Objective: Evaluating the efficacy of 3,6’‐dithioPomalidomide in 5xFAD Alzheimer's disease (AD) mice to test the hypothesis that neuroinflammation is directly involved in the development of synaptic/neuronal loss and cognitive decline.Background: Amyloid‐β (Aβ) or tau‐focused clinical trials have proved unsuccessful in mitigating AD‐associated cognitive impairment. Identification of new drug targets is needed. Neuroinflammation is a therapeutic target in neurodegenerative disorders, and TNF‐α a pivotal neuroinflammatory driver.New hypothesis: AD‐associated chronic neuroinflammation directly drives progressive synaptic/neuronal loss and cognitive decline. Pharmacologically mitigating microglial/astrocyte activation without altering Aβ generation will define the role of neuroinflammation in AD progression.Major challenges: Difficulty of TNF‐α‐lowering compounds reaching brain, and identification of a therapeutic‐time window to preserve the beneficial role of neuroinflammatory processes.Linkage to other major theories: Microglia/astroglia are heavily implicated in maintenance of synaptic plasticity/function in healthy brain and are disrupted by Aβ. Mitigation of chronic gliosis can restore synaptic homeostasis/cognitive function.

Lentinus (L.) edodes (shiitake mushroom) is used as a traditional medicine in Asia. One of the components of L. edodes, eritadenine (an adenosine analog alkaloid), has been shown to reduce cholesterol levels. The hypocholesterolemic action of eritadenine appears to be achieved through the modification of hepatic phospholipid metabolism. In the present study, the effects of L. edodes in a mouse model of hypercholesterolemia were investigated. Hypercholesterolemia was induced by the consumption of a high-fat diet (HFD). The animals were divided into six groups, which were fed a normal diet, HFD alone, HFD containing eritadenine [10 mg/kg of body weight (BW)] or HFD with 5, 10 or 20% L. edodes, respectively, for 4 weeks (from 5 to 9 weeks of age). The mice in the six groups had similar BW gains. Total serum cholesterol (T-CHO), low-density lipoprotein (LDL) and triglyceride (TG) levels were increased in the HFD-fed group compared with those in the normal diet group. However, the levels of high-density lipoprotein (HDL) were not significantly altered. In mice treated with L. edodes (5, 10 or 20%), the T-CHO, LDL and TG serum levels were reduced in a dose-dependent manner. The mRNA expression of cholesterol 7-α-hydroxylase 1 (CYP7A1) was decreased in hypercholesterolemic mice and increased by eritadenine and L. edodes (5, 10 and 20%) supplementation. In liver tissues, it was observed that lipid accumulation was reduced by treatment with eritadenine and L. edodes. In addition, it was revealed that the formation of atherosclerotic plaques due to the HFD was also suppressed by eritadenine and L. edodes. The results of the study indicated that the consumption of an HFD may inhibit CYP7A1 expression in the liver by increasing serum T-CHO, LDL and TG levels. L. edodes may help regulate lipid metabolism, suggesting that this fungus ameliorates hypercholesterolemia in mice by regulating CYP7A1 expression in the liver.

Calcium absorption is regulated by both active (transcellular) and passive (paracellular) pathways. Although each pathway has been studied, correlations between the two pathways have not been well elucidated. In previous investigations, the critical transcellular proteins, calbindin-D_9k (CaBP-9k) and -D_28k (CaBP-28k), were shown to affect other transcellular pathways by buffering intracellular calcium concentrations. The rate of paracellular calcium transport in the duodenum is generally determined by the expression of tight junction genes. In the present study, the effect of dietary calcium and/or vitamin D supplementation on the expression of tight junction genes (occludin, ZO-1 and claudin 2, 10b, 12 and 15) in the duodenum of CaBP-9k- and/or -28k-deficient mice was examined. With a normal diet, the expression of most tight junction genes in the duodenum was significantly increased in CaBP-9k knockout (KO) mice compared to wild-type (WT) animals. With a calcium- and vitamin D-deficient diet, tight junction gene expression was significantly decreased in the duodenum of the CaBP-9k KO mice. These findings suggest that expression of paracellular tight junction genes is regulated by transcellular CaBP proteins, suggesting that active and passive calcium transport pathways may function cooperatively.

Background: Quelling microglial-induced excessive neuroinflammation is a potential treatment strategy across neurological disorders, including traumatic brain injury (TBI), and can be achieved by thalidomide-like drugs albeit this approved drug class is compromised by potential teratogenicity. Tetrafluorobornylphthalimide (TFBP) and tetrafluoronorbornylphthalimide (TFNBP) were generated to retain the core phthalimide structure of thalidomide immunomodulatory imide drug (IMiD) class. However, the classical glutarimide ring was replaced by a bridged ring structure. TFBP/TFNBP were hence designed to retain beneficial anti-inflammatory properties of IMiDs but, importantly, hinder cereblon binding that underlies the adverse action of thalidomide-like drugs. Methods: TFBP/TFNBP were synthesized and evaluated for cereblon binding and anti-inflammatory actions in human and rodent cell cultures. Teratogenic potential was assessed in chicken embryos, and in vivo anti-inflammatory actions in rodents challenged with either lipopolysaccharide (LPS) or controlled cortical impact (CCI) moderate traumatic brain injury (TBI). Molecular modeling was performed to provide insight into drug/cereblon binding interactions. Results: TFBP/TFNBP reduced markers of inflammation in mouse macrophage-like RAW264.7 cell cultures and in rodents challenged with LPS, lowering proinflammatory cytokines. Binding studies demonstrated minimal interaction with cereblon, with no resulting degradation of teratogenicity-associated transcription factor SALL4 or of teratogenicity in chicken embryo assays. To evaluate the biological relevance of its anti-inflammatory actions, two doses of TFBP were administered to mice at 1 and 24 h post-injury following CCI TBI. Compared to vehicle treatment, TFBP reduced TBI lesion size together with TBI-induction of an activated microglial phenotype, as evaluated by immunohistochemistry 2-weeks post-injury. Behavioral evaluations at 1- and 2-weeks post-injury demonstrated TFBP provided more rapid recovery of TBI-induced motor coordination and balance impairments, versus vehicle treated mice. Conclusion: TFBP and TFNBP represent a new class of thalidomide-like IMiDs that lower proinflammatory cytokine generation but lack binding to cereblon, the main teratogenicity-associated mechanism. This aspect makes TFBP and TFNBP potentially safer than classic IMiDs for clinical use. TFBP provides a strategy to mitigate excessive neuroinflammation associated with moderate severity TBI to, thereby, improve behavioral outcome measures and warrants further investigation in neurological disorders involving a neuroinflammatory component. Graphical