Low and high doses of oral maslinic acid protect against Parkinson's disease via distinct gut microbiota-related mechanisms.

The use of oral agents that can modify the gut microbiota (GM) could be a novel preventative or therapeutic option for Parkinson's disease (PD). Maslinic acid (MA), a pentacyclic triterpene acid with GM-dependent biological activities when it is taken orally, has not yet been reported to be effective against PD. The present study found both low and high dose MA treatment significantly prevented dopaminergic neuronal loss in a classical chronic PD mouse model by ameliorating motor functions and improving tyrosine hydroxylase expressions in the substantia nigra pars compacta (SNpc) and increasing dopamine and its metabolite homovanillic acid levels in the striatum. However, the effects of MA in PD mice were not dose-responsive, since similar beneficial effects for low and high doses of MA were observed. Further mechanism studies indicated that low dose MA administration favored probiotic bacterial growth in PD mice, which helped to increase striatal serotonin, 5-hydroxyindole acetic acid, and γ-aminobutyric acid levels. High dose MA treatment did not influence GM composition in PD mice but significantly inhibited neuroinflammation as indicated by reduced levels of tumor necrosis factor alpha and interleukin 1ß in the SNpc; moreover, these effects were mainly mediated by microbially-derived acetic acid in the colon. In conclusion, oral MA at different doses protected against PD via distinct mechanisms related to GM. Nevertheless, our study lacked in-depth investigations of the underlying mechanisms involved; future studies will be designed to further delineate the signaling pathways involved in the interactive actions between different doses of MA and GM.

Copper-catalyzed 4-HO-TEMPOH mediated phosphorylation of alkenes.

An efficient, practical and regioselective synthesis of (E)-alkenylphosphine oxides has been developed starting from alkenes under copper catalysis and 4-HO-TEMPOH oxidation. Preliminary mechanistic studies clearly reveal that a phosphinoyl radical is involved in this process. Moreover, this method features mild reaction conditions, good functional group tolerance, and excellent regioselectivity and also promises to be efficient for the late-stage functionalization of drug molecular skeletons. The reaction will create an opportunity for the synthesis of complex phosphorus containing bioactive molecules.

Alginate and its Two Components Acted Differently Against Dopaminergic Neuronal Loss in Parkinson's Disease Mice Model.

SCOPE: This study aims to investigate and compare the potentially neuroprotective effects and underlying mechanisms for brown seaweed polysaccharides (PS) of Alginate (Alg) and its two components, including polymannuronic acid (PM) and polyguluronic acid (PG), against Parkinson's disease (PD) pathogenesis. METHODS AND RESULTS: Model mice of PD are pretreated with Alg or PM or PG, separately via oral gavage once per day for four weeks. Our results found PM improved motor functions of PD mice, but Alg or PG did not. PM or PG, but not Alg, can prevent dopaminergic neuronal loss by increasing tyrosine hydroxylase (TH) expressions in midbrain of PD mice. The neuroprotective effects of PM rely on its anti-inflammation effects and its ability to improve striatal neurotransmitters (serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA)) levels in PD mice. PM inhibits inflammation, but PG or Alg induces inflammation in systemic circulation of PD mice. The neuroprotection provided by PG might be related to its ability to increase striatal neurotransmitter of 5-hydroxyindole acetic acid levels in PD mice. CONCLUSION: PM plays better than PG to provide neuroprotection, but Alg did not show any neuroprotection against PD. Alg and its two components acted differently in preventing dopaminergic neuronal loss in PD mice.

Atractylenolide I stimulates intestinal epithelial repair through polyamine-mediated Ca2+ signaling pathway.

BACKGROUND: An impairment of the integrity of the mucosal epithelial barrier can be observed in the course of various gastrointestinal diseases. The migration and proliferation of the intestinal epithelial (IEC-6) cells are essential repair modalities to the healing of mucosal ulcers and wounds. Atractylenolide I (AT-I), one of the major bioactive components in the rhizome of Atractylodes macrocephala Koidz. (AMR), possesses multiple pharmacological activities. This study was designed to investigate the therapeutic effects and the underlying molecular mechanisms of AT-I on gastrointestinal mucosal injury. METHODS: Scratch method with a gel-loading microtip was used to detect IEC-6 cell migration. The real-time cell analyzer (RTCA) system was adopted to evaluate IEC-6 cell proliferation. Intracellular polyamines content was determined using high performance liquid chromatography (HPLC). Flow cytometry was used to measure cytosolic free Ca2+ concentration ([Ca2+]c). mRNA and protein expression of TRPC1 and PLC-γ1 were determined by real-time PCR and Western blotting assay respectively. RESULTS: Treatment of IEC-6 cells with AT-I promoted cell migration and proliferation, increased polyamines content, raised cytosolic free Ca2+ concentration ([Ca2+]c), and enhanced TRPC1 and PLC-γ1 mRNA and protein expression. Depletion of cellular polyamines by DL-a-difluoromethylornithine (DFMO, an inhibitor of polyamine synthesis) suppressed cell migration and proliferation, decreased polyamines content, and reduced [Ca2+]c, which was paralleled by a decrease in TRPC1 and PLC-γ1 mRNA and protein expression in IEC-6 cells. AT-I reversed the effects of DFMO on polyamines content, [Ca2+]c, TRPC1 and PLC-γ1 mRNA and protein expression, and restored IEC-6 cell migration and proliferation to near normal levels. CONCLUSION: Our data demonstrate that AT-I stimulates intestinal epithelial cell migration and proliferation via the polyamine-mediated Ca2+ signaling pathway. Therefore, AT-I may have the potential to be further developed as a promising therapeutic agent to treat diseases associated with gastrointestinal mucosal injury, such as inflammatory bowel disease and peptic ulcer.