Alkannin Attenuates Amyloid ß Aggregation and Alzheimer's Disease Pathology.

Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid ß formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid ß aggregation may be useful for treatment. Based on this hypothesis, we screened plant compounds used in Kampo medicine for chemical chaperone activity and identified that alkannin had this property. Further analysis indicated that alkannin could inhibit amyloid ß aggregation. Importantly, we also found that alkannin inhibited amyloid ß aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit ß-sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid ß-induced neuronal cell death in PC12 cells, ameliorated amyloid ß aggregation in the AD model of Caenorhabditis elegans (C. elegans), and inhibited chemotaxis observed in AD C. elegans, suggesting that alkannin could potentially inhibit neurodegeneration in vivo. Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid ß aggregation and neuronal cell death in AD. SIGNIFICANCE STATEMENT: Aggregated amyloid ß formation and accumulation is one of the underlying mechanisms of the pathophysiology of Alzheimer's disease. We found that alkannin had chemical chaperone activity, which can inhibit ß-sheet structure formation of amyloid ß and its aggregation, neuronal cell death, and Alzheimer's disease phenotype in C. elegans. Overall, alkannin may have novel pharmacological properties for inhibiting amyloid ß aggregation and neuronal cell death in Alzheimer's disease.

The possible role of biochanin A in ameliorating endoplasmic reticulum stress-induced leptin resistance.

Leptin plays an important role in energy intake and body weight homeostasis. Leptin is secreted mainly from white adipose tissue and circulates in the bloodstream, inhibiting food intake by activating the leptin receptor expressed on hypothalamic neurons. Recent studies have demonstrated leptin resistance as the main factor involved in the development of obesity. We and others have reported that leptin resistance is caused by endoplasmic reticulum (ER) stress due to the accumulation of unfolded protein in the ER. In the present study, we investigated whether isoflavones could affect ER stress and the subsequent development of leptin resistance. We showed that biochanin A, a family of isoflavones, strongly attenuated cell death induced by ER stress in neuronal cells, improved ER stress-induced impairments in leptin signaling, and suppressed ER stress-induced expression of glucose-regulated protein 78. These results suggest that biochanin A may have pharmacological properties that can ameliorate leptin resistance by reducing ER stress.

Endospanin1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling.

The hypothalamic arcuate nucleus (ARC) is a major integration center for energy and glucose homeostasis that responds to leptin. Resistance to leptin in the ARC is an important component of the development of obesity and type 2 diabetes. Recently, we showed that Endospanin1 (Endo1) is a negative regulator of the leptin receptor (OBR) that interacts with OBR and retains the receptor inside the cell, leading to a decreased activation of the anorectic STAT3 pathway. Endo1 is up-regulated in the ARC of high fat diet (HFD)-fed mice, and its silencing in the ARC of lean and obese mice prevents and reverses the development of obesity. OBJECTIVE: Herein we investigated whether decreased Endo1 expression in the hypothalamic ARC, associated with reduced obesity, could also ameliorate glucose homeostasis accordingly. METHODS: We studied glucose homeostasis in lean or obese mice silenced for Endo1 in the ARC via stereotactic injection of shRNA-expressing lentiviral vectors. RESULTS: We observed that despite being leaner, Endo1-silenced mice showed impaired glucose homeostasis on HFD. Mechanistically, we show that Endo1 interacts with p85, the regulatory subunit of PI3K, and mediates leptin-induced PI3K activation. CONCLUSIONS: Our results thus define Endo1 as an important hypothalamic integrator of leptin signaling, and its silencing differentially regulates the OBR-dependent functions.

Immobilization stress-induced anorexia is mediated independent of MyD88.

MyD88 is an adaptor protein for the toll-like receptor, which is involved in regulating innate immune function. Lipopolysaccharide-induced activation of toll-like receptor 4 signaling induces hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation and anorexia through MyD88. In the present study, we investigated the possible role of MyD88 in psychological stress-induced anorexia. We found that immobilization stress inhibited food intake in both wild-type mice and MyD88-deficient mice. Immobilization stress slightly increased STAT3 phosphorylation in the hypothalamus, but it was weaker than the lipopolysaccharide-induced increase in STAT3 phosphorylation. These observations suggest that the mechanisms involved in psychological stress-induced anorexia may be regulated differently from those involved in anorexia that is induced by infection.

The Mechanisms and Pharmacological Strategy for Treatment of ER Stress-induced Metabolic Syndrome.

Obesity is one of the major risk factors of metabolic syndrome, such as hypertension, hyperlipidemia, and diabetes. Leptin exerts an anti-obesity effect through the Ob-Rb leptin receptor, which is mainly expressed on hypothalamic neuronal cells. Recent evidence indicated that one of the mechanisms of obesity may be the development of leptin resistance. In the present review, we discuss the mechanisms of leptin resistance in obesity, focusing on endoplasmic reticulum (ER) stress. We previously found that flurbiprofen is a candidate drug for attenuating ER stress and the subsequent development of leptin resistance. We will discuss a possible pharmacological strategy for treating obesity by ameliorating ER stress.

MyD88 plays a key role in LPS-induced Stat3 activation in the hypothalamus.

Infection causes the production of proinflammatory cytokines, which act on the central nervous system (CNS) and can result in fever, sleep disorders, depression-like behavior, and even anorexia, although precisely how cytokines regulate the functions of the CNS remain unclear. In the present study, we investigated the regulatory-molecular mechanisms by which cytokines affect hypothalamic function in a state of infection. The intraperitoneal administration of lipopolysaccharide (LPS), a ligand of Toll-like receptor 4 (TLR4), time-dependently (2-24 h) increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in the hypothalamus and liver, which corresponded with anorexia observed within 24 h. Interestingly, the pattern of phosphorylation in response to LPS differed between the hypothalamus and liver. In the hypothalamus, LPS increased STAT3 phosphorylation from 2 h, with a peak at 4 h and a decline thereafter, whereas, in the liver, the peak activation of STAT3 persisted from 2 to 8 h. The time course of the LPS-induced expression of suppressor of cytokine signaling 3 (SOCS3), a STAT3-induced negative regulator of the Janus kinase-STAT pathway, was similar to that of STAT3 phosphorylation. Using mice deficient in myeloid differentiation primary-response protein 88 (MyD88), an adapter protein of TLR4, we found that LPS-induced STAT3 phosphorylation and SOCS3 expression in the hypothalamus and liver were predominantly mediated through MyD88. Moreover, we observed that MyD88-deficient mice were resistant to LPS-induced anorexia. Taken together, our findings reveal a novel mechanism, i.e., MyD88 plays a key role in mediating STAT3 phosphorylation and anorexia in the CNS in a state of infection and inflammation.

Development of clinical application for a nutritional prescription support system for total parenteral/enteral nutrition.

One of the important roles of pharmacists as members of a nutrition support team is nutritional prescription support. We developed a nutritional prescription support system (NPSS) that facilitates prescription support and analysis and evaluated its usefulness in nutritional therapy. An NPSS for prescription support and the management of patient information was created. With this NPSS, the nutritional status was assessed, and, on the basis of the results, such variables as the total energy expenditure were calculated. This system allows prescription support for parenteral nutrition (PN) therapy, enteral nutrition (EN) therapy, and the transition period between them. This system was used for 2 representative patients and evaluated. In a malnourished patient receiving oral warfarin, EN solutions were compared by means of the NPSS, and an appropriate EN solution was selected. In addition, the prothrombin time-international normalized ratio was monitored, and favorable results were obtained regarding the adjustment of the warfarin dose and nutritional management. In a patient with aspiration pneumonia, continuous nutritional management to EN from PN therapy was straightforwardly performed with the NPSS. This NPSS allows rapid, comprehensive nutritional management during the transition period to EN from PN therapy, despite these therapies being considered separately in conventional nutritional management. The NPSS is useful for simplifying prescription support and facilitating information sharing among members of a nutrition support team.