A NIR-Light-Activated and Lysosomal-Targeted Pt (II) Metallacycle for Highly Potent Evoking of Immunogenic Cell Death that Potentiates Cancer Immunotherapy of Deep-Seated Tumors.

Though platinum (Pt)-based complexes have been recently exploited as immunogenic cell death (ICD) inducers for activating immunotherapy, the effective activation of sufficient immune responses with minimal side effects in deep-seated tumors remains a formidable challenge. Herein, we propose the first example of a near-infrared (NIR) light-activated and lysosomal targeted Pt(II) metallacycle (1) as a supramolecular ICD inducer. 1 synergistically potentiates immunomodulatory response in deep-seated tumors via multiple-regulated approaches, involving NIR light excitation, boosted reactive oxygen species (ROS) generation, good selectivity between normal and tumor cells, and enhanced tumor penetration/retention capabilities. Specifically, 1 has excellent depth-activated ROS production (~ 7 mm), accompanied by strong anti-diffusion and anti-ROS quenching ability. In vitro experiments demonstrate that 1 exhibits significant cellular uptake and ROS generation in tumor cells as well as respective multicellular tumor spheroids. Based on these advantages, 1 induces a more efficient ICD in an ultralow dose (i.e., 5 µM) compared with the clinical ICD inducer-oxaliplatin (300 µM). In vivo, vaccination experiments further demonstrate that 1 serves as a potent ICD inducer through eliciting CD8+/CD4+ T cell response and Foxp3+ T cell depletion with negligible adverse effects. This study pioneers a promising avenue for safe and effective metal-based ICD agents in immunotherapy.

De Novo Designed Ru(II) Metallacycle as a Microenvironment-Adaptive Sonosensitizer and Sonocatalyst for Multidrug-Resistant Biofilms Eradication.

Albeit sonodynamic therapy (SDT) has achieved encouraging progress in microbial sterilization, the scarcity of guidelines for designing highly effective sonosensitizers and the intricate biofilm microenvironment (BME), substantially hamper the therapeutic efficacy against biofilm infections. To address the bottlenecks, we innovatively design a Ru(II) metallacycle-based sonosensitizer/sonocatalyst (named Ru-A3-TTD) to enhance the potency of sonotherapy by employing molecular engineering strategies tailored to BME. Our approach involves augmenting Ru-A3-TTD's production of ultrasonic-triggered reactive oxygen species (ROS), surpassing the performance of commercial sonosensitizers, through a straightforward but potent π-expansion approach. Within the BME, Ru-A3-TTD synergistically amplifies sonotherapeutic efficacy via triple-modulated approaches: (i) effective alleviation of hypoxia, leading to increased ROS generation, (ii) disruption of the antioxidant defense system, which shields ROS from glutathione consumption, and (iii) enhanced biofilm penetration, enabling ROS production in deep sites. Notably, Ru-A3-TTD sono-catalytically oxidizes NADPH, a critical coenzyme involved in antioxidant defenses. Consequently, Ru-A3-TTD demonstrates superior biofilm eradication potency against multidrug-resistant Escherichia coli compared to conventional clinical antibiotics, both in vitro and in vivo. To our knowledge, this study represents the pioneering instance of a supramolecular sonosensitizer/sonocatalyst. It provides valuable insights into the structure-activity relationship of sonosensitizers and paves a promising pathway for the treatment of biofilm infections.

Effects of Dietary Zinc on Growth Performance, Digestive Enzyme Activities, Antioxidant Status, and Immune Responses of Sea Cucumber Apostichopus japonicus.

Zinc is an essential micronutrient for organisms involved in regulating various biological processes. This study evaluated the effects of dietary zinc on growth performance, digestive enzyme activities, antioxidant status, and immune responses of sea cucumber Apostichopus japonicus. Five experimental diets were formulated with graded levels of zinc (0, 20, 40, 60, and 80 mg/kg, respectively), and the actual dietary zinc values were 31.4, 51.0, 68.2, 91.9, and 110.8 mg/kg diet, respectively. Sea cucumbers were fed with diets for 2 months. The results showed the growth performance, amylase, and trypsin activities of sea cucumber increased significantly with zinc supplementation, and the best growth performance and enzyme activities were observed at 40 mg/kg zinc diet. Zinc supplementation significantly increased activities of superoxide dismutase, catalase, anti-superoxide anion, and inhibiting hydroxyl radical, while significantly reduced the malondialdehyde content. Furthermore, the higher zinc supplementation levels resulted in significantly upregulated immune-related genes of hsp90, p105, rel, and lsz, suggesting that excessive zinc caused oxidative stress. The broken-line regression analysis of specific growth rate indicated dietary zinc requirement in juvenile sea cucumber was ~ 66.3 mg/kg diet. Overall, dietary zinc contributes to the growth and immune resistance of juvenile sea cucumber, and our study will provide insights into the rational use of dietary zinc in aquaculture.

Research status and prospects of organic photocatalysts in algal inhibition and sterilization: a review.

An increasing amount of sewage has been discharged into water bodies in the progression of industrialization and urbanization, causing serious water pollution. Meanwhile, the increase of nutrients in the water induces water eutrophication and rapid growth of algae. Photocatalysis is a common technique for algal inhibition and sterilization. To improve the utilization of visible light and the conversion efficiency of solar energy, more organic photocatalytic materials have been gradually developed. In addition to ultraviolet light, partial infrared light and visible light could also be used by organic photocatalysts compared with inorganic photocatalysts. Simultaneously, organic photocatalysts also exhibit favorable stability. Most organic photocatalysts can maintain a high degradation rate for algae and bacteria after several cycles. There are various organic semiconductors, mainly including small organic molecules, such as perylene diimide (PDI), porphyrin (TCPP), and new carbon materials (fullerene (C60), graphene (GO), and carbon nanotubes (CNT)), and large organic polymers, such as graphite phase carbon nitride (g-C3N4), polypyrrole (PPy), polythiophene (PTH), polyaniline (PANI), and polyimide (PI). In this review, the classification and synthesis methods of organic photocatalytic materials were elucidated. It was demonstrated that the full visible spectral response (400-750 nm) could be stimulated by modifying organic photocatalysts. Moreover, some problems were summarized based on the research status related to algae and bacteria, and corresponding suggestions were also provided for the development of organic photocatalytic materials.

Metal-Organic Framework-Based Artificial Organelle Corrects Microenvironment Interference for Accurate Intratumoral Glucose Analysis.

Enzymatic catalysis with high efficiency allows them a great prospect in metabolite monitoring in living cells. However, complex tumor microenvironments, such as acidity, H2 O2 , and hypoxia, are bound to disturb catalytic reactions for misleading results. Here, we report a spatially compartmentalized artificial organelle to correct intratumoral glucose analysis, where the zeolitic imidazolate framework-8 immobilized glucose oxidase-horseradish peroxidase cascade core and catalase-directed shell act as signal transduction and guarding rooms respectively. The acid-digested core and stable shell provide appropriate spaces to boost biocatalytic efficiency with good tolerability. Notably, the endogenous H2 O2 is in situ decomposed to O2 by catalase, which not only overcomes the interference in signal output but also alleviates the hypoxic states to maximize glucose oxidation. The marked protective effect and biocompatibility render artificial organelles to correct the signal transduction for dynamic monitoring glucose in vitro and in vivo, achieving our goal of accurate intratumoral metabolite analysis.

Structure-based discovery of pyrazole-benzothiadiazole hybrid as human HPPD inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) has attracted increasing attention as a target for treating type I tyrosinemia and other diseases with defects in tyrosine catabolism. Only one commercial drug, 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), clinically treat type I tyrosinemia, but show some severe side effects in clinical application. Here, we determined the structure of human HPPD-NTBC complex, and developed new pyrazole-benzothiadiazole 2,2-dioxide hybrids from the binding of NTBC. These compounds showed improved inhibition against human HPPD, among which compound a10 was the most active candidate. The Absorption Distribution Metabolism Excretion Toxicity (ADMET) predicted properties suggested that a10 had good druggability, and was with lower toxicity than NTBC. The structure comparison between inhibitor-bound and ligand-free form human HPPD showed a large conformational change of the C-terminal helix. Furthermore, the loop 1 and α7 helix were found adopting different conformations to assist the gating of the cavity, which explains the gating mechanism of human HPPD.

Geniposide ameliorates atherosclerosis by regulating macrophage polarization via perivascular adipocyte-derived CXCL14.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides Ellis is a traditional Chinese medicine that has been used for treatment of various diseases, including atherosclerosis by clearing heat and detoxication. Geniposide is considered as the effective compounds responsible for the therapeutic efficacy of Gardenia jasminoides Ellis against atherosclerosis. AIM OF THE STUDY: To investigate the effect of geniposide on atherosclerosis burden and plaque macrophage polarization, with focus on its potential impact on CXCL14 expression by perivascular adipose tissue (PVAT). MATERIALS AND METHODS: ApoE-/- mice fed a western diet (WD) were used to model atherosclerosis. In vitro cultures of mouse 3T3-L1 preadipocytes and RAW264.7 macrophages were used for molecular assays. RESULTS: The results revealed that geniposide treatment reduced atherosclerotic lesions in ApoE-/- mice, and this effect was correlated with increased M2 and decreased M1 polarization of plaque macrophages. Of note, geniposide increased the expression of CXCL14 in PVAT, and both the anti-atherosclerotic effect of geniposide, as well as its regulatory influence on macrophage polarization, were abrogated upon in vivo CXCL14 knockdown. In line with these findings, exposure to conditioned medium from geniposide-treated 3T3-L1 adipocytes (or to recombinant CXCL14 protein) enhanced M2 polarization in interleukin-4 (IL-4) treated RAW264.7 macrophages, and this effect was negated after CXCL14 silencing in 3T3-L1 cells. CONCLUSION: In summary, our findings suggest that geniposide protects ApoE-/- mice against WD-induced atherosclerosis by inducing M2 polarization of plaque macrophages via enhanced expression of CXCL14 in PVAT. These data provide novel insights into PVAT paracrine function in atherosclerosis and reaffirm geniposide as a therapeutic drug candidate for atherosclerosis treatment.

Acceptor engineering of metallacycles with high phototoxicity indices for safe and effective photodynamic therapy.

Although metallacycle-based photosensitizers have attracted increasing attention in biomedicine, their clinical application has been hindered by their inherent dark toxicity and unsatisfactory phototherapeutic efficiency. Herein, we employ a π-expansion strategy for ruthenium acceptors to develop a series of Ru(ii) metallacycles (Ru1-Ru4), while simultaneously reducing dark toxicity and enhancing phototoxicity, thus obtaining a high phototoxicity index (PI). These metallacycles enable deep-tissue (∼7 mm) fluorescence imaging and reactive oxygen species (ROS) production and exhibit remarkable anti-tumor activity even under hypoxic conditions. Notably, Ru4 has the lowest dark toxicity, highest ROS generation ability and an optimal PI (∼146). Theoretical calculations verify that Ru4 exhibits the largest steric bulk and the lowest singlet-triplet energy gap (ΔE ST, 0.62 eV). In vivo studies confirm that Ru4 allows for effective and safe phototherapy against A549 tumors. This work thus is expected to open a new avenue for the design of high-performance metal-based photosensitizers for potential clinical applications.

Liproxstatin­1 induces cell cycle arrest, apoptosis, and caspase­3/GSDME­dependent secondary pyroptosis in K562 cells.

Leukemia is a fatal hematopoietic disorder with a poor prognosis. Drug resistance is inevitable after the long­term use of chemotherapeutic agents. Liproxstatin­1, commonly known as a ferroptosis inhibitor, has never been reported to have anticancer effects. In the present study, the antileukemic role of liproxstatin­1 in K562 leukemia cells was investigated. Liproxstatin­1 inhibited K562 cell proliferation in a dose­ and time­dependent manner. RNA sequencing revealed several pathways that were affected by liproxstatin­1, such as the G1/S transition of the mitotic cell cycle and extrinsic or intrinsic apoptotic signaling pathways. The results of flow cytometry indicated that liproxstatin­1 arrests the cell cycle at the G1 phase, and even at the G2/M phase. p21WAF1/CIP1, a cyclin­dependent kinase inhibitor, was upregulated. It was also determined that liproxstatin­1 induced BAX and TNF­α expression, which was accompanied by cleavage of caspase­3 and PARP. The caspase­3­specific inhibitor z­DEVD­FMK rescued some of the apoptotic cells. Interestingly, K562 cells were characterized by swelling and plasma membrane rupture when treated with a high concentration of liproxstatin­1, which was inconsistent with the typical apoptotic appearance. Thus, it was hypothesized that apoptosis­mediated pyroptosis occurs during liproxstatin­1­induced cell death. The expression of the hallmark of pyroptosis, the cleaved N­terminal GSDME, increased. Additionally, it was observed that endoplasmic reticulum stress and autophagy were involved in liproxstatin­1­induced cell death. Collectively, liproxstatin­1 induced cell cycle arrest, apoptosis, and caspase­3/GSDME­dependent secondary pyroptosis in K562 leukemia cells, which provides new hope for the treatment of leukemia.

Long wavelength-emissive Ru(II) metallacycle-based photosensitizer assisting in vivo bacterial diagnosis and antibacterial treatment.

Ruthenium (Ru) complexes are developed as latent emissive photosensitizers for cancer and pathogen photodiagnosis and therapy. Nevertheless, most existing Ru complexes are limited as photosensitizers in terms of short excitation and emission wavelengths. Herein, we present an emissive Ru(II) metallacycle (herein referred to as 1) that is excited by 808-nm laser and emits at a wavelength of ∼1,000 nm via coordination-driven self-assembly. Metallacycle 1 exhibits good optical penetration (∼7 mm) and satisfactory reactive oxygen species production properties. Furthermore, 1 shows broad-spectrum antibacterial activity (including against drug-resistant Escherichia coli) as well as low cytotoxicity to normal mammalian cells. In vivo studies reveal that 1 is employed in precise, second near-infrared biomedical window fluorescent imaging-guided, photo-triggered treatments in Staphylococcus aureus-infected mice models, with negligible side effects. This work thus broads the applications of supramolecular photosensitizers through the strategy of lengthening their wavelengths.

Rationally designed Ru(ii)-metallacycle chemo-phototheranostic that emits beyond 1000 nm.

Ruthenium complexes are emerging as potential complements to platinum drugs. They also show promise as photo-diagnostic and therapeutic agents. However, most ruthenium species studied to date as potential drugs are characterized by short excitation/emission wavelengths. This limits their applicability for deep-tissue fluorescence imaging and light-based therapeutic treatments. Here, we report a Ru(ii) metallacycle (Ru1100) that emits at ≥1000 nm. This system possesses excellent deep-tissue penetration capability (∼7 mm) and displays good chemo-phototherapeutic performance. In vitro studies revealed that Ru1100 benefits from good cellular uptake and produces a strong anticancer response against several cancer cell lines, including a cisplatin-resistant A549 cell line (IC50 = 1.6 µM vs. 51.4 µM for cisplatin). On the basis of in vitro studies, it is concluded that Ru1100 exerts its anticancer action by regulating cell cycle progression and triggering cancer cell apoptosis. In vivo studies involving the use of a nanoparticle formulation served to confirm that Ru1100 allows for high-performance NIR-II fluorescence imaging-guided precise chemo-phototherapy in the case of A549 tumour mouse xenografts with no obvious side effects. This work thus provides a paradigm for the development of long-wavelength emissive supramolecular theranostic agents based on ruthenium.

Construction of emissive ruthenium(II) metallacycle over 1000 nm wavelength for in vivo biomedical applications.

Although Ru(II)-based agents are expected to be promising candidates for substituting Pt-drug, their in vivo biomedical applications are still limited by the short excitation/emission wavelengths and unsatisfactory therapeutic efficiency. Herein, we rationally design a Ru(II) metallacycle with excitation at 808 nm and emission over 1000 nm, namely Ru1085, which holds deep optical penetration (up to 6 mm) and enhanced chemo-phototherapy activity. In vitro studies indicate that Ru1085 exhibits prominent cell uptake and desirable anticancer capability against various cancer cell lines, especially for cisplatin-resistant A549 cells. Further studies reveal Ru1085 induces mitochondria-mediated apoptosis along with S and G2/M phase cell cycle arrest. Finally, Ru1085 shows precise NIR-II fluorescence imaging guided and long-term monitored chemo-phototherapy against A549 tumor with minimal side effects. We envision that the design of long-wavelength emissive metallacycle will offer emerging opportunities of metal-based agents for in vivo biomedical applications.

Exosomal LBH inhibits epithelial-mesenchymal transition and angiogenesis in nasopharyngeal carcinoma via downregulating VEGFA signaling.

The limb-bud and heart (LBH) gene was reported to suppress nasopharyngeal carcinoma (NPC) progression in our previous study. Distant metastasis predominantly accounts for the unsatisfactory prognosis of NPC treatment, in which epithelial-mesenchymal transition (EMT) and tumor angiogenesis are of great significance. The roles of exosomes in mediating NPC progression have been highlighted in recent researches, and attempts have been made to explore the clinical application of NPC exosomes. Here we investigated the function of the LBH gene in NPC exosomes, and its potential mechanism. NPC xenografts were constructed, showing that vascular endothelial growth factor A (VEGFA) expression and neovascularity were attenuated by LBH overexpression, together with diminished EMT progression. NPC-derived exosomes were isolated, identified and applied for in vitro/in vivo experiments, and the exosomal distribution of LBH was elevated in exosomes derived from LBH-upregulated cells. Ectopic LBH, αB-crystallin (CRYAB) and VEGFA expression was induced by lentiviral infection or plasmid transfection to explore their functions in modulating EMT and angiogenesis in NPC. The addition of LBH+ NPC exosomes during a Matrigel plug assay in mice suppressed in vivo angiogenesis, and the treatment of human umbilical vein endothelial cells (HUVECs) with LBH+ NPC exosomes inhibited cellular proliferation, migration and tube formation. The interactions among LBH, CRYAB and VEGFA were confirmed by colocalization and fluorescence resonance energy transfer (FRET) assays, and extracellular VEGFA secretion from both HUVECs and NPC cells under the treatment with LBH+ NPC exosomes was diminished according to ELISA results. We concluded that exosomal LBH inhibits EMT progression and angiogenesis in the NPC microenvironment, and that its effects are partially implemented by modulation of VEGFA expression, secretion and related signaling. Thus, LBH could serve as a promising therapeutic target in VEGFA-focused NPC treatment.

Folic Acid Inhibited Vasculogenic Mimicry in Esophageal Cancer Cell Line Eca-109, the One Target Was EphA2.

The degree of vasculogenic mimicry(VM) is correlated with the prognosis of esophageal cancer, and folic acid supplementation could decrease esophagus cancer deaths among populations. This study aimed to explore the effect of folic acid on VM formation of esophageal cancer cell, and the target. Human esophageal squamous cancer cell lines(Eca-109) were cultured with different concentrations of folic acid (0,1,10,100,200,400, 600,800 µg/ml). A cell counting kit-8 (CCK-8) assay was used to measure the cell proliferation. Then, the amount of VM under the effect of different concentrations of folic acid was observed. Target genes were screened out from several possible targets genes including MMP2, MMP9, EphA2, VE-cad or Ln-5γ2 by employing reverse transcription-quantitative polymerase chain reaction(RT-qPCR). Finally, western blot analysis was used to verify the target proteins. In conclusion, this study found that folic acid inhibited the formation of VM in Eca-109 cells, and the one target protein was EphA2.

LUBAC regulates ciliogenesis by promoting CP110 removal from the mother centriole.

Primary cilia transduce diverse signals in embryonic development and adult tissues. Defective ciliogenesis results in a series of human disorders collectively known as ciliopathies. The CP110-CEP97 complex removal from the mother centriole is an early critical step for ciliogenesis, but the underlying mechanism for this step remains largely obscure. Here, we reveal that the linear ubiquitin chain assembly complex (LUBAC) plays an essential role in ciliogenesis by targeting the CP110-CEP97 complex. LUBAC specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole in ciliogenesis. We further identify that a pre-mRNA splicing factor, PRPF8, at the distal end of the mother centriole acts as the receptor of the linear ubiquitin chains to facilitate CP110 removal at the initial stage of ciliogenesis. Thus, our study reveals a direct mechanism of regulating CP110 removal in ciliogenesis and implicates the E3 ligase LUBAC as a potential therapy target of cilia-associated diseases, including ciliopathies and cancers.

Beta1-integrin/Hedgehog-Gli1 signaling pathway fuels the diameter-dependent osteoblast differentiation on different TiO2 nanotubes: The optimal-diameter nanotubes for osteoblast differentiation.

Micro/nanotextured topographies (MNTs) can modulate cell-biomaterial interactions mostly by their controllable geometrics. Among them, TiO2 nanotubes, regarded as having a highly controllable nanoscale geometry, have been extensively investigated and applied and significantly affect diameter-dependent cell biological behaviors. In this study, we used five typical MNTs decorated with TiO2 nanotubes with diameters of 30, 50, 70, 100 and 120 nm to explore the optimal nanotube diameter for improving the biofunctional properties and to more deeply understand the underlying mechanisms by which these MNTs affect osteogenic differentiation by revealing the effect of beta1-integrin/Hedgehog-Gli1 signaling on this process. The MNTs affected MG63 osteoblast-like cell spreading, osteogenic gene expression (BMP-2, Runx2 and ALP), mineralization and ALP activity in a diameter-dependent pattern, and the optimal TiO2 nanotube diameter of 70 nm provided the best microenvironment for osteogenic differentiation as well as beta1-integrin/Hedgehog-Gli1 signaling activation. This enhanced osteogenic differentiation by the optimal-diameter TiO2 nanotubes of 70 nm was attenuated via suppression of the beta1-integrin/ Hedgehog-Gli1 signaling, which indicated a significant role of this pathway in mediating the diameter-dependent osteogenic differentiation promotional effect of MNTs with different TiO2 nanotube diameters. These results might provide deeper insights into the signal transduction mechanisms by which different nanoscale geometries influence cellular functions for biomaterial modification and biofunctionalization.

Effects of Supplementary Selenium and Vitamin E on the Growth Performance, Antioxidant Enzyme Activity, and Gene Expression of Sea Cucumber Apostichopus japonicus.

A 60-day feeding experiment was conducted to evaluate the effects of single selenomethionine (Se) and its mixture with vitamin E (VE) on the growth, antioxidant enzyme activities, and gene expression of juvenile sea cucumber Apostichopus japonicus. The design of the experiment contained two factors and 5 × 2 levels by means of adding various levels of Se and VE in the feed, i.e., combination of 0, 0.3, 0.6, 0.9, or 1.2 mg Se kg-1 and 0 or 200 mg VE kg-1. The results revealed that the specific growth rate and weight gain rate were the highest in the group with 0.3 mg Se kg-1 and 200 mg VE kg-1, followed by the group with 0.6 mg Se kg-1 without VE. Se significantly improved the activities of amylase and protease with VE also imposed positive effect on the amylase activity. Glutathione peroxidase (GPX) activity was highest in the group with 1.2 mg Se kg-1 and lowest with the basal diet. The activity of catalase (CAT) was increased while glutathione reductase (GR) activity was decreased in response to the addition of Se. No significant interactive effects of Se and VE on the enzyme activities were found except superoxide dismutase (SOD) activity. While relative expressions of GPX, CAT, and SOD genes were significantly responsive to the addition of dietary Se, VE significantly promoted the gene expression of SOD. The results suggested that Se and VE might have beneficial effects on the growth and antioxidant responses of A. japonicus.

Prognostic significance of microRNA miR-24 in cancers: a meta-analysis.

The prognostic significance of miR-24 in tumors has not been determined. Therefore, we conducted a meta-analysis to systematically assess the correlation between miR-24 and its prognostic value in cancers PubMed, EMBASE, and Web of Science databases were used to search relevant articles (up to 1 October 2020). Studies that evaluated the prognostic value of miR-24 in tumors were included. The hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to evaluate survival outcomes and clinical characteristics. All data analyses were implemented using STATA 12.0 software. A total of 17 studies from 15 articles involving 1705 patients were collected for the meta-analysis. The pooled analysis revealed that elevated miR-24 expression was obviously associated with poor overall survival (OS) (HR = 1.66, 95% CI: 1.20-2.31). Furthermore, we also found that elevated miR-24 expression was positively correlated with tumor size (large or small) and tumor stage (III-IV vs I-II). Elevated miR-24 expression indicates poor prognosis and may be a promising prognostic marker in different cancers. Our findings needed to be verified through further investigations. [Figure: see text].

CEP55 promotes cilia disassembly through stabilizing Aurora A kinase.

Primary cilia protrude from the cell surface and have diverse roles during development and disease, which depends on the precise timing and control of cilia assembly and disassembly. Inactivation of assembly often causes cilia defects and underlies ciliopathy, while diseases caused by dysfunction in disassembly remain largely unknown. Here, we demonstrate that CEP55 functions as a cilia disassembly regulator to participate in ciliopathy. Cep55-/- mice display clinical manifestations of Meckel-Gruber syndrome, including perinatal death, polycystic kidneys, and abnormalities in the CNS. Interestingly, Cep55-/- mice exhibit an abnormal elongation of cilia on these tissues. Mechanistically, CEP55 promotes cilia disassembly by interacting with and stabilizing Aurora A kinase, which is achieved through facilitating the chaperonin CCT complex to Aurora A. In addition, CEP55 mutation in Meckel-Gruber syndrome causes the failure of cilia disassembly. Thus, our study establishes a cilia disassembly role for CEP55 in vivo, coupling defects in cilia disassembly to ciliopathy and further suggesting that proper cilia dynamics are critical for mammalian development.

Geniposide Enhances Macrophage Autophagy through Downregulation of TREM2 in Atherosclerosis.

Macrophage autophagy defect is closely related to the progression of atherosclerosis (AS) and is regulated by the triggering receptor expressed on myeloid cell 2 (TREM2). TREM2 is a key factor in the development of Alzheimer's disease (AD), the deficiency of which leads to anomalous autophagy in microglia. However, the role of TREM2 in the autophagy of plaque macrophages is still unclear. Geniposide (GP) can inhibit AS progression and enhance macrophage autophagy, although the underlying mechanisms remain unknown. We found that high-fat diet (HFD) feeding significantly increased TREM2 levels and inhibited autophagy in the macrophages of ApoE[Formula: see text] mice. TREM2 overexpression in RAW264.7 macrophages decreased autophagy via activation of mTOR signaling. GP inhibited the progression of AS in ApoE[Formula: see text] mice, reinforced macrophage autophagy, and downregulated TREM2 by inhibiting mTOR signaling. Taken together, augmenting the autophagy levels in plaque macrophages by inhibiting the TREM2/mTOR axis can potentially impede atherosclerotic progression. The promising therapeutic effects of GP seen in this study should be validated in future trials, and the underlying mechanisms have to be elucidated in greater detail.