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There are several therapeutic approaches in type 2 diabetes mellitus (T2DM). When diet and exercise fail to control hyperglycemia, patients are forced to start therapy with antidiabetic agents. However, these drugs present several drawbacks that can affect the course of treatment. The major disadvantages of current oral modalities for the treatment of T2DM are mainly depicted in the low bioavailability and the immediate release of the drug, generating the need for an increase in frequency of dosing. In conjugation with the manifestation of adverse side effects, patient compliance to therapy is reduced. Over the past few years nanotechnology has found fertile ground in the development of novel delivery modalities that can potentially enhance anti-diabetic regimes efficacy. All efforts have been targeted towards two main vital steps: (a) to protect the drug by encapsulating it into a nano-carrier system and (b) efficiently release the drug in a gradual as well as controllable manner. However, only a limited number of studies published in the literature used in vivo techniques in order to support findings. Here we discuss the current disadvantages of modern T2DM marketed drugs, and the nanotechnology advances supported by in vivo in mouse/rat models of glucose homeostasis. The generation of drug nanocarriers may increase bioavailability, prolong release and therefore reduce dosing and thus, improve patient compliance. This novel approach might substantially improve quality of life for diabetics. Application of metal nanoformulations as indirect hypoglycemic agents is also discussed., Graphical abstract Image, graphical abstract

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) represent two major chronic diseases that affect a large percentage of the population and share common pathogenetic mechanisms, including oxidative stress and inflammation. Considering their common mechanistic aspects, and given the current lack of effective therapies for AD, accumulating research has focused on the therapeutic potential of antidiabetic drugs in the treatment or prevention of AD.This review examines the latest preclinical and clinical evidence on the potential of antidiabetic drugs as candidates for AD treatment. Numerous approved drugs for T2DM, including insulin, metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium glucose cotransporter 2 inhibitors (SGLT2i), are in the spotlight and may constitute novel approaches for AD treatment.Among other pharmacologic agents, GLP-1 RA and SGLT2i have so far exhibited promising results as novel treatment approaches for AD, while current research has centered on deciphering their action on the central nervous system (CNS). Further investigation is crucial to reveal the most effective pharmacological agents and their optimal combinations, maximize their beneficial effects on neurons, and find ways to increase their distribution to the CNS.

The cytotoxic and antitumour activities of five organotin complexes (1–5) with o-hydroxy-benzoic or p-hydroxy-benzoic acids were evaluated in a series of in vitro and in vivo experiments. All complexes exhibited strong cytotoxic activity against all cancer cells lines, whereas complexes 1, 2 and 4 induced apoptosis at significantly lower doses than complexes 3 and 5. Human cancer cells treated with increasing concentrations of complexes 1, 2 and 4 gradually lost their ability to form colonies. Only complexes 1 and 2 inhibited colony formation efficiency in rat leiomyosarcoma cells. Histopathology of liver and kidney showed mild damage and lung oedema after a single injection of 10 mg/kg body wt of complex 1 to Wistar rats. At higher doses (100 mg/kg body wt) brain stem oedema was observed. Daily administration of tumour-bearing Wistar rats (leiomyosarcoma) with 1 mg/kg body wt of complex 1 until death reduced the mean tumour growth rate by more than 3× fold and prolonged mean survival time by 120%. These findings indicate that the organotin complexes with ortho- or para-hydroxy-benzoic acids possess potent cytotoxic and antitumour activity and they could be used as potential chemotherapeutic agents.

Background. Cisplatin (cis-diamminedichloroplatinum) is a widely used chemotherapeutic agent for the treatment of various cancers. Although it represents an effective regimen, its application is accompanied by side effects to normal tissues, especially to the kidneys. Cisplatin generates free radicals and impairs the function of antioxidant enzymes. Modulation of cisplatin-induced oxidative stress by specific antioxidant molecules represents an attractive approach to minimize side effects. Methods. We studied the ability of curcumin to sensitize leiomyosarcoma (LMS) cells to cisplatin. Assays for cell proliferation, mitochondrial function, induction of apoptosis, and cell cycle arrest were performed using various concentrations of cisplatin and a concentration of curcumin that caused a nonsignificant reduction in cell viability. Moreover, the effect of curcumin was examined against cisplatin-induced experimental nephrotoxicity. Renal injury was assessed by measuring serum creatinine, blood urea nitrogen (BUN), and the kidney’s relative weight. Oxidative stress was measured by means of enzymatic activities of superoxide dismutase and glutathione peroxidase in the rats’ blood and malondialdehyde levels in rats’ urine. Results. In our study, we found that curcumin sensitizes LMS cells to cisplatin by enhancing apoptosis and impairing mitochondrial function. In an in vivo model of cisplatin-induced experimental nephrotoxicity, intraperitoneal administration of curcumin failed to preserve blood’s antioxidant enzyme activity and decrease lipid peroxidation. Nevertheless, curcumin was able to protect nephrons’ histology from cisplatin’s toxic effect. Conclusion. Our results showed that curcumin can act as chemosensitizer, but its role as an adjunctive cisplatin-induced oxidative stress inhibitor requires further dose-finding studies to maximize the effectiveness of chemotherapy.

Since the initial success of cisplatin, metal complexes and organometallic compounds have been gaining growing interest in cancer therapy. It is well known that organotin(IV) compounds display strong biological activity. The triorganotin compound [(C(6)H(5))(3)Sn(cmbzt)] (cmbzt=5-chloro-2-mercaptobenzothiazole) (SnCMB), was tested for its antiproliferative and antitumour activities. Two sets of experimental procedures were followed: (1) In vitro and ex vivo procedures included the study of the cytotoxic activity of the complex against leiomyosarcoma cells (LMS) and on a normal human fibroblast line (MRC5) by the MTT assay (cell proliferation), colony formation efficiency and flow cytometric analysis with Annexin V-FITC. The anticoagulation properties of the complex were also studied. (2) In vivo procedures included acute toxicity studies and finally administration of the complex to tumour bearing Wistar rats. The results showed that the complex exhibited potent cytotoxic activity (LMS IC(50)=155 nM) and induced significant apoptosis against LMS cells. Acute toxicity studies on Wistar rats presented kidney and liver toxicity at a single dose of 40 mg/kg body wt. Furthermore, antitumour activity studies on sarcoma bearing Wistar rats revealed that SnCMB complex, administrated in two different therapeutic schemes (treated with 4 × 2 mg/kg body wt every 5 days and 3 × 2.67 mg/kg body wt every 10 days of SnCMB complex), prolonged mean survival time (by 50% and 70% respectively), but failed to decrease the mean tumour growth rate (MTGR) compared to the control group (p

Objectives The objective of this study was to investigate the effects of catechin and epicatechin on the activity of the endogenous antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) (as well as the total antioxidant capacity (TAC)) of rats after intra-peritoneal (i.p.) administration. Methods Twenty-four Wistar rats were randomly divided into two groups: the experimental group which was administered daily with a 1:1 mixture of epicatechin and catechin at a concentration of 23 mg/kg body weight for 10 days and the control group which was injected daily with an equal amount of saline. Blood and urine samples were collected before and after the administration period, as well as 10 days after (follow-up). Results Intra-peritoneal administration of catechins led to a potent decrease in GPx levels and a significant increase in SOD levels. TAC was significantly increased in plasma and urine. Malonaldehyde levels in urine remained stable. In the animals treated with catechins, SOD activity showed a moderate negative correlation with GPx activity. Discussion Boosting the activity of the antioxidant enzymes could be a potential adjuvant approach for the treatment of the oxidative stress-related diseases.

PurposeKefir is a probiotic grown with milk, with a slightly sour flavor and has been consumed for thousands of years. Kefir grains contain bacteria and yeast. In the past, kefir was administrated as a drug against tuberculosis, cancer and gastrointestinal disorders. The purpose of this paper is to investigate the potential anticancer properties of kefir and its ability to affect natural killer cells' (NKCs') activity.Design/methodology/approachThe assay of cytotoxic activity of NKCs by cytometric analysis was used, which included four stages: isolation of natural killers; quantification of target cells; incubation of natural killers with target cells at ratios of 12.5:1, 25:1 and 50:1 in CO2 incubator; and measurement of cells with flow cytometer. The same procedures were repeated, but the third stage was modified with the addition and incubation of 50, 75, and 100 μL kefir (of 24 hour culture with 3.5 per cent fresh milk) with K562 and leiomyosarcoma cells lines, and kefir and NK cells with K562 or LMS cell lines.FindingsThe results showed that kefir's cytotoxic activity without the presence of NKCs reached an average of 85 per cent in both cell lines. With the addition of NK cells in kefir, the cytotoxic activity further increased by 10 per cent. Kefir alone did not cause any statistically significant death in NK cells. Kefir seems to have significant cytotoxic action by itself without stimulating NK cells in a significant manner. However, further studies are needed to establish the role of kefir in the prevention and treatment of neoplasmatic diseases.Originality/valueThe paper provides information and new data, for nutritionists and clinical dietitians, about the effects of kefir in the prevention of cancer.

There is significant scientific investigation taking place into the function and the mechanisms of action of natural killer (NK) cells (NKCs). Many plant extracts and vitamin supplements may play an immunoregulatory role by stimulating the functionality of the NKCs. The present study was designed to evaluate the in vitro and in vivo effects of vitamin C and Aloe vera juice on NK activity. In the in vitro experiments the activity of various concentrations of vitamin C (ranging from 3 · 10 � 3 Mt o 3· 10 � 9 M) and Aloe vera juice (50 ll) were examined in the modulation of the NKCs functionality, taken from blood samples collected from 12 healthy volunteers. The in vivo experiments were performed on 15 healthy volunteers, who took supplements of a combination of 1 g/day of vitamin C and 50 ml of Aloe vera juice for 45 consecutive days. The in vitro results showed that both substances increased NKC cytotoxicity against K562 cancer cell line. Furthermore, in the in vivo experiment the cytotoxicity of the NK was significantly increased compared to the pre-supplementation values (p < 0.05) under all three conditions tested. These results indicate that vitamin C and Aloe vera juice can modulate NK cells cytotoxicity and has the potential to enhance the immune system.

Platelets play an important role in homeostasis, inflammation and regulation of immune response. Natural Killer cells (NKC) on the other hand are the first line of defense of the immune system against viruses, bacteria and cancer cells. Platelets directly protect tumor cells from NK lysis. Thus, platelet aggregation around migrating cancer cells as well as the response of the immune system constitutes important mechanisms, which influence the progression of malignant diseases. The present study was designed to evaluate the possible effects of flavonoids (genistein, apigenin and quercetin) on the stimulation of the immune system and the inhibition of platelet aggregation. Two experimental protocols were used: a) Â ex vivo aggregation of human platelets, production of thromboxane A 2 (TXA 2 ) and estimation of the expression of the platelet membranic receptor GpIIb/IIIa, and b) functional activity of human NK lymphocytes against K562 target cells in vitro . All substances were found to induce a dose dependent inhibition of platelet aggregation and to reduce production of TXA 2 in platelets. There was a decrease in the number of the GpIIb/IIIa receptors on the platelets surface membrane. Flow cytometry analysis revealed that all substances powerfully reinforce cytotoxic activity of NKC against K562 cells. These results show that flavonoids increase the susceptibility of tumor cells to NK cells by decreasing platelet aggregation and stimulating the NK lymphocyte activity.

Nowadays, investigation for possible therapeutic applications of various metal-based drugs attracts the scientific interest worldwide. The triorganotin compound bis[triphenyltin(IV)](3-carboxy-pyridine-2-thionato) (SnMNA), was tested for its anti-proliferative and antitumor activities. Cytotoxic activity was assessed by Trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT). SnMNA exhibited potent cytotoxic effects against leiomyosarcoma cells (LMS) and human breast adenocarcinoma cells (MCF-7), which is 200 times stronger than that of cisplatin. Moreover, SnMNA induced significant apoptosis in LMS and MCF-7 cells characterized by flow cytometry analysis and DNA fragmentation. Acute and chronic toxicity studies on Wistar rats caused kidney and lung toxicity at a single dose of 80 mg/kg Body Weight (BW) or four repeated doses of 8 mg/kg BW once per week. Furthermore, antitumor activity studies on sarcoma bearing Wistar rats revealed that SnMNA complex at four repeated doses of 5.4 mg/kg BW every three days prolonged mean survival time of the animal at 200% and decreased mean tumor growth rate (MTGR) compared to the control group (p < 0.05). It is noteworthy to mention that the 30% (3 out of 10) of the bearing animals were totally cured. These findings indicate that SnMNA might be a promising new antitumor agent. (C) 2010 Elsevier B.V. All rights reserved. European Journal of Pharmaceutical Sciences

The main catecholamine end-metabolites have been considered biologically inactive, but accumulated evidence indicates a variety of pharmacological actions after exogenous administration. We examined the dose-related haemodynamic effects of vanillylmandelic acid in the in vivo rat-model. One hundred and sixteen Wistar rats (250 ± 20 g) were studied under continuous electrocardiographic monitoring; invasive blood pressure was recorded for 60 min through a catheter in the right common carotid artery. Measurements were performed at baseline and after vanillylmandelic acid (1, 10, 100mg/kg) and homovanillic acid (10mg/kg) intra-arterial administration. To examine the underlying mechanisms, the haemodynamic effects were compared with those (a) after trimetazidine administration, which has similar structure due to a tri-methylated phenolic ring; (b) after epinephrine and isoprenaline administration following vanillylmandelic acid pretreatment; (c) after vanillylmandelic acid administration post-bilateral vagotomy. Vanillylmandelic acid, homovanillic acid and (to a lesser extent) trimetazidine decreased heart rate and mean arterial blood pressure. This effect was blunted in vagotomized animals. Comparable effects were noted in heart rate and blood pressure after adrenaline and isoprenaline infusion, with and without vanillylmandelic acid-pretreatment. In conclusion, vanillylmandelic acid administration decreases heart rate dose-dependently, mediated by increased vagal tone, without α- or β-adrenergic-receptor blocking effects. The pharmacological properties of compounds with a mono- and tri-methylated phenolic ring merit further investigation.

Exposure to various types of electromagnetic fields (EMFs) affects pain specificity (nociception) and pain inhibition (analgesia). Previous study of ours has shown that exposure to the resonant spectra derived from biologically active substances' NMR may induce to live targets the same effects as the substances themselves. The purpose of this study is to investigate the potential analgesic effect of the resonant EMFs derived from the NMR spectrum of morphine. Twenty five Wistar rats were divided into five groups: control group; intraperitoneal administration of morphine 10 mg/kg body wt; exposure of rats to resonant EMFs of morphine; exposure of rats to randomly selected non resonant EMFs; and intraperitoneal administration of naloxone and simultaneous exposure of rats to the resonant EMFs of morphine. Tail Flick and Hot Plate tests were performed for estimation of the latency time. Results showed that rats exposed to NMR spectrum of morphine induced a significant increase in latency time at time points (p 0.05), while exposure to the non resonant random EMFs exerted no effects. Additionally, naloxone administration inhibited the analgesic effects of the NMR spectrum of morphine. Our results indicate that exposure of rats to the resonant EMFs derived from the NMR spectrum of morphine may exert on animals similar analgesic effects to morphine itself.

Oxidative stress is considered as a prominent feature of many acute and chronic diseases as well as of the normal aging process. We examined the effects of intra-peritoneal administration of catechins and EGCG as in vivo inhibitors of oxidative stress induced by ozone administration in two groups of Wistar rats. The first group was treated by intra-peritoneal administration of catechins and EGCG after the administration of ozone and the second group was pretreated by intra-peritoneal administration of catechins and EGCG prior to ozone administration. We determined in blood the activity of the enzymes superoxide dismutase and glutathione peroxidase, total antioxidant capacity, levels of copper and zinc and in urine malonaldehyde contents. Ozone administration resulted in significant reduction of glutathione peroxidase activity, plasma zinc levels and plasma and Red Blood Cells antioxidant capacity. Catechins and EGCG upregulate superoxide dismutase activity and maintain plasma and Red Blood Cells antioxidant capacity. Malonaldehyde levels at the end of the study were significantly increased only in the first group. Our data demonstrate that treatment with catechins and EGCG cannot reverse or prevent the effects of oxidative stress although some modulation occurs. Phytomedicine