A NOVEL TARGETED FORMULATION FOR OSTEOARTHRITIS: EXPLORING SYNERGISTIC BENEFITS OF CISSUS QUADRANGULARIS, BOSWELLIA SERRATA, PROPOLIS AND PALMITOYLETHANOLAMIDE: EXPLORING SYNERGISTIC BENEFITS OF CISSUS QUADRANGULARIS, BOSWELLIA SERRATA, PROPOLIS AND PALMITOYLETHANOLAMIDE

DHARANI B; SUBA A

doi:10.56782/pps.479

Published : 2025-10-01

No. 2025 (Early Access)

A NOVEL TARGETED FORMULATION FOR OSTEOARTHRITIS: EXPLORING SYNERGISTIC BENEFITS OF CISSUS QUADRANGULARIS, BOSWELLIA SERRATA, PROPOLIS AND PALMITOYLETHANOLAMIDE

DHARANI B

SUBA A

DOI: https://doi.org/10.56782/pps.479

EXPLORING SYNERGISTIC BENEFITS OF CISSUS QUADRANGULARIS, BOSWELLIA SERRATA, PROPOLIS AND PALMITOYLETHANOLAMIDE

Abstract

Osteoarthritis (OA) is known as a debilitating form of arthritis that is marked by progressive degradation of cartilage, synovial inflammation, chronic pain and subchondral bone remodelling. OA causes progressive stiffness and decreased mobility, significantly affecting the overall quality of life of the person affected. In spite of vast research in this area, the present pharmacological interventions are purely symptomatic. Consequently, there is an expanding interest in exploring multi-dimensional targeting of pathophysiological pathways using natural treatment options, while improving patient compliance by enhancing the safety profile. The current review focusses on a novel, innovative and conceptual formulation that is designed by the authors with the scientific-evidence packed natural compounds for management of OA. This review targets to evaluate the rationale behind formulating a conceptual novel tablet consisting of Cissus quadrangularis, Boswellia serrata, Propolis and Palmitoylethanolamide (PEA) for definitive management of OA. To our knowledge, this is the first article to explore this combination. It is designed in such a way that it targets oxidative stress, inflammation, cartilage destruction and pain in OA simultaneously in a synergistic manner. In contrast to conventional treatment options which primarily provide symptom relief, this novel conceptual formulation could offer analgesic, chondroprotective and regenerative effects with reasonable safety profile making it suitable for long-term use. This formulation has a potential to emerge as an effective and safer alternatives for treatment of OA, by helping to bridge the gap between integrative and conventional medicine.

Keywords:

Propolis, Boswellia, Palmitoylethanolamide,, Drug Formulation, Cissus, osteoarthritis

Similar Articles

Lucky Vasave, Shivraj Jadhav, Rushikesh Bachhav, Sunil Mahajan, Deepak Sonawane, A Formulation and Evaluation of Gastro-retentive In-Situ Gel of Anti-Ulcer Drug Misoprostol , Prospects in Pharmaceutical Sciences: No. 2025 (Early Access)
Magdalena Makarewicz, Anna Łysiak, Katarzyna Łysiak, Barbara Maziarz, Evaluation of the effectiveness of platelet-rich plasma therapy in the treatment of osteoarthritis compared to other treatment methods , Prospects in Pharmaceutical Sciences: Vol. 22 No. 4 (2024)
Komal Parmar, Rishi Bharatia, Novel flucytosine loaded in-situ gel for the management of ocular infections , Prospects in Pharmaceutical Sciences: Vol. 23 No. 3 (2025)
Rushikesh Mahale, Shivraj Jadhav, Sunil Mahajan, Development and optimization of gastro retentive floating tablets of dapsone for controlled release , Prospects in Pharmaceutical Sciences: No. 2025 (Early Access)
Michalina Skóra, Michał Nowacki, Maciej Dawidowski, Sulfoximine Derivatives — Their Pharmacochemical Properties, Synthesis, and Potential in Drug Discovery , Prospects in Pharmaceutical Sciences: No. 2025 (Early Access)
Prathamesh V Chaudhari, Reshma Jadhav, Ashish Jain, Priya D Jagtap, Bhavesh D Mahajan, Prapti Gawand, A comprehensive review on drug-induced diseases and teratogenicity , Prospects in Pharmaceutical Sciences: Vol. 23 No. 1 (2025)
Shivaji Patil, Sushil Bhargav, Advanced invasomal delivery system for enhanced topical application of bifonazole in fungal infections , Prospects in Pharmaceutical Sciences: Vol. 23 No. 1 (2025)
Pratiksha Nahar, Dinesh Patil, Yash Bachhav, Jayesh Musale, Pallavi Bachhav, Design and Characterization of a Gastro-Retentive Floating Atorvastatin Calcium Tablet , Prospects in Pharmaceutical Sciences: Vol. 23 No. 3 (2025)
Rama Devi Korni, Thanmaisree Bora, Akhil Majji, Jagadeesh Panda, Liquisolid technique for solubility enhancement of a poorly soluble thrombin inhibitor: optimization using design of experiments and artificial neural networks , Prospects in Pharmaceutical Sciences: Vol. 23 No. 3 (2025)
Bartłomiej Kot, Mateusz Moczulski, Agnieszka Czajkowska, Arkadiusz Kocur, Pharmacotherapy of apnea in the premature neonatological subpopulation – therapeutic opportunities, pharmacokinetic implications and recommendations for therapeutic drug monitoring , Prospects in Pharmaceutical Sciences: Vol. 22 No. 2 (2024)

1 2 3 4 5 6 7 8 9 > >>

You may also start an advanced similarity search for this article.

Details

References

Statistics

Authors

Download files

PDF

Citation rules

B, D., & A, S. (2025). A NOVEL TARGETED FORMULATION FOR OSTEOARTHRITIS: EXPLORING SYNERGISTIC BENEFITS OF CISSUS QUADRANGULARIS, BOSWELLIA SERRATA, PROPOLIS AND PALMITOYLETHANOLAMIDE: EXPLORING SYNERGISTIC BENEFITS OF CISSUS QUADRANGULARIS, BOSWELLIA SERRATA, PROPOLIS AND PALMITOYLETHANOLAMIDE. Prospects in Pharmaceutical Sciences, (2025 (Early Access). https://doi.org/10.56782/pps.479

Altmetric indicators

Cited by / Share

Licence

This work is licensed under a Creative Commons Attribution 4.0 International License.

References

1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 354 Diseases and Injuries for 195 Countries and Territories, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017. Lancet 2018, 392, 1789–1858, doi:10.1016/S0140-6736(18)32279-7. DOI: https://doi.org/10.1016/S0140-6736(18)32279-7

2. Clynes, M.A.; Jameson, K.A.; Edwards, M.H.; Cooper, C.; Dennison, E.M. Impact of Osteoarthritis on Activities of Daily Living: Does Joint Site Matter? Aging Clin. Exp. Res. 2019, 31, 1049–1056, doi:10.1007/s40520-019-01163-0. DOI: https://doi.org/10.1007/s40520-019-01163-0

3. Ranjithkumar, N.; Paul, J.; Alagesan, J.; Viswanathan, R. Comparative Effectiveness of Extracorporeal Short Wave Therapy, Low-Level Laser Therapy, and Ultrasound in the Treatment of Rotator Cuff Tendinopathy. Biomed. Pharmacol. J. 2025, 18, 849–866, doi:10.13005/bpj/3134. DOI: https://doi.org/10.13005/bpj/3134

4. Oleshchuk, O.; Pinyazhko, O.; Klantsa, M.; Posokhova, K.; Lukanyuk, M.; Mahanova, T.; Shanaida, M. Critical Assessment of Effectiveness and Safety of Tramadol and Evaluation of Its Market in Ukraine. Biomed. Pharmacol. J. 2024, 17, 2087–2109, doi:10.13005/bpj/3010. DOI: https://doi.org/10.13005/bpj/3010

5. Fu, K.; Si, S.; Jin, X.; Zhang, Y.; Duong, V.; Cai, Q.; Li, G.; Oo, W.M.; Zheng, X.; Boer, C.G.; et al. Exploring Antidiabetic Drug Targets as Potential Disease-Modifying Agents in Osteoarthritis. EBioMedicine 2024, 107, 105285, doi:10.1016/j.ebiom.2024.105285. DOI: https://doi.org/10.1016/j.ebiom.2024.105285

6. Li, S.; Cao, P.; Chen, T.; Ding, C. Latest Insights in Disease-Modifying Osteoarthritis Drugs Development. Ther. Adv. Musculoskelet. Dis. 2023, 15, 1759720X231169839, doi:10.1177/1759720X231169839. DOI: https://doi.org/10.1177/1759720X231169839

7. Kim, H.; Seo, J.; Lee, Y.; Park, K.; Perry, T.A.; Arden, N.K.; Mobasheri, A.; Choi, H. The Current State of the Osteoarthritis Drug Development Pipeline: A Comprehensive Narrative Review of the Present Challenges and Future Opportunities. Ther. Adv. Musculoskelet. Dis. 2022, 14, 1759720X221085952, doi:10.1177/1759720X221085952. DOI: https://doi.org/10.1177/1759720X221085952

8. Maouche, A.; Boumediene, K.; Baugé, C. Bioactive Compounds in Osteoarthritis: Molecular Mechanisms and Therapeutic Roles. Int. J. Mol. Sci. 2024, 25, 11656, doi:10.3390/ijms252111656. DOI: https://doi.org/10.3390/ijms252111656

9. Azam, Z.; Sapra, L.; Baghel, K.; Sinha, N.; Gupta, R.K.; Soni, V.; Saini, C.; Mishra, P.K.; Srivastava, R.K. Cissus Quadrangularis (Hadjod) Inhibits RANKL-Induced Osteoclastogenesis and Augments Bone Health in an Estrogen-Deficient Preclinical Model of Osteoporosis via Modulating the Host Osteoimmune System. Cells 2023, 12, 216, doi:10.3390/cells12020216. DOI: https://doi.org/10.3390/cells12020216

10. Nath, R.; Kar, B.K.; Dhadiwal, R.K.; Daftary, G.V.; Khemnar, B.M.; Patil, N.N. Role of Cissus Quadrangularis in Bone Loss Pathologies. Int J Orthop Sci 2024, 10, 196–201. DOI: https://doi.org/10.22271/ortho.2024.v10.i1c.3521

11. Alluri, V.K.; Kundimi, S.; Sengupta, K.; Golakoti, T.; Kilari, E.K. An Anti-Inflammatory Composition of Boswellia Serrata Resin Extracts Alleviates Pain and Protects Cartilage in Monoiodoacetate-Induced Osteoarthritis in Rats. Evid. Based. Complement. Alternat. Med. 2020, 2020, 7381625, doi:10.1155/2020/7381625. DOI: https://doi.org/10.1155/2020/7381625

12. Kurek-Górecka, A.; Rzepecka-Stojko, A.; Górecki, M.; Stojko, J.; Sosada, M.; Swierczek-Zieba, G. Structure and Antioxidant Activity of Polyphenols Derived from Propolis. Molecules 2013, 19, 78–101, doi:10.3390/molecules19010078. DOI: https://doi.org/10.3390/molecules19010078

13. Branković, M.; Gmizić, T.; Dukić, M.; Zdravković, M.; Daskalović, B.; Mrda, D.; Nikolić, N.; Brajković, M.; Gojgić, M.; Lalatović, J.; et al. Therapeutic Potential of Palmitoylethanolamide in Gastrointestinal Disorders. Antioxidants (Basel) 2024, 13, 600, doi:10.3390/antiox13050600. DOI: https://doi.org/10.3390/antiox13050600

14. Costa, B.; Comelli, F.; Bettoni, I.; Colleoni, M.; Giagnoni, G. The Endogenous Fatty Acid Amide, Palmitoylethanolamide, Has Anti-Allodynic and Anti-Hyperalgesic Effects in a Murine Model of Neuropathic Pain: Involvement of CB(1), TRPV1 and PPARgamma Receptors and Neurotrophic Factors. Pain 2008, 139, 541–550, doi:10.1016/j.pain.2008.06.003. DOI: https://doi.org/10.1016/j.pain.2008.06.003

15. Yao, Q.; Wu, X.; Tao, C.; Gong, W.; Chen, M.; Qu, M.; Zhong, Y.; He, T.; Chen, S.; Xiao, G. Osteoarthritis: Pathogenic Signaling Pathways and Therapeutic Targets. Signal Transduct. Target. Ther. 2023, 8, 56, doi:10.1038/s41392-023-01330-w. DOI: https://doi.org/10.1038/s41392-023-01330-w

16.Yunus, M.H.M.; Nordin, A.; Kamal, H. Pathophysiological Perspective of Osteoarthritis. Medicina (Kaunas) 2020, 56, 614, doi:10.3390/medicina56110614. DOI: https://doi.org/10.3390/medicina56110614

17. Berenbaum, F. Osteoarthritis as an Inflammatory Disease (Osteoarthritis Is Not Osteoarthrosis!). Osteoarthritis Cartilage 2013, 21, 16–21, doi:10.1016/j.joca.2012.11.012. DOI: https://doi.org/10.1016/j.joca.2012.11.012

18. Wojdasiewicz, P.; Poniatowski, Ł.A.; Szukiewicz, D. The Role of Inflammatory and Anti-Inflammatory Cytokines in the Pathogenesis of Osteoarthritis. Mediators Inflamm. 2014, 2014, 561459, doi:10.1155/2014/561459. DOI: https://doi.org/10.1155/2014/561459

19. Zheng, L.; Zhang, Z.; Sheng, P.; Mobasheri, A. The Role of Metabolism in Chondrocyte Dysfunction and the Progression of Osteoarthritis. Ageing Res. Rev. 2021, 66, 101249, doi:10.1016/j.arr.2020.101249. DOI: https://doi.org/10.1016/j.arr.2020.101249

20. Chen, C.; Xie, J.; Rajappa, R.; Deng, L.; Fredberg, J.; Yang, L. Interleukin-1β and Tumor Necrosis Factor-α Increase Stiffness and Impair Contractile Function of Articular Chondrocytes. Acta Biochim. Biophys. Sin. (Shanghai) 2015, 47, 121–129, doi:10.1093/abbs/gmu116. DOI: https://doi.org/10.1093/abbs/gmu116

21. Pratta, M.A.; Yao, W.; Decicco, C.; Tortorella, M.D.; Liu, R.-Q.; Copeland, R.A.; Magolda, R.; Newton, R.C.; Trzaskos, J.M.; Arner, E.C. Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage. J. Biol. Chem. 2003, 278, 45539–45545, doi:10.1074/jbc.M303737200. DOI: https://doi.org/10.1074/jbc.M303737200

22. Akkiraju, H.; Nohe, A. Role of Chondrocytes in Cartilage Formation, Progression of Osteoarthritis and Cartilage Regeneration. J. Dev. Biol. 2015, 3, 177–192, doi:10.3390/jdb3040177. DOI: https://doi.org/10.3390/jdb3040177

23. Pulik, Ł.; Łęgosz, P.; Motyl, G. Matrix Metalloproteinases in Rheumatoid Arthritis and Osteoarthritis: A State of the Art Review. Reumatologia 2023, 61, 191–201, doi:10.5114/reum/168503. DOI: https://doi.org/10.5114/reum/168503

24. Tajdari, M.; Peyrovinasab, A.; Bayanati, M.; Ismail Mahboubi Rabbani, M.; Abdolghaffari, A.H.; Zarghi, A. Dual COX-2/TNF-α Inhibitors as Promising Anti-Inflammatory and Cancer Chemopreventive Agents: A Review. Iran. J. Pharm. Res. 2024, 23, e151312, doi:10.5812/ijpr-151312. DOI: https://doi.org/10.5812/ijpr-151312

25. Wang, Y.; Che, M.; Xin, J.; Zheng, Z.; Li, J.; Zhang, S. The Role of IL-1β and TNF-α in Intervertebral Disc Degeneration. Biomed. Pharmacother. 2020, 131, 110660, doi:10.1016/j.biopha.2020.110660. DOI: https://doi.org/10.1016/j.biopha.2020.110660

26. Robinson, W.H.; Lepus, C.M.; Wang, Q.; Raghu, H.; Mao, R.; Lindstrom, T.M.; Sokolove, J. Low-Grade Inflammation as a Key Mediator of the Pathogenesis of Osteoarthritis. Nat. Rev. Rheumatol. 2016, 12, 580–592, doi:10.1038/nrrheum.2016.136. DOI: https://doi.org/10.1038/nrrheum.2016.136

27. Link, T.M.; Li, X. Establishing Compositional MRI of Cartilage as a Biomarker for Clinical Practice. Osteoarthritis Cartilage 2018, 26, 1137–1139, doi:10.1016/j.joca.2018.02.902. DOI: https://doi.org/10.1016/j.joca.2018.02.902

28. Lepetsos, P.; Papavassiliou, A.G. ROS/Oxidative Stress Signaling in Osteoarthritis. Biochim. Biophys. Acta 2016, 1862, 576–591, doi:10.1016/j.bbadis.2016.01.003. DOI: https://doi.org/10.1016/j.bbadis.2016.01.003

29. Ansari, M.Y.; Ahmad, N.; Haqqi, T.M. Oxidative Stress and Inflammation in Osteoarthritis Pathogenesis: Role of Polyphenols. Biomed. Pharmacother. 2020, 129, 110452, doi:10.1016/j.biopha.2020.110452. DOI: https://doi.org/10.1016/j.biopha.2020.110452

30. Bolduc, J.A.; Collins, J.A.; Loeser, R.F. Reactive Oxygen Species, Aging and Articular Cartilage Homeostasis. Free Radic. Biol. Med. 2019, 132, 73–82, doi:10.1016/j.freeradbiomed.2018.08.038. DOI: https://doi.org/10.1016/j.freeradbiomed.2018.08.038

31. Guo, P.; Alhaskawi, A.; Adel Abdo Moqbel, S.; Pan, Z. Recent Development of Mitochondrial Metabolism and Dysfunction in Osteoarthritis. Front. Pharmacol. 2025, 16, 1538662, doi:10.3389/fphar.2025.1538662. DOI: https://doi.org/10.3389/fphar.2025.1538662

32. Li, S.; Xiong, Y.; Zhu, H.; Ma, T.; Sun, X.; Xiao, J. Microenvironment-Responsive Nanosystems for Osteoarthritis Therapy. Engineered Regeneration 2024, 5, 92–110, doi:10.1016/j.engreg.2023.12.002. DOI: https://doi.org/10.1016/j.engreg.2023.12.002

33. Kim, J.-H.; Jeon, J.; Shin, M.; Won, Y.; Lee, M.; Kwak, J.-S.; Lee, G.; Rhee, J.; Ryu, J.-H.; Chun, C.-H.; et al. Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 Axis. Cell 2014, 156, 730–743, doi:10.1016/j.cell.2014.01.007. DOI: https://doi.org/10.1016/j.cell.2014.01.007

34. Fox, S.; Bedi, A.J.; Rodeo, A. The Basic Science of Articular Cartilage: Structure, Composition, and Function. Sports Health 2009, 1, 461–468. DOI: https://doi.org/10.1177/1941738109350438

35. Troeberg, L.; Nagase, H. Proteases Involved in Cartilage Matrix Degradation in Osteoarthritis. Biochim. Biophys. Acta 2012, 1824, 133–145, doi:10.1016/j.bbapap.2011.06.020. DOI: https://doi.org/10.1016/j.bbapap.2011.06.020

36. Ur Rehman, S.; Iqbal, S.; Shahid, U.; Jahangir, S.; Malik, L. Cartilage: Structure, Function, and the Pathogenesis of Osteoarthritis. In Advancements in Synovial Joint Science - Structure, Function, and Beyond. IntechOpen; 2024. DOI: https://doi.org/10.5772/intechopen.1003264

37. Henao-Murillo, L.; Pastrama, M.-I.; Ito, K.; van Donkelaar, C.C. The Relationship between Proteoglycan Loss, Overloading-Induced Collagen Damage, and Cyclic Loading in Articular Cartilage. Cartilage 2021, 13, 1501S-1512S, doi:10.1177/1947603519885005. DOI: https://doi.org/10.1177/1947603519885005

38. Mukherjee, A.; Das, B. The Role of Inflammatory Mediators and Matrix Metalloproteinases (MMPs) in the Progression of Osteoarthritis. Biomater. Biosyst. 2024, 13, 100090, doi:10.1016/j.bbiosy.2024.100090. DOI: https://doi.org/10.1016/j.bbiosy.2024.100090

39. Sanchez-Lopez, E.; Coras, R.; Torres, A.; Lane, N.E.; Guma, M. Synovial Inflammation in Osteoarthritis Progression. Nat. Rev. Rheumatol. 2022, 18, 258–275, doi:10.1038/s41584-022-00749-9. DOI: https://doi.org/10.1038/s41584-022-00749-9

40. Mathiessen, A.; Conaghan, P.G. Synovitis in Osteoarthritis: Current Understanding with Therapeutic Implications. Arthritis Res. Ther. 2017, 19, 18, doi:10.1186/s13075-017-1229-9. DOI: https://doi.org/10.1186/s13075-017-1229-9

41. Schaible, H.-G.; Ebersberger, A.; Natura, G. Update on Peripheral Mechanisms of Pain: Beyond Prostaglandins and Cytokines. Arthritis Res. Ther. 2011, 13, 210, doi:10.1186/ar3305. DOI: https://doi.org/10.1186/ar3305

42. Eitner, A.; Hofmann, G.O.; Schaible, H.-G. Mechanisms of Osteoarthritic Pain. Studies in Humans and Experimental Models. Front. Mol. Neurosci. 2017, 10, 349, doi:10.3389/fnmol.2017.00349. DOI: https://doi.org/10.3389/fnmol.2017.00349

43. Volcheck, M.M.; Graham, S.M.; Fleming, K.C.; Mohabbat, A.B.; Luedtke, C.A. Central Sensitization, Chronic Pain, and Other Symptoms: Better Understanding, Better Management. Cleve. Clin. J. Med. 2023, 90, 245–254, doi:10.3949/ccjm.90a.22019. DOI: https://doi.org/10.3949/ccjm.90a.22019

44. Wen, B.; Pan, Y.; Cheng, J.; Xu, L.; Xu, J. The Role of Neuroinflammation in Complex Regional Pain Syndrome: A Comprehensive Review. J. Pain Res. 2023, 16, 3061–3073, doi:10.2147/JPR.S423733. DOI: https://doi.org/10.2147/JPR.S423733

45. Yang, D.; Xu, J.; Xu, K.; Xu, P. Skeletal Interoception in Osteoarthritis. Bone Res. 2024, 12, 22, doi:10.1038/s41413-024-00328-6. DOI: https://doi.org/10.1038/s41413-024-00328-6

46. Hu, Y.; Chen, X.; Wang, S.; Jing, Y.; Su, J. Subchondral Bone Microenvironment in Osteoarthritis and Pain. Bone Res. 2021, 9, 20, doi:10.1038/s41413-021-00147-z. DOI: https://doi.org/10.1038/s41413-021-00147-z

47. Zhu, S.; Zhu, J.; Zhen, G.; Hu, Y.; An, S.; Li, Y.; Zheng, Q.; Chen, Z.; Yang, Y.; Wan, M.; et al. Subchondral Bone Osteoclasts Induce Sensory Innervation and Osteoarthritis Pain. J. Clin. Invest. 2019, 129, 1076–1093, doi:10.1172/JCI121561. DOI: https://doi.org/10.1172/JCI121561

48. Singh, P.; Gupta, A.; Qayoom, I.; Singh, S.; Kumar, A. Orthobiologics with Phytobioactive Cues: A Paradigm in Bone Regeneration. Biomed. Pharmacother. 2020, 130, 110754, doi:10.1016/j.biopha.2020.110754. DOI: https://doi.org/10.1016/j.biopha.2020.110754

49. Mishra, G.; Srivastava, S.; Nagori, B.P. Pharmacological and Therapeutic Activity of Cissus Quadrangularis: An Overview. International Journal of PharmTech Research 2010, 2, 1298–1310.

50. Bhujade, A.M.; Talmale, S.; Kumar, N.; Gupta, G.; Reddanna, P.; Das, S.K.; Patil, M.B. Evaluation of Cissus Quadrangularis Extracts as an Inhibitor of COX, 5-LOX, and Proinflammatory Mediators. J. Ethnopharmacol. 2012, 141, 989–996, doi:10.1016/j.jep.2012.03.044. DOI: https://doi.org/10.1016/j.jep.2012.03.044

51. Bloomer, R.J.; Farney, T.M.; McCarthy, C.G.; Lee, S.-R. Cissus Quadrangularis Reduces Joint Pain in Exercise-Trained Men: A Pilot Study. Phys. Sportsmed. 2013, 41, 29–35, doi:10.3810/psm.2013.09.2021. DOI: https://doi.org/10.3810/psm.2013.09.2021

52. Kanwar, J.; Samarasinghe, R.; Kumar, K.; Arya, R.; Sharma, S.; Zhou, S.-F.; Sasidharan, S.; Kanwar, R. Cissus Quadrangularis Inhibits IL-1β Induced Inflammatory Responses on Chondrocytes and Alleviates Bone Deterioration in Osteotomized Rats via P38 MAPK Signaling [Corrigendum]. Drug Des. Devel. Ther. 2017, 11, 2683–2684, doi:10.2147/dddt.s148615. DOI: https://doi.org/10.2147/DDDT.S148615

53. Banu, J.; Varela, E.; Bahadur, A.N.; Soomro, R.; Kazi, N.; Fernandes, G. Inhibition of Bone Loss by Cissus Quadrangularis in Mice: A Preliminary Report. J. Osteoporos. 2012, 2012, 101206, doi:10.1155/2012/101206. DOI: https://doi.org/10.1155/2012/101206

54. Iram, F.; Khan, S.A.; Husain, A. Phytochemistry and Potential Therapeutic Actions of Boswellic Acids: A Mini-Review. Asian Pac. J. Trop. Biomed. 2017, 7, 513–523, doi:10.1016/j.apjtb.2017.05.001. DOI: https://doi.org/10.1016/j.apjtb.2017.05.001

55. Siddiqui, M.Z. Boswellia Serrata, a Potential Antiinflammatory Agent: An Overview. Indian J. Pharm. Sci. 2011, 73, 255–261, doi:10.4103/0250-474X.93507.

56. Sengupta, K.; Alluri, K.V.; Satish, A.R.; Mishra, S.; Golakoti, T.; Sarma, K.V.; Dey, D.; Raychaudhuri, S.P. A Double Blind, Randomized, Placebo Controlled Study of the Efficacy and Safety of 5-Loxin for Treatment of Osteoarthritis of the Knee. Arthritis Res. Ther. 2008, 10, R85, doi:10.1186/ar2461. DOI: https://doi.org/10.1186/ar2461

57. Yu, G.; Xiang, W.; Zhang, T.; Zeng, L.; Yang, K.; Li, J. Effectiveness of Boswellia and Boswellia Extract for Osteoarthritis Patients: A Systematic Review and Meta-Analysis. BMC Complement. Med. Ther. 2020, 20, 225, doi:10.1186/s12906-020-02985-6. DOI: https://doi.org/10.1186/s12906-020-02985-6

58. Vishal, A.A.; Mishra, A.; Raychaudhuri, S.P. A Double Blind, Randomized, Placebo Controlled Clinical Study Evaluates the Early Efficacy of Aflapin in Subjects with Osteoarthritis of Knee. Int. J. Med. Sci. 2011, 8, 615–622, doi:10.7150/ijms.8.615. DOI: https://doi.org/10.7150/ijms.8.615

59. Sukhikh, S.; Noskova, S.; Ivanova, S.; Ulrikh, E.; Izgaryshev, A.; Babich, O. Chondroprotection and Molecular Mechanism of Action of Phytonutraceuticals on Osteoarthritis. Molecules 2021, 26, 2391, doi:10.3390/molecules26082391. DOI: https://doi.org/10.3390/molecules26082391

60. Hossain, R.; Quispe, C.; Khan, R.A.; Saikat, A.S.M.; Ray, P.; Ongalbek, D.; Yeskaliyeva, B.; Jain, D.; Smeriglio, A.; Trombetta, D.; et al. Propolis: An Update on Its Chemistry and Pharmacological Applications. Chin. Med. 2022, 17, 100, doi:10.1186/s13020-022-00651-2. DOI: https://doi.org/10.1186/s13020-022-00651-2

61. Oršolić, N.; Jazvinšćak Jembrek, M. Potential Strategies for Overcoming Drug Resistance Pathways Using Propolis and Its Polyphenolic/Flavonoid Compounds in Combination with Chemotherapy and Radiotherapy. Nutrients 2024, 16, doi:10.3390/nu16213741. DOI: https://doi.org/10.3390/nu16213741

62. Altabbal, S.; Athamnah, K.; Rahma, A.; Wali, A.F.; Eid, A.H.; Iratni, R.; Al Dhaheri, Y. Propolis: A Detailed Insight of Its Anticancer Molecular Mechanisms. Pharmaceuticals (Basel) 2023, 16, doi:10.3390/ph16030450. DOI: https://doi.org/10.3390/ph16030450

63. Arias, C.; Vásquez, B.; Salazar, L.A. Propolis as a Potential Therapeutic Agent to Counteract Age-Related Changes in Cartilage: An in Vivo Study. Int. J. Mol. Sci. 2023, 24, doi:10.3390/ijms241814272. DOI: https://doi.org/10.3390/ijms241814272

64. Petrosino, S.; Marzo, D. The Pharmacology of Palmitoylethanolamide and First Data on the Therapeutic Efficacy of Some of Its New Formulations: Palmitoylethanolamide and Its New Formulations. Br J Pharmacol 2017, 174, 1349–1365. DOI: https://doi.org/10.1111/bph.13580

65. Skaper, S.D.; Facci, L.; Fusco, M.; Della Valle, M.F.; Zusso, M.; Costa, B.; Giusti, P. Palmitoylethanolamide, a Naturally Occurring Disease-Modifying Agent in Neuropathic Pain. Inflammopharmacology 2014, 22, 79–94, doi:10.1007/s10787-013-0191-7. DOI: https://doi.org/10.1007/s10787-013-0191-7

66. Gabrielsson, L.; Mattsson, S.; Fowler, C.J. Palmitoylethanolamide for the Treatment of Pain: Pharmacokinetics, Safety and Efficacy. Br. J. Clin. Pharmacol. 2016, 82, 932–942, doi:10.1111/bcp.13020. DOI: https://doi.org/10.1111/bcp.13020

67. Sengupta, K.; Kolla, J.N.; Krishnaraju, A.V.; Yalamanchili, N.; Rao, C.V.; Golakoti, T.; Raychaudhuri, S.; Raychaudhuri, S.P. Cellular and Molecular Mechanisms of Anti-Inflammatory Effect of Aflapin: A Novel Boswellia Serrata Extract. Mol. Cell. Biochem. 2011, 354, 189–197, doi:10.1007/s11010-011-0818-1. DOI: https://doi.org/10.1007/s11010-011-0818-1

68. Sengupta, K.; Krishnaraju, A.V.; Vishal, A.A.; Mishra, A.; Trimurtulu, G.; Sarma, K.V.S.; Raychaudhuri, S.K.; Raychaudhuri, S.P. Comparative Efficacy and Tolerability of 5-Loxin and AflapinAgainst Osteoarthritis of the Knee: A Double Blind, Randomized, Placebo Controlled Clinical Study. Int. J. Med. Sci. 2010, 7, 366–377, doi:10.7150/ijms.7.366. DOI: https://doi.org/10.7150/ijms.7.366

69. Bannuru, R.R.; Osani, M.C.; Al-Eid, F.; Wang, C. Efficacy of Curcumin and Boswellia for Knee Osteoarthritis: Systematic Review and Meta-Analysis. Semin. Arthritis Rheum. 2018, 48, 416–429, doi:10.1016/j.semarthrit.2018.03.001. DOI: https://doi.org/10.1016/j.semarthrit.2018.03.001

70. Umar, S.; Umar, K.; Sarwar, A.H.M.G.; Khan, A.; Ahmad, N.; Ahmad, S.; Katiyar, C.K.; Husain, S.A.; Khan, H.A. Boswellia Serrata Extract Attenuates Inflammatory Mediators and Oxidative Stress in Collagen Induced Arthritis. Phytomedicine 2014, 21, 847–856, doi:10.1016/j.phymed.2014.02.001. DOI: https://doi.org/10.1016/j.phymed.2014.02.001

71. Riva, A.; Ronchi, M.; Petrangolini, G.; Bosisio, S.; Allegrini, P. Improved Oral Absorption of Quercetin from Quercetin Phytosome®, a New Delivery System Based on Food Grade Lecithin. Eur. J. Drug Metab. Pharmacokinet. 2019, 44, 169–177, doi:10.1007/s13318-018-0517-3. DOI: https://doi.org/10.1007/s13318-018-0517-3

72. Lang-Illievich, K.; Klivinyi, C.; Lasser, C.; Brenna, C.T.A.; Szilagyi, I.S.; Bornemann-Cimenti, H. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials. Nutrients 2023, 15, doi:10.3390/nu15061350. DOI: https://doi.org/10.3390/nu15061350

73. Steels, E.; Venkatesh, R.; Steels, E.; Vitetta, G.; Vitetta, L. A Double-Blind Randomized Placebo Controlled Study Assessing Safety, Tolerability and Efficacy of Palmitoylethanolamide for Symptoms of Knee Osteoarthritis. Inflammopharmacology 2019, 27, 475–485, doi:10.1007/s10787-019-00582-9. DOI: https://doi.org/10.1007/s10787-019-00582-9

74. Jung, J.I.; Lee, H.S.; Jeon, Y.E.; Kim, S.M.; Hong, S.H.; Moon, J.M.; Lim, C.Y.; Kim, Y.H.; Kim, E.J. Anti-Inflammatory Activity of Palmitoylethanolamide Ameliorates Osteoarthritis Induced by Monosodium Iodoacetate in Sprague-Dawley Rats. Inflammopharmacology 2021, 29, 1475–1486, doi:10.1007/s10787-021-00870-3. DOI: https://doi.org/10.1007/s10787-021-00870-3

75.Gugliandolo, E.; Fusco, R.; Biundo, F.; D’Amico, R.; Benedetto, F.; Di Paola, R.; Cuzzocrea, S. Palmitoylethanolamide and Polydatin Combination Reduces Inflammation and Oxidative Stress in Vascular Injury. Pharmacol. Res. 2017, 123, 83–92, doi:10.1016/j.phrs.2017.06.014. DOI: https://doi.org/10.1016/j.phrs.2017.06.014

76.Marini, I.; Bartolucci, M.L.; Bortolotti, F.; Gatto, M.R.; Bonetti, G.A. Palmitoylethanolamide versus a Nonsteroidal Anti-Inflammatory Drug in the Treatment of Temporomandibular Joint Inflammatory Pain. J. Orofac. Pain 2012, 26, 99–104.

77.Berretta, A.A.; Silveira, M.A.D.; Cóndor Capcha, J.M.; De Jong, D. Propolis and Its Potential against SARS-CoV-2 Infection Mechanisms and COVID-19 Disease: Running Title: Propolis against SARS-CoV-2 Infection and COVID-19. Biomed. Pharmacother. 2020, 131, 110622, doi:10.1016/j.biopha.2020.110622. DOI: https://doi.org/10.1016/j.biopha.2020.110622

78.Kurek-Górecka, A.; Górecki, M.; Rzepecka-Stojko, A.; Balwierz, R.; Stojko, J. Bee Products in Dermatology and Skin Care. Molecules 2020, 25, 556, doi:10.3390/molecules25030556. DOI: https://doi.org/10.3390/molecules25030556

79.Pahlavani, N.; Malekahmadi, M.; Firouzi, S.; Rostami, D.; Sedaghat, A.; Moghaddam, A.B.; Ferns, G.A.; Navashenaq, J.G.; Reazvani, R.; Safarian, M.; et al. Molecular and Cellular Mechanisms of the Effects of Propolis in Inflammation, Oxidative Stress and Glycemic Control in Chronic Diseases. Nutr. Metab. (Lond.) 2020, 17, 65, doi:10.1186/s12986-020-00485-5. DOI: https://doi.org/10.1186/s12986-020-00485-5

80.Xuan, H.; Yuan, W.; Chang, H.; Liu, M.; Hu, F. Anti-Inflammatory Effects of Chinese Propolis in Lipopolysaccharide-Stimulated Human Umbilical Vein Endothelial Cells by Suppressing Autophagy and MAPK/NF-κB Signaling Pathway. Inflammopharmacology 2019, 27, 561–571, doi:10.1007/s10787-018-0533-6. DOI: https://doi.org/10.1007/s10787-018-0533-6

81.Zulhendri, F.; Lesmana, R.; Tandean, S.; Christoper, A.; Chandrasekaran, K.; Irsyam, I.; Suwantika, A.A.; Abdulah, R.; Wathoni, N. Recent Update on the Anti-Inflammatory Activities of Propolis. Molecules 2022, 27, 8473, doi:10.3390/molecules27238473. DOI: https://doi.org/10.3390/molecules27238473

82.Majeed, M.; Majeed, S.; Narayanan, N.K.; Nagabhushanam, K. A Pilot, Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety and Efficacy of a Novel Boswellia Serrata Extract in the Management of Osteoarthritis of the Knee: A Novel B. Serrata Extract for Knee Osteoarthritis. Phytother Res 2019, 33, 1457–1468. DOI: https://doi.org/10.1002/ptr.6338

83.Minoretti, P.; Santiago Sáez, A.; Liaño Riera, M.; Gómez Serrano, M.; García Martín, Á. Efficacy and Safety of Two Chondroprotective Supplements in Patients with Knee Osteoarthritis: A Randomized, Single-Blind, Pilot Study. Cureus 2024, 16, e57579, doi:10.7759/cureus.57579. DOI: https://doi.org/10.7759/cureus.57579

84.Hussain, H.; Wang, D.; El-Seedi, H.R.; Rashan, L.; Ahmed, I.; Abbas, M.; Mamadalieva, N.Z.; Sultani, H.N.; Hussain, M.I.; Shah, S.T.A. Therapeutic Potential of Boswellic Acids: An Update Patent Review (2016-2023). Expert Opin. Ther. Pat. 2024, 34, 723–732, doi:10.1080/13543776.2024.2369626. DOI: https://doi.org/10.1080/13543776.2024.2369626

85.Villalvilla, A.; da Silva, J.A.; Largo, R.; Gualillo, O.; Vieira, P.C.; Herrero-Beaumont, G.; Gómez, R. 6-Shogaol Inhibits Chondrocytes’ Innate Immune Responses and Cathepsin-K Activity. Mol. Nutr. Food Res. 2014, 58, 256–266, doi:10.1002/mnfr.201200833. DOI: https://doi.org/10.1002/mnfr.201200833

86.Shin, M.-R.; Kim, H.-Y.; Choi, H.-Y.; Park, K.S.; Choi, H.J.; Roh, S.-S. Boswellia Serrata Extract, 5-Loxin®, Prevents Joint Pain and Cartilage Degeneration in a Rat Model of Osteoarthritis through Inhibition of Inflammatory Responses and Restoration of Matrix Homeostasis. Evid. Based. Complement. Alternat. Med. 2022, 2022, 3067526, doi:10.1155/2022/3067526. DOI: https://doi.org/10.1155/2022/3067526

87.Potu, B.K.; Bhat, K.M.R.; Rao, M.S.; Nampurath, G.K.; Chamallamudi, M.R.; Nayak, S.R.; Muttigi, M.S. Petroleum Ether Extract of Cissus Quadrangularis (Linn.) Enhances Bone Marrow Mesenchymal Stem Cell Proliferation and Facilitates Osteoblastogenesis. Clinics (Sao Paulo) 2009, 64, 993–998, doi:10.1590/S1807-59322009001000010. DOI: https://doi.org/10.1590/S1807-59322009001000010

88.Bafna, P.S.; Patil, P.H.; Maru, S.K.; Mutha, R.E. Cissus Quadrangularis L: A Comprehensive Multidisciplinary Review. J. Ethnopharmacol. 2021, 279, 114355, doi:10.1016/j.jep.2021.114355. DOI: https://doi.org/10.1016/j.jep.2021.114355

89.Sawangjit, R.; Puttarak, P.; Saokaew, S.; Chaiyakunapruk, N. Efficacy and Safety of Cissus Quadrangularis L. in Clinical Use: A Systematic Review and Meta-Analysis of Randomized Controlled Trials: Efficacy and Safety of Cissus in Clinical Use. Phytother Res 2017, 31, 555–567. DOI: https://doi.org/10.1002/ptr.5783

90.Sen, M.; Dash, B. A Review on Phytochemical and Pharmacological Aspects ofCissus quadrangularisL. Int. J. Green Pharm. 2012, 6, 169, doi:10.4103/0973-8258.104924. DOI: https://doi.org/10.4103/0973-8258.104924

91.Martinotti, S.; Ranzato, E. Propolis: A New Frontier for Wound Healing? Burns Trauma 2015, 3, 9, doi:10.1186/s41038-015-0010-z. DOI: https://doi.org/10.1186/s41038-015-0010-z

92.Bolfa, P.; Vidrighinescu, R.; Petruta, A.; Dezmirean, D.; Stan, L.; Vlase, L.; Damian, G.; Catoi, C.; Filip, A.; Clichici, S. Photoprotective Effects of Romanian Propolis on Skin of Mice Exposed to UVB Irradiation. Food Chem. Toxicol. 2013, 62, 329–342, doi:10.1016/j.fct.2013.08.078 DOI: https://doi.org/10.1016/j.fct.2013.08.078

93. Miryan, M.; Soleimani, D.; Dehghani, L.; Sohrabi, K.; Khorvash, F.; Bagherniya, M.; Sayedi, S.M.; Askari, G. The Effect of Propolis Supplementation on Clinical Symptoms in Patients with Coronavirus (COVID-19): A Structured Summary of a Study Protocol for a Randomised Controlled Trial. Trials 2020, 21, 996, doi:10.1186/s13063-020-04934-7. DOI: https://doi.org/10.1186/s13063-020-04934-7

94.Nazari-Bonab, H.; Jamilian, P.; Radkhah, N.; Zarezadeh, M.; Ebrahimi-Mameghani, M. The Effect of Propolis Supplementation in Improving Antioxidant Status: A Systematic Review and Meta-Analysis of Controlled Clinical Trials. Phytother. Res. 2023, 37, 3712–3723, doi:10.1002/ptr.7899. DOI: https://doi.org/10.1002/ptr.7899

95.Hori, J.I.; Zamboni, D.S.; Carrão, D.B.; Goldman, G.H.; Berretta, A.A. The Inhibition of Inflammasome by Brazilian Propolis (EPP-AF). Evid. Based. Complement. Alternat. Med. 2013, 2013, 418508, doi:10.1155/2013/418508. DOI: https://doi.org/10.1155/2013/418508

96.Dalmonte, T.; Andreani, G.; Rudelli, C.; Isani, G. Efficacy of Extracts of Oleogum Resin of Boswellia in the Treatment of Knee Osteoarthritis: A Systematic Review and Meta-Analysis. Phytother. Res. 2024, 38, 5672–5689, doi:10.1002/ptr.8336. DOI: https://doi.org/10.1002/ptr.8336

97.Abdel-Tawab, M.; Werz, O.; Schubert-Zsilavecz, M. Boswellia Serrata: An Overall Assessment of in Vitro, Preclinical, Pharmacokinetic and Clinical Data: An Overall Assessment of in Vitro, Preclinical, Pharmacokinetic and Clinical Data. Clin Pharmacokinet 2011, 50, 349–369. DOI: https://doi.org/10.2165/11586800-000000000-00000

98.Doaee, P.; Rajaei, Z.; Roghani, M.; Alaei, H.; Kamalinejad, M. Effects of Boswellia Serrata Resin Extract on Motor Dysfunction and Brain Oxidative Stress in an Experimental Model of Parkinson’s Disease. Avicenna J. Phytomed. 2019, 9, 281–290.

99.Sailer, E.R.; Subramanian, L.R.; Rall, B.; Hoernlein, R.F.; Ammon, H.P.; Safayhi, H. Acetyl-11-Keto-Beta-Boswellic Acid (AKBA): Structure Requirements for Binding and 5-Lipoxygenase Inhibitory Activity. Br. J. Pharmacol. 1996, 117, 615–618, doi:10.1111/j.1476-5381.1996.tb15235.x. DOI: https://doi.org/10.1111/j.1476-5381.1996.tb15235.x

100.Hesselink, K.; De Boer, J.M.; Witkamp, T. Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. Int J Inflam 2013. DOI: https://doi.org/10.1155/2013/151028

101.Clayton, P.; Subah, S.; Venkatesh, R.; Hill, M.; Bogoda, N. Palmitoylethanolamide: A Potential Alternative to Cannabidiol. J. Diet. Suppl. 2023, 20, 505–530, doi:10.1080/19390211.2021.2005733. DOI: https://doi.org/10.1080/19390211.2021.2005733

102.Varrassi, G.; Rekatsina, M.; Leoni, M.L.G.; Cascella, M.; Finco, G.; Sardo, S.; Corno, C.; Tiso, D.; Schweiger, V.; Fornasari, D.M.M.; et al. A Decades-Long Journey of Palmitoylethanolamide (PEA) for Chronic Neuropathic Pain Management: A Comprehensive Narrative Review. Pain Ther. 2025, 14, 81–101, doi:10.1007/s40122-024-00685-4. DOI: https://doi.org/10.1007/s40122-024-00685-4

103.Petrosino, S.; Cordaro, M.; Verde, R.; Schiano Moriello, A.; Marcolongo, G.; Schievano, C.; Siracusa, R.; Piscitelli, F.; Peritore, A.F.; Crupi, R.; et al. Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-Hyperalgesic Effect. Front. Pharmacol. 2018, 9, 249, doi:10.3389/fphar.2018.00249. DOI: https://doi.org/10.3389/fphar.2018.00249

104.Passavanti, M.B.; Alfieri, A.; Pace, M.C.; Pota, V.; Sansone, P.; Piccinno, G.; Barbarisi, M.; Aurilio, C.; Fiore, M. Clinical Applications of Palmitoylethanolamide in Pain Management: Protocol for a Scoping Review. Syst. Rev. 2019, 8, 9, doi:10.1186/s13643-018-0934-z. DOI: https://doi.org/10.1186/s13643-018-0934-z

105.Artukoglu, B.B.; Beyer, C.; Zuloff-Shani, A.; Brener, E.; Bloch, M.H. Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain Physician 2017, 20, 353–362.

106.Nestmann, E.R. Safety of Micronized Palmitoylethanolamide (microPEA): Lack of Toxicity and Genotoxic Potential. Food Sci. Nutr. 2017, 5, 292–309, doi:10.1002/fsn3.392. DOI: https://doi.org/10.1002/fsn3.392

107.Schweiger, V.; Schievano, C.; Martini, A.; Polati, L.; Del Balzo, G.; Simari, S.; Milan, B.; Finco, G.; Varrassi, G.; Polati, E. Extended Treatment with Micron-Size Oral Palmitoylethanolamide (PEA) in Chronic Pain: A Systematic Review and Meta-Analysis. Nutrients 2024, 16, 1653, doi:10.3390/nu16111653. DOI: https://doi.org/10.3390/nu16111653

108.Shamraiz, U.; Hussain, H.; Ur Rehman, N.; Al-Shidhani, S.; Saeed, A.; Khan, H.Y.; Khan, A.; Fischer, L.; Csuk, R.; Badshah, A.; et al. Synthesis of New Boswellic Acid Derivatives as Potential Antiproliferative Agents. Nat. Prod. Res. 2020, 34, 1845–1852, doi:10.1080/14786419.2018.1564295. DOI: https://doi.org/10.1080/14786419.2018.1564295

109.Sharma, S.; Gupta, S.; Khajuria, V.; Bhagat, A.; Ahmed, Z.; Shah, B.A. Analogues of Boswellic Acids as Inhibitors of Pro-Inflammatory Cytokines TNF-α and IL-6. Bioorg. Med. Chem. Lett. 2016, 26, 695–698, doi:10.1016/j.bmcl.2015.11.035. DOI: https://doi.org/10.1016/j.bmcl.2015.11.035

110.Mbiantcha, M.; Khalid, R.; Atsamo, D.A.; Njoku, I.S.; Mehreen, A.; Ateufack, G.; Hamza, D.; Nana, W.Y.; Naeem, R.U.; Izhar, A. Anti-Hypernociceptive Effects of Methanol Extract of Boswellia Dalzielii on STZ-Induced Diabetic Neuropathic Pain. Advances in Traditional Medicine 2020, 20, 405–417, doi:10.1007/s13596-019-00411-y. DOI: https://doi.org/10.1007/s13596-019-00411-y

111.Majeed, A.; Majeed, S.; Satish, G.; Manjunatha, R.; Rabbani, S.N.; Patil, N.V.P.; Mundkur, L. A Standardized Boswellia Serrata Extract Shows Improvements in Knee Osteoarthritis within Five Days-a Double-Blind, Randomized, Three-Arm, Parallel-Group, Multi-Center, Placebo-Controlled Trial. Front. Pharmacol. 2024, 15, 1428440, doi:10.3389/fphar.2024.1428440. DOI: https://doi.org/10.3389/fphar.2024.1428440

112.Roy, N.K.; Parama, D.; Banik, K.; Bordoloi, D.; Devi, A.K.; Thakur, K.K.; Padmavathi, G.; Shakibaei, M.; Fan, L.; Sethi, G.; et al. An Update on Pharmacological Potential of Boswellic Acids against Chronic Diseases. Int. J. Mol. Sci. 2019, 20, 4101, doi:10.3390/ijms20174101. DOI: https://doi.org/10.3390/ijms20174101

113.Machado, J.L.; Assunção, A.K.M.; da Silva, M.C.P.; Dos Reis, A.S.; Costa, G.C.; Arruda, D. de S.; Rocha, B.A.; Vaz, M.M. de O.L.L.; Paes, A.M. de A.; Guerra, R.N.M.; et al. Brazilian Green Propolis: Anti-Inflammatory Property by an Immunomodulatory Activity. Evid. Based. Complement. Alternat. Med. 2012, 2012, 157652, doi:10.1155/2012/157652. DOI: https://doi.org/10.1155/2012/157652

114.Kasote, D.; Bankova, V.; Viljoen, A.M. Propolis: Chemical Diversity and Challenges in Quality Control. Phytochem. Rev. 2022, 21, 1887–1911, doi:10.1007/s11101-022-09816-1. DOI: https://doi.org/10.1007/s11101-022-09816-1

115.Katiyar, D. Propolis: A Natural Biomaterial. Mater. Today 2023, doi:10.1016/j.matpr.2023.05.522. DOI: https://doi.org/10.1016/j.matpr.2023.05.522

116.Xu, W.; Lu, H.; Yuan, Y.; Deng, Z.; Zheng, L.; Li, H. The Antioxidant and Anti-Inflammatory Effects of Flavonoids from Propolis via Nrf2 and NF-κB Pathways. Foods 2022, 11, 2439, doi:10.3390/foods11162439. DOI: https://doi.org/10.3390/foods11162439

117.Muthusami, S.; Ramachandran, I.; Krishnamoorthy, S.; Govindan, R.; Narasimhan, S. Cissus Quadrangularis Augments IGF System Components in Human Osteoblast like SaOS-2 Cells. Growth Horm. IGF Res. 2011, 21, 343–348, doi:10.1016/j.ghir.2011.09.002. DOI: https://doi.org/10.1016/j.ghir.2011.09.002

118.Dhanasekaran, S. Phytochemical Characteristics of Aerial Part of Cissus Quadrangularis (L) and Its in-Vitro Inhibitory Activity against Leukemic Cells and Antioxidant Properties. Saudi J. Biol. Sci. 2020, 27, 1302–1309, doi:10.1016/j.sjbs.2020.01.005. DOI: https://doi.org/10.1016/j.sjbs.2020.01.005

119.Guerra, J.M.; Hanes, M.A.; Rasa, C.; Loganathan, N.; Innis-Whitehouse, W.; Gutierrez, E.; Nair, S.; Banu, J. Modulation of Bone Turnover by Cissus Quadrangularis after Ovariectomy in Rats. J. Bone Miner. Metab. 2019, 37, 780–795, doi:10.1007/s00774-018-0983-3. DOI: https://doi.org/10.1007/s00774-018-0983-3

120.Tasadduq, R.; Gordon, J.; Al-Ghanim, K.A.; Lian, J.B.; Van Wijnen, A.J.; Stein, J.L.; Stein, G.S.; Shakoori, A.R. Ethanol Extract of Cissus Quadrangularis Enhances Osteoblast Differentiation and Mineralization of Murine Pre-Osteoblastic MC3T3-E1 Cells: Effect of Herbal Extract on Osteoblast Differentiation. J. Cell. Physiol. 2017, 232, 540–547, doi:10.1002/jcp.25449. DOI: https://doi.org/10.1002/jcp.25449

121.Liao, L.; Zhu, W.; Tao, C.; Li, D.; Mao, M. Cissus Quadrangularis L Extract-Loaded Tricalcium Phosphate Reinforced Natural Polymer Composite for Guided Bone Regeneration. J. Mater. Sci. Mater. Med. 2023, 34, 33, doi:10.1007/s10856-023-06739-x. DOI: https://doi.org/10.1007/s10856-023-06739-x

122.Sadeghnia, H.R.; Arjmand, F.; Ghorbani, A. Neuroprotective Effect of Boswellia Serrata and Its Active Constituent Acetyl 11-Keto-β-Boswellic Acid against Oxygen-Glucose-Serum Deprivation-Induced Cell Injury. Acta Pol. Pharm. 2017, 74, 911–920.

123.Nakhaei, K.; Bagheri-Hosseini, S.; Sabbaghzade, N.; Behmadi, J.; Boozari, M. Boswellic Acid Nanoparticles: Promising Strategies for Increasing Therapeutic Effects. Rev. Bras. Farmacogn. 2023, 33, 713–723, doi:10.1007/s43450-023-00405-7. DOI: https://doi.org/10.1007/s43450-023-00405-7

124.Li, W.; Ren, L.; Zheng, X.; Liu, J.; Wang, J.; Ji, T.; Du, G. 3-O-Acetyl-11-Keto- β -Boswellic Acid Ameliorated Aberrant Metabolic Landscape and Inhibited Autophagy in Glioblastoma. Acta Pharm. Sin. B. 2020, 10, 301–312, doi:10.1016/j.apsb.2019.12.012. DOI: https://doi.org/10.1016/j.apsb.2019.12.012

125. Bartolucci, M.L.; Marini, I.; Bortolotti, F.; Impellizzeri, D.; Di Paola, R.; Bruschetta, G.; Crupi, R.; Portelli, M.; Militi, A.; Oteri, G.; et al. Micronized Palmitoylethanolamide Reduces Joint Pain and Glial Cell Activation. Inflamm. Res. 2018, 67, 891–901, doi:10.1007/s00011-018-1179-y. DOI: https://doi.org/10.1007/s00011-018-1179-y

126. Loi, S.; Pontis, E.; Cofelice, A.; Pirarba, V.; Fais, S.; Daniilidis, M.F. Effect of Ultramicronized-Palmitoylethanolamide and Co-Micronized Palmitoylethanolamide/Polydatin on Chronic Pelvic Pain and Quality of Life in Endometriosis Patients: An Open-Label Pilot Study. Int J Womens Health 2019, 11, 443–449. DOI: https://doi.org/10.2147/IJWH.S204275

127.Lama, A.; Pirozzi, C.; Severi, I.; Morgese, M.G.; Senzacqua, M.; Annunziata, C.; Comella, F.; Del Piano, F.; Schiavone, S.; Petrosino, S.; et al. Palmitoylethanolamide Dampens Neuroinflammation and Anxiety-like Behavior in Obese Mice. Brain Behav. Immun. 2022, 102, 110–123, doi:10.1016/j.bbi.2022.02.008. DOI: https://doi.org/10.1016/j.bbi.2022.02.008

128.Bueno-Silva, B.; Kawamoto, D.; Ando-Suguimoto, E.S.; Casarin, R.C.V.; Alencar, S.M.; Rosalen, P.L.; Mayer, M.P.A. Brazilian Red Propolis Effects on Peritoneal Macrophage Activity: Nitric Oxide, Cell Viability, pro-Inflammatory Cytokines and Gene Expression. J. Ethnopharmacol. 2017, 207, 100–107, doi:10.1016/j.jep.2017.06.015. DOI: https://doi.org/10.1016/j.jep.2017.06.015

129. Šuran, J.; Cepanec, I.; Mašek, T.; Radić, B.; Radić, S.; Tlak Gajger, I.; Vlainić, J. Propolis Extract and Its Bioactive Compounds-from Traditional to Modern Extraction Technologies. Molecules 2021, 26, 2930, doi:10.3390/molecules26102930. DOI: https://doi.org/10.3390/molecules26102930

130.Javed, S.; Mangla, B.; Ahsan, W. From Propolis to Nanopropolis: An Exemplary Journey and a Paradigm Shift of a Resinous Substance Produced by Bees. Phytother. Res. 2022, 36, 2016–2041, doi:10.1002/ptr.7435. DOI: https://doi.org/10.1002/ptr.7435

131.Lv, L.; Cui, H.; Ma, Z.; Liu, X.; Yang, L. Recent Progresses in the Pharmacological Activities of Caffeic Acid Phenethyl Ester. Naunyn. Schmiedebergs. Arch. Pharmacol. 2021, 394, 1327–1339, doi:10.1007/s00210-021-02054-w. DOI: https://doi.org/10.1007/s00210-021-02054-w

132.Kumar, R.; Singh, S.; Saksena, A.K.; Pal, R.; Jaiswal, R.; Kumar, R. Effect of Boswellia Serrata Extract on Acute Inflammatory Parameters and Tumor Necrosis Factor-α in Complete Freund’s Adjuvant-Induced Animal Model of Rheumatoid Arthritis. Int. J. Appl. Basic Med. Res. 2019, 9, 100–106, doi:10.4103/ijabmr.IJABMR_248_18. DOI: https://doi.org/10.4103/ijabmr.IJABMR_248_18

133.Choi, Y.-J.; Jung, J.I.; Bae, J.; Lee, J.K.; Kim, E.J. Evaluating the Anti-Osteoarthritis Potential of Standardized Boswellia Serrata Gum Resin Extract in Alleviating Knee Joint Pathology and Inflammation in Osteoarthritis-Induced Models. Int. J. Mol. Sci. 2024, 25, 3218, doi:10.3390/ijms25063218. DOI: https://doi.org/10.3390/ijms25063218

134.Majeed, M.; Nagabhushanam, K.; Lawrence, L.; Nallathambi, R.; Thiyagarajan, V.; Mundkur, L. Boswellia Serrata Extract Containing 30% 3-Acetyl-11-Keto-Boswellic Acid Attenuates Inflammatory Mediators and Preserves Extracellular Matrix in Collagen-Induced Arthritis. Front. Physiol. 2021, 12, 735247, doi:10.3389/fphys.2021.735247. DOI: https://doi.org/10.3389/fphys.2021.735247

135.Ammon, H.P.T. Boswellic Acids and Their Role in Chronic Inflammatory Diseases. Adv. Exp. Med. Biol. 2016, 928, 291–327, doi:10.1007/978-3-319-41334-1_13. DOI: https://doi.org/10.1007/978-3-319-41334-1_13

136.De Carvalho Fm De, A.; Schneider, J.K.; De Jesus, C.; De Andrade, L.N.; Amaral, R.G.; David, J.M. Brazilian Red Propolis: Extracts Production, Physicochemical Characterization, and Cytotoxicity Profile for Antitumor Activity. Biomolecules 2020, 10. DOI: https://doi.org/10.3390/biom10050726

137.Fonseca, L.; Ribeiro, M.; Schultz, J.; Borges, N.A.; Cardozo, L.; Leal, V.O.; Ribeiro-Alves, M.; Paiva, B.R.; Leite, P.E.C.; Sanz, C.L.; et al. Effects of Propolis Supplementation on Gut Microbiota and Uremic Toxin Profiles of Patients Undergoing Hemodialysis. Toxins (Basel) 2024, 16, 416, doi:10.3390/toxins16100416. DOI: https://doi.org/10.3390/toxins16100416

138.Okamoto, Y.; Hara, T.; Ebato, T.; Fukui, T.; Masuzawa, T. Brazilian Propolis Ameliorates Trinitrobenzene Sulfonic Acid-Induced Colitis in Mice by Inhibiting Th1 Differentiation. Int. Immunopharmacol. 2013, 16, 178–183, doi:10.1016/j.intimp.2013.04.004. DOI: https://doi.org/10.1016/j.intimp.2013.04.004

139.Kurek-Górecka, A.; Keskin, Ş.; Bobis, O.; Felitti, R.; Górecki, M.; Otręba, M.; Stojko, J.; Olczyk, P.; Kolayli, S.; Rzepecka-Stojko, A. Comparison of the Antioxidant Activity of Propolis Samples from Different Geographical Regions. Plants 2022, 11, 1203, doi:10.3390/plants11091203. DOI: https://doi.org/10.3390/plants11091203

140.Cristiano, C.; Pirozzi, C.; Coretti, L.; Cavaliere, G.; Lama, A.; Russo, R.; Lembo, F.; Mollica, M.P.; Meli, R.; Calignano, A.; et al. Palmitoylethanolamide Counteracts Autistic-like Behaviours in BTBR T+tf/J Mice: Contribution of Central and Peripheral Mechanisms. Brain Behav. Immun. 2018, 74, 166–175, doi:10.1016/j.bbi.2018.09.003. DOI: https://doi.org/10.1016/j.bbi.2018.09.003

141.Roviezzo, F.; Rossi, A.; Caiazzo, E.; Orlando, P.; Riemma, M.A.; Iacono, V.M.; Guarino, A.; Ialenti, A.; Cicala, C.; Peritore, A.; et al. Palmitoylethanolamide Supplementation during Sensitization Prevents Airway Allergic Symptoms in the Mouse. Front. Pharmacol. 2017, 8, 857, doi:10.3389/fphar.2017.00857. DOI: https://doi.org/10.3389/fphar.2017.00857

142.Impellizzeri, D.; Di Paola, R.; Cordaro, M.; Gugliandolo, E.; Casili, G.; Morittu, V.M.; Britti, D.; Esposito, E.; Cuzzocrea, S. Adelmidrol, a Palmitoylethanolamide Analogue, as a New Pharmacological Treatment for the Management of Acute and Chronic Inflammation. Biochem. Pharmacol. 2016, 119, 27–41, doi:10.1016/j.bcp.2016.09.001. DOI: https://doi.org/10.1016/j.bcp.2016.09.001

143.Pirozzi, C.; Coretti, L.; Opallo, N.; Bove, M.; Annunziata, C.; Comella, F.; Turco, L.; Lama, A.; Trabace, L.; Meli, R.; et al. Palmitoylethanolamide Counteracts High-Fat Diet-Induced Gut Dysfunction by Reprogramming Microbiota Composition and Affecting Tryptophan Metabolism. Front. Nutr. 2023, 10, 1143004, doi:10.3389/fnut.2023.1143004. DOI: https://doi.org/10.3389/fnut.2023.1143004

144.Wang, Z.; Singh, A.; Jones, G.; Aitken, D.; Laslett, L.L.; Hussain, S. Boswellia for Osteoarthritis. Cochrane Libr; 2022; DOI: https://doi.org/10.1002/14651858.CD014969

145.Ragab, E.A.; Abd El-Wahab, M.F.; Doghish, A.S.; Salama, R.M.; Eissa, N.; Darwish, S.F. The Journey of Boswellic Acids from Synthesis to Pharmacological Activities. Naunyn. Schmiedebergs. Arch. Pharmacol. 2024, 397, 1477–1504, doi:10.1007/s00210-023-02725-w. DOI: https://doi.org/10.1007/s00210-023-02725-w

146.Shen, J.; Abu-Amer, Y.; O’Keefe, R.J.; McAlinden, A. Inflammation and Epigenetic Regulation in Osteoarthritis. Connect. Tissue Res. 2017, 58, 49–63, doi:10.1080/03008207.2016.1208655. DOI: https://doi.org/10.1080/03008207.2016.1208655

147.Gong, Y.; Jiang, X.; Yang, S.; Huang, Y.; Hong, J.; Ma, Y.; Fang, X.; Fang, Y.; Wu, J. The Biological Activity of 3-O-Acetyl-11-Keto-β-Boswellic Acid in Nervous System Diseases. Neuromolecular Med. 2022, 24, 374–384, doi:10.1007/s12017-022-08707-0. DOI: https://doi.org/10.1007/s12017-022-08707-0

148.Rajeshkumar, S.; Menon, S.; Kumar, V.; Ponnanikajamideen, M.; Ali, D.; Arunachalam, K. Anti-Inflammatory and Antimicrobial Potential of Cissus Quadrangularis-Assisted Copper Oxide Nanoparticles. J. Nanomater. 2021, 2021, 1–11, doi:10.1155/2021/5742981. DOI: https://doi.org/10.1155/2021/5742981

149.Coutinho de Almeida, R.; Ramos, Y.F.M.; Mahfouz, A.; den Hollander, W.; Lakenberg, N.; Houtman, E.; van Hoolwerff, M.; Suchiman, H.E.D.; Rodríguez Ruiz, A.; Slagboom, P.E.; et al. RNA Sequencing Data Integration Reveals an miRNA Interactome of Osteoarthritis Cartilage. Ann. Rheum. Dis. 2019, 78, 270–277, doi:10.1136/annrheumdis-2018-213882. DOI: https://doi.org/10.1136/annrheumdis-2018-213882

150.Muthusami, S.; Senthilkumar, K.; Vignesh, C.; Ilangovan, R.; Stanley, J.; Selvamurugan, N.; Srinivasan, N. Effects of Cissus Quadrangularis on the Proliferation, Differentiation and Matrix Mineralization of Human Osteoblast like SaOS-2 Cells. J. Cell. Biochem. 2011, 112, 1035–1045, doi:10.1002/jcb.23016. DOI: https://doi.org/10.1002/jcb.23016

151.Awari, V.S.; Barvkar, V.T.; Ade, A.B.; Borde, M.Y. Endophytic Fungi from Cissus Quadrangularis Plant a Promising Source of Bioactive Compounds. Braz. J. Microbiol. 2024, 55, 3733–3750, doi:10.1007/s42770-024-01500-0. DOI: https://doi.org/10.1007/s42770-024-01500-0

152.Abdel-Tawab, M.; Werz, O.; Schubert-Zsilavecz, M. Boswellia Serrata: An Overall Assessment of Its Clinical Efficacy and Safety. Phytomedicine 2011, 18, 1207–1218.

153.Rajaab, K.M.; Surendran, S.; Vijayakumar, K. Efficacy of Boswellia Serrata Extract in Osteoarthritis Management: A Systematic Review. Complement Ther Med 2020, 50.

154.Daily, J.W.; Yang, M.; Park, S. Natural Products for the Management of Osteoarthritis: A Comprehensive Review. Evid Based Complement Alternat Med 2016.

155.Takeda, S.; Yamada, N.; Inaba, T. Propolis-Derived Compounds Exhibit Anti-Inflammatory and Antioxidant Properties in Osteoarthritis Model. Evid Based Complement Alternat Med 2014.

156.Sforcin, J.M. Propolis and the Immune System: A Review. J. Ethnopharmacol. 2007, 113, 1–14, doi:10.1016/j.jep.2007.05.012. DOI: https://doi.org/10.1016/j.jep.2007.05.012

157.Mcalindon, T.E.; Lavalley, M.P.; Harvey, W.F. Effectiveness of Intra-Articular Corticosteroids for Knee Osteoarthritis: A Systematic Review. Ann Intern Med 2017, 166, 255–266.

158.Gopukumar, K.; Raveendran, R.; Rao, M.N. Bone Healing Potential of Cissus Quadrangularis: A Systematic Review. J Ayurveda Integr Med 2019, 10, 165–172.

159.Pande, S.; Pathak, P. Molecular Mechanisms of Cissus Quadrangularis in Bone Regeneration. Phytother Res 2016, 30, 1517–1526.

160.Coxib and traditional NSAID Trialists’ (CNT) Collaboration; Bhala, N.; Emberson, J.; Merhi, A.; Abramson, S.; Arber, N.; Baron, J.A.; Bombardier, C.; Cannon, C.; Farkouh, M.E.; et al. Vascular and Upper Gastrointestinal Effects of Non-Steroidal Anti-Inflammatory Drugs: Meta-Analyses of Individual Participant Data from Randomised Trials. Lancet 2013, 382, 769–779, doi:10.1016/S0140-6736(13)60900-9. DOI: https://doi.org/10.1016/S0140-6736(13)60900-9

161.Hesselink, J.M.K.; Hekker, T.A. Therapeutic Utility of Palmitoylethanolamide in the Treatment of Neuropathic Pain Associated with Various Pathological Conditions: A Case Series. J. Pain Res. 2012, 5, 437–442, doi:10.2147/JPR.S32143. DOI: https://doi.org/10.2147/JPR.S32143

162.Paladini, A.; Fusco, M.; Cenacchi, T. Palmitoylethanolamide: A Potential Therapeutic Agent in Pain Management. Clin Drug Investig 2017, 37, 729–737.

163.Oo, W.M.; Hunter, D.J. Disease-Modifying Treatments in Osteoarthritis: Current Status and Future Therapeutic Targets. Drugs 2018, 78, 469–493.

164.Hunter, D.J.; Mcdougall, J.J.; Keefe, F.J. The Potential for Novel Disease-Modifying Pharmacological Therapies in Osteoarthritis. Osteoarthr Cartil 2017, 25, 235–242.

165.Kalayil, N.; Budar, A.A.; Dave, R.K. Nanofibers for Drug Delivery: Design and Fabrication Strategies. BIO Integr. 2024, 5, doi:10.15212/bioi-2024-0023. DOI: https://doi.org/10.15212/bioi-2024-0023