Modulators of diabetic neuropathy and inflammation from Saponaria officinalis: Isolation of active phytochemicals and potential mechanisms of action

10.1016/j.jtcme.2023.01.001

Karim Raafat ；Mazen al Haj

Saponaria officinalis ； Quillaic acid ； Diabetic neuropathy ； Inflammation

Journal of Traditional and Complementary Medicine

13卷3期（2023 / 05 / 01）

226 - 235

英文

Background and aim: Natural metabolites are rich in neuroactive and anti-inflammatory phytochemicals. Soapwort or Saponaria officinalis (Sap) has been utilized for its immunomodulatory and ant-rheumatic properties. Thus, the aim is to exploit Sap phytochemically and to investigate Sap isolated active phytochemicals effect to modulate diabetic neuropathy and inflammation, and their possible mechanisms of action. Experimental procedure: Bio-guided chromatographic fractionation and phytochemical isolation of the most abundant Sap phytochemicals utilizing RP-HPLC, ^(13)C, and ^1H NMR, in-vivo models of diabetes, diabetic neuropathy, and inflammation were used. Glucometers, HbA1c micro-columns, in-vivo hind-paw edema, tail-flick, hot plate, and Von-Frey filaments methods were utilized to investigate the acute, subchronic, and long term diabetes, inflammation, hyperalgesia, and mechanical allodynia. In-vivo antioxidant, inhibitory alpha-amylase, and alpha-glucosidase, and serum insulin levels, IL-6, IL-10, and TNF-alpha cytokines levels were utilized to investigate Sap mechanisms of action. Results and conclusion: The phytochemical post-hydrolysis RP-HPLC investigation results show six major peaks; Quillaic acid (12.5%), Quillaic acid 22 β-OH (11.25%), Gypsogenin (21.25%), Phytolaccinic acid (18.75%), Phytolaccinic acid (17.50%), and Echynocystic acid (15.10%). The bio-guided chromatographic fractionation investigation utilizing reversed phase HPLC, ^(13)C and ^1H NMR has shown that Quillaic acid (QA) is the most abundant and biologically active compound. Sap 20 mg/kg has shown the highest potency in normalization of blood glucose level (BGL) acutely (6-h), subchronically (eight-days), and longer-term (eight-weeks) correlated to Sap 10 and 7 mg/kg, and QA 0.7, 1.0, 2.0 mg/kg. The highest amelioration of diabetic neuropathy (thermal hyperalgesia and mechanical allodynia) was Sap 20 mg/kg. The anti-inflammatory potentials of Sap 20 mg/kg have shown dominance in decreasing carrageenan-induced in-vivo hind-paw edema. The anti-nociceptive mechanism of action might be due to Sap insulin secretagogue and the in-vivo antioxidant potentials. The reduction of IL-6 cytokines and TNF-alpha, along with the elevation of the IL-10 cytokine level might be the underlying Sap anti-inflammatory mechanism. Phytochemically, QA has shown to be the most abundant and biologically active compound in Sap extract. Sap has shown significant (p < 0.05) anti-diabetic, anti-diabetic neuropathy, and anti-inflammatory effects. Our results provide new insights into the potential effects of Saponaria and Quillaic acid as future alternative therapies against diabetic neuropathy and inflammation.

1. Arulselvan, P,Fard, MT,Tan, WS(2016).Role of antioxidants and natural products in inflammation.Oxid Med Cell Longev,2016,5276130-5276130.
2. Avula, B,Wang, YH,Rumalla, CS,Ali, Z,Smillie, TJ,Khan, IA(2011).Analytical methods for determination of magnoflorine and saponins from roots of Caulophyllum thalictroides (L.) Michx. using UPLC, HPLC and HPTLC.J Pharm Biomed Anal,56(5),895-903.
3. Bakirel, T,Bakirel, U,Keles, OU,Ulgen, SG,Yardibi, H(2008).In vivo assessment of antidiabetic and antioxidant activities of rosemary (Rosmarinus officinalis) in alloxan-diabetic rabbits.J Ethnopharmacol,116(1),64-73.
4. Bolshakov, AP,Stepanichev, MY,Dobryakova, YV,Spivak, YS,Markevich, VA(2020).Saporin from Saponaria officinalis as a tool for experimental research, modeling, and therapy in neuroscience.Toxins,11(9)
5. Boukhary, R,Raafat, K,Ghoneim, AI,Aboul-Ela, M,El-Lakany, A(2016).Anti-inflammatory and antioxidant activities of salvia fruticosa: an HPLC determination of phenolic contents.Evid base Compl Alternative Med,2016,6.
6. Cameron, NE,Cotter, MA(2008).Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway.Curr Drug Targets,9(1),60-67.
7. Choi, JH,Cha, DS,Jeon, H(2012).Anti-inflammatory and anti-nociceptive properties of Prunus padus.J Ethnopharmacol,144(2),379-386.
8. Diwan, FH,Abdel-Hassan, IA,Mohammed, ST(2000).Effect of saponin on mortality and histopathological changes in mice.East Mediterr Health J.,6(2-3),345-351.
9. Elgamal, MHA,Soliman, HSM,Karawya, MS,Duddeck, H(1994).Isolation of two triterpene saponins from gypsophila capillaris (forssk.).Nat Prod Lett,4(3),217-222.
10. Jesch, ED,Carr, TP(2017).Food ingredients that inhibit cholesterol absorption.Prev Nutr Food Sci.,22(2),67-80.
11. Khansari, N,Shakiba, Y,Mahmoudi, M(2009).Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer.Recent Pat Inflamm Allergy Drug Discov,3(1),73-80.
12. Liu, Y,Li, X,Jiang, S,Ge, Q(2018).Inhibitory effect of Gypsophila oldhamiana gypsogenin on NCI-N87 gastric cancer cell line.Eur J Inflamm,16,2058739218818958.
13. Long, SH,Yu, ZQ,Shuai, L(2012).The hypoglycemic effect of the kelp on diabetes mellitus model induced by alloxan in rats.Int J Mol Sci.,13(3),3354-3365.
14. Marrelli, M,Conforti, F,Araniti, F,Statti, GA(2016).Effects of saponins on lipid metabolism: a Review of potential health benefits in the treatment of obesity.Molecules,21(10)
15. Petrovic, GM,Ilic, MD,Stankov-Jovanovic, VP,Stojanovic, GS,Jovanovic, SC(2018).Phytochemical analysis of Saponaria officinalis L. shoots and flowers essential oils.Nat Prod Res,32(3),331-334.
16. Raafat, K(2018).Phytochemical analysis of Juglans regia oil and kernel exploring their antinociceptive and anti-inflammatory potentials utilizing combined bioguided GC-FID, GC-MS and HPLC analyses.Revista Brasileira de Farmacognosia,28(3),358-368.
17. Raafat, K(2019).Combating diabetes and its emerging complications utilizing natural phytochemicals.Phcog J.,11(3)
18. Raafat, K.(2016).The Top 100 Phytoremedies and Caregiving.Beirut:Dar Al-Nahda Al-Arabia.
19. Raafat, K,El-Darra, N,Saleh, F,Rajha, H,Louka, N.(2019).Optimization of infraredassisted extraction of bioactive lactones from Saussurea lappa L. and their effects against gestational diabetes.Phcog Mag,15(61),208-218.
20. Raafat, K,El-Darra, N,Saleh, FA,Rajha, HN,Maroun, RG,Louka, N(2017).Infrared-Assisted extraction and HPLC-analysis of prunus armeniaca L. Pomace and detoxified-kernel and their antidiabetic effects.Phytochem Anal,1-12.
21. Raafat, K,El-Lakany, A(2018).Combination of rheum ribes and metformin against diabetes, thermal hyperalgesia, and tactile allodynia in a mice model.Alternative Ther Health Med,24(5),33-43.
22. Raafat, K,El-Lakany, A(2015).Acute and subchronic in-vivo effects of Ferula hermonis L. and Sambucus nigra L. and their potential active isolates in a diabetic mouse model of neuropathic pain.BMC Compl Alternative Med,15,257.
23. Raafat, K,El-Lakany, A(2018).Phytochemical and antinociceptive investigations of anemone coronaria active Part Ameliorating diabetic neuropathy pain.PMIO.,5(01),e5-e13.
24. Raafat, K,Habib, J(2018).Phytochemical compositions and antidiabetic potentials of Salvia sclarea L. Essential oils.J Oleo Sci.,67(8),1015-1025.
25. Raafat, K,Hdaib, F(2017).Neuroprotective effects of Moringa oleifera: bio-guided GC-MS identification of active compounds in diabetic neuropathic pain model.Chin J Integr Med
26. Raafat, K,Samy, W(2014).Amelioration of diabetes and painful diabetic neuropathy by punica granatum L. Extract and its spray dried biopolymeric dispersions.Evid Based Complement Alternat Med,2014,180495.
27. Raafat, K,Wurglics, M,Schubert-Zsilavecz, M(2016).Prunella vulgaris L. active components and their hypoglycemic and antinociceptive effects in alloxan-induced diabetic mice.Biomed Pharmacother,84,1008-1018.
28. Raafat, KM(2019).Anti-inflammatory and anti-neuropathic effects of a novel quinic acid derivative from Acanthus syriacus.Avicenna Journal of Phytomedicine,9(3),221-236.
29. Raafat, KM(2019).Anti-inflammatory and anti-neuropathic effects of a novel quinic acid derivative from Acanthus syriacus.Avicenna J Phytomed,9(3),221-236.
30. Raafat, KM,El-Zahaby, SA(2020).Niosomes of active Fumaria officinalis phytochemicals: antidiabetic, antineuropathic, anti-inflammatory, and possible mechanisms of action.Chin Med,15(1),40.
31. Raafat, KM,Omar, AG(2015).Phytotherapeutic activity of curcumol: isolation, GC-MS identification, and assessing potentials against acute and subchronic hyperglycemia, tactile allodynia, and hyperalgesia.Pharm Biol,1-11.
32. Raafat, KM,Omar, AG(2016).Phytotherapeutic activity of curcumol: isolation, GC-MS identification, and assessing potentials against acute and subchronic hyperglycemia, tactile allodynia, and hyperalgesia.Pharm Biol,54(8),1334-1344.
33. Rozza, AL,Meira de Faria, F,Souza Brito, AR,Pellizzon, CH(2014).The gastroprotective effect of menthol: involvement of anti-apoptotic, antioxidant and anti-inflammatory activities.PLoS One,9(1),e86686-e86686.
34. Saeedi, P,Petersohn, I,Salpea, P(2019).Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas.Diabetes Research and Clinical Practice,157,107843.
35. Saleh, FA,El-Darra, N,Raafat, K(2017).Hypoglycemic effects of Prunus cerasus L. pulp and seed extracts on Alloxan-Induced Diabetic Mice with histopathological evaluation.Biomed Pharmacother,88,870-877.
36. Sarkhel, S(2015).Evaluation of the anti-inflammatory activities of Quillaja saponaria Mol. saponin extract in mice.Toxicol Rep,3,1-3.
37. Sengul, M,Ercisli, S,Yildiz, H,Gungor, N,Kavaz, A,Cetin, B(2011).Antioxidant, antimicrobial activity and total phenolic content within the aerial parts of Artemisia absinthum, artemisia santonicum and Saponaria officinalis.Iran J Pharm Res,10(1),49-56.
38. Thomford, NE,Senthebane, DA,Rowe, A(2018).Natural products for drug discovery in the 21st century: innovations for novel drug discovery.Int J Mol Sci.,19(6),1578.
39. Tulunay, M,Aypak, C,Yikilkan, H,Gorpelioglu, S(2015).Herbal medicine use among patients with chronic diseases.J Intercult Ethnopharmacol,4(3),217-220.
40. Vinarova, L,Vinarov, Z,Atanasov, V(2015).Lowering of cholesterol bioaccessibility and serum concentrations by saponins: in vitro and in vivo studies.Food Funct,6(2),501-512.
41. Wallace, JL,Ma, L(2001).Inflammatory mediators in gastrointestinal defense and injury.Exp Biol Med,226(11),1003-1015.
42. Wang, Y,Lu, X,Xu, G(2008).Development of a comprehensive two-dimensional hydrophilic interaction chromatography/quadrupole time-of-flight mass spectrometry system and its application in separation and identification of saponins from Quillaja saponaria.J Chromatogr A.,1181(1-2),51-59.
43. Yang, SC,Hsu, CY,Chou, WL,Fang, JY,Chuang, SY(2020).Bioactive agent discovery from the natural compounds for the treatment of type 2 diabetes rat model.Molecules,25(23)
44. Yasmineh, WG,Kaur, TP,Blazar, BR,Theologides, A(1995).Serum catalase as marker of graft-vs-host disease in allogeneic bone marrow transplant recipients: pilot study.Clin Chem,41(11),1574-1580.
45. Yu, H,Li, W,Cao, X(2019).Echinocystic acid, a natural plant extract, alleviates cerebral ischemia/reperfusion injury via inhibiting the JNK signaling pathway.Eur J Pharmacol,861,172610.