Adenylate kinase phosphate energy shuttle underlies energetic communication in flagellar axonemes

The complexities of energy transfer mechanisms in the flagella of mammalian sperm flagella have been intensively investigated and demonstrate significant diversity across species.Enzymatic shuttles,particularly adenylate kinase(AK)and creatine kinase(CK),are pivotal in the efficient transfer of intracellular ATP,showing distinct tissue-and species-specificity.Here,the expression profiles of AK and CK were investigated in mice and found to fall into four subgroups,of which Subgroup III AKs were observed to be unique to the male reproductive system and conserved across chordates.Both AK8 and AK9 were found to be indispensable to male reproduction after analysis of an infertile male cohort.Knockout mouse models showed that AK8 and AK9 were central to promoting sperm motility.Immunoprecipitation combined with mass spectrometry revealed that AK8 and AK9 interact with the radial spoke(RS)of the axoneme.Examination of various human and mouse sperm samples with substructural damage,including the presence of multiple RS subunits,showed that the head of radial spoke 3 acts as an adapter for AK9 in the flagellar axoneme.Using an ATP probe together with metabolomic analysis,it was found that AK8 and AK9 cooperatively regulated ATP transfer in the axoneme,and were concentrated at sites associated with energy consumption in the flagellum.These findings indicate a novel function for RS beyond its structural role,namely,the regulation of ATP transfer.In conclusion,the results expand the functional spectrum of AK proteins and suggest a fresh model regarding ATP transfer within mammalian flagella.

Signaling pathways in brain tumors and therapeutic interventions

Brain tumors,although rare,contribute to distinct mortality and morbidity at all ages.Although there are few therapeutic options for brain tumors,enhanced biological understanding and unexampled innovations in targeted therapies and immunotherapies have considerably improved patients’prognoses.Nonetheless,the reduced response rates and unavoidable drug resistance of currently available treatment approaches have become a barrier to further improvement in brain tumor(glioma,meningioma,CNS germ cell tumors,and CNS lymphoma)treatment.Previous literature data revealed that several different signaling pathways are dysregulated in brain tumor.Importantly,a better understanding of targeting signaling pathways that influences malignant behavior of brain tumor cells might open the way for the development of novel targeted therapies.Thus,there is an urgent need for a more comprehensive understanding of the pathogenesis of these brain tumors,which might result in greater progress in therapeutic approaches.This paper began with a brief description of the epidemiology,incidence,risk factors,as well as survival of brain tumors.Next,the major signaling pathways underlying these brain tumors’pathogenesis and current progress in therapies,including clinical trials,targeted therapies,immunotherapies,and system therapies,have been systemically reviewed and discussed.Finally,future perspective and challenges of development of novel therapeutic strategies in brain tumor were emphasized.

Liposomal Honokiol induces ROS-mediated apoptosis via regulation of ERK/p38-MAPK signaling and autophagic inhibition in human medulloblastoma

Dear Editor,Nowadays,medulloblastoma accounts for approximately 25% of all pediatric brain tumors.1 Even with the successful treatment of primary tumors,there are still serious side effects.Honokiol(HNK)is defined as small bisphenol lignin extracted from the bark and seed cones of several species of Magnolia.