Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy.

Aging is a major risk factor for most chronic disorders, for which cellular senescence is one of the central hallmarks. Senescent cells develop the pro-inflammatory senescence-associated secretory phenotype (SASP), which significantly contributes to organismal aging and age-related disorders. Development of senotherapeutics, an emerging class of therapeutic agents to target senescent cells, allows to effectively delay aging and alleviate chronic pathologies. Here we report preliminary outputs from screening of a natural medicinal agent (NMA) library for senotherapeutic candidates and validated several agents with prominent potential as senomorphics. Rutin, a phytochemical constituent found in a number of plants, showed remarkable capacity in targeting senescent cells by dampening expression of the full spectrum SASP. Further analysis indicated that rutin restrains the acute stress-associated phenotype (ASAP) by specifically interfering with the interactions of ATM with HIF1α, a master regulator of cellular and systemic homeostasis activated during senescence, and of ATM with TRAF6, part of a key signaling axis supporting the ASAP development toward the SASP. Conditioned media produced by senescent stromal cells enhanced the malignant phenotypes of prostate cancer cells, including in vitro proliferation, migration, invasion, and more importantly, chemoresistance, while rutin remarkably downregulated these gain-of-functions. Although classic chemotherapy reduced tumor progression, the treatment outcome was substantially improved upon combination of a chemotherapeutic agent with rutin. Our study provides a proof of concept for rutin as an emerging natural senomorphic agent, and presents an effective therapeutic avenue for alleviating age-related pathologies including cancer.

Association between sensation, perception, negative socio-psychological factors and cognitive impairment.

Background: Evidence has suggested that sensation and socio-psychological factors may be associated with cognitive impairment separately in older adults. However, the association between those risk factors and cognitive impairment is still unknown. Objective: To investigate the association between sensation, perception, negative socio-psychological factors, and cognitive impairment in institutionalized older adults. Methods: From two public aged care facilities, 215 participants were investigated. The Mini-mental State Examination was applied to assess cognitive function. The sensory function was bifurcated into auditory and somatosensory realms which were evaluated using pure tone audiometry and Nottingham Sensory Assessment, respectively. Albert's test, left and right resolution, and visuospatial distribution were used to evaluate perception. Depression and social isolation were selected as negative socio-psychological factors and were evaluated by the Geriatric Depression Scale and the Lubben Social Network Scale. The multivariate analysis was performed utilizing binary logistic regression. Results: Participants with moderately severe or severe hearing loss exhibited significant cognitive impairment compared to those with mild hearing loss. It was observed that perceptual dysfunction and depression were independently related to cognitive impairment. However, there was no significant association between somatosensory function, social isolation, and cognitive impairment in the institutionalized older adults. Conclusion: More profound hearing loss, abnormal perception, and depression are associated with cognitive impairment in older adults. Subsequent research endeavors should delve into the causal mechanisms underpinning these associations and explore whether combined interventions have the potential to postpone the onset of cognitive impairment.

Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies.

The tumor microenvironment (TME) is a major contributor to cancer malignancy including development of therapeutic resistance, a process mediated in part through intercellular crosstalk. Besides diverse soluble factors responsible for pro-survival pathway activation, immune evasion and extracellular matrix (ECM) remodeling further promote cancer resistance. Importantly, therapy-induced senescence (TIS) of cells in the TME is frequently observed in anticancer regimens, an off-target effect that can generate profound impacts on disease progression. By conferring the resistance and fueling the repopulation of remaining cancerous cells, TIS is responsible for tumor relapse and distant metastasis in posttreatment stage. This pathological trajectory can be substantially driven by the pro-inflammatory feature of senescent cells, termed as the senescence-associated secretory phenotype (SASP). Targeting strategies to selectively and efficiently remove senescent cells before they exert non-autonomous but largely deleterious effects, are emerging as an effective solution to prevent drug resistance acquired from a treatment-remodeled TME. In this review, we summarize the TME composition and key activities that affect tissue homeostasis and support treatment resistance. Promising opportunities that allow TME-manipulation and senescent cell-targeting (senotherapy) are discussed, with translational pipelines to overcome therapeutic barriers in clinical oncology projected.

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of prostate cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq, and expression profiling through RNA-seq, reveal global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment (TME), and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a novel therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies including cancer.

Cluster equilibrium scheduling method based on backpressure flow control in railway power supply systems.

The purpose of the study is to solve problems, i.e., increasingly significant processing delay of massive monitoring data and imbalanced tasks in the scheduling and monitoring center for a railway network. To tackle these problems, a method by using a smooth weighted round-robin scheduling based on backpressure flow control (BF-SWRR) is proposed. The method is developed based on a model for message queues and real-time streaming computing. By using telemetry data flow as input data sources, the fields of data sources are segmented into different sets by using a distributed model of stream computing parallel processing. Moreover, the round-robin (RR) scheduling method for the distributed server is improved. The parallelism, memory occupancy, and system delay are tested by taking a high-speed train section of a certain line as an example. The result showed that the BF-SWRR method for clusters can control the delay to within 1 s. When the parallelism of distributed clusters is set to 8, occupancy rates of the CPU and memory can be decreased by about 15%. In this way, the overall load of the cluster during stream computing is more balanced.

Orange to Red, Emission-Tunable Mn-Doped Two-Dimensional Perovskites with High Luminescence and Stability.

Lead halide perovskites are emerging as promising candidates for high-efficiency light-emitting diode (LED) applications because of their tunable band gaps and high quantum yield (QY). However, it remains a challenge to obtain stable red emitting materials with high QY. Herein, we report a facile and convenient hot-injection strategy to synthesize Mn-doped two-dimensional (2D) perovskite nanosheets. The emission peak can be tuned from 597 to 658 nm by manipulating the crystal field strength. In particular, a QY as high as 97% for 2D perovskite is achieved. The as-prepared perovskite also possesses excellent stability, whose emission property can be maintained for almost one year. A monochrome LED is further fabricated by employing the as-prepared perovskite as phosphor, which also shows high long-term stability. We believe that these highly efficient and stable perovskites will open up new opportunities in LED applications.

Integration of Environmental Friendly Perovskites for High-efficiency White Light-emitting Diodes.

Perovskite quantum dots (QDs) have been widely used in white light-emitting diodes (WLEDs), due to their high quantum yield (QY), tunable bandgap, and simple preparation. However, the red-emitting perovskite QDs are usually containing iodine (I), which is not stable under continuous light irradiation. Herein, perovskite-based WLED is fabricated by lead-free bismuth (Bi)-doped inorganic perovskites Cs2SnCl6 and less-lead Mn-doped CsPbCl3 QDs, which emits white light with color coordinates of (0.334, 0.297). The Bi-doped Cs2SnCl6 and Mn-doped CsPbCl3 QDs both show excellent stability when kept in the ambient air. As benefits from this desired characteristic, the as-prepared WLED shows excellent stability along with operating time. These results can promote the application of inorganic perovskite QDs in the field of WLEDs.

White light-emitting diodes based on carbon dots and Mn-doped CsPbMnCl3 nanocrystals.

CsPbX3 perovskite nanocrystals (NCs) are becoming a promising material for optoelectronic devices that possess an optically tunable bandgap, and bright photoluminescence. However, the toxic Pb is not environmentally friendly and the quantum yield (QY) of blue emitting NCs is relatively low. In addition, the red emitting perovskite containing iodine is not stable under light illumination. In this paper, high QY, blue emitting, non-toxic fluorescent nanomaterial carbon dots and orange-emitting CsPb0.81Mn0.19Cl3 NCs with partial Pb replacement are combined to fabricate white light-emitting diodes (WLEDs). A WLED with color coordinates of (0.337, 0.324) and a correlated color temperature of 4804 K is fabricated. Compared to red emitting perovskite containing iodine, the CsPb0.81Mn0.19Cl3 NCs are stable no matter whether they are stored in the air or exposed under ultraviolet light. Therefore, the as-fabricated WLED shows good color stability against increasing currents and long-term working stability.

Stimuli-Responsive Inks Based on Perovskite Quantum Dots for Advanced Full-Color Information Encryption and Decryption.

For data security applications, the use of fluorescent inks has become the most promising approach because of their convenience and low cost. However, traditional fluorescent inks are usually visible either under ambient light or UV light, whereas the improved stimuli-responsive inks are restricted to a single color. For the first time, full-color stimuli-responsive inks for information coding, encryption, and decryption are reported, which rely on the facile preparation and conversion of perovskite quantum dots. The information printed by the halide salt solution is invisible under ambient and UV light but becomes readable under UV light after spraying a unique developer. Besides, the primitive information can be stored for many years, even decades. Even after the decryption process, it still can be stored for at least several weeks. Most importantly, using butyl amine and acetic acid as encryption and decryption reagents, respectively, can switch off/on the luminescence. In this way, the printed information can be encrypted and decrypted, which shows great potential for information security applications.

A new method to discover the reaction mechanism of perovskite nanocrystals.

A novel and simple pathway for revealing the reaction mechanism of perovskite nanocrystals (NCs) is reported, which involves injecting a halogen source into a solution of Pb and Cs sources so that the nucleation and growth kinetics can be decoupled. Unlike previously reported methods, there is no pre-existing [PbX6]4- octahedron in the reactant because of the separation of the halogen and lead, and it is formed only afterwards when the halogen source is injected. Since the formation speed and the number of [PbX6]4- octahedral domains are crucial to the nucleation process, the formation mechanism can be revealed by controlling the reaction process. The halogen source is identified to be the key factor in controlling the nucleation process of the perovskite NCs. Besides, the perovskite NCs with different dimensionalities can be synthesized by tuning the feed ratio.

[Quantitative analysis of serum troponin I and myoglobin in patients with acute myocardial infarction].

OBJECTIVE: To investigate the clinical implications of cardiac troponin I (cTnI), myoglobin (Mb), creatine kinase (CK) and creatine kinase isoenzyme (CK-MB) in patients with acute myocardial infarction (AMI). METHODS: The serum concentrations of cTnI and Mb were determined in 50 patients with AMI 2 to 4 h after chest pain onset and compared with those measured in 50 age-matched healthy subjects. RESULTS: The serum levels of cTnI, CK-MB and CK in patients with AMI were significantly higher than those in the control group. Mb levels in AMI group were above the normal range. Mb, CK-MB, CK and cTnI reached the peak levels at 8+/-2.2, 18.1+/-3.2, 19.4+/-4.1 and 18.6+/-2.9 h after the onset, respectively, and their levels increased with the aggravation of AMI and were reduced to the normal levels with the amelioration of the disease. All the 4 indices were normal in the control group. CONCLUSION: cTnI and Mb are reliable biochemical markers for early diagnosis of AMI and the changes in their serum levels have clinical significance in diagnoses and prognostic judgment of AMI.