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Synergistic anti-diabetic effect of phloroglucinol and total procyanidin dimer isolated from Vitis vinifera methanolic seed extract potentiates via suppressing oxidative stress: in-vitro evaluation studies

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Abstract

Diabetes is often associated with increased oxidative stress caused by an imbalance between detoxification and ROS production. Unfortunately, many commercial drugs available today for treating this disease have adverse side effects and ultimately fail to restore glucose homeostasis. Therefore, finding a dietary anti-diabetic remedy that is safe, effective, and economical is crucial. In this study, GC–MS analysis, subsequent HPLC-assisted fractionation, and SPE-based purification led to identifying and purifying of key components such as phloroglucinol and total procyanidin dimer (procyanidin dimer and procyanidin dimer gallate) from methanolic seed extract of Vitis vinifera. In-vitro anti-diabetic screening of various fractions derived from methanolic extract along with individual components and their combinations revealed the potential synergistic behaviour of phloroglucinol and total procyanidin dimer with the lowest IC50 of 48.21 ± 3.54 µg/mL for α-glucosidase and 63.06 ± 5.38 µg/mL for α-amylase inhibition which is found to be superior to the effect shown by the standard Epigallocatechin gallate. Later Glucose utilization studies demonstrated the concentration-dependent effect of Phloroglucinol and total procyanidin dimer, and that has raised the glucose uptake by approximately 36–57% in HepG2 cells and 35–58% in L6 myocytes over a concentration of 50–100 µg/mL. The superior anti-diabetic effect of Phloroglucinol and total procyanidin dimer was proved by the suppression of oxidative stress with an IC50 of 7.92 ± 0.36 µg/mL for DPPH scavenging and 16.87 ± 1.24 µg/mL for SOD scavenging which is competent with the standard ascorbic acid. According to this study, suppressing ROS levels by phloroglucinol and total procyanidin dimer would be the underlying mechanism for the synergistic anti-diabetic effect of this combination.

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Data availability

All the data required for this research is available in the form of Supplementary information.

Abbreviations

DM:

Diabetes mellitus

EGCG:

Epigallocatechin gallate

MID:

Metabolic disorders

NIST:

National Institute of Standards and Technology

PC:

Procyanidins

PCD:

Procyanidin dimer

PDG:

Procyanidin dimer gallate

PG:

Phloroglucinol

ROS:

Reactive oxygen species

Rt:

Retention times

SEM:

Standard error of the mean

SPE:

Solid phase extraction

T2D:

Type II diabetes

References

  • Abdelmoaty MA, Ibrahim M, Ahmed N, Abdelaziz M (2010) Confirmatory studies on the antioxidant and antidiabetic effect of quercetin in rats. Indian J Clin Biochem 25(2):188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Agarwal S, Singh V, Chauhan K (2023) Antidiabetic potential of seaweed and their bioactive compounds: a review of developments in last decade. Crit Rev Food Sci Nutr 63(22):5739–5770

    Article  PubMed  Google Scholar 

  • Appeldoorn MM, Sanders M, Vincken J-P, Cheynier V, Le Guernevé C, Hollman PC, Gruppen H (2009) Efficient isolation of major procyanidin A-type dimers from peanut skins and B-type dimers from grape seeds. Food Chem 117(4):713–720

    Article  CAS  Google Scholar 

  • Arapitsas P, Perenzoni D, Guella G, Mattivi F (2021) Improving the phloroglucinolysis protocol and characterization of sagrantino wines proanthocyanidins. Molecules 26(4):1087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barber TM, Kabisch S, Randeva HS, Pfeiffer AF, Weickert MO (2022) Implications of resveratrol in obesity and insulin resistance: a state-of-the-art review. Nutrients 14(14):2870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bicker J, Petereit F, Hensel A (2009) Proanthocyanidins and a phloroglucinol derivative from Rumex acetosa L. Fitoterapia 80(8):483–495

    Article  CAS  PubMed  Google Scholar 

  • Bourebaba Y, Marycz K, Mularczyk M, Bourebaba L (2022) Postbiotics as potential new therapeutic agents for metabolic disorders management. Biomed Pharmacother 153:113138

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Cao G, Chen D-Q, Wang M, Vaziri ND, Zhang Z-H, Mao J-R, Bai X, Zhao Y-Y (2016) Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression. Redox Biol 10:168–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crockett SL, Kunert O, Pferschy-Wenzig E-M, Jacob M, Schuehly W, Bauer R (2016) Phloroglucinol and terpenoid derivatives from Hypericum cistifolium and H. galioides (Hypericaceae). Front Plant Sci 7:961

    Article  PubMed  PubMed Central  Google Scholar 

  • Dai T, Chen J, McClements DJ, Hu P, Ye X, Liu C, Li T (2019) Protein–polyphenol interactions enhance the antioxidant capacity of phenolics: analysis of rice glutelin–procyanidin dimer interactions. Food Funct 10(2):765–774

    Article  CAS  PubMed  Google Scholar 

  • Delfanian M, Sahari MA, Barzegar M, Ahmadi Gavlighi H (2021) Structure–antioxidant activity relationships of gallic acid and phloroglucinol. J Food Meas Charact 15(6):5036–5046

    Article  Google Scholar 

  • Dunkley A, Charles K, Gray L, Camosso-Stefinovic J, Davies M, Khunti K (2012) Effectiveness of interventions for reducing diabetes and cardiovascular disease risk in people with metabolic syndrome: systematic review and mixed treatment comparison meta-analysis. Diabetes Obes Metab 14(7):616–625

    Article  CAS  PubMed  Google Scholar 

  • El Hadi H, Di Vincenzo A, Vettor R, Rossato M (2019) Cardio-metabolic disorders in non-alcoholic fatty liver disease. Int J Mol Sci 20(9):2215

    Article  PubMed  PubMed Central  Google Scholar 

  • Gardin A, Giammello F, Toscano A, Musolino RF (2022) Severe hypomagnesaemia as new potential stroke mimic: a case report. Neurol Sci 43(6):4007–4009

    Article  PubMed  PubMed Central  Google Scholar 

  • Goufo P, Singh RK, Cortez I (2020) A reference list of phenolic compounds (including stilbenes) in grapevine (Vitis vinifera L.) roots, woods, canes, stems, and leaves. Antioxidants 9(5):398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goyal MR, Birwal P, Mishra SK (2022) Phytochemicals and medicinal plants in food design: strategies and technologies for improved healthcare. CRC Press

    Book  Google Scholar 

  • Ioannidis I (2014) Diabetes treatment in patients with renal disease: is the landscape clear enough? World J Diabetes 5(5):651

    Article  PubMed  PubMed Central  Google Scholar 

  • Jayaprakasha G, Selvi T, Sakariah K (2003) Antibacterial and antioxidant activities of grape (Vitis vinifera) seed extracts. Food Res Int 36(2):117–122

    Article  CAS  Google Scholar 

  • Jung TW, Yoo HJ, Choi KM (2016) Implication of hepatokines in metabolic disorders and cardiovascular diseases. BBA Clin 5:108–113

    Article  PubMed  PubMed Central  Google Scholar 

  • Khursheed R, Singh SK, Wadhwa S, Kapoor B, Gulati M, Kumar R, Ramanunny AK, Awasthi A, Dua K (2019) Treatment strategies against diabetes: success so far and challenges ahead. Eur J Pharmacol 862:172625

    Article  CAS  PubMed  Google Scholar 

  • Kim HK, Choi YH, Verpoorte R (2010) NMR-based metabolomic analysis of plants. Nat Protoc 5(3):536–549

    Article  CAS  PubMed  Google Scholar 

  • Kim Y, Keogh JB, Clifton PM (2016) Polyphenols and glycemic control. Nutrients 8(1):17

    Article  PubMed  PubMed Central  Google Scholar 

  • Koszewicz M, Jaroch J, Brzecka A, Ejma M, Budrewicz S, Mikhaleva LM, Muresanu C, Schield P, Somasundaram SG, Kirkland CE (2021) Dysbiosis is one of the risk factor for stroke and cognitive impairment and potential target for treatment. Pharmacol Res 164:105277

    Article  CAS  PubMed  Google Scholar 

  • Lankatillake C, Huynh T, Dias DA (2019) Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants. Plant Methods 15(1):1–35

    Article  CAS  Google Scholar 

  • Lee H-W, Hakim P, Rabu A, Sani HA (2012) Antidiabetic effect of Gynura procumbens leaves extracts involve modulation of hepatic carbohydrate metabolism in streptozotocin-induced diabetic rats. J Med Plants Res 6(5):796–812

    Google Scholar 

  • Lee J, Noh S, Lim S, Kim B (2021) Plant extracts for type 2 diabetes: from traditional medicine to modern drug discovery. Antioxidants 10(1):81

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Jiang B, Zhang T, Mu W, Liu J (2008) Antioxidant and free radical-scavenging activities of chickpea protein hydrolysate (CPH). Food Chem 106(2):444–450

    Article  CAS  Google Scholar 

  • Li N, Khan SI, Qiu S, Li X-C (2018) Synthesis and anti-inflammatory activities of phloroglucinol-based derivatives. Molecules 23(12):3232

    Article  PubMed  PubMed Central  Google Scholar 

  • Liang Y, Chen H, Liu Y, Hou X, Wei L, Bao Y, Yang C, Zong G, Wu J, Jia W (2022) Association of MAFLD with diabetes, chronic kidney disease, and cardiovascular disease: a 4.6-year cohort study in China. J Clin Endocrinol Metab 107(1):88–97

    Article  PubMed  Google Scholar 

  • Lin D, Xiao M, Zhao J, Li Z, Xing B, Li X, Kong M, Li L, Zhang Q, Liu Y (2016) An overview of plant phenolic compounds and their importance in human nutrition and management of type 2 diabetes. Molecules 21(10):1374

    Article  PubMed  PubMed Central  Google Scholar 

  • Mafra D, Borges NA, Lindholm B, Shiels PG, Evenepoel P, Stenvinkel P (2021) Food as medicine: targeting the uraemic phenotype in chronic kidney disease. Nat Rev Nephrol 17(3):153–171

    Article  PubMed  Google Scholar 

  • Masri A, Al-Ammouri I (2016) Clinical presentation, etiology, and outcome of stroke in children: a hospital-based study. Brain Dev 38(2):204–208

    Article  PubMed  Google Scholar 

  • Misra S, Aguilar-Salinas CA, Chikowore T, Konradsen F, Ma RC, Mbau L, Mohan V, Morton RW, Nyirenda MJ, Tapela N (2023) The case for precision medicine in the prevention, diagnosis, and treatment of cardiometabolic diseases in low-income and middle-income countries. Lancet Diabetes Endocrinol 11(11):836–847

    Article  PubMed  Google Scholar 

  • Nain P, Saini V, Sharma S, Nain J (2012) Antidiabetic and antioxidant potential of Emblica officinalis Gaertn. leaves extract in streptozotocin-induced type-2 diabetes mellitus (T2DM) rats. J Ethnopharmacol 142(1):65–71

    Article  CAS  PubMed  Google Scholar 

  • Naseri R, Farzaei F, Fakhri S, El-Senduny FF, Altouhamy M, Bahramsoltani R, Ebrahimi F, Rahimi R, Farzaei MH (2019) Polyphenols for diabetes associated neuropathy: pharmacological targets and clinical perspective. DARU J Pharm Sci 27:781–798

    Article  CAS  Google Scholar 

  • Navab M, Gharavi N, Watson AD (2008) Inflammation and metabolic disorders. Curr Opin Clin Nutr Metab Care 11(4):459–464

    Article  CAS  PubMed  Google Scholar 

  • Ngo D-H, Ngo D-N, Vo TTN, Vo TS (2019) Mechanism of action of Mangifera indica leaves for anti-diabetic activity. Sci Pharm 87(2):13

    Article  CAS  Google Scholar 

  • Odeyemi SW, Afolayan AJ (2018) Identification of antidiabetic compounds from polyphenolic-rich fractions of Bulbine abyssinica A. rich leaves. Pharmacognosy Res 10(1):72

    CAS  PubMed  PubMed Central  Google Scholar 

  • Olorunnisola O, Adetutu A, Fadahunsi O (2017) Anti-allergy potential and possible modes of action of Sphenocentrum jollyanum Pierre fruit extracts. J Phytopharm 6:20–26

    Article  Google Scholar 

  • Peters K, Treutler H, Döll S, Kindt AS, Hankemeier T, Neumann S (2019) Chemical diversity and classification of secondary metabolites in nine bryophyte species. Metabolites 9(10):222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Platania V, Douglas TE, Zubko MK, Ward D, Pietryga K, Chatzinikolaidou M (2021) Phloroglucinol-enhanced whey protein isolate hydrogels with antimicrobial activity for tissue engineering. Mater Sci Eng C 129:112412

    Article  CAS  Google Scholar 

  • Portal IB (2016) Online portal of India biodiversity. Online Portal of India Biodiversity, http://indiabiodiversity.org/species/list

  • Quéguineur B, Goya L, Ramos S, Martín MA, Mateos R, Bravo L (2012) Phloroglucinol: antioxidant properties and effects on cellular oxidative markers in human HepG2 cell line. Food Chem Toxicol 50(8):2886–2893

    Article  PubMed  Google Scholar 

  • Rehana D, Mahendiran D, Kumar RS, Rahiman AK (2017) In vitro antioxidant and antidiabetic activities of zinc oxide nanoparticles synthesized using different plant extracts. Bioprocess Biosyst Eng 40(6):943–957

    Article  CAS  PubMed  Google Scholar 

  • Rathore R, Rai N (2022) Pharmacological action and underlying molecular mechanism of Callistemon: a genus of promising medicinal herbs. Phytomedicine 99:154013

    Article  CAS  PubMed  Google Scholar 

  • Sergeeva V, Rodionova AY (2013) Contemporary approach to assess arterial hypertension combined with metabolic disturbances. Arter Hypertens 19(5):397–404

    Google Scholar 

  • Singh IP, Bharate SB (2006) Phloroglucinol compounds of natural origin. Nat Prod Rep 23(4):558–591

    Article  CAS  Google Scholar 

  • Singh S, Sarma DK, Verma V, Nagpal R, Kumar M (2023) Unveiling the future of metabolic medicine: omics technologies driving personalized solutions for precision treatment of metabolic disorders. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2023.09.064

    Article  PubMed  Google Scholar 

  • Stagos D (2019) Antioxidant activity of polyphenolic plant extracts. Antioxidants 9:19

    Article  PubMed  PubMed Central  Google Scholar 

  • Swargiary A, Verma AK, Singh S, Roy MK, Daimari M (2021) Antioxidant and antiproliferative activity of selected medicinal plants of lower Assam, India: An in vitro and in silico study. Anti-Cancer Agents Med Chem (former Curr Med Chem-Anti-Cancer Agents) 21(2):267–277

    CAS  Google Scholar 

  • Szkudelski T, Szkudelska K (2015) Resveratrol and diabetes: from animal to human studies. Biochimica Et Biophysica Acta (BBA) Mol Basis Dis 6:1145–1154

    Article  Google Scholar 

  • Turkoglu A, Duru ME, Mercan N, Kivrak I, Gezer K (2007) Antioxidant and antimicrobial activities of Laetiporus sulphureus (Bull.) Murrill. Food Chem 101(1):267–273

    Article  CAS  Google Scholar 

  • Tyagi K, Maoz I, Lewinsohn E, Lerno L, Ebeler SE, Lichter A (2020) Girdling of table grapes at fruit set can divert the phenylpropanoid pathway towards accumulation of proanthocyanidins and change the volatile composition. Plant Sci 296:110495

    Article  CAS  PubMed  Google Scholar 

  • van de Venter M, Roux S, Bungu LC, Louw J, Crouch NR, Grace OM, Maharaj V, Pillay P, Sewnarian P, Bhagwandin N (2008) Antidiabetic screening and scoring of 11 plants traditionally used in South Africa. J Ethnopharmacol 119(1):81–86

    Article  PubMed  Google Scholar 

  • Van Meerloo J, Kaspers GJ, Cloos J (2011) Cell sensitivity assays: the MTT assay. Cancer cell culture: methods and protocols. Humana press, pp 237–245

    Chapter  Google Scholar 

  • Vyshnava SS, Pandluru G, Kanderi DK, Panjala SP, Banapuram S, Paramasivam K, Anupalli RR, Bontha RR, Dowlatabad MR (2020) Gram scale synthesis of QD 450 core–shell quantum dots for cellular imaging and sorting. Appl Nanosci 10:1257–1268

    Article  CAS  ADS  Google Scholar 

  • Vyshnava SS, Kanderi DK, Dowlathabad MR (2022a) Confocal laser scanning microscopy study of intercellular events in filopodia using 3-mercaptopropoinc acid capped CdSe/ZnS quantum dots. Micron 153:103200

    Article  CAS  PubMed  Google Scholar 

  • Vyshnava SS, Pandluru G, Kumar KD, Panjala SP, Banapuram S, Paramasivam K, Devi KV, Anupalli RR, Dowlatabad MR (2022b) Quantum dots based in-vitro co-culture cancer model for identification of rare cancer cell heterogeneity. Sci Rep 12(1):5868

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  • Wagner K-H, Schwingshackl L, Draxler A, Franzke B (2021) Impact of dietary and lifestyle interventions in elderly or people diagnosed with diabetes, metabolic disorders, cardiovascular disease, cancer and micronutrient deficiency on micronuclei frequency–a systematic review and meta-analysis. Mutat Res Rev Mutat Res 787:108367

    Article  CAS  PubMed  Google Scholar 

  • Waltenberger B, Mocan A, Šmejkal K, Heiss EH, Atanasov AG (2016) Natural products to counteract the epidemic of cardiovascular and metabolic disorders. Molecules 21(6):807

    Article  PubMed  PubMed Central  Google Scholar 

  • Yan L, Vaghari-Tabari M, Malakoti F, Moein S, Qujeq D, Yousefi B, Asemi Z (2023) Quercetin: an effective polyphenol in alleviating diabetes and diabetic complications. Crit Rev Food Sci Nutr 63(28):9163–9186

    Article  CAS  PubMed  Google Scholar 

  • Zhang F, Lai Q, Lai W, Li M, Jin X, Ye L (2022) Phloroglucinol derivatives as anti-tumor agents: synthesis, biological activity evaluation and molecular docking studies. Med Chem Res 31(1):165–176

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to thank Osmania University for providing technical facility and support to accomplish this research work.

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This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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  1. Department of Biochemistry, University College of Science, Osmania University, Amberpet, Hyderabad, Telangana State, 500007, India

    Sreenu Thupakula, Shiva Shankar Reddy Nimmala, Shauq Mumtaz Dawood & Raju Padiya

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  1. Sreenu Thupakula
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Thupakula, S., Nimmala, S.S.R., Dawood, S.M. et al. Synergistic anti-diabetic effect of phloroglucinol and total procyanidin dimer isolated from Vitis vinifera methanolic seed extract potentiates via suppressing oxidative stress: in-vitro evaluation studies. 3 Biotech 14, 76 (2024). https://doi.org/10.1007/s13205-024-03929-4

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