Article Data

  • Views 315
  • Dowloads 135

Original Research

Open Access

Cinnamon and ginger extracts attenuate diabetes-induced inflammatory testicular injury in rats and modulating SIRT1 expression

  • Ghadeer I. Alrefaei1
  • Hailah M. Almohaimeed2
  • Sami A. Algaidi3
  • Mohammed Saad Almuhayawi4
  • Fatma Mohamed AbdAllah5
  • Nouf S. Al-Abbas6
  • Nehad A. Shaer7
  • Zuhair M. Mohammedsaleh8
  • Fayez M Saleh9
  • Nasra Ayuob10,*,

1Department of Biology, College of Science, University of Jeddah, 21589 Jeddah, Saudi Arabia

2Department of Basic Sciences, Medical College, Princess Nourah bint Abdulrahman University, 11671 Riyadh, Saudi Arabia

3Department of Anatomy, Faculty of Medicine, Taibah University, 42353 Medina, Saudi Arabia

4Department of Clinical Microbiology and Immunology, Faculty of Medicine, King Abdulaziz University, 21589 Jeddah, Saudi Arabia

5Histology department, Damietta Faculty of medicine, Al-Azhar University, 34517 New Damietta, Egypt

6Department of Biology, Jamoum University College, Umm Al-Qura University, 21955 Makkah, Saudi Arabia

7Department of Chemistry, Al Lieth University College, Umm Al-Qura University, 21955 Makkah, Saudi Arabia

8Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, 71491 Tabuk, Saudi Arabia

9Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, 71491 Tabuk, Saudi Arabia

10Department of Medical Histology, Faculty of Medicine, Damietta University, 34517 Damietta, Egypt

DOI: 10.22514/jomh.2023.067 Vol.19,Issue 8,August 2023 pp.22-32

Submitted: 02 March 2023 Accepted: 20 April 2023

Published: 30 August 2023

*Corresponding Author(s): Nasra Ayuob E-mail:


The current study aimed to evaluate the efficacy of simultaneous administration of Zingiber officinale (ginger) and Cinnamomum cassia (cinnamon) extracts in mitigating testicular changes associated with diabetes mellitus in rats and to investigate its molecular mode of action. After induction of diabetes using streptozotocin, 36 male rats were divided to six groups namely control, diabetic, metformin-treated, cinnamon-treated, ginger-treated and combined, each group having 6 rats. Fasting blood glucose, serum insulin, testosterone was measured. Expression of inflammatory mediators; tumor necrosis factor-alpha (TNF-α), Nuclear factor kappa B (NF-κB) and Sirtuin 1 (SIRT1) was assessed in the testicular tissue. Histopathological changes in the testis were observed and spermatogenesis and apoptosis were assessed immunohistochemically. The histological and biochemical studies of the untreated group confirmed structural changes in testes induced by diabetes. Oral administration of ginger and cinnamon increased insulin level significantly increased while the blood glucose level significantly decreased in diabetic rats, improving structural testicular changes considerably. Joint intake of ginger and cinnamon increased antihyperglycemic, antioxidant and anti-inflammatory effects markedly improving the testicular injury compared to the administration of either of them. SIRT1 expression in the testis significantly increased in ginger plus cinnamon-treated rats. These results indicate that when administrated together, ginger and cinnamon synergistically enhanced antioxidant, antiapoptotic and anti-inflammatory effects and induced antihyperglycemic effect comparable to metformin. The combination of ginger and cinnamon also upregulated SIRT1 in the testis.


Diabetes mellitus; Apoptosis; Ginger; Cinnamon; NF-κB; TNF-α

Cite and Share

Ghadeer I. Alrefaei,Hailah M. Almohaimeed,Sami A. Algaidi,Mohammed Saad Almuhayawi,Fatma Mohamed AbdAllah,Nouf S. Al-Abbas,Nehad A. Shaer,Zuhair M. Mohammedsaleh,Fayez M Saleh,Nasra Ayuob. Cinnamon and ginger extracts attenuate diabetes-induced inflammatory testicular injury in rats and modulating SIRT1 expression. Journal of Men's Health. 2023. 19(8);22-32.


[1] Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Research and Clinical Practice. 2022; 183: 109119.

[2] Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update. European Journal of Pharmacology. 2016; 791: 8–24.

[3] Luc K, Schramm-Luc A, Guzik TJ, Mikolajczyk TP. Oxidative stress and inflammatory markers in prediabetes and diabetes. Journal of Physiology and Pharmacology. 2019; 70: 809–824.

[4] Huang T, Zhou Y, Lu X, Tang C, Ren C, Bao X, et al. Cordycepin, a major bioactive component of cordyceps militaris, ameliorates diabetes-induced testicular damage through the Sirt1/Foxo3a pathway. Andrologia. 2022; 54: e14294.

[5] Ren H, Hu K. Inflammatory and oxidative stress-associated factors in chronic intermittent hypoxia in Chinese patients, rats, lymphocytes and endotheliocytes. Molecular Medicine Reports. 2017; 16: 8092–8102.

[6] Nna VU, Abu Bakar AB, Ahmad A, Eleazu CO, Mohamed M. Oxidative stress, NF-κB-mediated inflammation and apoptosis in the testes of streptozotocin-induced diabetic rats: combined protective effects of Malaysian Propolis and metformin. Antioxidants. 2019; 8: 465.

[7] Thirupathi A, de Souza CT. Multi-regulatory network of ROS: the interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise. Journal of Physiology and Biochemistry. 2017; 73: 487–494.

[8] Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009; 460: 587–591.

[9] Conde E, Alegre L, Blanco-Sánchez I, Sáenz-Morales D, Aguado-Fraile E, Ponte B, et al. Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. PLOS ONE. 2012; 7: e33258.

[10] Bell EL, Nagamori I, Williams EO, Del Rosario AM, Bryson BD, Watson N, et al. SirT1 is required in the male germ cell for differentiation and fecundity in mice. Development. 2014; 141: 3495–3504.

[11] ALmohaimeed HM, Mohammedsaleh ZM, Batawi AH, Balgoon MJ, Ramadan OI, Baz HA, et al. Synergistic anti-inflammatory and neuro-protective effects of Cinnamomum cassia and Zingiber officinale alleviate diabetes-induced hippocampal changes in male albino rats: structural and molecular evidence. Frontiers in Cell and Developmental Biology. 2021; 9: 727049.

[12] Sharifi-Rad J, Dey A, Koirala N, Shaheen S, El Omari N, Salehi B, et al. Cinnamomum species: bridging phytochemistry knowledge, pharmacological properties and toxicological safety for health benefits. Frontiers in Pharmacology. 2021; 12: 600139.

[13] Hayward NJ, McDougall GJ, Farag S, Allwood JW, Austin C, Campbell F, et al. Cinnamon shows antidiabetic properties that are species-specific: effects on enzyme activity inhibition and starch digestion. Plant Foods for Human Nutrition. 2019; 74: 544–552.

[14] Kashif M, Imran A, Saeed F, Chatha SAS, Arshad MU. Catechins, theaflavins and ginger freeze-dried extract based functional drink significantly mitigate the hepatic, diabetic and lipid abnormalities in rat model. Cellular and Molecular Biology. 2021; 67: 132–141.

[15] ALmohaimeed HM, Mohammedsaleh ZM, Batawi AH, Balgoon MJ, Ramadan OI, Baz HA, et al. Synergistic anti-inflammatory and neuro-protective effects of Cinnamomum cassia and Zingiber officinale alleviate diabetes-induced hippocampal changes in male albino rats: structural and molecular evidence. Frontiers in Cell and Developmental Biology. 2021; 9: 727049.

[16] Ayuob N, Al-Shathly MR, Bakhshwin A, Al-Abbas NS, Shaer NA, Al Jaouni S, et al. p53 rather than β-Catenin mediated the combined hypoglycemic effect of Cinnamomum cassia (L.) and Zingiber officinale roscoe in the streptozotocin-induced diabetic model. Frontiers in Pharmacology. 2021; 12: 664248.

[17] Pushparaj P, Tan CH, Tan BK. Effects of Averrhoa bilimbi leaf extract on blood glucose and lipids in streptozotocin-diabetic rats. Journal of Ethnopharmacology. 2000; 72: 69–76.

[18] Salemi Z, Rafie E, Goodarzi MT, Ghaffari MA. Effect of metformin, acarbose and their combination on the serum visfatin level in nicotinamide/streptozocin-induced type 2 diabetic rats. Iranian Red Crescent Medical Journal. 2016; 18: e23814.

[19] Chaudhary S. Flora of the Kingdom of Saudi Arabia: illustrated. 2nd edn. Ministry of Agriculture and Water, National Herbarium, National Agriculture and Water Research Center: Riyadh. 2001.

[20] Al-Amin ZM, Thomson M, Al-Qattan KK, Peltonen-Shalaby R, Ali M. Anti-diabetic and hypolipidaemic properties of ginger (Zingiber officinale) in streptozotocin-induced diabetic rats. British Journal of Nutrition. 2006; 96: 660–666.

[21] Longe A, Momoh J, Adepoju P. Effects of cinnamon aqueous extract on blood glucose level, liver biomarker enzymes, hematological and lipid profile parameters in alloxan-induced diabetic male albino rats. European Scientific Journal. 2015; 1: 1857–7431.

[22] Ahmad RA, Serati-Nouri H, Majid FA, Sarmidi MR, Aziz RA. Assessment of potential toxicological effects of cinnamon bark aqueous extract in rats. International Journal of Bioscience, Biochemistry and Bioinformatics. 2015; 5: 36–44.

[23] Nie R, Zhou Q, Jassim E, Saunders PT, Hess RA. Differential expression of estrogen receptors α and β in the reproductive tractsof adult male dogs and cats. Biology of Reproduction. 2002; 66: 1161–1168.

[24] ALmohaimeed HM, Mohammedsaleh ZM, Batawi AH, Balgoon MJ, Ramadan OI, Baz HA, et al. Synergistic anti-inflammatory and neuro-protective effects of Cinnamomum cassia and Zingiber officinale alleviate diabetes-induced hippocampal changes in male albino rats: structural and molecular evidence. Frontiers in Cell and Developmental Biology. 2021; 9: 727049.

[25] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28: 412–419.

[26] Wang J, Ke W, Bao R, Hu X, Chen F. Beneficial effects of ginger Zingiber officinale Roscoe on obesity and metabolic syndrome: a review. Annals of the New York Academy of Sciences. 2017; 1398: 83–98.

[27] Pikor LA, Enfield KS, Cameron H, Lam WL. DNA extraction from paraffin embedded material for genetic and epigenetic analyses. Journal of Visualized Experiments. 2011; e2763.

[28] Zhou Q, Nie R, Prins GS, Saunders PT, Katzenellenbogen BS, Hess RA. Localization of androgen and estrogen receptors in adult male mouse reproductive tract. Journal of Andrology. 2002; 23: 870–881.

[29] Rajeh NA, Plant N, Al Saggaf SM, Aly HA, Ayuob NN, ElAssouli SM. Acrylamide-mediated subacute testicular and genotoxicity, is it reversible? The Egyptian Journal of Histology. 2012; 35: 424–436.

[30] Farazandeh M, Mahmoudabady M, Asghari AA, Niazmand S. Diabetic cardiomyopathy was attenuated by cinnamon treatment through the inhibition of fibro‐inflammatory response and ventricular hypertrophy in diabetic rats. Journal of Food Biochemistry. 2022; 46: e14206.

[31] Koroglu Aydın P, Karabulut-Bulan O, Bugan I, Turkyilmaz IB, Altun S, Yanardag R. The protective effect of metformin against testicular damage in diabetes and prostate cancer model. Cell Biochemistry and Function. 2022; 40: 60–70.

[32] Nurinda E, Kusumawardaniet N, Wulandari AS, Fatmawati A, Emelda E, Nisa H, et al. Pharmacological study: synergistic antidiabetic activity of cinnamon bark and Zingiber extract in streptozotocin-induced diabetic rats. Open Access Macedonian Journal of Medical Sciences. 2022; 10: 1–6.

[33] Damasceno DC, Netto AO, Iessi IL, Gallego FQ, Corvino SB, Dallaqua B, et al. Streptozotocin-induced diabetes models: pathophysiological mechanisms and fetal outcomes. BioMed Research International. 2014; 2014: 819065.

[34] Widyasti JH, Widodo GP, Herowati R. The antihyperglicemic activity of ethanol extract of fenugreek seed (Trigonella foenum graecum L) and its effect on the GLUT-2 expression of streptozotocin nicotinamide induced rats. Indonesian Journal of Pharmacy. 2018; 29: 10.

[35] Al Hayek AA, Robert AA, Alshammari G, Hakami H, Al Dawish MA. Assessment of hypogonadism in men with type 2 diabetes: a cross-sectional study from Saudi Arabia. Clinical Medicine Insights: Endocrinology and Diabetes. 2017; 10: 1179551417710209.

[36] Ahangarpour A, Oroojan AA, Heidari H, Ghaedi E, Taherkhani R. Effects of hydro-alcoholic extract from arctium lappa l. (burdock) root on gonadotropins, testosterone, and sperm count and viability in male mice with nicotinamide/streptozotocin-induced type 2 diabetes. Malaysian Journal of Medical Sciences. 2015; 22: 25–32.

[37] Stanworth RD, Kapoor D, Channer KS, Jones TH. Statin therapy is associated with lower total but not bioavailable or free testosterone in men with type 2 diabetes. Diabetes Care. 2009; 32: 541–546.

[38] Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, et al. Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. The Journal of Clinical Endocrinology & Metabolism. 2005; 90: 2636–2641.

[39] Hasan MM, El‐Shal AS, Mackawy AMH, Ibrahim EM, Abdelghany EMMA, Saeed AA, et al. Ameliorative effect of combined low dose of Pioglitazone and omega-3 on spermatogenesis and steroidogenesis in diabetic rats. Journal of Cellular Biochemistry. 2020; 121: 1524–1540.

[40] Al-Shathly MR, Ali SS, Ayuob NN. Zingiber officinale preserves testicular structure and the expression of androgen receptors and proliferating cell nuclear antigen in diabetic rats. Andrologia. 2020; 52: e13528.

[41] Kanter M, Aktas C, Erboga M. Curcumin attenuates testicular damage, apoptotic germ cell death, and oxidative stress in streptozotocin-induced diabetic rats. Molecular Nutrition & Food Research. 2013; 57: 1578–1585.

[42] Jiang X, Bai Y, Zhang Z, Xin Y, Cai L. Protection by sulforaphane from type 1 diabetes-induced testicular apoptosis is associated with the up-regulation of Nrf2 expression and function. Toxicology and Applied Pharmacology. 2014; 279: 198–210.

[43] Joshi D, Sarkar D, Singh SK. Decreased expression of orexin 1 receptor in adult mice testes during alloxan-induced diabetes mellitus perturbs testicular steroidogenesis and glucose homeostasis. Biochemical and Biophysical Research Communications. 2017; 490: 1346–1354.

[44] Ayuob NN, Murad HA, Ali SS. Impaired expression of sex hormone receptors in male reproductive organs of diabetic rat in response to oral antidiabetic drugs. Folia Histochemica et Cytobiologica. 2015; 53: 35–48.

[45] Khosravi Z, Sedaghat R, Baluchnejadmojarad T, Roghani M. Diosgenin ameliorates testicular damage in streptozotocin-diabetic rats through attenuation of apoptosis, oxidative stress, and inflammation. International Immunopharmacology. 2019; 70: 37–46.

[46] Chen Y, Jiao N, Jiang M, Liu L, Zhu Y, Wu H, et al. Loganin alleviates testicular damage and germ cell apoptosis induced by AGEs upon diabetes mellitus by suppressing the RAGE/p38MAPK/NF-κB pathway. Journal of Cellular and Molecular Medicine. 2020; 24: 6083–6095.

[47] Ahad A, Ahsan H, Mujeeb M, Siddiqui WA. Gallic acid ameliorates renal functions by inhibiting the activation of p38 MAPK in experimentally induced type 2 diabetic rats and cultured rat proximal tubular epithelial cells. Chemico-Biological Interactions. 2015; 240: 292–303.

[48] Song S, Dang M, Kumar M. Anti-inflammatory and renal protective effect of gingerol in high-fat diet/streptozotocin-induced diabetic rats via inflammatory mechanism. Inflammopharmacology. 2019; 27: 1243–1254.

[49] Zhao LL, Makinde EA, Olatunji OJ. Protective effects of ethyl acetate extract from Shorea roxburghii against diabetes induced testicular damage in rats. Environmental Toxicology. 2021; 36: 374–385.

[50] Heeba GH, Hamza AA. Rosuvastatin ameliorates diabetes-induced reproductive damage via suppression of oxidative stress, inflammatory and apoptotic pathways in male rats. Life Sciences. 2015; 141: 13–19.

[51] Han X, Jiang Y, Liu N, Wu J, Yang J, Li Y, et al. Protective effects of Astragalin on spermatogenesis in streptozotocin-induced diabetes in male mice by improving antioxidant activity and inhibiting inflammation. Biomedicine & Pharmacotherapy Journal. 2019; 110: 561–570.

[52] Selvaratnam J, Robaire B. Overexpression of catalase in mice reduces age-related oxidative stress and maintains sperm production. Experimen-tal Gerontology. 2016; 84: 12–20.

[53] Lei X, Huo P, Wang Y, Xie Y, Shi Q, Tu H, et al. Lycium barbarum polysaccharides improve testicular spermatogenic function in streptozotocin-induced diabetic rats. Frontiers in Endocrinology. 2020; 11: 164.

[54] Joo HY, Yun M, Jeong J, Park ER, Shin HJ, Woo SR, et al. SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1α (HIF-1α) via direct interactions during hypoxia. Biochemical and Biophysical Research Communications. 2015. 462: 294–300.

[55] Liang F, Kume S, Koya D. SIRT1 and insulin resistance. Nature Reviews Endocrinology. 2009; 5: 367–373.

[56] Naik A, Adeyemi SB, Vyas B, Krishnamurthy R. Effect of co-administration of metformin and extracts of Costus pictus D. Don leaves on alloxan-induced diabetes in rats. Journal of Traditional and Complementary Medicine. 2022; 12: 269–280.

[57] Koroglu Aydın P, Karabulut-Bulan O, Bugan I, Turkyilmaz IB, Altun S, Yanardag R. The protective effect of metformin against testicular damage in diabetes and prostate cancer model. Cell Biochemistry and Function. 2022; 40: 60–70.

[58] Singh SK, Apata T, Singh S, McFadden M, Singh R. Clinical implication of metformin in relation to diabetes mellitus and ovarian cancer. Biomedicines. 2021; 9: 1020.

[59] Chen D, Xia D, Pan Z, Xu D, Zhou Y, Wu Y, et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death & Disease. 2016; 7: e2441.

[60] Huang KY, Que JQ, Hu ZS, Yu YW, Zhou YY, Wang L, et al. Metformin suppresses inflammation and apoptosis of myocardiocytes by inhibiting autophagy in a model of ischemia-reperfusion injury. International Journal of Biological Sciences. 2020; 16: 2559–2579.

[61] Atanassova M, Georgieva S, Ivancheva K. Total phenolic and total flavonoid contents, antioxidant capacity and biological contaminants in medicinal herbs. Journal of the University of Chemical Technology and Metallurgy. 2011; 46: 81–88.

[62] Mazani M, Ojarudi M, Banaei S, Salimnejad R, Latifi M, Azizi H, et al. The protective effect of cinnamon and ginger hydro-alcoholic extract on carbon tetrachloride-induced testicular damage in rats. Andrologia. 2020; 52: e13651

[63] Hemayatkhah Jahromi V, Parivar K, Forozanfar M. The effect of cinnamon extract on spermatogenesis hormonal axis of pituitary gonad in mice. Iranian Journal of Applied Animal Science. 2011; 1: 99–103.

[64] Davari M, Hashemi R, Mirmiran P, Hedayati M, Sahranavard S, Bahreini S, et al. Effects of cinnamon supplementation on expression of systemic inflammation factors, NF-kB and Sirtuin-1 (SIRT1) in type 2 diabetes: a randomized, double blind, and controlled clinical trial. Nutrition Journal. 2020; 19: 1.

[65] Han X, Yang Y, Zhang M, Chu X, Zheng B, Liu C, et al. Protective effects of 6-Gingerol on cardiotoxicity induced by arsenic trioxide through AMPK/SIRT1/PGC-1α Signaling Pathway. Frontiers in Pharmacology. 2022; 13: 868393.

[66] Lee GH, Cheng P, Jeong SY, Park SA, Lee HY, Hoang TH, et al. Ginger extract controls mTOR-SREBP1-ER stress-mitochondria dysfunction through AMPK activation in obesity model. Journal of Functional Foods. 2021; 87: 104628.

Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Directory of Open Access Journals (DOAJ) DOAJ is a unique and extensive index of diverse open access journals from around the world, driven by a growing community, committed to ensuring quality content is freely available online for everyone.

SCImago The SCImago Journal & Country Rank is a publicly available portal that includes the journals and country scientific indicators developed from the information contained in the Scopus® database (Elsevier B.V.)

Publication Forum - JUFO (Federation of Finnish Learned Societies) Publication Forum is a classification of publication channels created by the Finnish scientific community to support the quality assessment of academic research.

Scopus: CiteScore 0.7 (2022) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.

Norwegian Register for Scientific Journals, Series and Publishers Search for publication channels (journals, series and publishers) in the Norwegian Register for Scientific Journals, Series and Publishers to see if they are considered as scientific. (

Submission Turnaround Time