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Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with no currently approved treatment. The natural compound silybin (SLN) has versatile hepatoprotective efficacy with negligible adverse effects; however, poor absorption limits its clinical applications. Gut microbiota has been proposed to play a crucial role in the pathophysiology of NAFLD and targeted for disease control. Cyclodextrins, the cyclic oligosaccharides, were documented to have various health benefits with potential prebiotic properties. This study aimed to develop a silybin-2-hydroxypropyl-β-cyclodextrin inclusion (SHβCD) to improve the therapeutic efficacy of SLN and elucidate the mechanisms of improvement. The results showed that SLN formed a 1:1 stoichiometric inclusion complex with HP-β-CD. The solubility of SLN was increased by generating SHβCD, resulting in improved drug permeability and bioavailability. In high-fat diet (HFD)-fed hamsters, SHβCD modulated gut health by restoring the gut microbiota and intestinal integrity. SHβCD showed superior anti-lipid accumulation, antioxidant, and anti-inflammatory effects compared with SLN alone. Transcriptome analysis in the liver tissue implied that the improved inflammation and/or energy homeostasis was the potential mechanism. Therefore, SHβCD may be a promising alternative for the treatment of NAFLD, attributing to the dual functions of HβCD on drug absorption and gut microbial homeostasis.

Chronic administration of methamphetamine (METH) leads to physical and psychological dependence. It is generally accepted that METH exerts rewarding effects via competitive inhibition of the dopamine transporter (DAT), but the molecular mechanism of METH addiction remains largely unknown. Accumulating evidence shows that mitochondrial function is important in regulation of drug addiction. In this study, we investigated the role of Clk1, an essential mitochondrial hydroxylase for ubiquinone (UQ), in METH reward effects. We showed that Clk1(+/−) mutation significantly suppressed METH-induced conditioned place preference (CPP), accompanied by increased expression of DAT in plasma membrane of striatum and hippocampus due to Clk1 deficiency-induced inhibition of DAT degradation without influencing de novo synthesis of DAT. Notably, significantly decreased iron content in striatum and hippocampus was evident in both Clk1(+/−) mutant mice and PC12 cells with Clk1 knockdown. The decreased iron content was attributed to increased expression of iron exporter ferroportin 1 (FPN1) that was associated with elevated expression of hypoxia-inducible factor-1α (HIF-1α) in response to Clk1 deficiency both in vivo and in vitro. Furthermore, we showed that iron played a critical role in mediating Clk1 deficiency-induced alteration in DAT expression, presumably via upstream HIF-1α. Taken together, these data demonstrated that HIF-1α-mediated changes in iron homostasis are involved in the Clk1 deficiency-altered METH reward behaviors.

The growth and activity of sulfate-reducing prokaryotes (SRP) in oilfield environments could produce large amounts of H

Major depressive disorder (MDD) is a highly prevalent illness that affects large populations across the world, and increasing evidence suggests that neuroinflammation and levels of brain-derived neurotrophic factor (BDNF) are closely related to depression. Dihydromyricetin (DHM) is a kind of flavonoid natural product that has been reported to display multiple pharmacological effects, including anti-inflammatory and anti-oxidative properties, and these may contribute to ameliorate MDD. This study investigated the effect of DHM on depression-related phenotypes in various experimental animal models. The antidepressant-like effect of DHM was validated via depression-related behavioral tests in naive male C57BL/6 mice, as well as in the acute lipopolysaccharide-induced mouse model of depression. The chronic unpredicted mild stress (CUMS) mouse model of depression was also used to assess the rapid antidepressant-like effect of DHM by tail suspension test (TST), forced swimming test (FST), locomotor activity, and sucrose preference test (SPT). The expression of BDNF and inflammatory factors were determined through Western blotting and enzyme-linked immunosorbent assay, respectively. DHM reduced immobility time in the TST and FST both in mice and the acute LPS-induced mouse model of depression. Seven days of DHM treatment ameliorated depression-related behaviors induced by CUMS, whereas similar treatment with the typical antidepressant venlafaxine did not. DHM activated the ERK1/2-CREB pathway and increased glycogen synthase kinase-3 beta (GSK-3β) phosphorylation at ser-9, with upregulation of BDNF expression, in both hippocampal tissues and cultured hippocampal cells. The present data indicate that DHM exerts a more rapid antidepressant-like effect than does a typical antidepressant, in association with enhancement of BDNF expression and inhibition of neuroinflammation.