Novel compound FLZ alleviates rotenoneinduced PD mouse model by suppressing TLR4/MyD88/NF-kB pathway through microbiotaegutebrain axis

Parkinson’s disease(PD)is the second most common neurodegenerative disease,but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis.In PD development,the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis.However,the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet.FLZ,a novel squamosamide derivative,has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China.Moreover,our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo.The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool.In the current study,chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD.Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions,motor symptoms,and dopaminergic neuron death in rotenone-challenged mice.16 S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment.Remarkably,FLZ administration attenuated intestinal inflammation and gut barrier destruction,which subsequently inhibited systemic inflammation.Eventually,FLZ treatment restored blood-brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra(SN).Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon.Collectively,FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway,which contributes to one of the underlying mechanisms beneath its neuroprotective effects.Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis,suggesting its potential role as a novel therapeutic target for PD treatment.

Gut microbiota mediates the absorption of FLZ,a new drug for Parkinson’s disease treatment

The gut microbiota plays an important role in regulating the pharmacokinetics and pharmacodynamics of many drugs.FLZ,a novel squamosamide derivative,has been shown to have neuroprotective effects on experimental Parkinson’s disease(PD)models.FLZ is under phase I clinical trial now,while the underlying mechanisms contributing to the absorption of FLZ are still not fully elucidated.Due to the main metabolite of FLZ was abundant in feces but rare in urine and bile of mice,we focused on the gut microbiota to address how FLZ was metabolized and absorbed.In vitro studies revealed that FLZ could be exclusively metabolized to its major metabolite M1 by the lanosterol 14 alpha-demethylase(CYP51)in the gut microbiota,but was almost not metabolized by any other metabolism-related organs,such as liver,kidney,and small intestine.M1 was quickly absorbed into the blood and then remethylated to FLZ by catechol O-methyltransferase(COMT).Notably,dysbacteriosis reduced the therapeutic efficacy of FLZ on the PD mouse model by inhibiting its absorption.The results show that the gut microbiota mediate the absorption of FLZ through a FLZ-M1-FLZ circulation.Our research elucidates the vital role of the gut microbiota in the absorption of FLZ and provides a theoretical basis for clinical pharmacokinetic studies and clinical application of FLZ in the treatment of PD.

Identification of a key G-protein coupled receptor in mediating appressorium formation and fungal virulence against insects

Fungal G-protein coupled receptors(GPCRs)play essential roles in sensing environmental cues including host signals.The study of GPCR in mediating fungus-insect interactions is still limited.Here we report the evolution of GPCR genes encoded in the entomopathogenic Metarhizium species and found the expansion of Pth11-like GPCRs in the generalist species with a wide host range.By deletion of ten candidate genes MrGpr1–MrGpr10 selected from the six obtained subfamilies in the generalist M.robertsii,we found that each of them played a varied level of roles in mediating appressorium formation.In particular,deletion of MrGpr8 resulted in the failure of appressorium formation on different substrates and the loss of virulence during topical infection of insects but not during injection assays when compared with the wild-type(WT)strain.Further analysis revealed that disruption of MrGpr8 substantially impaired the nucleus translocation of the mitogen-activated protein kinase(MAPK)Mero-Fus3 but not the MAPK Mero-Slt2 during appressorium formation.We also found that the defect ofΔMrGpr8 could not be rescued with the addition of cyclic AMP for appressorium formation.Relative to the WT,differential expression of the selected genes have also been detected inΔMrGpr8.The results of this study may benefit the understanding of fungus-interactions mediated by GPCRs.