Molecular mechanisms of action of metformin: latest advances and therapeutic implications.

Metformin is among the most widely used antidiabetic drugs. Studies over the past few years have identified multiple novel molecular targets and pathways that metformin acts on to exert its beneficial effects in treating type 2 diabetes as well as other disorders involving dysregulated inflammation and redox homeostasis. In this mini-review, we discuss the latest cutting-edge research discoveries on novel molecular targets of metformin in glycemic control, cardiovascular protection, cancer intervention, anti-inflammation, antiaging, and weight control. Identification of these novel targets and pathways not only deepens our understanding of the molecular mechanisms by which metformin exerts diverse beneficial biological effects, but also provides opportunities for developing new mechanistically based drugs for human diseases.

Role of Peroxiredoxins in Protecting Against Cardiovascular and Related Disorders.

Peroxiredoxin (Prx) refers to a family of thiol-dependent peroxidases that decompose hydrogen peroxide, lipid hydroperoxides, as well as peroxynitrite, and protect against oxidative and inflammatory stress. There are six mammalian Prx isozymes (Prx1-6), classified as typical 2-Cys, atypical 2-Cys, or 1-Cys Prxs based on the mechanism and the number of cysteine residues involved during catalysis. In addition to their well-established peroxide-scavenging activity, some Prxs also participate in the regulation of various cell signaling pathways. Extensive animal studies employing primarily gene knockout models provide substantial evidence supporting a critical protective role of Prxs in various disease processes involving oxidative and inflammatory stress. This review surveys recent research findings, published primarily in influential journals, on the involvement of various Prx isozymes in protecting against cardiovascular injury and related disorders, including diabetes, metabolic syndromes, and sepsis, whose pathophysiology all intimately involves oxidative stress and inflammation.

Management of gastroesophageal reflux disease: Patient and physician communication challenges and shared decision making.

Gastroesophageal reflux disease (GERD) is a common upper esophageal condition and typical symptoms can include heartburn and sensation of regurgitation while atypical symptoms include chronic cough, asthma, hoarseness, dyspepsia and nausea. Typically, diagnosis is presumptive given the presence of typical and atypical symptoms and is an indication for empiric therapy. Treatment management can include lifestyle modifications and/or medication therapy with proton pump inhibitor (PPI) class being the preferred and most effective. Complete symptom resolution is not always achieved and long-term PPI therapy can put patients at risk for serious side effects and needless expense. The brain-gut connection and hypervigilance plays an important role in symptom resolution and treatment success, especially in the case of non-PPI responders. Hypervigilance is a combination of increased esophageal sensory sensitivity in combination with exaggerated threat perception surrounding esophageal symptoms. Hypervigilance requires a different approach to GERD managements, where continued PPI therapy and surgery are usually not recommended. Rather, helping physicians and patients understand the brain-gut connection can guide and improve care. Education and reassurance should be the main pillars or treatment. However, it is important not to suggest the symptoms are due to anxiety alone, this often leads to patient dissatisfaction. Patient dissatisfaction with treatment reveals the need for a more patient-centered approach to GERD management and better communication between patients and providers. Shared decision making (SDM) with the incorporation of patient-reported outcomes (PRO) promotes patient adherence and satisfaction. SDM is a joint discussion between clinician and patient in which a mutually shared solution is explored for GERD symptoms. For SDM to work the physician needs to capture patients' perceptions which may not be obtained in the standard interview. This can be done through the use of PROs which promote a dialogue with patients about their symptoms and treatment priorities in the context of the SDM patient encounter. SDM could potentially help in the management of patient expectations for GERD treatment, ultimately positively impacting their health-related quality of life.

Doxorubicin Redox Biology: Redox Cycling, Topoisomerase Inhibition, and Oxidative Stress.

Doxorubicin (also called Adriamycin) is effective in treating a wide range of human cancers and currently considered as one of the most important drugs in cancer chemotherapeutics. The clinical use of doxorubicin is, however, associated with dosage-dependent cardiotoxicity and development of heart failure, which diminish the therapeutic index of this widely used anticancer drug. This article first surveys key research findings on doxorubicin redox biology that may impact its cardiotoxicity as well as anticancer activity. It then discusses emerging concepts, especially the topoisomerase IIb-p53-mitochondrion axis that may lead to the development of mechanistically based novel strategies to protect against cardiotoxicity and enhance the effectiveness of doxorubicin therapy.

Paraoxonases function as unique protectors against cardiovascular diseases and diabetes: Updated experimental and clinical data.

Paraoxonase (PON) refers to a family of three enzymes, namely PON1, PON2, and PON3. PON1 and PON3 are found in circulation bound to high-density lipoprotein, whereas PON2 is an intracellular protein. PON1 was first discovered as an enzyme to hydrolyze the organophosphate pesticide paraoxon, an activity that both PON2 and PON3 lack. All three PON enzymes are able to degrade oxidized lipids and protect against oxidative stress. PON enzymes also act to suppress inflammation. Animal studies show a critical role for PON enzymes, especially PON1 in protecting against cardiovascular diseases and related disorders, including diabetes and metabolic syndrome. In line with the findings in experimental animals, accumulating evidence from clinical research also indicates that PON enzymes function as potential protectors in human cardiovascular diseases and related disorders. Identification of PON enzymes as important players in cardiovascular health will facilitate the development of novel preventive and therapeutic modalities targeting PON enzymes to combat cardiovascular diseases and related disorders, which collectively constitute the chief contributors to the global burden of disease. This review describes the biochemical properties and molecular regulation of PON and summarizes the major recent findings on the functions of PON in protecting against cardiovascular diseases and related disorders.

Maintenance of myocardial levels of vitamin A in heart failure due to adriamycin.

The therapeutic use of adriamycin (doxorubicin), a potent antitumor antibiotic, is limited by the development of dose-dependent cardiomyopathy. Increased oxidative stress due to adriamycin is considered to play a role in the pathogenesis of this toxic effect. In this study, we examined the levels and redistribution of vitamin A (a potent non-enzymatic antioxidant) in adriamycin-induced cardiomyopathy in rats. Three weeks after the adriamycin (ADR) treatment, animals were hemodynamically assessed and different tissues were analyzed for total retinol (vitamin A), (3)H-radio-labeled retinol, retinol palmitate and vitamin E. At 3 weeks, animals in the ADR group were hemodynamically and clinically confirmed to be in heart failure. In the ADR group, total retinol levels in heart and plasma were unchanged. However, levels of the (3)H radio-labeled fraction of retinol were significantly increased in both organs suggesting increased turnover. In the liver, the levels of total retinol and retinol palmitate were significantly decreased, while the radio-labeled fraction of retinol was significantly increased suggesting mobilization of retinol from this organ. Alpha tocopherol (vitamin E) levels were found unchanged in hearts of the ADR animals, while its levels in the plasma and liver were significantly increased. Increased radio-labeled fraction, without any change in the total retinol in the heart, suggested that vitamin A is utilized more by the heart under increased oxidative stress due to adriamycin. Its levels in the plasma and the heart may have been maintained at the expense of the loss from the liver.

Early changes in myocardial antioxidant enzymes in rats treated with adriamycin.

Increased oxidative stress and antioxidant deficit have been suggested to play a major role in adriamycin-induced cardiomyopathy and congestive heart failure due to multiple treatments with adriamycin (doxorubicin). In this study, we investigated the acute effects of a single dose of adriamycin on myocardial antioxidant enzymes in rats. Adriamycin (2.5 mg/kg) was injected (i.p.) and myocardial antioxidant enzyme activities, mRNA abundance and protein levels at 1, 2, 4 and 24 h were examined. While manganese superoxide dismutase (MnSOD), glutathione peroxidase (GSHPx) and catalase (CAT) activities were not significantly changed, copper-zinc superoxide dismutase (CuZnSOD) activity was reduced at all time points and this change correlated with a decrease in its protein content. CuZnSOD mRNA was increased at 1 and 24 h. GSHPx mRNA and protein levels were transiently decreased by 20 and 25% respectively at 2 h. MnSOD mRNA was not significantly changed, but its protein levels were significantly decreased at 1 h. Lipid peroxidation was increased transiently at 1, 2 and 4 h. A transient depression in antioxidant enzyme as well as transient increase in oxidative stress with a single dose of adriamycin may precede more sustained changes seen with the repeated administration of the drug and contribute to the development of cardiomyopathy and heart failure.