Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Exhibits Antioxidant Mechanism for Abrogation of Cyclophosphamide-Induced Cardiac Damage and Oxidative Hepatorenal Toxicity in Rats.

Cyclophosphamide (CYP) is a potent DNA-interactive anticancer drug; however, its clinical drawbacks are chiefly associated with induction of oxidative multi-organ toxicity. Sitagliptin (STG) is an antidiabetic dipeptidyl peptidase-4 inhibitor drug with antioxidant efficacy. Herein, we have explored whether STG could abrogate the CYP-induced oxidative stress-mediated cardiac and hepatorenal toxicities in male rats. Sitagliptin (20 mg/kg, o.p) was administered to rats for 5 consecutive days against organ toxicities induced by CYP (200 mg/kg, i.p) on day 5 only. CYP induced marked injuries in the liver, kidney and heart underscored by prominent increases in serum activities of ALT, AST, LDH, creatine kinase and levels of urea, uric acid and creatinine, while albumin level significantly decreased compared to normal control rats. Further, CYP considerably reduced the activities of SOD, CAT, GPx, and levels of GSH, whereas MDA level increased significantly in comparison to control rats. These biochemical alterations were confirmed by multiple histopathological lesions in the tissues. Interestingly, the STG pretreatment abrogated the biochemical and histopathological changes induced by CYP. These results provide first evidence that repurposing STG may protect the liver, kidney and heart from the oxidative deterioration associated with CYP chemotherapy.

Effects of honey supplementation on renal dysfunction and metabolic acidosis in rats with high-fat diet-induced chronic kidney disease.

Background Metabolic diseases are associated with impaired renal function which accelerates chronic kidney disease (CKD) progression. The aim of this study was to investigate the effects of 16-week honey supplementation on renal function, metabolic acidosis and renal abnormalities in Wistar rats fed a high-fat diet (HFD). Methods Wistar rats were fed a HFD and sucrose (30%) solution and randomly grouped and treated. Group 1 was fed rat chow and treated with drinking water while groups 2, 3, 4 and 5 were fed a HFD and treated with drinking water, 1, 2 and 3 g/kg body weight (BW) of honey, respectively, once daily for 16 weeks. After the rats were sacrificed, the serum samples were obtained and used for the analysis of total cholesterol, urea, creatinine, sodium, potassium, calcium, bicarbonates and chloride ions. Histopathological examinations of the kidneys were performed. Results The serum creatinine and anion gap levels were significantly (p < 0.01) higher while the levels of serum total calcium and ionized fraction were significantly (p < 0.01) lower in HFD-fed control rats than in chow-fed rats. The kidney of HFD-fed control rats was characterized by tubular necrosis, glomerular atrophy, hemorrhage and severe focal aggregate inflammatory (FAIC) cells. Honey treatment (1, 2 or 3 g/kg BW) prevented elevations in serum creatinine while it restored serum levels of total calcium and ionized calcium towards those in rats fed chow only. All the three doses of honey also significantly (p < 0.01) reduced anion gap and ameliorated renal lesions. Honey treatment (2 g/kg BW) significantly (p < 0.05) increased bicarbonate and chloride ion in HFD-fed rats compared with HFD-fed control rats. Conclusions Sixteen-week honey supplementation ameliorates renal dysfunction, metabolic acidosis and renal morphological abnormalities in HFD-fed Wistar rats.

Erratum to "Nonpharmacologic Interventions in Prevention and Treatment of Hypertension".

[This corrects the article DOI: 10.1155/2019/6709817.].

Spices Mixture Containing Garlic, Ginger and Nutmeg Has Protective Effects on the Kidneys and Liver of Cadmium Exposed Rats.

PURPOSE: To determine the potential protective effect of spice mixture containing garlic, ginger and nutmeg on the liver and kidney of cadmium exposed rats. METHODS: Male albino rats (n=30) weighing 120 - 180 g, grouped into five (1-5) of 6 rats/group were studied. Group 1 (NC) rats were administered distilled water (1 ml) orally for 4 weeks and served as the negative control while group 2 (PC) rats were administered low dose (LD) cadmium (25 mg/kg body weight) orally for 4 weeks and served as positive control. Group 3 (TBE) rats were treated with spice mixture (SM); 300 mg/kg body weight orally for 2 weeks and then administered LD cadmium for 4 weeks. While group 4 (CET) rats were concurrently administered LD cadmium and SM for 4 weeks, group 5 (TAE) rats were administered LD cadmium for 4 weeks and then treated with SM for 2 weeks. The whole experiment lasted for 42 day after which the animals were sacrificed and blood collected for determination of biochemical parameters using standard procedures and techniques. RESULTS: Exposure to Cd produced greater increases in the liver function parameters. However treatment with SM significantly (p<0.05) reduced ALT in animals treated after exposure, AST and bilirubin in those treated before exposure and significant (p<0.05) increased serum albumin in animals treated before exposure to Cd. The altered renal function parameters and total serum cholesterol were restored to near normal values following treatment with SM. CONCLUSION: It may be concluded that concurrent intake of garlic, ginger and nutmeg at culinary dose in the diet has both therapeutic and prophylactic effect at mitigating Cd toxicity and reaffirms the safely of spices combinations as being currently practiced.

Nigerian Honey Ameliorates Hyperglycemia and Dyslipidemia in Alloxan-Induced Diabetic Rats.

Diabetic dyslipidemia contributes to an increased risk of cardiovascular disease. Hence, its treatment is necessary to reduce cardiovascular events. Honey reduces hyperglycemia and dyslipidemia. The reproducibility of these beneficial effects and their generalization to honey samples of other geographical parts of the world remain controversial. Currently, data are limited and findings are inconclusive especially with evidence showing honey increased glycosylated hemoglobin in diabetic patients. It was hypothesized that this deteriorating effect might be due to administered high doses. This study investigated if Nigerian honey could ameliorate hyperglycemia and hyperlipidemia. It also evaluated if high doses of honey could worsen glucose and lipid abnormalities. Honey (1.0, 2.0 or 3.0 g/kg) was administered to diabetic rats for three weeks. Honey (1.0 or 2.0 g/kg) significantly (p < 0.05) increased high density lipoprotein (HDL) cholesterol while it significantly (p < 0.05) reduced hyperglycemia, triglycerides (TGs), very low density lipoprotein (VLDL) cholesterol, non-HDL cholesterol, coronary risk index (CRI) and cardiovascular risk index (CVRI). In contrast, honey (3.0 g/kg) significantly (p < 0.05) reduced TGs and VLDL cholesterol. This study confirms the reproducibility of glucose lowering and hypolipidemic effects of honey using Nigerian honey. However, none of the doses deteriorated hyperglycemia and dyslipidemia.

Modulation of gut microbiota in the management of metabolic disorders: the prospects and challenges.

The gut microbiota plays a number of important roles including digestion, metabolism, extraction of nutrients, synthesis of vitamins, prevention against pathogen colonization, and modulation of the immune system. Alterations or changes in composition and biodiversity of the gut microbiota have been associated with many gastrointestinal tract (GIT) disorders such as inflammatory bowel disease and colon cancer. Recent evidence suggests that altered composition and diversity of gut microbiota may play a role in the increased prevalence of metabolic diseases. This review article has two main objectives. First, it underscores approaches (such as probiotics, prebiotics, antimicrobial agents, bariatric surgery, and weight loss strategies) and their prospects in modulating the gut microbiota in the management of metabolic diseases. Second, it highlights some of the current challenges and discusses areas of future research as it relates to the gut microbiota and metabolic diseases. The prospect of modulating the gut microbiota seems promising. However, considering that research investigating the role of gut microbiota in metabolic diseases is still in its infancy, more rigorous and well-designed in vitro, animal and clinical studies are needed.

Effects of honey and its mechanisms of action on the development and progression of cancer.

Honey is a natural product known for its varied biological or pharmacological activities-ranging from anti-inflammatory, antioxidant, antibacterial, antihypertensive to hypoglycemic effects. This review article focuses on the role of honey in modulating the development and progression of tumors or cancers. It reviews available evidence (some of which is very recent) with regards to the antimetastatic, antiproliferative and anticancer effects of honey in various forms of cancer. These effects of honey have been thoroughly investigated in certain cancers such as breast, liver and colorectal cancer cell lines. In contrast, limited but promising data are available for other forms of cancers including prostate, bladder, endometrial, kidney, skin, cervical, oral and bone cancer cells. The article also underscores the various possible mechanisms by which honey may inhibit growth and proliferation of tumors or cancers. These include regulation of cell cycle, activation of mitochondrial pathway, induction of mitochondrial outer membrane permeabilization, induction of apoptosis, modulation of oxidative stress, amelioration of inflammation, modulation of insulin signaling and inhibition of angiogenesis. Honey is highly cytotoxic against tumor or cancer cells while it is non-cytotoxic to normal cells. The data indicate that honey can inhibit carcinogenesis by modulating the molecular processes of initiation, promotion, and progression stages. Thus, it may serve as a potential and promising anticancer agent which warrants further experimental and clinical studies.

Effect of honey in diabetes mellitus: matters arising.

Diabetes mellitus remains an incurable disorder in spite of intense research. As result of limitations and unmet goals associated with the use of anti-diabetic drugs, an increased number of diabetic populations globally now resort to complementary and alternative medicine (CAM) such as herbs and other natural products. There has been a renewed interest in the use of honey in the treatment of diabetes mellitus, partly due to an increase in the availability of evidence-based data demonstrating its benefits in diabetic rodents and patients. This commentary aims to underscore some of the research implications, issues and questions raised from these studies which show the beneficial effects of honey in the treatment of diabetes mellitus. Some of the issues highlighted in this article include: considering honey is sweet and rich in sugars, how could it be beneficial in the management of diabetes mellitus? Are the observed effects of honey or combined with anti-diabetic drugs exclusive to certain honey such as tualang honey? Could these beneficial effects be reproduced with other honey samples? Anti-diabetic drugs in combination with honey improve glycemic control, enhance antioxidant defenses and reduce oxidative damage. These effects are believed to be mediated partly via antioxidant mechanism of honey. This raises another question. Could similar data be obtained if anti-diabetic drugs are co-administered with other potent antioxidants such as vitamin C or E? As the evidence has revealed, the prospect of managing diabetes mellitus with honey or antioxidants (such as vitamin C or E) as an adjunct to conventional diabetes therapy is vast. However, more well-designed, rigorously conducted randomized controlled studies are necessary to further validate these findings.

Evidence in support of potential applications of lipid peroxidation products in cancer treatment.

Cancer cells generate reactive oxygen species (ROS) resulting from mitochondrial dysfunction, stimulation of oncogenes, abnormal metabolism, and aggravated inflammatory activities. Available evidence also suggests that cancer cells depend on intrinsic ROS level for proliferation and survival. Both physiological and pathophysiological roles have been ascribed to ROS which cause lipid peroxidation. In spite of their injurious effects, the ROS and the resulting lipid peroxidation products could be beneficial in cancer treatment. This review presents research findings suggesting that ROS and the resulting lipid peroxidation products could be utilized to inhibit cancer growth or induce cancer cell death. It also underscores the potential of lipid peroxidation products to potentiate the antitumor effect of other anticancer agents. The review also highlights evidence demonstrating other potential applications of lipid peroxidation products in cancer treatment. These include the prospect of lipid peroxidation products as a diagnostic tool to predict the chances of cancer recurrence, to monitor treatment progress or how well cancer patients respond to therapy. Further and detailed research is required on how best to successfully, effectively, and selectively target cancer cells in humans using lipid peroxidation products. This may prove to be an important strategy to complement current treatment regimens for cancer patients.

Honey--a novel antidiabetic agent.

Diabetes mellitus remains a burden worldwide in spite of the availability of numerous antidiabetic drugs. Honey is a natural substance produced by bees from nectar. Several evidence-based health benefits have been ascribed to honey in the recent years. In this review article, we highlight findings which demonstrate the beneficial or potential effects of honey in the gastrointestinal tract (GIT), on the gut microbiota, in the liver, in the pancreas and how these effects could improve glycemic control and metabolic derangements. In healthy subjects or patients with impaired glucose tolerance or diabetes mellitus, various studies revealed that honey reduced blood glucose or was more tolerable than most common sugars or sweeteners. Pre-clinical studies provided more convincing evidence in support of honey as a potential antidiabetic agent than clinical studies did. The not-too-impressive clinical data could mainly be attributed to poor study designs or due to the fact that the clinical studies were preliminary. Based on the key constituents of honey, the possible mechanisms of action of antidiabetic effect of honey are proposed. The paper also highlights the potential impacts and future perspectives on the use of honey as an antidiabetic agent. It makes recommendations for further clinical studies on the potential antidiabetic effect of honey. This review provides insight on the potential use of honey, especially as a complementary agent, in the management of diabetes mellitus. Hence, it is very important to have well-designed, randomized controlled clinical trials that investigate the reproducibility (or otherwise) of these experimental data in diabetic human subjects.

Honey: a novel antioxidant.

The global prevalence of chronic diseases such as diabetes mellitus, hypertension, atherosclerosis, cancer and Alzheimer's disease is on the rise. These diseases, which constitute the major causes of death globally, are associated with oxidative stress. Oxidative stress is defined as an "imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to damage". Individuals with chronic diseases are more susceptible to oxidative stress and damage because they have elevated levels of oxidants and/or reduced antioxidants. This, therefore, necessitates supplementation with antioxidants so as to delay, prevent or remove oxidative damage. Honey is a natural substance with many medicinal effects such as antibacterial, hepatoprotective, hypoglycemic, reproductive, antihypertensive and antioxidant effects. This review presents findings that indicate honey may ameliorate oxidative stress in the gastrointestinal tract (GIT), liver, pancreas, kidney, reproductive organs and plasma/serum. Besides, the review highlights data that demonstrate the synergistic antioxidant effect of honey and antidiabetic drugs in the pancreas, kidney and serum of diabetic rats. These data suggest that honey, administered alone or in combination with conventional therapy, might be a novel antioxidant in the management of chronic diseases commonly associated with oxidative stress. In view of the fact that the majority of these data emanate from animal studies, there is an urgent need to investigate this antioxidant effect of honey in human subjects with chronic or degenerative diseases.

Management of diabetes mellitus: could simultaneous targeting of hyperglycemia and oxidative stress be a better panacea?

The primary aim of the current management of diabetes mellitus is to achieve and/or maintain a glycated hemoglobin level of ≤6.5%. However, recent evidence indicates that intensive treatment of hyperglycemia is characterized by increased weight gain, severe hypoglycemia and higher mortality. Besides, evidence suggests that it is difficult to achieve and/or maintain optimal glycemic control in many diabetic patients; and that the benefits of intensively-treated hyperglycemia are restricted to microvascular complications only. In view of these adverse effects and limitations of intensive treatment of hyperglycemia in preventing diabetic complications, which is linked to oxidative stress, this commentary proposes a hypothesis that "simultaneous targeting of hyperglycemia and oxidative stress" could be more effective than "intensive treatment of hyperglycemia" in the management of diabetes mellitus.

Fructose might contribute to the hypoglycemic effect of honey.

Honey is a natural substance with many medicinal properties, including antibacterial, hepatoprotective, hypoglycemic, antioxidant and antihypertensive effects. It reduces hyperglycemia in diabetic rats and humans. However, the mechanism(s) of its hypoglycemic effect remain(s) unknown. Honey comprises many constituents, making it difficult to ascertain which component(s) contribute(s) to its hypoglycemic effect. Nevertheless, available evidence indicates that honey consists of predominantly fructose and glucose. The objective of this review is to summarize findings which indicate that fructose exerts a hypoglycemic effect. The data show that glucose and fructose exert a synergistic effect in the gastrointestinal tract and pancreas. This synergistic effect might enhance intestinal fructose absorption and/or stimulate insulin secretion. The results indicate that fructose enhances hepatic glucose uptake and glycogen synthesis and storage via activation of hepatic glucokinase and glycogen synthase, respectively. The data also demonstrate the beneficial effects of fructose on glycemic control, glucose- and appetite-regulating hormones, body weight, food intake, oxidation of carbohydrate and energy expenditure. In view of the similarities of these effects of fructose with those of honey, the evidence may support the role of fructose in honey in mediating the hypoglycemic effect of honey.

Honey supplementation in spontaneously hypertensive rats elicits antihypertensive effect via amelioration of renal oxidative stress.

Oxidative stress is implicated in the pathogenesis and/or maintenance of elevated blood pressure in hypertension. This study investigated the effect of honey on elevated systolic blood pressure (SBP) in spontaneously hypertensive rats (SHR). It also evaluated the effect of honey on the amelioration of oxidative stress in the kidney of SHR as a possible mechanism of its antihypertensive effect. SHR and Wistar Kyoto (WKY) rats were randomly divided into 2 groups and administered distilled water or honey by oral gavage once daily for 12 weeks. The control SHR had significantly higher SBP and renal malondialdehyde (MDA) levels than did control WKY. The mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione S-transferase (GST) were significantly downregulated while total antioxidant status (TAS) and activities of GST and catalase (CAT) were higher in the kidney of control SHR. Honey supplementation significantly reduced SBP and MDA levels in SHR. Honey significantly reduced the activities of GST and CAT while it moderately but insignificantly upregulated the Nrf2 mRNA expression level in the kidney of SHR. These results indicate that Nrf2 expression is impaired in the kidney of SHR. Honey supplementation considerably reduces elevated SBP via amelioration of oxidative stress in the kidney of SHR.

Oligosaccharides might contribute to the antidiabetic effect of honey: a review of the literature.

Evidence shows that honey improves glycemic control in diabetes mellitus. Besides its hypoglycemic effect, studies indicate that honey ameliorates lipid abnormalities in rats and humans with diabetes. The majority of these studies do not examine the mechanisms by which honey ameliorates glycemic and/or lipid derangements. The gut microbiota is now recognized for its ability to increase energy harvest from the diet and alter lipid metabolism of the host. Recently available data implicate a causal role of these gut microbes in the pathophysiology of obesity, insulin resistance, and diabetes mellitus. In this review, we present some of the latest findings linking gut microbiota to pathogenesis of obesity, insulin resistance, and diabetes mellitus. The review also underlines data that demonstrate the beneficial effects of oligosaccharides on various abnormalities commonly associated with these disorders. Based on the similarities of some of these findings with those of honey, together with the evidence that honey contains oligosaccharides, we hypothesize that oligosaccharides present in honey might contribute to the antidiabetic and other health-related beneficial effects of honey. We anticipate that the possibility of oligosaccharides in honey contributing to the antidiabetic and other health-related effects of honey will stimulate a renewed research interest in this field.

Differential responses to blood pressure and oxidative stress in streptozotocin-induced diabetic Wistar-Kyoto rats and spontaneously hypertensive rats: effects of antioxidant (honey) treatment.

Oxidative stress is implicated in the pathogenesis and/or complications of hypertension and/or diabetes mellitus. A combination of these disorders increases the risk of developing cardiovascular events. This study investigated the effects of streptozotocin (60 mg/kg; ip)-induced diabetes on blood pressure, oxidative stress and effects of honey on these parameters in the kidneys of streptozotocin-induced diabetic Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Diabetic WKY and SHR were randomized into four groups and received distilled water (0.5 mL) and honey (1.0 g/kg) orally once daily for three weeks. Control SHR had reduced malondialdehyde (MDA) and increased systolic blood pressure (SBP), catalase (CAT) activity, and total antioxidant status (TAS). SBP, activities of glutathione peroxidase (GPx) and glutathione reductase (GR) were elevated while TAS was reduced in diabetic WKY. In contrast, SBP, TAS, activities of GPx and GR were reduced in diabetic SHR. Antioxidant (honey) treatment further reduced SBP in diabetic SHR but not in diabetic WKY. It also increased TAS, GSH, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, activities of GPx and GR in diabetic SHR. These data suggest that differences in types, severity, and complications of diseases as well as strains may influence responses to blood pressure and oxidative stress.