural products and issues of bioavailability. Food Funct. 2010;1(1):15–31.
31. Bent S. Herbal medicine in the United States: review of safety, efficacy, and quality concerns. J Gen Intern Med. 2008;23(6):854–859.
32. Barnes J, Anderson LA, Phillipson JD. Herbal Medicines: Quality, Safety and Efficacy. London: Pharmaceutical Press; 2007.
33. Calixto JB. Twenty-five years of research on medicinal plants: new developments and future perspectives. Planta Med. 2000;66(2): 105–113.
34. Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and development of natural products as future therapeutics. Nat Rev Drug Discov. 2015;14(3): 200–216.
35. Ekor M. The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol. 2014;4:177.