Challenges and opportunities with glycogen synthase kinase-3 inhibitors for insulin resistance and Type 2 diabetes treatment

The role of the serine/threonine protein kinase, glycogen synthase kinase-3 (GSK-3), in attenuating the insulin signalling pathway has led to the concept that inhibition of GSK-3 may have therapeutic benefits in the treatment of insulin resistance and Type 2 diabetes. Indeed, various selective GSK-3 inhibitors have been developed recently and have proven to promote insulin-like effects and to act as insulin sensitisers in both in vitro and in vivo systems. GSK-3 inhibition may thus present a new, effective approach for the treatment of insulin resistance and Type 2 diabetes. This review describes the qualifications of GSK-3 as a novel drug-discovery target for Type 2 diabetes and discusses the strategies and challenges in developing small-molecule inhibitors for this important protein kinase.     

Inhibition of serotonin re-uptake by licorice constituents

Ovarian steroid hormones, estrogen and progestin, affect the function of the serotonin neural system by inhibiting serotonin re-uptake through allosteric interaction with the serotonin transporter (SERT) in a nongenomic mechanism. Blocking or reducing serotonin re-uptake at the synapse alleviates depression. The aim of this study was to test the effect of compounds of the isoflavan and isoflavene groups, subclasses of the flavonoids family, on serotonin re-uptake and to compare the results with the effect of other known phytoestrogens like genistein and daidzein to relate the activity of these compounds to their structure. The effect of these compounds on the re-uptake of radioactive serotonin was assayed in HEK-293 cells stably expressed the recombinant human serotonin transporter (hSERT). The results demonstrated that the isoflavans glabridin and 4'-O-methylglabridin (4'-OMeG) and the isoflavene glabrene inhibited serotonin re-uptake by 60, 53 and 47%, respectively, at 50 microM, whereas resorcinol, the isoflavan 2'-O-methylglabridin (2'-OMeG), and the isoflavones genistein and daidzein were inactive. The inhibition of serotonin re-uptake is dose dependant with glabridin and estradiol. These results emphasize the importance of the lipophilic part of the isoflavans, as well as the hydroxyl at position 2' on ring B. In conclusion, this study showed that several isoflavans are unique phytoestrogens, which like estradiol, affects the serotonergic system and inhibits serotonin re-uptake and, thus, potentially may be beneficial for mild to moderate depression in pre- and postmenopausal women.     

Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin 1alpha expression

Expression of cytokines in malignant cells represents a novel approach for therapeutic treatment of tumors. Previously, we demonstrated the immunostimulatory effectiveness of interleukin 1alpha (IL-1alpha) gene transfer in experimental fibrosarcoma tumors. Here, we report the antitumor and immunotherapeutic effects of short-term expression of IL-1alpha by malignant T lymphoma cells. Activation in culture of T lymphoma cells with lipopolysaccharide-stimulated macrophages induces the expression of IL-1alpha. The short-term expression of IL-1alpha persists in the malignant T cells for a few days (approximately 3-6 days) after termination of the in vitro activation procedure and, thus, has the potential to stimulate antitumor immune responses in vivo. As an experimental tumor model, we used the RO1 invasive T lymphoma cell line. Upon i.v. inoculation, these cells invade the vertebral column and compress the spinal cord, resulting in hind leg paralysis and death of the mice. Activated RO1 cells, induced to express IL-1alpha in a short-term manner, manifested reduced tumorigenicity: approximately 75% of the mice injected with activated RO1 cells remained tumor free. IL-1 was shown to be essential for the eradication of activated T lymphoma cells because injection of activated RO1 cells together with IL-1-specific inhibitors, i.e., the IL-1 receptor antagonist or the M 20 IL-1 inhibitor, reversed reduced tumorigenicity patterns and led to progressive tumor growth and death of the mice. Furthermore, activated RO1 cells could serve as a treatment by intervening in the growth of violent RO1 cells after tumor take. Thus, when activated RO1 cells were injected 6 or 9 days after the inoculation of violent cells, mortality was significantly reduced. IL-1alpha, in its unique membrane-associated form, in addition to its cytosolic and secreted forms, may represent a focused adjuvant for potentiating antitumor immune responses at low levels of expression, below those that are toxic to the host. Further assessment of the immunotherapeutic potential of short-term expression of IL-1alpha in activated tumor cells may allow its improved application in the treatment of malignancies.     

Little video-gaming in adolescents can be protective,but too much is associated with increased substance use

Background: Studies have demonstrated inconsistent results regarding the association between video gaming time and substance use in teenagers. Understating intricacies of this association can help with substance use reduction in teenagers. Objectives: This study aimed to untangle this complex relationship by theorizing and examining a U-shaped association. Methods: We analyzed two large samples (n₁ = 7313 [52.5% female] and n₂ = 8079 [51.6% female]) of 8th and 10th graders in the United States. Substance use was operationalized as the sum of self-reported number of lifetime use instances of 14 unprescribed substances. Video game use time (hours per week) was self-reported on a 1 (none) to 9 (40+) scale. Common covariates/risk factors were included. Results: Consistently across datasets, partial-correlation between squared video gaming time and substance use (r?=?.10, p?<?.001 in 2014 and r?=?.08, p?<?.001 in 2015) supported the hypothesized u-shaped association. Analysis of covariance revealed that teenagers playing video games for 1–5?h a week report on significantly fewer instances of substance use compared with non-gamers (p?<?.001–.007). Post hoc analyses revealed that those who play at least 30?h per week report on significantly (p?<?.001) more instances of substance use (3.92 in 2014 and 3.38 in 2015) compared with teenagers playing video games for 1–5?h a week (2.17 in 2015 and 1.96 in 2015). Conclusions: Video gaming time and substance use follow a u-shaped association; light video gaming can be protective in terms of substance use, while too much video gaming is associated with increased substance use.     

Evaluation of the NiTi Shape Memory BioDynamix ColonRing™ in colorectal anastomosis: first in human multi-center study

Background   

Shape-memory compression bowel anastomosis using a nickel and titanium alloy may reduce leak rates and eliminate foreign anastomotic material. Its safety and efficacy had been demonstrated by animal studies. We conducted the first prospective multi-center clinical evaluation of the safety and effectiveness of BioDynamix anastomosis with ColonRing™ for large-bowel end-to-end or side-to-end anastomosis.     

Post-traumatic stress disorder is not over-represented in a sample population of migraine patients

IntroductionExposure to extreme stress can result in a variety of clinical sequelae, in terms of severity and type, of which post-traumatic stress disorder (PTSD) is the prototype. PTSD was previously associated with chronic pain and primary pain disorders.ObjectiveTo evaluate the prevalence of PTSD among migraine patients and to assess its relation to migraine severity.MethodsWe evaluated 92 consecutive patients fulfilling the international headache society criteria for migraine with and without aura treated in the Headache Clinic of the Soroka University Medical Center in Beer-Sheva using the Clinician Administered PTSD Scale (CAPS), and headache severity scales (HIT-6 and MIDAS).ResultsThe prevalence of specific traumatic events in migraine patients was 16.3% (n = 15). Six patients (6.5%) of the 92 patients met the DSM-IV criteria for PTSD. Migraine patients with co-morbid PTSD had higher MIDAS scores than other migraine patients.ConclusionsMigraine patients do not suffer from PTSD more than the general population. When they do suffer from PTSD they report high levels of disability.     

Targeted drug-carrying bacteriophages as antibacterial nanomedicines

While the resistance of bacteria to traditional antibiotics is a major public health concern, the use of extremely potent antibacterial agents is limited by their lack of selectivity. As in cancer therapy, antibacterial targeted therapy could provide an opportunity to reintroduce toxic substances to the antibacterial arsenal. A desirable targeted antibacterial agent should combine binding specificity, a large drug payload per binding event, and a programmed drug release mechanism. Recently, we presented a novel application of filamentous bacteriophages as targeted drug carriers that could partially inhibit the growth of Staphylococcus aureus bacteria. This partial success was due to limitations of drug-loading capacity that resulted from the hydrophobicity of the drug. Here we present a novel drug conjugation chemistry which is based on connecting hydrophobic drugs to the phage via aminoglycoside antibiotics that serve as solubility-enhancing branched linkers. This new formulation allowed a significantly larger drug-carrying capacity of the phages, resulting in a drastic improvement in their performance as targeted drug-carrying nanoparticles. As an example for a potential systemic use for potent agents that are limited for topical use, we present antibody-targeted phage nanoparticles that carry a large payload of the hemolytic antibiotic chloramphenicol connected through the aminoglycoside neomycin. We demonstrate complete growth inhibition toward the pathogens Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli with an improvement in potency by a factor of approximately 20,000 compared to the free drug.     

Comorbidity of fibromyalgia and psychiatric disorders

There are mounting data supporting comorbidity of fibromyalgia syndrome (FMS) and psychiatric conditions. These include depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). The nature of the relationship between depression and FMS is not fully understood, and it was hypothesized that chronic pain causes depression, or vice versa, and that chronic pain syndromes are variants of depression. A link between PTSD symptoms and FMS has been reported, and both conditions share similar symptomatology and pathogenetic mechanisms. Assessment of comorbid psychiatric disorders in FMS patients has clinical implications because treatment in these patients should focus both on physical and emotional dimensions of dysfunction.