New potentials for 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase inhibitors: Possible applications in retarding diabetic complications.

The prevalence of diabetes mellitus is increasing all over the world and it is apparent that treatment of diabetic complications has the same importance as primary diabetes treatment and glycemic control. Diabetic complications occur as a result of prolonged hyperglycemia and its consequences, such as advanced glycation end products and reactive oxygen species. Impairment of lipid profile is also contributed to worsening diabetic complications. Therefore, it seems that the application of lipid-lowering agents may have positive effects on reversing diabetic complications besides glycemic control. Statins, a group of lipid-lowering compounds, have been shown to exert antioxidant, immunomodulatory, anti-inflammatory, and antiproliferative properties beyond their lipid-lowering effects. Furthermore, they have been reported to improve diabetic complications with different pathways. In this review, we will discuss the clinical importance, molecular biology of the most important microvascular/macrovascular diabetic complications, possible application of statins and their mechanism of action in retarding these complications.

Polyelectrolyte Carboxymethyl Cellulose for Enhanced Delivery of Doxorubicin in MCF7 Breast Cancer Cells: Toxicological Evaluations in Mice Model.

PURPOSE: Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems have opened a new window to overcome these problems. METHODS: A polyelectrolyte carboxymethyl cellulose polymer as a magnetic nanocarrier was synthesized for enhancing delivery and uptake of doxorubicin in MCF7 breast cancer cells and decreasing the adverse toxic effects to healthy tissues. RESULTS: The physicochemical properties of developed nanocarrier showed that it can be used in drug delivery purposes. The efficiency of the delivery system was assessed by loading and release studies. Besides, biological assays including protein-particle interaction, hemolysis assay, cytotoxicity study, cellular uptake, and apoptosis analysis were performed. All results persuaded us to investigate the cytotoxic effects of nanocarrier in an animal model by determining the biochemical parameters attributed to organ injuries, and hematoxylin and eosin (H&E) staining for histopathological manifestations. We observed that the nanocarrier has no toxic effect on healthy tissues, while, it is capable of reducing the toxic side effects of doxorubicin by more cellular internalization. CONCLUSION: Chemical characterizations and biological studies confirmed that developed nanocarrier with permanent cationic groups of imidazolium and anionic carboxylic acid groups is an effective candidate for anticancer drug delivery.

ß-LAPachone is renoprotective in streptozotocin-induced diabetic mice via regulating the PI3K/Akt/mTOR signaling pathway.

OBJECTIVES: ß-LAPachone (B-LAP) is a natural product with established anti-inflammatory properties. In this study, we investigated the protective potential of B-LAP against diabetic nephropathy in streptozotocin (STZ) induced diabetic mice. MATERIALS AND METHODS: Diabetes induction in mice was carried out by a single intraperitoneal injection of STZ. 2.5 mg/kg/day and 5 mg/kg/day doses of B-LAP were administered orally for twelve weeks and renal histoarchitecture, caspase-3, tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), glutathione peroxidase (GPX), as well as urinary nephrin and neutrophil gelatinase-associated lipocalin (NGAL) were evaluated. Additionally, kidney levels of PI3K, phosphorylated (p)-Akt, p-mTOR, p-CREB, and SIRT1 were assessed in the present investigation. RESULTS: 5 mg/kg B-LAP significantly decreased urinary excretions of nephrin and NGAL. It also mitigated renal TNF-α and MDA levels and simultaneously improved GPX activities. 5 mg/kg B-LAP improved renal function in diabetic mice as indicated by elevated values of creatinine clearance. While B-LAP elevated renal levels of SIRT1, it alleviated PI3K, p-Akt, p-mTOR, and p-CREB levels in the kidneys of diabetic mice. CONCLUSION: Collectively, these findings suggest B-LAP as a potential renoprotective agent in STZ-induced diabetic mice probably via modulating the PI3K/Akt/mTOR pathway.

Pro-oxidant and degenerative effects of haloperidol under inflammatory conditions in rat; the involvement of SIRT1 and NF-κB signaling pathways.

The present study was conducted to evaluate the effects of different doses of haloperidol (HP) on induction of oxidative stress in blood and liver cell degeneration in comparison with influences of HP pre-treatment on inflammatory process induced by intraperitoneal (IP) administration of lipopolysaccharide (LPS). One hundred twenty male albino Wistar rats were randomly divided into eight groups (15 in each), including: Control group, LPS group, three groups as HP administration in three divided doses (0.50, 1.00 and 2.00 mg kg-1), and three treatment groups that HP was administered in three doses (0.50, 1.00 and 2.00 mg kg-1) prior to LPS administration. Concentrations of malondialdehyde, activities of antioxidant enzymes including glutathione peroxidase, superoxide dismutase and also the levels of tumor necrosis factor-alpha and interleukin 1-beta were measured in blood and serum. In addition to liver histopathological changes evaluation, hepatic silent information regulator of transcription 1 (SIRT1) and phosphorylated-nuclear factor-κB (p-NF-κB) levels were quantitated. Our findings indicated that sole administration of HP (particularly higher doses) can induce oxidative stress in blood and cell degeneration in liver, while it can attenuate inflammatory process induced by LPS administration presumably via SIRT1 up-regulation and preventing the induction of p-NF-κB. The oxidative and degenerative effects of HP and its impact on inflammatory status were completely dose- dependent according to our results. The possible anti-inflammatory effects of HP may affect reparative mechanisms and hepatic cell degeneration. However, the influences of HP on immune system need further investigations and its higher doses should be administered cautiously especially in patients with immune system dysfunctions.

Immune-mediated anti-tumor effects of metformin; targeting metabolic reprogramming of T cells as a new possible mechanism for anti-cancer effects of metformin.

Immunotherapy-based cancer treatment has revolutionized the era of cancer patients recuperation and it has brought a strong hope to treatment of some types of cancers. Metformin, a widely used antidiabetic drug, which has intensely been studied for its anticancer effects, is believed to have positive influences on immune responses against tumor cells. Metformin can affect metabolic pathways within cells mainly through activation of AMPK. Metabolic restriction of tumor microenvironment on effector immune cells is one of the important strategies favoring tumor cells to escape from immunogenic cell death. The metabolism of T cells has an axial role in shaping and supporting immune responses and may have an important role in anticancer immunity, suggesting that the functionality and durability of tumor-specific T cells need sufficient energy and nutrients. Energy biogenesis of tumor-specific cytotoxic T cells has become an interesting field of study and it is suggested that activation and maintenance of effector T cell responses in tumor microenvironment may occur by metabolic reprogramming of T cells. AMPK has been noticed as the main intracellular energy sensor and mitochondrial biogenesis key regulator which can control and regulate metabolic reprogramming in immune cells and increase antitumor immunity. Metabolic reprogramming of T cells to overcome metabolic restriction in tumor microenvironment, maiming effector T cell responses against tumor cells, has been noticed by several studies. Here we represent metformin, an AMPK activator, as a new candidate drug for metabolic reprogramming of tumor-specific T cells to increase the efficacy and accountability of cancer immunotherapy.

Targeting PPAR ligands as possible approaches for metabolic reprogramming of T cells in cancer immunotherapy.

Despite the prominent progress in understanding cancer immunosurveillance mechanisms, there are some types of problems which have been identified to hinder effective and successful immunotherapy of cancers. Such problems have been ascribed to the tumor abilities in the creation of a tolerant milieu that can impair immune responses against cancer cells. In the present study, we represent possible approaches for metabolic reprogramming of T cells in cancer immunotherapy to overcome tumor metabolic impositions on immune responses against cancer cells. Metabolic suppression of effector immune cells in tumor milieu is one of the important strategies recruited by tumor cells to escape from immunogenic cell death. We have investigated the metabolic reprogramming of T cells as a method and a possible new target for cancer immunotherapy. Synergic effects of PPAR ligands in immunotherapy of cancers on the metabolic reprogramming of T cells have been noticed by several studies as a new target of cancer immunotherapy. The current wealth of data like this promises a future scenario which the consideration of metabolic restriction in the tumor microenvironment and administration of therapeutic agents such as PPAR ligands to overcome metabolic restrictions on T cells (refreshing their functionality) may be effective and enhance the accountability and efficacy of cancer immunotherapy.

Major fundamental factors hindering immune system in defense against tumor cells: The link between insufficiency of innate immune responses, metabolism, and neurotransmitters with effector immune cells disability.

Despite the major progresses in comprehending the mechanisms of tumor immunosurveillance and the role of innate and adaptive immune systems in recent years, there are still a number of obstacles hindering successful and effective immunotherapy of cancer. Such obstacles have been mainly attributed to the ability of tumors in creating a tolerant microenvironment and exploiting a plethora of immunosuppressive factors that counter effective immune responses against tumor cells. Here we represent a new insight into probable links between immune system disability with metabolism and chronic psychological stress which is beyond the other strategies recruited by tumors to thwart tumor immunosurveillance. In addition, we underscore the prominent role of improper innate immune responses as one of the underlying causes of either pro-tumorigenic capability or tumor immunosurveillance failure. However the insufficiency of stimulatory factors in immune responses is a major fact leading to tumor survival, metabolic suppression of immune cells in tumor microenvironment, as well as the negative influences of chronic stress and depression in cancer patients are important parameters amplifying disability of immune responses which have mostly been underestimated in cancer immunotherapy. Stress-related catecholamines are suggested as immunosuppressive factors. In addition, tumor cells have distinct metabolic pathways and secrete various metabolites in the tumor microenvironment which may inhibit T cells activity. We believe that simultaneous control of metabolic and psychological negative influences on the tumor immunosurveillance, along with addressing the weak aspects of innate and adaptive immune responses in cancer immunotherapy may result in more successful treatment of tumors.

Possible Protective Effects of Thiazolidinediones Antidiabetic Drugs in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers worldwide, and it is considered the fourth most common cause of life-threatening cancers. Diabetes mellitus, especially type 2 diabetes, is an independent risk factor for CRC, due to shared risk factors like physical inactivity and obesity. Thiazolidinediones (TZDs) are among the most common medications for type 2 diabetes mellitus. Recent investigations have suggested a correlation between TZD usage (in a time-dependent manner) and reduced risk of CRC such that a longer period of TZDs treatment can lead to higher protection against CRC. TZDs have antitumor effects in a wide variety of in vitro and in vivo cancer models through different mechanisms such as the impacts on cell cycle, apoptosis, cell differentiation, and angiogenesis. These effects can be mediated via both peroxisome proliferator-activated receptors γ (PPARγ)-dependent and PPARγ-independent pathways. Due to the protective effects of TZDs in cancer prevention and treatment, they can be considered potent adjuvants in cancer treatment. In the current review, we discuss the effects of TZDs on prevention and treatment of cancers, with special emphasis on CRC and the association of TZD administration with metabolic regulation of T cells in defense against tumor cells.

Metformin; an old antidiabetic drug with new potentials in bone disorders.

The prevalence of diabetes mellitus especially type 2 diabetes mellitus is increasing all over the world. In addition to cardiomyopathy and nephropathy, diabetics are at higher risk of mortality and morbidity due to greater risk of bone fractures and skeletal abnormalities. Patients with diabetes mellitus have lower bone quality in comparison to their non-diabetic counterparts mainly because of hyperglycemia, toxic effects of advanced glycosylation end-products (AGEs) on bone tissue, and impaired bone microvascular system. AGEs may also contribute to the development of osteoarthritis further to osteoporosis. Therefore, glycemic control in diabetic patients is vital for bone health. Metformin, a widely used antidiabetic drug, has been shown to improve bone quality and decrease the risk of fractures in patients with diabetes in addition to glycemic control and improving insulin sensitivity. AMP activated protein kinase (AMPK), the key molecule in metformin antidiabetic mechanism of action, is also effective in signaling pathways involved in bone physiology. This review, discusses the molecules linking diabetes and bone turnover, role of AMPK in bone metabolism, and the effect of metformin as an activator of AMPK on bone disorders and malignancies.

ß-Lapachone protects against doxorubicin-induced nephrotoxicity via NAD+/AMPK/NF-kB in mice.

ß-Lapachone (B-LAP) is a natural naphtaquinone with established anti-oxidative stress and anti-cancer activities. We aimed to investigate B-LAP protective potential against doxorubicin (DOX)-induced nephrotoxicity in mice. The mice received an oral dose of B-LAP followed by a single intraperitoneal injection of 20 mg/kg DOX a day later. They were then treated for 4 days with 1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg doses of B-LAP. Renal levels of NAD+/NADH ratios, p-AMPKα, p-NF-κB p65, inducible nitric oxide synthase (iNOS), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) along with renal expressions of TNF-α, IL-1ß, and IL-6 were examined. Serum levels of kidney function markers as well as renal histopathology were also investigated. In addition to increasing the activities of p-AMPKα, B-LAP elevated NAD+/NADH ratios in the kidneys and decreased the renal levels of nuclear p-NF-κB and its correspondent downstream effectors TNF-α, IL-1ß, IL-6, and iNOS in the kidneys. Also, B-LAP effectively ameliorated renal architectural changes and attenuated serum levels of urea, creatinine, and cystatin C. Collectively, these findings suggest the protective actions of B-LAP against DOX-induced nephrotoxicity in mice.

Reduction of renal tubular injury with a RAGE inhibitor FPS-ZM1, valsartan and their combination in streptozotocin-induced diabetes in the rat.

Receptor for advanced glycation end-products (RAGE) is involved in the pathogenesis of diabetic nephropathy. FPS-ZM1, a selective RAGE inhibitor, in combination with valsartan were investigated for their protective potentials on the renal markers of tubular injury in streptozotocin-induced diabetic rats. Rats were assigned into groups of receiving FPS-ZM1 (1 mg/kg/day), valsartan (100 mg/kg/day), and FPS-ZM1 plus valsartan (1 mg/kg/day and 100 mg/kg/day, respectively) for one month. Kidney histology, renal inflammation and oxidative stress, and renal and urinary markers of tubular injury were investigated. FPS-ZM1 and valsartan in combination more significantly attenuated renal expressions of tumor necrosis factor-alpha and interleukin-6 genes and reduced urinary levels of interleukin-6. Moreover, the combination elevated renal NAD+/NADH ratios and Sirt1 activities, and mitigated nuclear acetylated NF-κB p65 levels. In addition to alleviating indices of oxidative stress i.e. malondialdehyde, superoxide dismutase and glutathione peroxidase, the combination of FPS-ZM1 and valsartan more effectively upregulated the renal levels of master antioxidant proteins Nrf2, heme oxygenase-1, and NAD(P)H:quinone oxidoreductase-1. Additionally, this dual therapy ameliorated more efficiently the indices of renal tubular injuries as indicated by decreased renal kidney injury molecule-1 levels as well as reduced urinary levels of cystatin C, retinol binding protein, and beta-2-microglobulin. While FPS-ZM1 alone had no appreciable effects on the renal fibrosis, the combination treatment ameliorated fibrosis better than valsartan in the kidneys. Collectively, these findings underline the extra benefits of FPS-ZM1 and valsartan dual administrations in obviating the renal tubular cell injury in streptozotocin-induced diabetic rats partly by suppressing renal inflammation and oxidative stress.