The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin–14-3-3β interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L–mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.

Cannabinoid hyperemesis is a clinical syndrome characterized by repeated vomiting and associated learned compulsive hot water bathing behavior due to long-term marijuana use. Research has indentified type 1 cannabinoid receptors in the intestinal nerve plexus that have an inhibitory effect on gastrointestinal motility. This inhibitory effect may lead to hyperemesis in marijuana users. The thermoregulatory role of endocannabinoids may be responsible for the patient's need to take hot showers. We report 2 cases of cannabinoid hyperemesis that demonstrate this unusual adverse effect of marijuana use. © 2009 Mayo Foundation for Medical Education and Research Cannabis is one of the most widely used illicit drugs in the United States. The prevalence of past-year cannabis use disorders has increased to 3 million cases during the past decade, 1 with a lifetime prevalence of 7.2% in adults.2 In 2004, Allen et al 3 reported a syndrome called cannabinoid hyperemesis in South Australia. Symptoms in long-term marijuana users included intractable vomiting that was unresponsive to antiemetics and associated with learned compulsive bathing behavior. Treatment was supportive care with intravenous fluids for 24 to 48 hours; symptoms resolved when patients stopped using cannabis. We report 2 cases of cannabinoid hyperemesis that, to our knowledge, are the first to be reported in the United States. Our goal is to increase awareness of this unusual adverse effect of marijuana use. REPORT OF CASES CASE 1An obese 25-year-old woman who was a long-term cannabinoid user presented to the emergency department with nausea, vomiting, and abdominal pain that worsened for several days. During the previous 5 years, the patient had noted intermittent episodes of similar symptoms, each lasting about a week and often requiring hospitalization for dehydration. Her symptoms were refractory to all types of antiemetic medications and only responded to prolonged hot showers, some lasting 6 hours or more. Her medical history included bipolar disorder, reflux esophagitis, polycystic ovarian disease, and mild cerebral palsy with chronic mild left facial droop. She had no history of surgery or known drug allergies and reported that she took only lamotrigine. She had begun smoking marijuana 6 to 7 years earlier and used the substance almost daily. Her last marijuana use was 1 day before admission to the hospital. She denied alcohol, tobacco, or other illicit drug use.On physical examination, the patient's vital signs included a temperature of 36.9°C, a pulse of 74 beats/min, a respiratory rate of 20 breaths/min, a blood pressure of 110/80 mm Hg, and an oxygen saturation of 98% while breathing room air. She was in moderate distress and found to be writhing in bed. She had a mild left facial droop, her pupils were equal and reactive to light, and extraocular movements were intact. She had moist mucous membranes. There was no lymphadenopathy or thyromegaly. Results of a cardiovascular examination were normal, and her chest was clear. The abdomen was soft and ...

The evidence of strong pathological associations between type 2 diabetes and Alzheimer's disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.

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The efficient delivery of small interfering RNA (siRNA) to tumor cells still remains a great challenge. Of the various nanocarriers, protein nanocages have attracted extensive interest due to their unique structure and suitable characteristics derived from their proteinaceous nature. However, most reported protein nanocages that are developed are based on virus capsid proteins, which may raise safety concerns, including those related to gene mutation and carcinogenesis. The development of nonviral protein-based systems for siRNA delivery is greatly needed. In this study, a novel siRNA delivery system based on heat shock protein (Hsp) nanocages is developed by a genetic engineering method. The delivery system could condense siRNA into stable complexes and protect the condensed siRNA from degradation. A cellular uptake analysis shows that siRNA is introduced into tumor cells mediated by Hsp-R9 nanocages. Green fluorescent protein (GFP) expression in HeLa-EGFP cells is significantly downregulated by Hsp-R9/siRNA complexes. The results indicate that Hsp nanocages may be a good platform for siRNA delivery into tumor cells.