PTH and the Regulation of Mesenchymal Cells within the Bone Marrow Niche.

Parathyroid hormone (PTH) plays a pivotal role in maintaining calcium homeostasis, largely by modulating bone remodeling processes. Its effects on bone are notably dependent on the duration and frequency of exposure. Specifically, PTH can initiate both bone formation and resorption, with the outcome being influenced by the manner of PTH administration: continuous or intermittent. In continuous administration, PTH tends to promote bone resorption, possibly by regulating certain genes within bone cells. Conversely, intermittent exposure generally favors bone formation, possibly through transient gene activation. PTH's role extends to various aspects of bone cell activity. It directly influences skeletal stem cells, osteoblastic lineage cells, osteocytes, and T cells, playing a critical role in bone generation. Simultaneously, it indirectly affects osteoclast precursor cells and osteoclasts, and has a direct impact on T cells, contributing to its role in bone resorption. Despite these insights, the intricate mechanisms through which PTH acts within the bone marrow niche are not entirely understood. This article reviews the dual roles of PTH-catabolic and anabolic-on bone cells, highlighting the cellular and molecular pathways involved in these processes. The complex interplay of these factors in bone remodeling underscores the need for further investigation to fully comprehend PTH's multifaceted influence on bone health.

Immunomodulatory nanomedicine for osteoporosis: Current practices and emerging prospects.

Osteoporosis results from the disruption of the balance between bone resorption and bone formation. However, classical anti-osteoporosis drugs exhibit several limitations in clinical applications, such as multiple adverse reactions and poor therapeutic effects. Therefore, there is an urgent need for alternative treatment strategies. With the evolution of immunomodulatory nanomedicine, a variety of nanomaterials have been designed for anti-osteoporosis treatment, offering prospects of minimal adverse reactions, enhanced bone induction, and high osteogenic activity. This review initially provides a brief overview of the fundamental principles of bone reconstruction, current osteogenic clinical methods in osteoporosis treatment, and the significance of osteogenic-angiogenic coupling, laying the groundwork for understanding the pathophysiology and therapeutics of osteoporosis. Subsequently, the article emphasizes the relationship between bone immunity and osteogenesis-angiogenesis coupling and provides a detailed analysis of the application of immunomodulatory nanomedicines in the treatment of osteoporosis, including various types of nanomaterials and their integration with carrier biomaterials. Importantly, we discuss the potential of some emerging strategies in immunomodulatory nanomedicine for osteoporosis treatment. This review introduces the innovative applications of immunomodulatory nanomedicine in the treatment of osteoporosis, aiming to serve as a reference for the application of immunomodulatory nanomedicine strategies in osteoporosis treatment. STATEMENT OF SIGNIFICANCE: Osteoporosis, as one of the most prevalent skeletal disorders, poses a significant threat to public health. To date, conventional anti-osteoporosis strategies have been limited in efficacy and plagued with numerous side effects. Fortunately, with the advancement of research in osteoimmunology and nanomedicine, strategies integrating these two fields show great promise in combating osteoporosis. Nanomedicine with immunomodulatory properties exhibits enhanced efficiency, prolonged effectiveness, and increased safety. However, as of now, there exists no comprehensive review amalgamating immunomodulation with nanomedicine to delineate the progress of immunomodulatory nanomedicine in osteoporosis treatment, as well as the future direction of this strategy.

Periodic Lamellae-Based Nanofibers for Precise Immunomodulation to Treat Inflammatory Bone Loss in Periodontitis.

Periodontitis is a common oral disease accompanied by inflammatory bone loss. The pathological characteristics of periodontitis usually accompany an imbalance in the periodontal immune microenvironment, leading to difficulty in bone regeneration. Therefore, effective treatment strategies are needed to modulate the immune environment in order to treat periodontitis. Here, we developed a highly-oriented periodic lamellae poly(ε-caprolactone) electrospun nanofibers (PLN) by surface-directed epitaxial crystallization. Our in vitro results showed that the PLN could precisely modulate macrophage polarization toward the M2 phenotype. Macrophages polarized by PLN significantly enhanced the migration and osteogenic differentiation of BMSCs. Notably, results suggested that the topographical cues presented by PLN can modulate macrophage polarization by activating YAP, which reciprocally inhibits the NF-κB signaling pathway. The in vivo results indicated that PLN can inhibit inflammatory bone loss and facilitate bone regeneration in periodontitis. Our findings suggest that topographical nanofibers with periodic lamellae is a promising strategy for modulating immune environment to treat inflammatory bone loss in periodontitis. This article is protected by copyright. All rights reserved.

Ameliorating Mitochondrial Dysfunction for the Therapy of Parkinson's Disease.

Parkinson's disease (PD) is currently the second most incurable central neurodegenerative disease resulting from various pathogenesis. As the "energy factory" of cells, mitochondria play an extremely important role in supporting neuronal signal transmission and other physiological activities. Mitochondrial dysfunction can cause and accelerate the occurrence and progression of PD. How to effectively prevent and suppress mitochondrial disorders is a key strategy for the treatment of PD from the root. Therefore, the emerging mitochondria-targeted therapy has attracted considerable interest. Herein, the relationship between mitochondrial dysfunction and PD, the causes and results of mitochondrial dysfunction, and major strategies for ameliorating mitochondrial dysfunction to treat PD are systematically reviewed. The study also prospects the main challenges for the treatment of PD.

Hippo/YAP1 promotes osteoporotic mice bone defect repair via the activating of Wnt signaling pathway.

BACKGROUND: This study is to investigate the role and mechanism of Hippo/YAP1 in the repair of osteoporotic bone defects in aged mice, both in vivo and in vitro. METHODS: We investigated the expression differences of the Hippo signaling in young and aged individuals both in vivo and in vitro. By manipulating the expression of Lats1/2 and Yap1, we investigated the role of Hippo/YAP1 in regulating osteogenic differentiation in aged BMSCs. In vivo, by intervening in the local and systemic expression of Lats1/2 and Yap1 respectively, we sought to demonstrate whether Hippo/YAP1 promotes the repair of bone defects in aged osteoporotic conditions. Finally, we delved into the underlying mechanisms of Hippo/YAP1 in regulating osteogenic differentiation. RESULTS: We observed differences in the expression of the Hippo signaling between young and aged individuals. After knocking out Lats1/2 in aged BMSCs, we observed that the upregulation of endogenous YAP1 promotes cellular osteogenic differentiation and proliferation capacity. Through interference with Yap1 expression, we provided strong evidence for the role of Hippo/YAP1 in promoting osteogenic differentiation in aged BMSCs. In vivo, we confirmed that Hippo/YAP1 promotes the repair of bone defects in aging osteoporosis. Moreover, we discovered an interaction relationship among YAP1, ß-catenin, and TEAD1. CONCLUSION: This study elucidates the role of Hippo/YAP1 in promoting the repair of osteoporotic bone defects in aged mice. Mechanistically, YAP1 functions by activating the Wnt/ß-catenin pathway, and this process is not independent of TEAD1.

SIRT1 activation promotes bone repair by enhancing the coupling of type H vessel formation and osteogenesis.

Bone repair is intricately correlated with vascular regeneration, especially of type H vessels. Sirtuin 1 (SIRT1) expression is closely associated with endothelial function and vascular regeneration; however, the role of SIRT1 in enhancing the coupling of type H vessel formation with osteogenesis to promote bone repair needs to be investigated. A co-culture system combining human umbilical vein endothelial cells and osteoblasts was constructed, and a SIRT1 agonist was used to evaluate the effects of SIRT1 activity. The angiogenic and osteogenic capacities of the co-culture system were examined using short interfering RNA. Mouse models with bone defects in the femur or mandible were established to explore changes in type H vessel formation and bone repair following modulated SIRT1 activity. SIRT1 activation augmented the angiogenic and osteogenic capacities of the co-culture system by activating the PI3K/AKT/FOXO1 signalling pathway and did not significantly regulate osteoblast differentiation. Inhibition of the PI3K/AKT/FOXO1 pathway attenuated SIRT1-mediated effects. The SIRT1 activity in bone defects was positively correlated with the formation of type H vessels and bone repair in vivo, whereas SIRT1 inhibition substantially weakened vascular and bone formation. Thus, SIRT1 is crucial to the coupling of type H vessels with osteogenesis during bone repair.

LATS1/YAP1 Axis Controls Bone Regeneration on Distraction Osteogenesis by Activating Wnt/ß-Catenin.

The Hippo signaling pathway inhibits cell growth, and its components and functions are highly conserved in mammals. LATS1 is a core component of the Hippo signaling pathway associated with lymphatic invasion, astrogliosis, apoptosis, and autophagy. Nevertheless, the role of Hippo/LATS1 in osteogenesis remains unclear. In this study, we used ribonucleic acid (RNA) lentiviruses to inhibit the expression of Lats1 in bone marrow-derived stem cells (BMSCs) and distraction osteogenic regions in rats. Increased osteogenic, proliferative, and migratory abilities of BMSCs were observed in Lats1-inhibited BMSCs, while these phenotypes were partially reversed by YAP1 inhibition. In vivo, we found that the LATS1/YAP1 axis promoted osteogenesis during distraction osteogenesis (DO). ß-catenin was positively correlated with YAP1 expression in vivo and in vitro. When YAP1 was strongly positive in the nucleus, ß-catenin expression was upregulated; when YAP1 expression was inhibited by verteporfin, ß-catenin was not expressed in the nucleus. These findings suggest that the LATS1/YAP1 signaling axis promotes DO by activating the Wnt/ß-catenin signaling pathway. This study provides insights into the molecular mechanism of osteogenesis and a potential therapeutic strategy for bone regeneration in DO by associating with LATS1/YAP1-ß-catenin.

The role of integrin αvß3 in biphasic calcium phosphate ceramics mediated M2 Macrophage polarization and the resultant osteoinduction.

Calcium phosphate ceramics-based biomaterials were reported to have good biocompatibility and osteoinductivity and have been widely applied for bone defect repair and regeneration. However, the mechanism of their osteoinductivity is still unclear. In our study, we established an ectopic bone formation in vivo model and an in vitro macrophage cell co-culture system with calcium phosphate ceramics to investigate the effect of biphasic calcium phosphate on osteogenesis via regulating macrophage M1/M2 polarization. Our micro-CT data suggested that biphasic calcium phosphate had significant osteoinductivity, and the fluorescence co-localization detection found increased F4/80+/integrin αvß3+ macrophages surrounding the biphasic calcium phosphate scaffolds. Besides, our study also revealed that biphasic calcium phosphate promoted M2 polarization of macrophages via upregulating integrin αvß3 expression compared to tricalcium phosphate, and the increased M2 macrophages could subsequently augment the osteogenic differentiation of MSCs in a TGFß mediated manner. In conclusion, we demonstrated that macrophages subjected to biphasic calcium phosphate could polarize toward M2 phenotype via triggering integrin αvß3 and secrete TGFß to increase the osteogenesis of MSCs, which subsequently enhances bone regeneration.

Boosting Microglial Lipid Metabolism via TREM2 Signaling by Biomimetic Nanoparticles to Attenuate the Sevoflurane-Induced Developmental Neurotoxicity.

Lipid metabolism has been considered as a potential therapeutic target in sevoflurane-induced neurotoxicity that can potentially affect the learning and memory function in the developmental brain. Recently, triggering receptor expressed on myeloid cells 2 (TREM2) is identified as a crucial step in regulating lipid metabolism and associated with the pathogenesis of neurodegenerative diseases. Herein, it is reported that quercetin modified Cu2- x Se (abbreviated as CSPQ) nanoparticles can ameliorate sevoflurane-induced neurotoxicity by tuning the microglial lipid metabolism and promoting microglial M2-like polarization via TREM2 signaling pathway, in which the apolipoprotein E (ApoE), and adenosine triphosphate-binding cassette transporters (ABCA1 and ABCG1) levels are upregulated. Furthermore, the protective effects of CSPQ nanoparticles against sevoflurane-induced neurotoxicity via TREM2 are further demonstrated by the small interfering RNA (siRNA)-TREM2 transfected BV2 cells, which are obviously not influenced by CSPQ nanoparticles. The cell membrane coated CSPQ (referred as CSPQ@CM) nanoparticles can significantly reduce sevoflurane-induced learning and memory deficits, improve lipid metabolism dysfunction, and promote the remyelination in the hippocampus of mice. The study shows great potential of targeting microglial lipid metabolism in promoting remyelination of neurons for treatment of neurotoxicity and neurodegenerative diseases.

The role of zinc finger proteins in the fate determination of mesenchymal stem cells during osteogenic and adipogenic differentiation.

Zinc finger proteins (ZFPs) constitute a crucial group of transcription factors widely present in various organisms. They act as transcription factors, nucleases, and RNA-binding proteins, playing significant roles in cell differentiation, growth, and development. With extensive research on ZFPs, their roles in the determination of mesenchymal stem cells (MSCs) fate during osteogenic and adipogenic differentiation processes have become increasingly clear. ZFP521, for instance, is identified as an inhibitor of the Wnt signaling pathway and RUNX2's transcriptional activity, effectively suppressing osteogenic differentiation. Moreover, ZFP217 contributes to the inhibition of adipogenic differentiation by reducing the M6A level of the cell cycle regulator cyclin D1 (CCND1). In addition, other ZFPs can also influence the fate of mesenchymal stem cells (MSCs) during osteogenic and adipogenic differentiation through various signaling pathways, transcription factors, and epigenetic controls, participating in the subsequent differentiation and maturation of precursor cells. Given the prevalent occurrence of osteoporosis, obesity, and related metabolic disorders, a comprehensive understanding of the regulatory mechanisms balancing bone and fat metabolism is essential, with a particular focus on the fate determination of MSCs in osteogenic and adipogenic differentiation. In this review, we provide a detailed summary of how zinc finger proteins influence the osteogenic and adipogenic differentiation of MSCs through different signaling pathways, transcription factors, and epigenetic mechanisms. Additionally, we outline the regulatory mechanisms of ZFPs in controlling osteogenic and adipogenic differentiation based on various stages of MSC differentiation.

Characterization of upper airway and analysis of potential risk factor associated with OSA in patients with unilateral temporomandibular ankylosis and micrognathia deformities.

OBJECTIVE: To ascertain the airway characteristics in patients with unilateral temporomandibular joint ankylosis and maxilla-mandibular deformities (UTMAMD) and investigate the potential risk factors associated with obstructive sleep apnea (OSA) among UTMAMD patients. METHODS: Authors conducted a retrospective single-center study to assess and compare study group consisting of a cohort of 32 patients diagnosed with UTMAMD between January 2011 and July 2022 with control group including 54 participants. The study group was further divided into two subgroups based on the presence or absence of OSA in patients. Parameters related to the upper airway were measured and analyzed using three-dimensional reconstruction of computed tomographic scans. The measurements of airway parameters were compared between study group and control group and between two subgroups. Pearson correlation analysis was used to identify the factors associated with the presence of OSA, and a multiple variable regression model was used to identify risk factors for OSA. RESULTS: Airway volume (VOL), Minimum cross-section area (min CSA), mean CSA, tilt in sagittal plane (TS), and tilt in sagittal plane (TC) in velopharynx; VOL, airway length (AL), min CSA, mean CSA, TS, TC, and airway deviation (AD) in glossopharynx; min CSA, TS, and AD in hypopharynx were found difference with significance between study group and control group. Lateral dimension/anterior-posterior dimension (LAT/AP) ratio in velopharynx and min CSA, TC, and LAT/AP ratio in glossopharynx were significant different between patients with UTMAMD with OSA and without OSA. CONCLUSIONS: The upper airway of patients with UTMAMD exhibits significant narrowing and distortion, rendering them susceptible to suffer from OSA. Patients with UTMAMD and OSA demonstrate more elliptical airways, and the glossopharyngeal LAT/AP ratio is a predictive indicator for the occurrence of OSA.

Metal ions: the unfading stars of bone regeneration-from bone metabolism regulation to biomaterial applications.

In recent years, bone regeneration has emerged as a remarkable field that offers promising guidance for treating bone-related diseases, such as bone defects, bone infections, and osteosarcoma. Among various bone regeneration approaches, the metal ion-based strategy has surfaced as a prospective candidate approach owing to the extensive regulatory role of metal ions in bone metabolism and the diversity of corresponding delivery strategies. Various metal ions can promote bone regeneration through three primary strategies: balancing the effects of osteoblasts and osteoclasts, regulating the immune microenvironment, and promoting bone angiogenesis. In the meantime, the complex molecular mechanisms behind these strategies are being consistently explored. Moreover, the accelerated development of biomaterials broadens the prospect of metal ions applied to bone regeneration. This review highlights the potential of metal ions for bone regeneration and their underlying mechanisms. We propose that future investigations focus on refining the clinical utilization of metal ions using both mechanistic inquiry and materials engineering to bolster the clinical effectiveness of metal ion-based approaches for bone regeneration.

Transcriptome and Proteome Association Analysis to Screen Candidate Genes Related to Salt Tolerance in Reaumuria soongorica Leaves under Salt Stress.

This work aims at studying the molecular mechanisms underlying the response of Reaumuria soongorica to salt stress. We used RNA sequencing (RNA-Seq) and Tandem Mass Tag (TMT) techniques to identify differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in R. soongorica leaves treated with 0, 200, and 500 mM NaCl for 72 h. The results indicated that compared with the 0 mM NaCl treatment group, 2391 and 6400 DEGs were identified in the 200 and 500 mM NaCl treatment groups, respectively, while 47 and 177 DEPs were also identified. Transcriptome and proteome association analysis was further performed on R. soongorica leaves in the 0/500 mM NaCl treatment group, and 32 genes with consistent mRNA and protein expression trends were identified. SYP71, CS, PCC13-62, PASN, ZIFL1, CHS2, and other differential genes are involved in photosynthesis, vesicle transport, auxin transport, and other functions of plants, and might play a key role in the salt tolerance of R. soongorica. In this study, transcriptome and proteome association techniques were used to screen candidate genes associated with salt tolerance in R. soongorica, which provides an important theoretical basis for understanding the molecular mechanism of salt tolerance in R. soongorica and breeding high-quality germplasm resources.

System Xc- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma.

OBJECTIVE: Emerging evidence suggests that glucose depletion (GD)-induced cell death depends on system Xc- , a glutamate/cystine antiporter extensively studied in ferroptosis. However, the underlying mechanism remains debated. Our study confirmed the correlation between system Xc- and GD-induced cell death and provided a strategic treatment for oral squamous cell carcinoma (OSCC). METHODS: qPCR and Western blotting were performed to detect changes in xCT and CD98 expression after glucose withdrawal. Then, the cell viability of OSCCs under the indicated conditions was measured. To identify the GD-responsible transcriptional factors of SLC7A11, we performed a luciferase reporter assay and a ChIP assay. Further, metabolomics was conducted to identify changes in metabolites. Finally, mitochondrial function and ATP production were evaluated using the seahorse assay, and NADP+ /NADPH dynamics were measured using a NADP+ /NADPH kit. RESULTS: In OSCCs, system Xc- promoted GD-induced cell death by increasing glutamate consumption, which promoted NADPH exhaustion and TCA blockade. Moreover, GD-induced xCT upregulation was governed by the p-eIF2α/ATF4 axis. CONCLUSIONS: System Xc- overexpression compromised the metabolic flexibility of OSCC under GD conditions, and thus, glucose starvation therapy is effective for killing OSCC cells.

Exogenous hydrogen sulfide improves salt stress tolerance of Reaumuria soongorica seedlings by regulating active oxygen metabolism.

Hydrogen sulfide (H2S), as an endogenous gas signaling molecule, plays an important role in plant growth regulation and resistance to abiotic stress. This study aims to investigate the mechanism of exogenous H2S on the growth and development of Reaumuria soongorica seedlings under salt stress and to determine the optimal concentration for foliar application. To investigate the regulatory effects of exogenous H2S (donor sodium hydrosulfide, NaHS) at concentrations ranging from 0 to 1 mM on reactive oxygen species (ROS), antioxidant system, and osmoregulation in R. soongorica seedlings under 300 mM NaCl stress. The growth of R. soongorica seedlings was inhibited by salt stress, which resulted in a decrease in the leaf relative water content (LRWC), specific leaf area (SLA), and soluble sugar content in leaves, elevated activity levels of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT); and accumulated superoxide anion (O2-), proline, malondialdehyde (MDA), and soluble protein content in leaves; and increased L-cysteine desulfhydrase (LCD) activity and endogenous H2S content. This indicated that a high level of ROS was produced in the leaves of R. soongorica seedlings and seriously affected the growth and development of R. soongorica seedlings. The exogenous application of different concentrations of NaHS reduced the content of O 2-, proline and MDA, increased the activity of antioxidant enzymes and the content of osmoregulators (soluble sugars and soluble proteins), while the LCD enzyme activity and the content of endogenous H2S were further increased with the continuous application of exogenous H2S. The inhibitory effects of salt stress on the growth rate of plant height and ground diameter, the LRWC, biomass, and SLA were effectively alleviated. A comprehensive analysis showed that the LRWC, POD, and proline could be used as the main indicators to evaluate the alleviating effect of exogenous H2S on R. soongorica seedlings under salt stress. The optimal concentration of exogenous H2S for R. soongorica seedlings under salt stress was 0.025 mM. This study provides an important theoretical foundation for understanding the salt tolerance mechanism of R. soongorica and for cultivating high-quality germplasm resources.

Dual-Signal Cascaded Nucleic Acid Amplification Circuit-Loaded Metal-Organic Frameworks for Accurate and Robust Imaging of Intracellular MicroRNA.

Cascaded signal amplification technologies play an important role in the sensitive detection of lowly expressed biomarkers of interests yet are constrained by severe background interference and low cellular accessibility. Herein, we constructed a metal-organic framework-encapsulating dual-signal cascaded nucleic acid sensor for precise intracellular miRNA imaging. ZIF-8 nanoparticles load and deliver FAM-labeled upstream catalytic hairpin assembly (CHA) and Cy5-modified downstream hybridization chain reaction (HCR) hairpin reactants to tumor cells, enabling visualization of the target-initiated signal amplification process for double-insurance detection of analytes. The pH-responsive ZIF-8 nanoparticles effectively protect DNA hairpins from degradation and allow the release of them in the acid tumor microenvironment. Then, intracellular target miRNAs orderly trigger cascaded nucleic acid signal amplification reaction, of which the exact progress is investigated through the analysis of the fluorescence recovering process of FAM and Cy5. In addition, DNA@ZIF-8 nanoparticles improve measurement accuracy by dual-signal colocalization imaging, effectively avoiding nonspecific false-positive signals and enabling in situ imaging of miRNAs in living cells. A dual-signal colocalization strategy allows accurate target detection in living cells, and DNA@ZIF-8 provides a promising intracellular sensing platform for signal amplification and visual monitoring.

PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner.

Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis, and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss of Zfp467 increased Pth1r expression and shifts mesenchymal progenitor cell fate toward osteogenesis and higher bone mass. PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion of Zfp467 in osteogenic precursors would lead to high bone mass in mice. Prrx1Cre; Zfp467fl/fl but not AdipoqCre; Zfp467fl/fl mice exhibit high bone mass and greater osteogenic differentiation similar to the Zfp467-/- mice. qPCR results revealed that PTH suppressed Zfp467 expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression of Zfp467 and gene silencing of Pth1r caused an increase in Zfp467 mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion of Zfp467 resulted in higher nuclear translocation of NFκB1 that binds to the P2 promoter of the Pth1r and increased its transcription. As expected, Zfp467-/- cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced in Zfp467-/- COBs, and the pro-osteogenic effect of Zfp467 deletion was blocked by gene silencing of Pth1r or a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression of Zfp467 results in a pathway that increases Pth1r transcription via NFκB1 and thus cellular responsiveness to PTH/PTHrP, ultimately leading to enhanced bone formation.

Ameliorating Mitochondrial Dysfunction of Neurons by Biomimetic Targeting Nanoparticles Mediated Mitochondrial Biogenesis to Boost the Therapy of Parkinson's Disease.

Mitochondrial dysfunction of neurons is the core pathogenesis of incurable Parkinson's disease (PD). It is crucial to ameliorate the mitochondrial dysfunction of neurons for boosting the therapy of PD. Herein, the remarkable promotion of mitochondrial biogenesis to ameliorate mitochondrial dysfunction of neurons and improve the treatment of PD by using mitochondria-targeted biomimetic nanoparticles, which are Cu2- x Se-based nanoparticles functionalized with curcumin and wrapped with DSPE-PEG2000 -TPP-modified macrophage membrane (denoted as CSCCT NPs), is reported. These nanoparticles can efficiently target mitochondria of damaged neurons in an inflammatory environment, and mediate the signaling pathway of NAD+ /SIRT1/PGC-1α/PPARγ/NRF1/TFAM to alleviate 1-methyl-4-phenylpyridinium (MPP+ )-induced neuronal toxicity. They can reduce the mitochondrial reactive oxygen species, restore mitochondrial membrane potential (MMP), protect the integrity of mitochondrial respiratory chain, and ameliorate mitochondrial dysfunction via promoting mitochondrial biogenesis, which synergistically improve the motor disorders and anxiety behavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. This study demonstrates that targeting mitochondrial biogenesis to ameliorate mitochondrial dysfunction has a great potential in the treatment of PD and mitochondria-related diseases.

Chemiluminescence resonance energy transfer-based multistage nucleic acid amplification circuits for MiRNA detection with low background.

Chemiluminescence resonance energy transfer (CRET)-based assays have shown great potential in biosensing due to their negligible background autofluorescence, yet are still limited by their low sensitivity and short half-life luminescence. Herein, a multistage CRET-based DNA circuit was constructed with amplified luminescence signals for accurate miRNA detection and fixed reactive oxygen species (ROS) signals for cell imaging. The DNA circuit is designed through an ingenious programmable catalytic hairpin assembly (CHA), hybridization chain reaction (HCR), and the use of DNAzyme to realize target-triggered precise regulation of distance between the donor and acceptor for CRET-mediated excitation of photosensitizers. In detail, the analyte catalyzes the hybridization of CHA reactants, which leads to the assembly of multiple HCR-mediated DNAzyme nanowires. Subsequently, DNAzymes catalyze the oxidation of luminol by H2O2, and the adjacent photosensitizer chlorin e6 (Ce6) anchored on the DNA nanostructure is stimulated by the CRET process, resulting in the amplified long-wavelength luminescence and the generation of single oxygen signals through further energy transfer to oxygen. The biomarker miRNA can be detected with great sensitivity by integrating the recognition module into a universal platform. Furthermore, the DNA circuit enables CRET-mediated intracellular miRNA imaging, by detecting singlet oxygen signals through a ROS probe. The significant amplification effect is attributed to the robust multiple recognition of the target and the guaranteed transduction of the CRET signal through programmable engineering of DNA nanostructures. The CRET-based DNA circuit achieves amplified long-wavelength luminescence for accurate miRNA detection with low background and ROS-mediated signal fixation for cell imaging, making it a promising candidate for early diagnosis and theranostics.