An altered reward system characterizes chronic migraine with medication overuse headache.

BACKGROUND: Medication overuse headache shares several characteristics with substance use disorders. However, key features of substance use disorders such as increased impulsivity and alterations in reward processing remain little explored in medication overuse headache. METHODS: Temporal discounting and impulsive decision making behavior and the associated brain mechanisms were assessed in 26 chronic migraine patients with medication overuse headache and in 28 healthy controls. Regions-of-interest analyses were first performed for task-related regions, namely the ventral striatum and the ventromedial and dorsomedial prefrontal cortices. Resting-state functional connectivity between these regions were then explored. An additional 27 chronic migraine patients without medication overuse headache were included for comparison in the latter analysis. RESULTS: Patients with medication overuse headache showed steeper temporal discounting behavior than healthy controls. They also showed weaker subjective value representations in the dorsomedial prefrontal cortex, when accepting larger delayed rewards, and in ventral striatum and ventromedial prefrontal cortex, when accepting the smaller immediate reward. Resting-state functional connectivity was reduced among the valuation regions when comparing patients with medication overuse headache to the other two control groups. CONCLUSIONS: Patients with medication overuse headache were characterized by altered processing and dysconnectivity in the reward system during intertemporal choices and in the resting-state.

Seed peptide lunasin ameliorates obesity-induced inflammation and regulates immune responses in C57BL/6J mice fed high-fat diet.

Obesity causes immune cells to infiltrate into adipose tissues and secrete proinflammatory mediators, promoting the development of chronic diseases. The seed peptide lunasin has been reported to have several bioactivities. We aimed to investigate the immunomodulatory properties of lunasin in obese models. Female and male C57BL/6J mice were divided into three groups: low-fat diet (LF), high-fat diet (HF), and HF with an intraperitoneal injection of lunasin (HFL). In females, lunasin decreased the levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1ß, and tumor necrosis factor (TNF-α) produced in peritoneal macrophages, indicating a decrease in F4/80+ macrophage infiltration, especially the CD11c + M1 phenotype. Serum leptin and tissue-oxidized lipid malondialdehyde levels were decreased in the HFL group. In males, lunasin normalized the obesity-induced increase in spleen size and splenocyte numbers. Moreover, lunasin inhibited IL-6 secretion while promoting interferon gamma (IFN-γ) and IL-2 production in the splenocytes. In vitro, lunasin increased EL-4 T-cell proliferation and IL-2 production in activated T cells under obese conditions. Thus, lunasin is a potential natural compound that promotes immunomodulation in both female and male obese mice in a sex-dependent manner. Furthermore, lunasin mediates the anti-inflammatory response and enhances the T helper type 1 cell response to obesity-related immune disorders.

Induction of ROS-independent JNK-activation-mediated apoptosis by a novel coumarin-derivative, DMAC, in human colon cancer cells.

In this study, we investigated the antitumor activity of a novel coumarin derivative, 5,7-dihydroxy-4-methyl-6-(3-methylbutanoyl)-coumarin (DMAC), on colorectal carcinoma. DMAC treatment resulted in substantial proapoptotic activity against colon cancer HCT116 and LoVo cells. Induction of apoptotic characteristics, including cellular shrinkage, chromatin condensation, and Annexin V detection, was observed following DMAC treatment. Mechanistically, we observed that DMAC elicited induction of proteolytic cascade activation including cleavage of caspase-3 and poly ADP-ribose polymerase (PARP) expression and loss of the antiapoptotic proteins, Mcl-1 and Bcl-XL, accompanied by an increase in expression of the proapoptotic protein, Bak. In addition, suppressing c-Jun N-terminal protein kinase (JNK), but not extracellular-regulated protein kinase (ERK) or p38, substantially diminished DMAC-induced cell death and caspase-3 and PARP cleavage. However, pretreatment with antioxidants, including N-acetyl-l-cysteine (NAC) and diphenylene iodonium (DPI), failed to protect against DMAC-elicited apoptosis. Pretreatment with the JNK inhibitor, SP600125, suppressed DMAC-induced JNK phosphorylation, which was accompanied by a reversal of Bcl-XL expression. Moreover, combining DMAC treatment with the conventional anticancer drugs, 5-FU and CPT-11, considerably enhanced their therapeutic efficacies. Structural-activity relationship analyses further revealed that an alkylation substitution at position 6 of the coumarin ring was critical for inducing apoptosis, and the phenyl group at position 4 might have enhanced its bioactivity. Our data showed that DMAC can be used as part of a promising strategy to enhance therapeutic efficacies, and could be used to develop an approach for structure-based drug design for cancer treatment.