Oxidative Stress, NF-κB-Mediated Inflammation and Apoptosis in the Testes of Streptozotocin–Induced Diabetic Rats: Combined Protective Effects of Malaysian Propolis and Metformin

Abstract

Oxidative stress, inflammation and apoptosis are major complications that trigger organ failure in diabetes mellitus (DM), and are proven to adversely affect the male reproductive system. Clinical and experimental studies have demonstrated the promising protective effects of propolis in DM and its associated systemic effects. Herein, we investigated the effect of Malaysian propolis (MP) on testicular oxidative stress, inflammation and apoptosis in diabetic rats. Further, the possibility of a complementary effect of MP with the anti-hyperglycaemic agent, metformin (Met), was studied with the idea of recommending its use in the event that Met alone is unable to contain the negative effects of DM on the male reproductive system in mind. Male Sprague-Dawley rats were either gavaged distilled water (normoglycaemic control and diabetic control groups), MP (diabetic rats on MP), Met (diabetic rats on Met) or MP+Met (diabetic rats on MP+Met), for 4 weeks. MP decreased oxidative stress by up-regulating (p < 0.05) testicular mRNA levels of nuclear factor erythroid 2-related factor 2, superoxide dismutase, catalase and glutathione peroxidase; increasing (p < 0.05) the activities of antioxidant enzymes; and decreasing (p < 0.05) lipid peroxidation in the testes and epididymis of diabetic rats. Further, MP down-regulated (p < 0.05) testicular mRNA and protein levels of pro-inflammatory mediators (nuclear factor kappa B, inducible nitric oxide synthase, tumour necrosis factor-α and interleukin (IL)-1β), decreased (p < 0.05) the nitric oxide level, and increased (p < 0.05) IL-10 mRNA and protein levels. MP also down-regulated (p < 0.05) Bax/Bcl-2, p53, casapase-8, caspase-9 and caspase-3 genes, and increased (p < 0.05) testicular germ cell proliferation. MP’s effects were comparable to Met. However, the best results were achieved following co-administration of MP and Met. Therefore, we concluded that administration of the MP+Met combination better attenuates testicular oxidative stress, inflammation and apoptosis in DM, relative to MP or Met monotherapy, and may improve the fertility of males with DM.

Momordica charantia Extract Protects against Diabetes-Related Spermatogenic Dysfunction in Male Rats: Molecular and Biochemical Study

“…Caspase-3, a sort of cysteine protease, is an important mediator of apoptosis. Many reports have indicated that caspase-3 is upregulated in diabetic conditions [54]. In this study, we show that there was an association between diabetic sexual dysfunction and caspase-3 expression, as evidenced by apparent downregulation of caspase-3 content in the germ cells of D+MC-treated rats, suggesting that inhibition of caspase-3 activity may be one of the mechanisms by which MC protects against diabetic testicular injury.…”

Phytochemical Constituents, Antioxidant, Cytotoxic, and Antimicrobial Activities of the Ethanolic Extract of Mexican Brown Propolis

“…The presence of pinocembrin (1), chrysin (2), galangin (3), ferulic acid (10), syringic acid (11), and caffeic acid (12) suggest that its main botanical source are a species of Populus typical of the country, such as Populus mexicana Wesmael, Populus guzmanantlensis Vazques and Cuevas and Populus simaroa Rzedowski. Although flavonoids without B-ring substituents appear common in temperate propolis from both the northern and southern hemispheres, in this study we report for the first time the presence of dillenetin (6) and isorhamnetin (7) with B-ring substitution as constituents of Mexican poplar propolis. To the best of our knowledge, this is the first report of dillenetin (6) as a propolis constituent.…”

“…The EtOH-soluble extract of sample GUA-4 was fractionated by chromatography on a VLC column and by Sephadex LH-20, giving 12 known compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The compounds were identified as pinocembrin (1, 405.4 mg) [33], chrysin (2, 126.3 mg) [34], galangin (3, 56.7 mg) [33], alpinetin (4, 15.6 mg) [35], 5-methyl-pinobanksin ether (5, 16.8 mg) [36], dillenetin (6, 12.3 mg) [37], isorhamnetin (7, 24.6 mg) [38], 5-methylgalangin ether (8, 9.8 mg) [39], 5-methylchrysin ether (9, 16.3 mg) [40], ferulic acid (10, 24.9 mg) [33], syringic acid (11, 6.7 mg), and caffeic acid (12, 8.9 mg) [33] ( Figure S1) by means of 1D (Table S1) and 2D NMR spectral analysis.…”

Malaysian propolis and metformin mitigate subfertility in streptozotocin‐induced diabetic male rats by targeting steroidogenesis, testicular lactate transport, spermatogenesis and mating behaviour

“…[23][24][25] Our group reported significant antioxidant, anti-inflammatory and anti-apoptotic effects of Malaysian propolis (MP) in the pancreas, liver, testes and epididymis of diabetic rats. 22,26,27 In the present study, therefore, we report for the first time, the effect of propolis on steroidogenesis, spermatogenesis, testicular lactate transport, sexual behaviour and fertility outcome in diabetic rats. Following our previously reported better blood glucose modulation in diabetic rats treated with MP + metformin combination relative to MP and metformin monotherapies, 22 we report the effect of this alliance on the above-mentioned reproductive function parameters in order to explore the benefits of the combination in the event that neither of the two therapies is able to significantly reverse these negative effects.…”

“…Intra-testicular oxidative stress, inflammation and germ cell apoptosis, which occur as a result of hyperglycaemia-induced overproduction of ROS, are implicated in DM-induced fertility decline. 27,34 We reported that these ROS-associated effects were significantly suppressed by MP, Met and MP + Met, with the best outcome following intervention with the combined therapy. 27 In the present study, therefore, we explored the benefits of these interventions on other indispensable target processes in the testes (steroidogenesis, lactate metabolism and spermatogenesis) which are required for male fertility, in addition to a post-testicular event, sexual behaviour.…”