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1.  Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats 
Streptozotocin (STZ) is currently the most used diabetogenic agent in testing insulin and new antidiabetic drugs in animals. Due to the toxic and disruptive nature of STZ on organs, apart from pancreas, involved in preserving the body’s normal glucose homeostasis, this study aims to reassess the action of STZ in inducing different glucose response states in diabetic rats while testing insulin. Diabetic Sprague-Dawley rats induced with STZ were classified according to their initial blood glucose levels into stages. The effect of randomizing rats in such a manner was investigated for the severity of interrupting normal liver, pancreas, and kidney functions. Pharmacokinetic and pharmacodynamic actions of subcutaneously injected insulin in diabetic and nondiabetic rats were compared. Interruption of glucose homeostasis by STZ was challenged by single and repeated administrations of injected insulin and oral glucose to diabetic rats. In diabetic rats with high glucose (451–750 mg/dL), noticeable changes were seen in the liver and kidney functions compared to rats with lower basal glucose levels. Increased serum levels of recombinant human insulin were clearly indicated by a significant increase in the calculated maximum serum concentration and area under the concentration–time curve. Reversion of serum glucose levels to normal levels pre- and postinsulin and oral glucose administrations to STZ diabetic rats were found to be variable. In conclusion, diabetic animals were more responsive to insulin than nondiabetic animals. STZ was capable of inducing different levels of normal glucose homeostasis disruption in rats. Both pharmacokinetic and pharmacodynamic actions of insulin were altered when different initial blood glucose levels of STZ diabetic rats were selected for testing. Such findings emphasize the importance of selecting predefined and unified glucose levels when using STZ as a diabetogenic agent in experimental protocols evaluating new antidiabetic agents and insulin delivery systems.
PMCID: PMC4427609  PMID: 26005328
protein delivery; animal model; diabetes mellitus; experimental; antidiabetic agents; streptozotocin
2.  Influence of Molecular Weight and Degree of Deacetylation of Low Molecular Weight Chitosan on the Bioactivity of Oral Insulin Preparations 
Marine Drugs  2015;13(4):1710-1725.
The objective of the present study was to prepare and characterize low molecular weight chitosan (LMWC) with different molecular weight and degrees of deacetylation (DDA) and to optimize their use in oral insulin nano delivery systems. Water in oil nanosized systems containing LMWC-insulin polyelectrolyte complexes were constructed and their ability to reduce blood glucose was assessed in vivo on diabetic rats. Upon acid depolymerization and testing by viscosity method, three molecular weights of LMWC namely, 1.3, 13 and 18 kDa were obtained. As for the DDA, three LMWCs of 55%, 80% and 100% DDA were prepared and characterized by spectroscopic methods for each molecular weight. The obtained LMWCs showed different morphological and in silico patterns. Following complexation of LMWCs with insulin, different aggregation sizes were obtained. Moreover, the in vivo tested formulations showed different activities of blood glucose reduction. The highest glucose reduction was achieved with 1.3 kDa LMWC of 55% DDA. The current study emphasizes the importance of optimizing the molecular weight along with the DDA of the incorporated LMWC in oral insulin delivery preparations in order to ensure the highest performance of such delivery systems.
PMCID: PMC4413183  PMID: 25826718
insulin; oral delivery; oligochitosan; low molecular weight chitosan; nanoparticles; spectroscopy; glucose; diabetic rats
3.  Dichloroacetate modulates cytokines toward T helper 1 function via induction of the interleukin-12–interferon-γ pathway 
OncoTargets and therapy  2014;7:193-201.
Dichloroacetate (DCA) is one of the new, promising anticancer drugs. DCA restores normal mitochondrial function and enables cancer cells to undergo apoptosis. In addition, DCA was found to modulate certain signaling pathways involving some transcription factors. The latter encouraged us to study DCA immunomodulatory activity on cytokines and their association with increasing DCA cancer cell cytotoxicity.
Methods and results
Cell viability assay was used to determine the effect of different concentrations of DCA on the survival of 3-methylcholanthrene (MCA) fibrosarcoma cell line. DCA decreased the percent survival of MCA fibrosarcoma in a dose-dependent manner (P<0.01). Furthermore, this percent survival was further reduced when MCA fibrosarcoma cells were cocultured with mouse splenocytes. The latter was observed at 10 mM DCA (P<0.01), and the inhibitory concentration at 50% dropped from 23 mM to 15.6 mM DCA (P<0.05). In addition, DCA significantly enhanced interferon (IFN)-γ but not interleukin (IL)-17 production levels in unstimulated and stimulated mouse spleen cells. To investigate the mechanism of DCA on IFN-γ production, DCA cytokine modulatory effect was tested on unstimulated macrophages, T-cells, and natural killer cells. DCA significantly increased IL-12 production from macrophages but did not modulate the production of IFN-γ from either T-cells or natural killer cells. Moreover, the DCA-enhancing effect on IFN-γ production was reversed by anti-IL-12 antibody. Also, the DCA cytokine modulatory effect was tested in vivo after inducing mouse skin inflammation using phorbol 12-myristate 13-acetate (PMA). DCA restored PMA-lowered IFN-γ and IL-12 levels and normalized PMA-increased transforming growth factor-β level, but it inhibited IL-10 levels even further (P<0.05).
DCA has immunomodulatory activity, mainly via activation of the IL-12–IFN-γ pathway and is able to modulate cytokines toward T helper 1 lymphocyte function. These DCA immunomodulatory effects are promising and further investigations are required to develop protocols for its use in cancer treatment.
PMCID: PMC3923616  PMID: 24532971
dichloroacetate; fibrosarcoma; cytokines; IL-12; IFN-γ; inflammation
4.  Analgesic and Toxicity Studies of Aminoacetylenic Isoindoline-1,3-dione Derivatives 
ISRN Pharmacology  2012;2012:657472.
We have developed a series of aminoacetylenic isoindoline-1,3-dione compounds and showed their anti-inflammatory activities by reducing carrageenan-induced rat paw edema and modulating proinflammatory and anti-inflammatory cytokines. In the present study and due to efficacy reasons, we are exploring only two of these compounds, namely, ZM4 and ZM5, to reveal their analgesic activity and toxicity. Following oral administration, both compounds were effective in reducing significantly (P < 0.05–0.001) acetic acid-induced writhing behavior, hot plate latency test, and formalin-induced paw licking time as antinociceptive indicators in mice and rats, respectively. Regarding the toxicity, the acute (20, 50, and 150 mg/kg) and repeated oral administration (10, 20, and 50 mg/kg) of these compounds for ten days did not produce any mortality and the compounds were considered well tolerated. However, repeated oral administration of 50 mg/kg of both compounds induced erythropoiesis by means of increasing significantly red blood cells, hemoglobin, and packed cell volume. Moreover, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic and anti-inflammatory activity compared to indomethacin as a positive control. The results indicate that ZM4 and ZM5 possess potential analgesic activity while being preliminarily safe and have minimal ulcerogenic activity.
PMCID: PMC3539427  PMID: 23316386
5.  Chitosan–Sodium Lauryl Sulfate Nanoparticles as a Carrier System for the In Vivo Delivery of Oral Insulin 
AAPS PharmSciTech  2011;12(3):958-964.
The present work explores the possibility of formulating an oral insulin delivery system using nanoparticulate complexes made from the interaction between biodegradable, natural polymer called chitosan and anionic surfactant called sodium lauryl sulfate (SLS). The interaction between chitosan and SLS was confirmed by Fourier transform infrared spectroscopy. The nanoparticles were prepared by simple gelation method under aqueous-based conditions. The nanoparticles were stable in simulated gastric fluids and could protect the encapsulated insulin from the GIT enzymes. Additionally, the in vivo results clearly indicated that the insulin-loaded nanoparticles could effectively reduce the blood glucose level in a diabetic rat model. However, additional formulation modifications are required to improve insulin oral bioavailability.
PMCID: PMC3167251  PMID: 21761276
chitosan; insulin; nanoparticles; oral delivery system; sodium lauryl sulfate
6.  Effects of Prickly Pear Dried Leaves, Artichoke Leaves, Turmeric and Garlic Extracts, and Their Combinations on Preventing Dyslipidemia in Rats 
ISRN Pharmacology  2012;2012:167979.
The successful use of herbal combinations in managing diseases or conditions over a single herb has lead us to evaluate the anti-dyslipidemic properties of the combination of the artichoke leaves extract, turmeric extract, prickly pear dried leaves (PPL) and garlic extract versus each one alone in two different hyperlipidemic animal models. A two-week treatment of each of the natural extracts, combination 1 (artichoke, turmeric and PPL) or combination 2 (artichoke, turmeric, PPL and garlic) prior to a single intraperitoneal injection of Pluronic F-127 resulted in decreasing significantly serum LDL levels by garlic and PPL extracts and serum LDL/HDL ratios by turmeric, PPL, combination 1 and 2. In a 10-day high fat diet model, only the combination 1 and 2 lowered serum cholesterol, LDL by 8–12%, decreased significantly triglycerides, LDL/HDL ratio; and increased significantly HDL (P < 0.0001). However, a long term treatment of each natural product for 7 weeks resulted in decreasing significantly serum LDL levels and LDL/HDL ratio (P < 0.05–0.0001). Furthermore, only artichoke and PPL inhibited significantly HMG-CoA reductase activity (P < 0.05). In conclusion, short term, as well as long term, treatment using the combination of artichoke, turmeric, PPL and garlic extract prevents dyslipidemia; partially through inhibiting HMG-CoA reductase.
PMCID: PMC3395130  PMID: 22811929
7.  Plasma concentrations of 25-hydroxyvitamin D among Jordanians: Effect of biological and habitual factors on vitamin D status 
Vitamin D is cutaneously synthesized following sun exposure (vitamin D3) as well as it is derived from dietary intake (vitamin D3 and D2). Vitamin D2 and D3 are metabolized in the liver to 25-hydroxyvitamin D (25(OH)D). This metabolite is considered the functional indicator of vitamin D stores in humans. Since Jordan latitude is 31°N, cutaneous synthesis of vitamin D3 should be sufficient all year round. However, many indications reveal that it is not the case. Thus, this study was conducted to determine the 25(OH)D status among Jordanians.
Three hundred healthy volunteers were enrolled in a cross sectional study; 201 females and 99 males. 25(OH)D and calcium concentrations were measured by enzyme linked immunosorbent assay and spectroscopy techniques, respectively. All participants filled a study questionnaire that covered age, sex, height, weight, diet, and dress style for females. Females were divided according to their dress style: Western style, Hijab (all body parts are covered except the face and hands), and Niqab (all body parts are covered including face and hands).
The average plasma 25(OH)D levels in males and females were 44.5 ± 10.0 nmol/l and 31.1 ± 12.0 nmol/l, respectively. However, when female 25(OH)D levels were categorized according to dress styles, the averages became 40.3, 31.3 and 28.5 nmol/l for the Western style, Hijab and Niqab groups, respectively. These 25(OH)D levels were significantly less than those of males (p < 0.05, 0.001, 0.001, respectively). In addition, the plasma 25(OH)D levels of the Western style group was significantly higher than those of Hijab and Niqab groups (p < 0.001). Furthermore, dairy consumption in males was a positive significant factor in vitamin D status. Even though calcium concentrations were within the reference range, the Hijab and Niqab-dressed females have significantly less plasma calcium levels than males (p < 0.01).
Very low plasma 25(OH)D levels in females wearing Hijab or Niqab are highly attributed to low sunlight or UVB exposure. In addition, most of males (76%) and Western style dressed females (90%) have 25(OH)D concentrations below the international recommended values (50 nmol/l), suggesting that although sun exposure should be enough, other factors do play a role in these low concentrations. These findings emphasize the importance of vitamin D supplementation especially among conservatively dressed females, and determining if single nucleotide polymorphisms of the genes involved in vitamin D metabolism do exist among Jordanians.
PMCID: PMC3163511  PMID: 21816088
(25-OHD); Vitamin D2; Vitamin D3; Diet; Dress Styles; Hypovitaminosis D; Jordan
8.  Eriobotrya japonica hydrophilic extract modulates cytokines in normal tissues, in the tumor of Meth-A-fibrosarcoma bearing mice, and enhances their survival time 
Cytokines play a key role in the immune response to developing tumors, and therefore modulating their levels and actions provides innovative strategies for enhancing the activity of antigen presenting cells and polarizing towards T helper 1 type response within tumor microenvironment. One of these approaches could be the employment of plant extracts that have cytokine immunomodulation capabilities. Previously, we have shown that the Eriobotrya japonica hydrophilic extract (EJHE) induces proinflammatory cytokines in vitro and in vivo.
The present study explored the in vivo immunomodulatory effect on interferon-gamma (IFN-γ), interleukin-17 (IL-17), and transforming growth factor-beta 1 (TGF-β1) evoked by two water-extracts prepared from EJ leaves in the tissues of normal and Meth-A-fibrosarcoma bearing mice.
Intraperitoneal (i.p.) administration of 10 μg of EJHE and EJHE-water residue (WR), prepared from butanol extraction, increased significantly IFN-γ production in the spleen (p < 0.01) and lung (p < 0.03) tissues at 6-48 hours and suppressed significantly TGF-β1 production levels (p < 0.001) in the spleen for as long as 48 hours. The latter responses, however, were not seen in Meth-A fibrosarcoma-bearing mice. On the contrary, triple i.p. injections, 24 hours apart; of 10 μg EJHE increased significantly IFN-γ production in the spleen (p < 0.02) while only EJHE-WR increased significantly IFN-γ, TGF-β1 and IL-17 (p < 0.03 - 0.005) production within the tumor microenvironment of Meth-A fibrosarcoma. In addition, the present work revealed a significant prolongation of survival time (median survival time 72 days vs. 27 days of control, p < 0.007) of mice inoculated i.p. with Meth-A cells followed by three times/week for eight weeks of i.p. administration of EJHE-WR. The latter prolonged survival effect was not seen with EJHE.
The therapeutic value of EJHE-WR as an anticancer agent merits further investigation of understanding the effect of immunomodulators' constituents on the cellular components of the tissue microenvironment. This can lead to the development of improved strategies for cancer treatment and thus opening up a new frontier for future studies.
PMCID: PMC3045389  PMID: 21294856
9.  Bioadhesive Controlled Metronidazole Release Matrix Based on Chitosan and Xanthan Gum 
Marine Drugs  2010;8(5):1716-1730.
Metronidazole, a common antibacterial drug, was incorporated into a hydrophilic polymer matrix composed of chitosan xanthan gum mixture. Hydrogel formation of this binary chitosan-xanthan gum combination was tested for its ability to control the release of metronidazole as a drug model. This preparation (MZ-CR) was characterized by in vitro, ex vivo bioadhesion and in vivo bioavailability study. For comparison purposes a commercial extended release formulation of metronidazole (CMZ) was used as a reference. The in vitro drug-release profiles of metronidazole preparation and CMZ were similar in 0.1 M HCl and phosphate buffer pH 6.8. Moreover, metronidazole preparation and CMZ showed a similar detachment force to sheep stomach mucosa, while the bioadhesion of the metronidazole preparation was higher three times than CMZ to sheep duodenum. The results of in vivo study indicated that the absorption of metronidazole from the preparation was faster than that of CMZ. Also, MZ-CR leads to higher metronidazole Cmax and AUC relative to that of the CMZ. This increase in bioavailability might be explained by the bioadhesion of the preparation at the upper part of the small intestine that could result in an increase in the overall intestinal transit time. As a conclusion, formulating chitosan-xanthan gum mixture as a hydrophilic polymer matrix resulted in a superior pharmacokinetic parameters translated by better rate and extent of absorption of metronidazole.
PMCID: PMC2885086  PMID: 20559494
metronidazole; chitosan; xanthan gum; bioadhesion; bioavailability

Results 1-9 (9)