Oridonin, a small molecule inhibitor of cancer stem cell with potent cytotoxicity and differentiation potential.

Cancer stem cells (CSCs) drive malignant tumor progression, recurrence, and metastasis with unique characteristics, including self-renewal and resistance to conventional treatments. Conventional differentiation inducers, although promising, have limited cytotoxicity and may inadvertently enhance CSC stemness. To address these challenges, ongoing efforts are dedicated to developing strategies that can effectively combine both cytotoxicity and differentiation-inducing effects. In this study, we introduce oridonin (Ori), a small molecule with dual differentiation-inducing and cytotoxicity properties capable of eliminating tumor CSCs. We isolated CSCs in B16F10 cells using the Hoechst side population method and assessed the differentiation effect of Ori. Ori's differentiation-inducing effect was further evaluated using human acute promyelocytic leukemia. The cytotoxic potential of Ori against MCF-7 and B16F10 cell lines was assessed through various methods. In vivo anti-tumor and anti-CSC efficacy of Ori was investigated using mouse melanoma and CSCs melanoma models. Safety evaluation included zebrafish embryotoxicity and mouse acute toxicity experiments. As a result, Ori effectively dismantles tumorspheres, inhibits proliferation, and reduces the expression of CSC-specific markers. It induces significant differentiation, especially in the case of NB4. Additionally, Ori upregulates TP53 expression, mitigates the hypoxic tumor microenvironment, suppresses stemness, and inhibits PD-L1 expression, prompting a robust anti-cancer immune response. Ori demonstrates pronounced cytotoxicity, inducing notable pro-apoptotic effects on B16F10 and MCF-7 cells, with specific triggering of mitochondrial apoptosis. Importantly, Ori maintains a commendable biosafety record. The dual-action prowess of Ori not only induces the differentiation of CSCs but also dispatches differentiated and residual tumor cells, effectively thwarting the relentless march of tumor progression.

Diosmetin as a promising natural therapeutic agent: In vivo, in vitro mechanisms, and clinical studies.

Diosmetin, a natural occurring flavonoid, is primarily found in citrus fruits, beans, and other plants. Diosmetin demonstrates a variety of pharmacological activities, including anticancer, antioxidant, anti-inflammatory, antibacterial, metabolic regulation, cardiovascular function improvement, estrogenic effects, and others. The process of literature search was done using PubMed, Web of Science and ClinicalTrials databases with search terms containing Diosmetin, content, anticancer, anti-inflammatory, antioxidant, pharmacological activity, pharmacokinetics, in vivo, and in vitro. The aim of this review is to summarize the in vivo, in vitro and clinical studies of Diosmetin over the last decade, focusing on studies related to its anticancer, anti-inflammatory, and antioxidant activities. It is found that DIO has significant therapeutic effects on skin and cardiovascular system diseases, and its research in pharmacokinetics and toxicology is summarized. It provides the latest information for researchers and points out the limitations of current research and areas that should be strengthened in future research, so as to facilitate the relevant scientific research and clinical application of DIO.

Plant-derived flavonoids are a potential source of drugs for the treatment of liver fibrosis.

Liver fibrosis is a dynamic pathological process that can be triggered by any chronic liver injury. If left unaddressed, it will inevitably progress to the severe outcomes of liver cirrhosis or even hepatocellular carcinoma. In the past few years, the prevalence and fatality of hepatic fibrosis have been steadily rising on a global scale. As a result of its intricate pathogenesis, the quest for pharmacological interventions targeting liver fibrosis has remained a formidable challenge. Currently, no pharmaceuticals are exhibiting substantial clinical efficacy in the management of hepatic fibrosis. Hence, it is of utmost importance to expedite the development of novel therapeutics for the treatment of this condition. Various research studies have revealed the ability of different natural flavonoid compounds to alleviate or reverse hepatic fibrosis through a range of mechanisms, which are related to the regulation of liver inflammation, oxidative stress, synthesis and secretion of fibrosis-related factors, hepatic stellate cells activation, and proliferation, and extracellular matrix synthesis and degradation by these compounds. This review summarizes the progress of research on different sources of natural flavonoids with inhibitory effects on liver fibrosis over the last decades. The anti-fibrotic effects of natural flavonoids have been increasingly studied, making them a potential source of drugs for the treatment of liver fibrosis due to their good efficacy and biosafety.

Triglyceride to high-density lipoprotein cholesterol ratio associated with long-term adverse clinical outcomes in patients deferred revascularization following fractional flow reserve.

BACKGROUND: Guidelines on coronary intermediate lesions strongly recommend deferred revascularization after detecting a normal fractional flow reserve (FFR). Researches about triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) on cardiovascular diseases has also been well conducted. However, the association of TG/HDL-C and long-term adverse clinical outcomes remains unknown for patients deferred revascularization following FFR. METHODS: This study retrospectively included 374 coronary artery disease (CAD) patients with non-significant coronary lesions diagnosed by coronary angiography (CAG) and FFR. The main outcome measure was the combination of major adverse cardiovascular and cerebrovascular events (MACCEs). All patients were categorized into three subgroups in terms of TG/HDL-C tertiles (T1 < 0.96, 0.96 ≤ T2 < 1.58, T3 ≥ 1.58). Three different Cox regression models were utilized to reveal the association between TG/HDL-C and prevalence of MACCEs. RESULTS: 47 MACCEs were recorded throughout a median monitoring period of 6.6 years. The Kaplan-Meier survival curves showed a higher MACCEs rate occurred in the higher TG/HDL-C group (5.6% vs. 12.9% vs. 19.4%, log-rank P < 0.01). After adjustment, patients in T3 suffered a 2.6-fold risk compared to the T1 group (T3 vs. T1: HR 2.55, 95% CI 1.05-6.21, P = 0.038; T2 vs. T1: HR 1.71, 95% CI 0.65-4.49, P = 0.075; P for trend = 0.001). The restricted cubic spline (RCS) analysis demonstrated that the HR for MACCEs rose as TG/HDL-C increased. Both the receiver operating characteristic (ROC) and time-dependent ROC proved the excellent predictive ability of TG/HDL-C. CONCLUSION: The study illustrates that TG/HDL-C correlates with the risk of MACCEs in CAD patients deferred revascularization following FFR. TG/HDL-C could serve as a dependable predictor of cardiovascular events over the long term in this population.

Evaluating the effectiveness of echocardiographic guidance in diminishing postoperative wound complications for left atrial appendage closure: A clinical retrospective study.

Echocardiographic guidance in left atrial appendage (LAA) closure procedures is increasingly recognized for its potential to enhance patient outcomes in atrial fibrillation (AF). This retrospective study assesses its impact on hospital stay duration, readmission rates and surgical site wound complications in 200 AF patients. Divided equally into an echocardiographically guided group (Group E) and a non-guided group (Group N), the analysis focused on detailed patient data encompassing hospital stay, 30-day readmission and wound complications. Findings revealed that Group E experienced a significantly shorter average hospital stay of 3.5 days, compared with 6.5 days in Group N, along with a lower 30-day readmission rate (5% vs. 18% in Group N). Furthermore, Group E showed a considerable reduction in surgical site wound complications, such as infections and hematomas. The study concludes that echocardiographic guidance in LAA closure procedures markedly improves postoperative wound outcomes, underscoring its potential as a standard practice in cardiac surgeries for AF patients. This approach not only optimizes patient safety and postoperative recovery but also enhances healthcare resource utilization.

Hierarchically Ordered Pore Engineering of Metal-Organic Framework-Based Materials for Electrocatalysis.

Ordered pore engineering that embeds uniform pores with periodic alignment in electrocatalysts opens up a new avenue for achieving further performance promotion. Hierarchically ordered porous metal-organic frameworks (HOP-MOFs) possessing multilevel pores with ordered distribution are the promising precursors for the exploration of ordered porous electrocatalysts, while the scalable acquisition of HOP-MOFs with editable components and adjustable pore size regimes is critical. This review presents recent progress on hierarchically ordered pore engineering of MOF-based materials for enhanced electrocatalysis. The synthetic strategies of HOP-MOFs with different pore size regimes, including the self-assembly guided by reticular chemistry, surfactant, nanoemulsion, and nanocasting, are first introduced. Then the applications of HOP-MOFs as the precursors for exploring hierarchically ordered porous electrocatalysts are summarized, selecting representatives to highlight the boosted performance. Especially, the intensification of molecule and ion transport integrated with optimized electron transfer and site exposure over the hierarchically ordered porous derivatives are emphasized to clarify the directional transfer and integration effect endowed by ordered pore engineering. Finally, the remaining scientific challenges and an outlook of this field are proposed. It is hoped that this review will guide the hierarchically ordered pore engineering of nanocatalysts for boosting the catalytic performance and promoting the practical applications.

Theoretical Insights into the Photophysical Properties of 4CzIPN Doped in Different Hosts: A Multiscale Study.

As a typical thermally activated delayed fluorescence (TADF) emitter with green emission, 4CzIPN has attracted much attention recently. Most studies indicated that 4CzIPN doped in different hosts presented different performances; thus, the hosts should have an obvious influence on its photophysical properties. Herein, the influence of four kinds of hosts, including m-CzPym, m-CzTrz, p-CzPym, and p-CzTrz, on the photophysical properties of 4CzIPN is investigated. Molecular dynamics simulations were performed to simulate the host-guest conformations, and the photophysical properties were studied using the combined quantum mechanics/molecular mechanics method coupled with the thermal-vibration correlation function method. It is found that 4CzIPN in doped films has larger transition dipole moments and spin-orbital coupling constants compared to that in nondoped films. Faster radiative decay, intersystem crossing rates, and higher fluorescence efficiency could be obtained in doped films. Our work helps to better understand the photophysical properties of 4CzIPN in doped films and may favor the design of new hosts.

Layer-dependent ultrafast carrier dynamics of PdSe2 investigated by photoemission electron microscopy.

For atomically thin two-dimensional materials, variations in layer thickness can result in significant changes in the electronic energy band structure and physicochemical properties, thereby influencing the carrier dynamics and device performance. In this work, we employ time- and energy-resolved photoemission electron microscopy to reveal the ultrafast carrier dynamics of PdSe2 with different layer thicknesses. We find that for few-layer PdSe2 with a semiconductor phase, an ultrafast hot carrier cooling on a timescale of approximately 0.3 ps and an ultrafast defect trapping on a timescale of approximately 1.3 ps are unveiled, followed by a slower decay of approximately tens of picoseconds. However, for bulk PdSe2 with a semimetal phase, only an ultrafast hot carrier cooling and a slower decay of approximately tens of picoseconds are observed, while the contribution of defect trapping is suppressed with the increase of layer number. Theoretical calculations of the electronic energy band structure further confirm the transition from a semiconductor to a semimetal. Our work demonstrates that TR- and ER-PEEM with ultrahigh spatiotemporal resolution and wide-field imaging capability has great advantages in revealing the intricate details of ultrafast carrier dynamics of nanomaterials.

Chronic Mucocutaneous Candidiasis Due to STAT1 Gene Variant.

This case report describes a man in his 40s who presented with a 5-month history of recurrent pruritic papular erythema with mild scaling on the face, left forearm, and groin.

Machine learning-based identification of colorectal advanced adenoma using clinical and laboratory data: a phase I exploratory study in accordance with updated World Endoscopy Organization guidelines for noninvasive colorectal cancer screening tests.

Objective: The recent World Endoscopy Organization (WEO) guidelines now recognize precursor lesions of colorectal cancer (CRC) as legitimate screening targets. However, an optimal screening method for detecting advanced adenoma (AA), a significant precursor lesion, remains elusive. Methods: We employed five machine learning methods, using clinical and laboratory data, to develop and validate a diagnostic model for identifying patients with AA (569 AAs vs. 3228 controls with normal colonoscopy). The best-performing model was selected based on sensitivity and specificity assessments. Its performance in recognizing adenoma-carcinoma sequence was evaluated in line with guidelines, and adjustable thresholds were established. For comparison, the Fecal Occult Blood Test (FOBT) was also selected. Results: The XGBoost model demonstrated superior performance in identifying AA, with a sensitivity of 70.8% and a specificity of 83.4%. It successfully detected 42.7% of non-advanced adenoma (NAA) and 80.1% of CRC. The model-transformed risk assessment scale provided diagnostic performance at different positivity thresholds. Compared to FOBT, the XGBoost model better identified AA and NAA, however, was less effective in CRC. Conclusion: The XGBoost model, compared to FOBT, offers improved accuracy in identifying AA patients. While it may not meet the recommendations of some organizations, it provides value for individuals who are unable to use FOBT for various reasons.

MiR-375 impairs breast cancer cell stemness by targeting the KLF5/G6PD signaling axis.

Recurrence of breast cancer may be due to the presence of breast cancer stem cells (BCSC). Abnormal tumor cell growth is closely associated with increased reactive oxygen species (ROS) and disruption of redox homeostasis, and BCSCs exhibit low levels of ROS. The detailed mechanism between the low levels of ROS in BCSCs and their maintenance of stemness characteristics has not been reported. A growing number of studies have shown that tumor development is often accompanied by metabolic reprogramming, which is an important hallmark of tumor cells. As the first rate-limiting enzyme of pentose phosphate pathway (PPP), the expression of G6PD is precisely regulated in tumor cells, and there is a certain correlation between PPP and BCSCs. MiR-375 has been shown to inhibit stem cell-like properties in breast cancer, but the exact mechanism is not clear. Here, KLF5, as a transcription factor, was identified to bind to the promoter of G6PD to promote its expression, whereas miR-375 inhibited the expression of KLF5 by binding to the 3'UTR region of KLF5 mRNA and thus reduced the expression of G6PD expression, inhibits PPP to reduce NADPH, and increases ROS levels in breast cancer cells, thereby weakening breast cancer cell stemness. Our study reveals the specific mechanism by which miR-375 targets the KLF5/G6PD signaling axis to diminish the stemness of breast cancer cells, providing a therapeutic strategy against BCSCs.

Hybrid Multi-Infeed Receiver Line Longitudinal Protection Scheme Based on Voltage Waveform Comprehensive Distance Similarity.

The coupling of AC and DC power will impact the protective actions on the AC side and pose a threat to the stable operation of the interconnection system. Therefore, a new longitudinal protection method is proposed based on the comprehensive distance similarity of voltage waveforms. Initially, the measured voltage and current data are extracted to calculate the reference voltage, and the voltage waveform fitting is optimized. Subsequently, the Euclidean dynamic time warp (DTW) distance and entropy weight method are utilized to process the voltage waveform, enabling the calculation of its comprehensive distance similarity. This similarity is adopted to determine fault location. A hybrid DC multi-feed AC/DC interconnection system, incorporating a line commutated converter-voltage source converter (LCC-VSC) and a line commutated converter-modular multilevel converter (LCC-MMC), was established in PSCAD, and fault data were simulated and output. The effectiveness of the protection scheme was validated using MATLAB. Simulation results demonstrate that the proposed method can accurately distinguish between faults inside and outside a region. When compared to existing protection methods, it demonstrates superior performance in resisting transition resistance and noise interference, while also mitigating the impact of data asynchronicity. The speed and reliability of the method are further enhanced.

Case Report: Enhancing lead extraction techniques: a novel approach using a loop formed by an ablation catheter and a gooseneck snare.

The difficulty and complexity of lead extraction procedures increase with the age of the lead to be extracted. The extraction of old (>20 years) leads is more time-consuming and requires advanced tools and a complex technique. In this case, we retrieved a very old (>30 years) lead using a loop formed by a catheter and a gooseneck snare. The catheter was rotated to remove the lead-bound sites. The lead was successfully retrieved using a Needle's Eye Snare.

Multi-omic analysis of precocious puberty girls: pathway changes and metabolite validation.

Objective: Precocious puberty (PP) is a prevalent endocrine disorder affecting the physical and mental wellbeing of children. Identifying the triggering factors of PP has become a central issue. This study seeks to investigate the metabolomic and transcriptomic alterations in PP. Material and methods: First, 37 school-aged girls diagnosed with PP and 25 age-matched prepubertal control girls were recruited, and the fecal samples were collected for non-targeted metabolomic analysis to screen for differentially expressed metabolites (DEMs). Subsequently, an animal model of PP was constructed by danazol administration to neonatal female rats, and both fecal non-targeted metabolomics and serum next-generation transcriptomic sequencing were performed to screen DEMs and differentially expressed genes (DEGs) in PP. Moreover, the DEM co-existing in clinical and animal models was administrated to PP rats to explore the role of the target metabolite in PP. Results: A total of 24 DEMs in PP clinical samples and 180 DEMs and 425 DEGs in PP animal samples were identified. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these DEMs and DEGs were enriched in disease-associated pathways, including fatty acid synthesis, glycerolipid metabolism, pyrimidine metabolism, steroid hormone biosynthesis, progesterone-mediated oocyte maturation, and gonadotropin-releasing hormone (GnRH) signaling pathway, forming a tight DEM-DEG pathway regulatory network. Further DEM validation demonstrated that thymine supplementation delayed the opening of the vagina and development of PP in model rats. Conclusion: This study reveals that the metabolomic and transcriptomic changes, along with enriched pathways, are implicated in PP based on clinical and animal analyses. The findings may provide new strategies and research avenues for PP treatment.

Large-Scale, Stretchable, Self-Protective, and Multifunctional Perovskite Luminescent Filament with Ultra-High Stability.

Lead halide perovskites possess great application potential in flexible displays and wearable optoelectronics owing to their prominent optoelectronic properties. However, the intrinsic instability upon moisture, heat, and ultraviolet (UV) light irradiation hinders their development and application. In this work, an ultra-stable CsPbX3 (X = Cl, Br, I) perovskite luminescent filament (PLF) with high stretchability (≈2400%) and luminescence performance (photoluminescence quantum yield (PLQY) of 24.5%, tunable emission spectrum, and high color purity) is introduced by a facile environmental-friendly wet-spinning technology via solvent extraction. Benefiting from the in situ encapsulation of the hydrophobic thermoplastic polyurethane (TPU) and the chelation of Lewis base CO in TPU with Lewis acid Pb2+, the CsPbBr3 PLF demonstrates ultra-high photoluminescence (PL) stability when stored in ambient air and high humidity circumstance, annealed at 50 °C, and dipped in water for 30 days, illuminated under ultraviolet light for 300 min, and immersed in organic solvents and solutions with pH of 1-13 for 5 min, respectively. Impressively, it retains 80% of its initial PL after being recycled five times. Overall, the CsPbX3 PLF demonstrates promising prospects in multifunctional applications, including organic dyes and tensile strain sensing, flexible pattern displays, secondary anti-counterfeiting, and hazard warning systems.

Mechanical strength affecting the penetration in microneedles and PLGA nanoparticle-assisted drug delivery: Importance of preparation and formulation.

Microneedles (MNs) prepared from polymeric materials are painless and minimally invasive, safe and efficient, but they hindered by low mechanical strength and single diverse drug release pattern. Due to the distinctive mechanical strength and dimensions of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), the integration of nano-technology with microneedles can effectively improve penetration and delivery efficiency through the stratum corneum. We herein designed a simple paroxetine (PAX)-loaded PLGA nanoparticles-integrated dissolving microneedles system (PAX-NPs-DMNs), aiming to improve the bioavailability of PAX through the synergistic permeation-enhancing effect of dissolving microneedles (DMNs) and NPs. PAX-NPs-DMNs had a complete tips molding rate (Neff) of (94.06 ± 2.16) %, a 15×15 quadrangular-conical microneedle array and an overall fracture force of 301.10 N, which were improved nearly 0.50 times compared with the blank microneedles (HA-DMNs) and PAX microneedles (PAX-DMNs). PAX-NPs-DMNs could extend the release duration of PAX from 1 h to 24 h and the cumulative permeability per unit area (Qn) was 47.66 times and 7.37 times higher than the PAX and the PAX-DMNs groups. PAX-NPs-DMNs could be rapidly dissolved within 10 min without hindering skin healing or causing adverse reactions. This study confirmed that PAX-NPs-DMNs can effectively improve the bioavailability of PAX and the mechanical strength of DMNs, which can easily penetrate the skin to provide sustained and painless delivery without causing adverse effects, thus offering a more convenient and effective method for central nervous diseases.

Association of altitude and frailty in Chinese older adults: using a cumulative frailty index model.

Objective: The population is aging exponentially and the resulting frailty is becoming increasingly evident. We aimed to explore the association between altitude and frailty, and to identify associated factors for frailty. Methods: This is a community-based cross-sectional survey. 1,298 participants aged ≥60 years from three different altitudes were included in the study. To quantify frailty, we constructed a frailty index (FI) and a frailty score (FS). The FI was divided into non-frailty, prefrailty, and frailty. The Odds Ratios and confidence intervals (ORs, 95%CIs) were used to evaluate the association between altitude and FI and FS in multivariate ordinal logistic regression and linear regression. Results: There were 560 (53.1%) participants in the prefrailty and 488 (37.6%) in the frailty group. The FS increased with higher altitude (P for trend <0.001). Multivariate ordinal logistic regression analysis revealed an association between altitude and frailty, OR = 1.91 (95% CI: 1.38-2.64) in mid-high altitude and 2.49 (95% CI:1.40-4.45) in high altitude. The same trend of association was found in the univariate analysis. The FS increased by 1.69 (95% CI: 0.78-2.60) at mid-high altitude and 3.24 (95%CI:1.66-4.81) at high altitude compared to medium altitude. Conclusion: The study indicates that high altitude exposure is an associated factor for frailty in older adults. This association become stronger with higher altitudes. As a result, it is essential to conduct early frailty screening for residents living at high altitudes.

Identification and characterization of the TetR family transcriptional regulator NffT in Rhizobium johnstonii.

Symbiotic nitrogen fixation (SNF) by rhizobia is not only the main natural bionitrogen-source for organisms but also a green process leveraged to increase the fertility of soil for agricultural production. However, an insufficient understanding of the regulatory mechanism of SNF hinders its practical application. During SNF, nifA-fixA signaling is essential for the biosynthesis of nitrogenases and electron transfer chain proteins. In the present study, the TetR regulator NffT, whose mutation increased fixA expression, was discovered through a fixA-promoter-ß-glucuronidase fusion assay performed with Rhizobium johnstonii. Real-time quantitative PCR analysis showed that nffT deletion increased the expression of symbiotic genes including nifA and fixA in nifA-fixA signaling, and fixL, fixK, fnrN, and fixN9 in fixL-fixN signaling. nffT overexpression resulted in disordered nodules and reduced nitrogen-fixing efficiency. Electrophoretic mobility shift assays revealed that NffT directly regulated the transcription of RL0091-93, which encode an ATP-binding ABC transporter predicted to be involved in carbohydrate transport. Purified His-tagged NffT bound to a 68 bp DNA sequence located -32 to -99 bp upstream of RL0091-93 and NffT deletion significantly increased the expression of RL0091-93. nffT-promoter-ß-glucuronidase fusion assay indicated that nffT expression was regulated by the cobNTS genes and cobalamin. Mutations in cobNTS significantly decreased the expression of nffT, and cobalamin restored its expression. These results revealed that NffT affects nodule development and nitrogen-fixing reaction by participating in a complex regulatory network of symbiotic and carbohydrate metabolic genes and, thus, plays a pivotal regulatory role during symbiosis of R. johnstonii-Pisum sativum.IMPORTANCESymbiotic nitrogen fixation (SNF) by rhizobia is a green way to maintain soil fertility without causing environmental pollution or consuming chemical energy. A detailed understanding of the regulatory mechanism of this complex process is essential for promoting sustainable agriculture. In this study, we discovered the TetR-type regulator NffT, which suppressed the expression of fixA in Rhizobium johnstonii. Furthermore, NffT was confirmed to play pleiotropic roles in R. johnstonii-Pisum sativum symbiosis; specifically, it inhibited rhizobial growth, nodule differentiation, and nitrogen-fixing reactions. We revealed that NffT indirectly affected R. johnstonii-P. sativum symbiosis by participating in a complex regulatory network of symbiotic and carbohydrate metabolic genes. Furthermore, cobalamin, a chemical molecule, was reported for the first time to be involved in TetR-type protein transcription during symbiosis. Thus, NffT identification connects SNF regulation with genetic, metabolic, and chemical signals and provides new insights into the complex regulation of SNF, laying an experimental basis for the targeted construction of rhizobial strains with highly efficient nitrogen-fixing capacity.