Near-Infrared Triggered Self-Accelerating Nanozyme Camouflaged with a Cancer Cell Membrane for Precise Targeted Imaging and Enhanced Cancer Immunotherapy.

Although cancer immunotherapy has made encouraging progress, clinical therapeutic efficiency is often modest due to inadequate immunogenicity and immune resistance. Developing promising nanoagents for simultaneously activating tumor-specific immunity and suppressing immune resistance to achieve efficient immunotherapy is still challenging. Herein, we developed a biomimetic nanozyme consisting of a gold nanorod@mesoporous ceria core-shell scaffold with gold nanoparticle deposition and cancer cell membrane camouflage. The nanozyme exhibited near-infrared (NIR)-enhanced GOx-mimicking activity at high temperatures and performed well under hypoxic environments due to an increased in situ oxygen supply. In cancer cells, the nanozyme induced and amplified hyperthermia by triggering self-accelerating cascade reactions to deplete glucose and inhibiting the expression of heat shock protein under NIR irradiation, which can cause mitochondrial dysfunction and redox balance disruption to activate pyroptosis and elicit a robust immune response. Additionally, the immune checkpoint blockade caused by encapsulated JQ1-mediated PD-L1 downregulation synergistically contributed to excellent immune therapeutic effects. Besides, we demonstrated that cancer cell membrane coating endows the nanozyme targeting ability to tumor. The proposed nanozyme will broaden the application of GOx and have the potential as the nanoplatform for imaging-guided and O2-consuming combined treatments.

A DNA Tetrahedron Nanoprobe with Controlled Distance of Dyes for Multiple Detection in Living Cells and in Vivo.

Multicomponent quantitative detection in living samples is becoming increasingly important; however, the current detection strategy may cause fluorescence self-quenching and reduce the sensitivity of detection. To solve the problem, we develop a DNA tetrahedral nanoprobe to control the dyes distance for simultaneous detection of multiple analytes. Compared to mesoporous silica nanoparticles based nanoprobes, the DNA tetrahedral nanoprobes display enhanced fluorescence intensities due to partially avoiding the fluorescence resonance energy transfer. Confocal fluorescence images show that the nanoprobes are capable of detecting and visualizing pH and O2•- in living cells under a single wavelength excitation. In an inflammation model for mice, the nanoprobes simultaneously image the down-regulation of pH and up-regulation of O2•-. We expect that the current strategy can provide new opportunities in designing probes for multiplexed detection with reduced self-quenching and enhanced sensitivity.

Fluorescent Nanocomposite for Visualizing Cross-Talk between MicroRNA-21 and Hydrogen Peroxide in Ischemia-Reperfusion Injury in Live Cells and In Vivo.

MicroRNAs (miRNAs) and reactive oxygen species (ROS) are concurrently implicated in heart ischemia-reperfusion (IR) injury. There may exist mutual cross-talk between miRNAs and ROS in cardiac IR injury process. In this study, we developed a novel crown-like silica@polydopamine-DNA-CeO2 nanocomposite by assembly of silica@polydopamine-DNA1 nanoparticles decorated with satellite CeO2-DNA2 nanoparticles for detecting and imaging of microRNA-21 (miR-21) and hydrogen peroxide (H2O2) in simulated IR injury in living cells and in vivo. The miRNA-21 was found to be regulated by H2O2 via PI3K/AKT signaling pathway for the first time in H9C2 cells in simulated ischemia-reperfusion injury. H2O2 and miRNA-21 are overproduced during mimicked heart ischemia-reperfusion injury, suggesting that they are closely related to reperfusion injury. All these results reveal that there is definite cross-talk between miR-21 and H2O2 in IR injury. The current method can provide a promising strategy to further explore the interplaying roles between ROS and miRNAs in other pathological processes.

Ratiometric Fluorescence Nanoprobes for Subcellular pH Imaging with a Single-Wavelength Excitation in Living Cells.

Abnormal pH values in the organelles are closely associated with inappropriate cellular functions and many diseases. Monitoring subcellular pH values and their variations is significant in biological processes occurring in living cells and tissues. Herein, we develop a series of ratiometric fluorescence nanoprobes for quantification and imaging of pH values with a single-wavelength excitation in cytoplasm, lysosomes, and mitochondria. The nanoprobes consist of mesoporous silica nanoparticles assembled with aminofluorescein as the recognition unit for pH measurement and ethidium bromide as reference fluorophore. Further conjugation of subcellular targeting moiety enables the nanoprobes to specifically target lysosome and mitochondria. Confocal fluorescence imaging demonstrated that the nanoprobes could effectively monitor the pH fluctuations from 5.0 to 8.3 in living cells by ratio imaging with 488 nm excitation. Subcellular pH determination and imaging in lysosome and mitochondria could also be achieved in different conditions. The current method can offer a general strategy to determine subcellular analytes and investigate the interactions in biological samples.

Real-time imaging of mitochondrial hydrogen peroxide and pH fluctuations in living cells using a fluorescent nanosensor.

Mitochondrial reactive oxygen species (ROS) and pH fluctuations are closely correlated with mitochondrial dysfunctions, which are implicated in various human diseases including neurodegenerative disorders and cancers. Simultaneously monitoring the changes of ROS and pH of mitochondria remains a major challenge in the mitochondrial biology. In this study, we develop a novel mitochondria-targeted fluorescent nanosensor for real-time imaging of the fluctuations of hydrogen peroxide (H2O2) and pH in living cells. The fluorescence probes for detecting pH and H2O2 were loaded in the small-sized mesoporous silica nanoparticles (MSN). Then the polyethylenimine was attached to cap the pores of MSN, the triphenylphosphonium was further modified to target mitochondria in living cells. Confocal fluorescence imaging indicated that the nanosensor could effectively target mitochondria and successfully achieved real-time imaging of mitochondrial H2O2 and pH fluctuations in living cells. Notably, this is a single nanosensing system that is capable of visualizing multiple subcellular analytes at the same time and position by multicolor fluorescence imaging. The current approach can provide a promising tool to investigate the interplaying roles of various subcellular analytes in living cells.

Efficient late-stage synthesis of quaternary phosphonium salts from organothianthrenium salts via photocatalysis.

Quaternary phosphonium salts (QPS) are significant structural motifs in drugs, materials, and catalysts. Here, a photoactivated approach for the selective late-stage synthesis of QPS utilizing organothianthrenium salts and tertiary phosphines is presented with high yields and broad functional group compatibility. Additionally, the synthetic utility of this protocol is demonstrated by in situ generation of QPS via C-H functionalization and its fluorescence confocal imaging of mitochondrial localization in cells.

Human Serum Albumin Mediated Controllable Synthesis of Defect-Rich Copper Hydroxide Nanowire for Cuproptosis-Based Anti-Tumor Therapy.

Cuproptosis, as a newly identified form of programmed cell death, shows great promise in cancer treatment. Efficient Cu+ delivery while avoiding systemic toxicity and elimination of the resistance from over-expressed intracellular copper chelator glutathione (GSH) are critical for cuproptosis. Herein, this work innovatively constructs a biocompatible and defect-rich copper hydroxide nanowire (HCu nanowire) through a human serum albumin (HSA) mediated biomineralization method. This work finds that the morphology and size of HCu nanowires can be controlled adjusted by the feed ratio of HSA and Cu2+. Remarkably, except for outstanding biocompatibility, HSA coordination endows HCu nanowires abundant oxygen vacancies (OVs), and the defect-rich HCu nanowire possesses excellent GSH consumption efficiency. Density functional theory studies indicate that OVs change GSH absorption energy on defective HCu nanowires. In cancer cells, HCu nanowires deplete GSH and simultaneously produce sufficient free Cu+ for enhanced cuproptosis. Meanwhile, Cu+ can catalyze endogenous H2O2 into hydroxyl radicals (·OH) via a Fenton-like reaction. Thus, synergetic cuproptosis and ROS mediated apoptosis against tumor are achieved. The experimental results show that HCu nanowires have a better performance in both antitumor efficiency and safety compared with chemotherapeutic drug Dox at the same dose, demonstrating its great potential in clinical applications.

The structure and function of FUN14 domain-containing protein 1 and its contribution to cardioprotection by mediating mitophagy.

Cardiovascular disease (CVD) is a serious public health risk, and prevention and treatment efforts are urgently needed. Effective preventive and therapeutic programs for cardiovascular disease are still lacking, as the causes of CVD are varied and may be the result of a multifactorial combination. Mitophagy is a form of cell-selective autophagy, and there is increasing evidence that mitophagy is involved in cardioprotective processes. Recently, many studies have shown that FUN14 domain-containing protein 1 (FUNDC1) levels and phosphorylation status are highly associated with many diseases, including heart disease. Here, we review the structure and functions of FUNDC1 and the path-ways of its mediated mitophagy, and show that mitophagy can be effectively activated by dephosphorylation of Ser13 and Tyr18 sites, phosphorylation of Ser17 site and ubiquitination of Lys119 site in FUNDC1. By effectively activating or inhibiting excessive mitophagy, the quality of mitochondria can be effectively controlled. The main reason is that, on the one hand, improper clearance of mitochondria and accumulation of damaged mitochondria are avoided, and on the other hand, excessive mitophagy causing apoptosis is avoided, both serving to protect the heart. In addition, we explore the possible mechanisms by which FUNDC1-mediated mitophagy is involved in exercise preconditioning (EP) for cardioprotection. Finally, we also point out unresolved issues in FUNDC1 and its mediated mitophagy and give directions where further research may be needed.

Effects of the different Tai Chi exercise cycles on patients with essential hypertension: A systematic review and meta-analysis.

Objective: The main treatment for essential hypertension at this stage is pharmacotherapy. Long-term pharmacotherapy is costly with some side effects. Tai Chi, a bright star in traditional Chinese arts, relaxes both mind and body and has been shown to relax blood vessels and lower blood pressure. This study aimed to systematically review the therapeutic effectiveness of the Tai Chi exercise cycle on blood pressure and cardiovascular risk factors of patients with essential hypertension. Methods: Searching CNKI, VIP, CBM, PubMed, EBSCO, Embase, Cochrane Library, and Web of Science to collect randomized controlled trials about Tai Chi exercise in the treatment of patients with essential hypertension according to the inclusion and exclusion criteria. The search time ranged from the date of database construction to December 2022. The Cochrane risk-of-bias tool was used to evaluate the included trials. The meta-analysis was performed with RevMan5.3 and Stata12.0 software. Results: According to the meta-analysis, compared with the controls, Tai Chi exercise with a cycle of more than 12 weeks may be better for the reduction of systolic blood pressure (SBP) [MD = -11.72, 95% CI (-15.52, -7.91)] and diastolic blood pressure (DBP) [MD = -4.68, 95% CI (-7.23, -2.12)], as well as increasing the content of nitric oxide (NO) [MD = 0.99, 95% CI (0.69, 1.28)]. The blood lipid metabolism ability may also be improved after more than 12 weeks of Tai Chi exercise, total cholesterol (TC) [SMD = -0.68, 95% CI (-0.89, -0.46), triglyceride (TG) [SMD = -0.84, 95% CI (-1.25, -0.43)], low-density lipoprotein cholesterol (LDL-C) [SMD = -1.58, 95% CI (-2.29, -0.86)]. However, the improvement of high-density lipoprotein cholesterol (HDL-C) [SMD = 0.54, 95% CI (0.28, 0.79)] was better with a less than 12 weeks exercise cycle. A subgroup analysis for exercise frequency and time showed that the exercise frequency should preferably be more than or equal to 5 times per week for patients with hypertension, and for patients with hypertension plus hyperlipidemia, the exercise frequency less than 5 times per week with exercise time less than 60 min each day may be more beneficial. Conclusion: The meta-analysis indicated that a more than 12 weeks Tai Chi exercise cycle with less than 60 min each time and more than 5 times per week may be more beneficial in blood pressure reduction, NO level increasing and blood lipid metabolism improving in the comparison with the other exercise cycles. For patients with hypertension plus hyperlipidemia, exercise frequency of less than 5 times per week may be better. Systematic Review Registration: [http://www.crd.york.ac.uk/prospero], identifier [CRD42022352035].

Efficacy of Pilates on Pain, Functional Disorders and Quality of Life in Patients with Chronic Low Back Pain: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic low back pain (CLBP) is a common health problem. Pilates is a unique exercise therapy. This meta-analysis aims to evaluate the efficacy of Pilates on pain, functional disorders, and quality of life in patients with chronic low back pain (CLBP). METHODS: PubMed, Web of Science, CNKI, VIP, Wanfang Data, CBM, EBSCO, and Embase were searched. Randomized controlled trials of Pilates in the treatment of CLBP were collected based on the inclusion and exclusion criteria. The meta-analysis was performed using RevMan 5.4 and Stata 12.2. RESULTS: 19 randomized controlled trials with a total of 1108 patients were included. Compared with the controls, the results showed the following values: Pain Scale [standard mean difference; SMD = -1.31, 95%CI (-1.80, -0.83), p < 0.00001], Oswestry Disability Index (ODI) [mean difference; MD = -4.35, 95%CI (-5.77, -2.94), p < 0.00001], Roland-Morris Disability Questionnaire (RMDQ) [MD = -2.26, 95%CI (-4.45, -0.08), p = 0.04], 36-item Short-Form (SF-36) (Physical Function (PF) [MD = 5.09, 95%CI (0.20, 9.99), p = 0.04], Role Physical (RP) [MD = 5.02, 95%CI (-1.03, 11.06), p = 0.10], Bodily Pain (BP) [MD = 8.79, 95%CI (-1.57, 19.16), p = 0.10], General Health (GH) [MD = 8.45, 95%CI (-5.61, 22.51), p = 0.24], Vitality (VT) [MD = 8.20, 95%CI(-2.30, 18.71), p = 0.13], Social Functioning (SF) [MD = -1.11, 95%CI (-7.70, 5.48), p = 0.74], Role Emotional (RE) [MD = 0.86, 95%CI (-5.53, 7.25), p = 0.79], Mental Health (MH) [MD = 11.04, 95%CI (-12.51, 34.59), p = 0.36]), Quebec Back in Disability Scale (QBPDS) [MD = -5.51, 95%CI (-23.84, 12.81), p = 0.56], and the sit-and-reach test [MD = 1.81, 95%CI (-0.25, 3.88), p = 0.09]. CONCLUSIONS: This meta-analysis reveals that Pilates may have positive efficacy for pain relief and the improvement of functional disorders in CLBP patients, but the improvement in quality of life seems to be less obvious. REGISTRATION: PROSPERO CRD42022348173.

An efficient biomimetic nano-regulator inducing simultaneous calcium ion/nitric oxide/energy metabolism triple homeostasis disruption for synergetic cancer therapy.

Inducing homeostasis disruption in cancer cells will cause severe cytotoxicity and apoptosis for cancer therapy. However, comprehensive intracellular active homeostatic mechanisms make it still a daunting challenge. Reported herein is a biomimetic nano-regulator for mutually reinforcing Ca2+/NO/energy metabolism triple homeostasis disruption via cascade reactions.

Harnessing Reconstructed Macrophage Modulation of Infiltration-Excluded Immune Microenvironments To Delineate Glioma Infiltrative Region.

High invasiveness of glioma produces residual glioma cells in the brain parenchyma after surgery and ultimately causes recurrence. Precise delineation of glioma infiltrative region is critical for an accurate complete resection, which is challenging. The glioma-infiltrating area constitutes infiltration-excluded immune microenvironments (I-E TIMEs), which recruits endogenous or adoptive macrophages to the invasive edge of glioma. Thus, combined with immune cell tracing technology, we provided a novel strategy for the preoperative precise definition of the glioma infiltration boundary, even satellite-like infiltration stoves. Herein, the biomimetic probe was constructed by internalizing fluorophore labeled PEGylated KMnF3 nanoparticles into bone-marrow-derived macrophages using magnetic resonance imaging (MRI)/fluorescence imaging (FI). The biomimetic probe was able to cross the blood-brain barrier and home to the orthotopic glioma infiltrates including satellite stove under MRI and FI tracing, which was validated using hematoxylin and eosin staining, indicating its excellent performance in distinguishing the margins between the glioma cell and normal tissues. This study guides the precise definition of glioma infiltration boundaries at the cellular level, including the observation of any residual glioma cells after surgery. Thus, it has the potential to guide surgery to maximize resection and predict recurrence in the clinic.

Effectiveness of the Rehabilitation Training Combined with Maitland Mobilization for the Treatment of Chronic Ankle Instability: A Randomized Controlled Trial.

The study aims to determine whether routine rehabilitation training combined with the Maitland mobilization is more effective than routine rehabilitation training alone in patients with chronic ankle instability, intending to provide a novel rehabilitation strategy for chronic ankle instability. A total of 48 subjects were divided into three groups: EG (Maitland mobilization and routine rehabilitation), CG (routine rehabilitation), and SG (sham mobilization and routine rehabilitation). The intervention was performed three times each week for 4 weeks, for a total of 12 sessions. Before and after the intervention, the muscle strength, star excursion balance test (SEBT), weight-bearing dorsiflexion range of motion (WB-DFROM), ankle range of movement, Cumberland ankle instability tool (CAIT), self-comfort visual analog scale (SCS-VAS), and self-induced stability scale (SISS-VAS) were assessed. The results showed that the improvement of SEBT, WB-DFROM, and active ankle range of movement without the pain in EG was more obvious than CG and SG, but the improvement of the self-report of ankle severity and muscle strength was not. Compared with routine rehabilitation training alone, routine rehabilitation training combined with Maitland mobilization for patients with chronic ankle instability may provide more benefit in terms of balance and ankle range of movement than routine rehabilitation alone, but the improvement in muscle strength was not evident enough.

Does whole-body vibration training have a positive effect on balance and walking function in patients with stroke? A meta-analysis.

Objective: After a stroke, patients usually suffer from dysfunction, such as decreased balance ability, and abnormal walking function. Whole-body vibration training can promote muscle contraction, stimulate the proprioceptive system, enhance the muscle strength of low limbs and improve motor control ability. The study aims to evaluate the effectiveness of whole-body vibration training on the balance and walking function of patients with stroke. Methods: PubMed, CNKI, VIP, CBM, EBSCO, Embase and Web of Science were searched. According to the inclusion and exclusion criteria, randomized controlled trials on the effectiveness of whole-body vibration training on the balance and walking function of patients with stroke were collected. The search time ranged from the date of database construction to November 2022. The included trials were evaluated by the Cochrane risk-of-bias tool. The meta-analysis was performed using two software packages, consisting of RevMan 5.4 and Stata 12.2. If the results included in the literature were continuous variables, use the mean difference (MD) and 95% confidence interval (CI) for statistics. Results: (1) A total of 22 randomized controlled trials (RCTs) with a total of 1089 patients were included. (2) The results of meta-analysis showed that: compared with the controls, step length (MD = 6.12, 95%CI [5.63, 6.62], p < 0.001), step speed (MD = 0.14, 95%CI [0.09, 0.20], p < 0.001), cadence (MD = 9.03, 95%CI [2.23, 15.83], p = 0.009), stride length (MD = 6.74, 95%CI [-3.47, 10.01], p < 0.001), Berg Balance Scale (BBS) (MD = 4.08, 95%CI [2.39, 5.76], p < 0.001), Timed Up-and-Go test (TUGT) (MD = -2.88, 95%CI [-4.94, 0.81], p = 0.006), 10-meter Walk Test (10MWT) (MD = -2.69, 95%CI [-3.35, -2.03], p < 0.001), functional ambulation category scale (FAC) (MD = 0.78, 95%CI [0.65, 0.91], p < 0.001), Fugl-Meyer motor assessment of lower extremity (FMA-LE) (MD = 4.10, 95%CI [2.01, 6.20], p = 0.0001). (3) The results of subgroup analysis showed that, compared with other vibration frequencies, at 20-30 Hz frequency, WBV training had an obvious improvement effect only in TUGT. (4) The safety analysis showed that WBV training may be safe. Conclusion: Whole-body vibration training has a positive effect on the balance and walking function of patients with stroke. Thus, whole-body vibration training is a safe treatment method to improve the motor dysfunction of patients with stroke. Systematic review registration: [http://www.crd.york.ac.uk/PROSPERO], identifier [CRD4202348263].

Simultaneous detection of intracellular tumor mRNA with bi-color imaging based on a gold nanoparticle/molecular beacon.

The successful treatment of most cancers depends on early detection. Tumor mRNA as a specific marker provides new avenues to monitor tumor progression in the early stages and assesses response to treatment. However, single tumor mRNA testing usually yields "false positive" results because cancer is associated with multiple tumor mRNA. It is indispensable to develop simple and effective approaches for the detection of multiple tumor mRNA. In this study, we used a combination of tumor-specific mRNA markers to avoid the inherent limitations associated with the single-marker technique. A gold nanoparticle (AuNP) was assembled with a bi-molecular beacon (bi-MB), and termed AuNP/bi-MB, which simultaneously targeted to two types of tumor mRNA in breast cancer cells. This imaging agent could prevent effectively false positive results and provide comprehensive and dependable information for the early detection of cancer. It would be beneficial to identify the stage of tumor progression and assess treatment decisions with the real-time detection of the relative expression levels of tumor mRNA in cancer cells. This strategy would offer an appealing approach toward the early detection of cancer by using multianalysis of tumor mRNA.

Functionalized nanoprobes for in situ detection of telomerase.

Telomerase, a special ribonucleoprotein reverse transcriptase, can maintain the length and stability of telomeres and plays an important role in cell proliferation and differentiation. Due to the distinguishable expression level in normal cells and cancer cells, telomerase has become an important biomarker for cancer diagnosis and prognosis evaluation. Despite major breakthroughs in the field of telomerase detection, the extracts in the cell lysate are still the first choice as the analyte nevertheless, which will bring serious inaccuracies compared with the real intracellular activity. With the development of nanotechnology and nanomaterials, extraordinary progress has been made in telomerase detection by employing different versatile nanoprobes. In this review, we list the superiority of nanoprobes and systematically summarize the applications of nanoprobes in telomerase detection from the aspects of various nanomaterials and discuss the current challenges and potential trends in the future design of nanoprobes.

Nanoenzymes in disease diagnosis and therapy.

Nanoenzymes, as a new generation of artificial enzymes with highly effective enzyme-like properties, have come into focus and have achieved great progress. Considering the enormous potential of nanoenzymes in the field of disease diagnosis and treatment, such as biological detection, anti-inflammatory, anti-oxidative damage and cancer treatments, etc., we firstly summarize the wide range of bio-applications of different nanoenzymes in these fields. In this review, we discuss the factors influencing the properties of nanoenzymes such as pH and temperature, surface modification and doping of other elements. In addition, we introduce five kinds of nanoenzymes and their bio-applications in various diseases. The current review will make researchers better understand the current state of the development of nanoenzymes and may be beneficial for new breakthroughs.

A cancer cell membrane-encapsulated MnO2 nanoreactor for combined photodynamic-starvation therapy.

We demonstrate a MnO2-based nanoreactor to achieve continuous oxygen generation and efficient conversion from glucose to singlet oxygen for combined photodynamic-starvation therapy.

A biomimetic nanoreactor for synergistic chemiexcited photodynamic therapy and starvation therapy against tumor metastasis.

Photodynamic therapy (PDT) is ineffective against deeply seated metastatic tumors due to poor penetration of the excitation light. Herein, we developed a biomimetic nanoreactor (bio-NR) to achieve synergistic chemiexcited photodynamic-starvation therapy against tumor metastasis. Photosensitizers on the hollow mesoporous silica nanoparticles (HMSNs) are excited by chemical energy in situ of the deep metastatic tumor to generate singlet oxygen (1O2) for PDT, and glucose oxidase (GOx) catalyzes glucose into hydrogen peroxide (H2O2). Remarkably, this process not only blocks the nutrient supply for starvation therapy but also provides H2O2 to synergistically enhance PDT. Cancer cell membrane coating endows the nanoparticle with biological properties of homologous adhesion and immune escape. Thus, bio-NRs can effectively convert the glucose into 1O2 in metastatic tumors. The excellent therapeutic effects of bio-NRs in vitro and in vivo indicate their great potential for cancer metastasis therapy.

A simple approach for glutathione functionalized persistent luminescence nanoparticles as versatile platforms for multiple in vivo applications.

We develop a simple method by constructing glutathione (GSH) conjugated persistent luminescence nanoparticles (PLNPs-GSH) as versatile platforms for multiple biological applications. PLNPs-GSH possess enhanced water solubility and contains a large number of active groups, which offer opportunities for further modification with different functional groups.