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.

Nickel-Catalyzed Reductive Dicarbofunctionalizations of Alkenes for the Synthesis of Difluorocarbonyl Oxindoles and Isoquinoline-1,3-diones.

A novel and efficient strategy for the construction of difluorocarbonyl-oxindole and difluorocarbonyl-isoquinoline-1,3-dione derivatives involving nickel-catalyzed intramolecular Heck-type cyclizations followed by intermolecular cross-couplings has been developed. This approach features high functional group tolerance, broad substrate scope, and operational simplicity under mild conditions, thus providing a new method for the rapid difluorocarbonyl-functionalization of alkenes to construct the structurally diversified five- and six-membered heterocycles.

Pro-efferocytic macrophage membrane biomimetic nanoparticles for the synergistic treatment of atherosclerosis via competition effect.

Macrophages participate in many links in the pathological process of atherosclerosis (AS) and the regulation of influence of macrophages at the molecular level might be a new avenue for AS treatment. For this aim, the macrophage membrane biomimetic nanoparticles, derived from macrophage membrane coated SHP1i-loaded liposome NPs (MM@Lips-SHP1i) was designed. Due to the reservation of intrinsic membrane proteins and function from macrophages, the biomimic nanoparticles could effectively evade clearance by the immune system, prolong blood circulation time and actively tend and aggregate to atherosclerotic plaques. More importantly, in the plaque area, MM@Lips-SHP1i nanoparticles could compete with macrophages in vivo to bind with oxidized low-density lipoprotein (oxLDL) and lipopolysaccharide (LPS), reduce uptake of new lipids by macrophages, reduce foam cell formation, and inhibit the expression of pro-inflammatory cytokines. In addition, small molecule inhibitor of SHP-1, the downstream effector molecule of CD47 loaded in macrophage membrane biomimetic nanoparticles could interrupt CD47-SIRPα signal transduction in monocytes and macrophages, thereby enhancing the efferocytosis of macrophages, inhibiting the progression of plaque, achieving synergistic treatment of atherosclerosis. This work focuses on the key process in the formation of AS, macrophage foaming and chronic inflammation, and is based on the fact that macrophage membrane biomimetic nanoparticles can preserve the key surface proteins of macrophages closely related to the formation of AS, providing a new avenue to inhibit the progression of AS by utilizing the biological characteristics of macrophage membrane in macrophage membrane biomimetic nanoparticles.

DNA aptamer-based dual-responsive nanoplatform for targeted MRI and combination therapy for cancer.

Accurate drug delivery is a common topic, and it has always been an aim that scientists strive to achieve. To address this need, multifunctional and stimulus-sensitive nanoplatforms have attracted significant attention. Here we fabricated a glutathione (GSH) and adenosine-5'-triphosphate (ATP) dual-sensitive nanoplatform for controlled drug release and activatable MRI of tumors based on DNA aptamer and manganese dioxide (MnO2) nanosheets. Cleverly utilizing the DNA tunability, AS1411 aptamer which binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells, was designed with ATP aptamer and its cDNA to load the anticancer drug, doxorubicin (Dox). The formed DNA-Dox complex was delivered to the tumor region with the help of MnO2 nanosheets and AS1411 aptamer. Then, the on-demand drug release in tumor cells was realized with the co-effect of the ATP aptamer and GSH reduction. It was found that without the structure of the MnO2 nanosheets being broken by GSH, Dox almost could not be released even in the presence of ATP. Similarly, without ATP, Dox was still maintained in the duplex even with GSH. Further combining the MRI ability and chemodynamic therapy of the produced Mn2+, an improved effect of the inhibition of tumor growth and imaging was achieved. Our designed DNA aptamer-based dual-responsive nanoplatform can realize the targeted drug delivery and MRI of breast tumor cells both in vitro and in vivo.

Theranostic nanoplatform to target macrophages enables the inhibition of atherosclerosis progression and fluorescence imaging of plaque in ApoE(-/-) mice.

BACKGROUND: Rupture of atherosclerotic plaque can cause acute malignant heart and cerebrovascular events, such as acute coronary heart disease, stroke and so on, which seriously threaten the safety of human life and property. Therefore, the early diagnosis and inhibition of atherosclerotic plaque progress still be a vital task. RESULTS: In this study, we presented the development of composite mesoporous silica nanoparticle (Ru(bpy)3@SiO2-mSiO2, CMSN)-based nanomedicines (NMs) (Ru(bpy)3@SiO2-mSiO2@SRT1720@AntiCD36, CMSN@SRT@Anti) for accurate diagnosis and treatment of atherosclerosis (AS). In vitro cell experiments showed that both RAW264.7 and oxidized low density lipoprotein (ox-LDL)-stimulated RAW264.7 cells could significantly uptake CMSN@SRT@Anti. Conversely, little fluorescence signal could be observed in CMSN@SRT group, showing the excellent targeting ability of CMSN@SRT@Anti to Class II scavenger receptor, CD36 on macrophage. Additionally, such fluorescence signal was significantly stronger in ox-LDL-stimulated RAW264.7 cells, which might benefit from the upregulated expression of CD36 on macrophages after ox-LDL treatment. For another, compared with free SRT1720, CMSN@SRT@Anti had a better and more significant effect on the inhibition of macrophage foaming process, which indicated that drug-carrying mesoporous silicon with targeting ability could enhance the efficacy of SRT1720. Animal experimental results showed that after the abdominal injection of CMSN@SRT@Anti, the aortic lesions of ApoE-/-mice could be observed with obvious and persistent fluorescence signals. After 4 weeks post-treatment, the serum total cholesterol, aortic plaque status and area were significantly improved in the mouse, and the effect was better than that in the free SRT1720 group or the CMSN@SRT group. CONCLUSIONS: The designed CMSN@SRT@Anti with excellent biocompatibility, high-performance and superior atherosclerosis-targeting ability has great potential for accurate identification and targeted therapy of atherosclerotic diseases.

The Opportunities and Challenges of Silica Nanomaterial for Atherosclerosis.

Atherosclerosis (AS) as the leading cause of cardiovascular and cerebrovascular events has been paid much attention all the time. With the continuous development of modern medical drug treatment, surgical treatment, interventional treatment and other methods, the mortality rate of AS has shown a downward trend, while the morbidity rate is still increasing. Oral lipid-lowering or anti-inflammatory drugs are generally used for early AS, but the relatively low accumulation efficiency in lesions and the unavoidable side effects required researchers to develop more effective drug delivery approaches for the therapy of AS. Mesoporous silica nanoparticles as nanocarrier for drug delivery have received extensive attentions due to their flexible size, high specific surface area, controlled pore volume, high drug loading capacity and excellent biocompatibility. Series of good reviews about the mesoporous silica nanoparticles loaded drugs for cancer therapy have been well documented. However, their roles as nanocarrier for drug delivery to treat AS have few reports. In this review, the applications and challenges of mesoporous silica nanomaterials in the field of the diagnosis and therapy of AS have been summarized. The classification, synthesis, formation mechanism, surface modification and functionalization of mesoporous silica nanomaterials which were closely related to the theranostic effect of AS have also been included. Last but not the least, the future prospects' suggestions of mesoporous silica nanomaterial-based drug delivery system for AS are also provided.