Hemodiafiltration with endogenous reinfusion for uremic toxin removal in patients undergoing maintenance hemodialysis: a pilot study.

OBJECTIVE: To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance hemodialysis (MHD). METHODS: Patients who have been on MHD for a period of at least 3 months were enrolled. Each subject underwent one HFR and one hemodiafiltration (HDF) treatment. Blood samples were collected before and after a single HFR or HDF treatment to test uremic toxin levels and to calculate clearance rate. The primary efficacy endpoint was to compare uremic toxin levels of indoxyl sulfate (IS), λ-free light chains (λFLC), and ß2-microglobulin (ß2-MG) before and after HFR treatment. Secondary efficacy endpoints was to compare the levels of urea, interleukin-6 (IL-6), P-cresol, chitinase-3-like protein 1 (YKL-40), leptin (LEP), hippuric acid (HPA), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), fibroblast growth factor 23 (FGF23) before and after HFR treatment. The study also undertook a comparative analysis of uremic toxin clearance between a single HFR and HDF treatment. Meanwhile, the lever of serum albumin and branched-chain amino acids before and after a single HFR or HDF treatment were compared. In terms of safety, the study was meticulous in recording vital signs and the incidence of adverse events throughout its duration. RESULTS: The study enrolled 20 patients. After a single HFR treatment, levels of IS, λFLC, ß2-MG, IL-6, P-cresol, YKL-40, LEP, HPA, TMAO, ADMA, TNF-α, and FGF23 significantly decreased (p < 0.001 for all). The clearance rates of λFLC, ß2-MG, IL-6, LEP, and TNF-α were significantly higher in HFR compared to HDF (p values: 0.036, 0.042, 0.041, 0.019, and 0.036, respectively). Compared with pre-HFR and post-HFR treatment, levels of serum albumin, valine, and isoleucine showed no significant difference (p > 0.05), while post-HDF, levels of serum albumin significantly decreased (p = 0.000). CONCLUSION: HFR treatment effectively eliminates uremic toxins from the bloodstream of patients undergoing MHD, especially protein-bound toxins and large middle-molecule toxins. Additionally, it retains essential physiological compounds like albumin and branched-chain amino acids, underscoring its commendable safety profile.

Deficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion.

The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

Prediction of rhinitis with class imbalance based on heterogeneous ensemble learning.

Common clinical rhinitis is characterized by different types of cases and class imbalance. Its prediction belongs to multiple output classification. Low recognition rate and poor generalization performance often occur for minority class. Therefore, we propose a novel integrated classification model, ARF-OOBEE, which transforms the multi-output classification to multi-label classification and multi-class classification. The multi-label classifier automatically adjusts the number and depth of integrated forest learners according to the imbalance ratio of single class label in a subset. It can effectively reduce the impact of class imbalance on classification and improve prediction performance of both majority or minority class concurrently. Also, we build a multi-class classification based on out-of-bag Extra-Tree to accomplish finer classification for the predicted labels. In addition, we calculate the feature importance for rhinitis on the grounds of the purity of nodes in decision-making tree inside Random Forest and study the correlation between rhinitis features. We conduct 12 folds cross-validation experiments on 461 cases of clinical rhinitis. The outcomes show that the evaluation indicators of ARF-OOBEE, such as Sensitivity, Specificity, Accuracy, F1-Score, AUC, and G-Mean are 74.9%,86.5%,92.0%,78.3%,95.3%, and 79.9%, respectively. In comparison to the other methods, ARF-OOBEE has better evaluation indicator and is more effective for the early clinical diagnosis of rhinitis.

Transforming medicine: artificial intelligence integration in the peripheral nervous system.

In recent years, artificial intelligence (AI) has undergone remarkable advancements, exerting a significant influence across a multitude of fields. One area that has particularly garnered attention and witnessed substantial progress is its integration into the realm of the nervous system. This article provides a comprehensive examination of AI's applications within the peripheral nervous system, with a specific focus on AI-enhanced diagnostics for peripheral nervous system disorders, AI-driven pain management, advancements in neuroprosthetics, and the development of neural network models. By illuminating these facets, we unveil the burgeoning opportunities for revolutionary medical interventions and the enhancement of human capabilities, thus paving the way for a future in which AI becomes an integral component of our nervous system's interface.

Integrin-Targeted Theranostic Nanoparticles for Clinical MRI-Traceable Treatment of Liver Fibrosis.

Liver fibrosis is the critical stage in the development of chronic liver disease (CLD), from simple injury to irreversible cirrhosis. Timely detection and intervention of liver fibrosis are crucial for preventing CLD from progressing into a fatal condition. Herein, we developed iron oxide (Fe3O4) nanoparticles (IONPs) and ferulic acid (FA) coencapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), followed by surface modification with cRGD peptides (cRGD-PLGA/IOFA) for integrin-targeted clinical magnetic resonance imaging (MRI)-traceable treatment of liver fibrosis. The cRGD peptide linked on the surface of the PLGA/IOFA NPs could specifically bind to the overexpressed integrin αvß3 on activated hepatic stellate cells (HSCs) in the fibrotic liver, enabling the high-sensitive clinical MR imaging (3 T) and precise staging of liver fibrosis. The FA encapsulated in cRGD-PLGA/IOFA showed excellent efficacy in reducing oxidative stress and inhibiting the activation of HSCs through the transforming growth factor-ß (TGF-ß)/Smad pathway. Notably, the IONPs encapsulated in cRGD-PLGA/IOFA NPs could alleviate liver fibrosis by regulating hepatic macrophages through the NF-κB pathway, lowering the proportion of Ly6Chigh/CD86+, and degrading collagen fibers. The FA and IONPs in the cRGD-PLGA/IOFA produced a synergistic enhancement effect on collagen degradation, which was more effective than the IONPs treatment alone. This study demonstrates that cRGD-PLGA/IOFA NPs could effectively relieve liver fibrosis by acting on macrophages and HSCs and provide a new strategy for the clinical MRI-traceable treatment of liver fibrosis.

Barriers and facilitators experienced in delivering alcohol screening and brief interventions in community pharmacy: a qualitative evidence synthesis.

BACKGROUND: Following increases in deaths due to alcohol during the COVID-19 pandemic, there have been renewed calls to increase resources in alcohol screening and brief intervention (SBI). Research has shown that community pharmacy could be a promising setting for SBI. This review aimed to investigate the barriers and facilitators to SBI delivery in community pharmacy to inform its further development. METHODS: A systematic search of four databases (MEDLINE, EMBASE, CINAHL, and PsycINFO) was conducted in October 2021 to identify relevant published qualitative or mixed-method studies. Relevant qualitative data were extracted from the included studies and a framework synthesis was performed using the Capability-Opportunity-Motivation-Behaviour (COM-B) model. RESULTS: Two thousand two hundred and ten articles were screened and nine studies were included in the review (seven in the United Kingdom and two in Australia). Identified barriers and facilitators to delivering SBI corresponded to all components of the COM-B model. Facilitators included non-confrontational communication skills, aligning SBI with existing pharmacy services and pharmacist role legitimacy. Barriers included multiple demands on staff time, a lack of staff experience with screening tools, and staff concerns of causing offence. Using the Behaviour Change Wheel (BCW), we propose five elements of a pharmacy SBI to address identified barriers. CONCLUSIONS: Research into SBI in community pharmacy is limited in comparison to other healthcare settings and this review provides an understanding of the barriers and facilitators to the delivery of SBI in community pharmacy from a behavioural perspective. Through the use of COM-B and BCW, our findings could inform the development of future pharmacy-based SBI.

Stressful life events and depressive symptoms during COVID-19: A gender comparison.

The COVID-19 pandemic precipitated a wide range of public health, economic, social, and political shocks, setting in motion life events that reverberated to affect individuals' mental health. Moving beyond a checklist approach, this study drew on individuals' own words to identify both conventional and novel sources of stress during COVID-19 and examine the role of stressful life events in producing gender disparities in depressive symptoms. Drawing on a 2021 U.S. nationally representative survey, we coded text responses to an open-ended question on stressful life events and conducted descriptive and regression analyses (n = 1733). The analyses revealed three key findings. First, men were more likely to report having experienced no stressful life events or else mention politics as a source of stress. Women, by comparison, were more likely to report the following as stressful-inability to socialize, paid work, care work, health, or the death of loved ones. Second, for both women and men, respondents reporting no stressful life events had the lowest, and those reporting finances as the most stressful life event had the highest, depressive symptoms. Third, women had higher depressive symptoms than men, and mediation analysis showed that stressful life events explained approximately a third of the gender gap in depressive symptoms. The findings indicate that policies attending to people's financial stress are important for mitigating mental health risks in turbulent times. Interventions that reduce women's exposure to stressful life events are also crucial to bridging gender disparities in mental health.

Adaptive lambda schemes for efficient relative binding free energy calculation.

The relative free energy perturbation (RFEP) calculation is one of the most theoretically sound computational chemistry approaches for the binding affinity prediction. However, its application is often hindered by the complexity of the calculation choices and the requirement of expertise in the field. Improper lambda scheme of RFEP may result in deviations from an accurate description of the perturbation process and is prone to erroneous affinity predictions. To address such challenges, an automated adaptive lambda method is proposed where the adaptive lambda schemes are obtained through a split-and-merge algorithm based on the pilot runs. The newly established workflow along with a series of improvements to the perturbation settings increases the consistency of the RFEP calculation results. Comparing the pilot and adaptive lambda schemes, the latter demonstrated improvements in convergence and reproducibility and lowered the mean unsigned error and the root-mean-square error. Overall, the adaptive lambda method is a reliable and robust choice to predict small molecule relative binding free energy and can be capitalized to benefit routine RFEP calculations for drug discovery projects.

Si Miao San relieves hyperuricemia by regulating intestinal flora.

This study seeks to investigate the therapeutic effects of Si Miao San (SMS) on hyperuricemia and its underlying mechanisms, particularly focusing on the role of intestinal flora. The key components of SMS were identified using high-performance liquid chromatography (HPLC). To establish a rat model of hyperuricemia, an intraperitoneal injection of potassium oxonate was performed, followed by oral administration of various concentrations of SMS. The study evaluated the status of hyperuricemia, renal pathology, xanthine oxidase (XO) activity, and intestinal flora. Utilizing HPLC, we identified five active components of SMS. Following SMS intervention, there was a significant reduction in serum levels of uric acid (UA), blood urea nitrogen, and creatinine, accompanied by an increase in urine UA levels in rats with hyperuricemia. Distinct pathological injuries were evident in the renal tissues of hyperuricemic rats, and these were partially alleviated following SMS intervention. Moreover, SMS exhibited a dose-dependent reduction in XO activity both in the serum and hepatic tissues. Notably, SMS contributed to an enhancement in the diversity of intestinal flora in hyperuricemic rats. The intervention of SMS resulted in a reduction in the abundance of certain bacterial species, including Parabacteroides johnsonii, Corynebacterium urealyticum, and Burkholderiales bacterium. This suggests that SMS may exert anti-hyperuricemia effects, potentially by modulating the composition of intestinal flora.

The Early 2020 COVID-19 Outbreak in China and Subsequent Flourishing: Medium-Term Effects and Intervening Mechanisms.

In early 2020, a COVID-19 outbreak occurred in Hubei Province of China. Exploiting the geographic concentration of China's COVID-19 cases in Hubei (the initial epicenter), we compare Hubei and non-Hubei residents to examine the medium-term effect of exposure to the COVID-19 outbreak on mental well-being. We examine flourishing-a comprehensive assessment of well-being that is not merely the absence of mental illness-and investigate a broad set of psychosocial and economic mediators that may link initial outbreak exposure to subsequent flourishing. We use ordinary least squares regression models to analyze national panel data collected in early 2020 and late 2021 (N = 3,169). Results show that flourishing scores remain lower for Hubei than non-Hubei residents almost two years following the early 2020 COVID-19 outbreak. Mediation analysis reveals that Hubei residents' lower incidences of job promotion and lower sense of control are the two most important mediators accounting for their lower flourishing relative to non-Hubei residents. Combined, this study provides the first evidence of the medium-term psychological vulnerability borne by individuals who lived in the initial epicenter of the COVID-19 pandemic. Findings on the intervening mechanisms shed light on the policy initiatives needed for post-pandemic mental well-being recovery in China and other countries.

Activating ryanodine receptor improves isoflurane-induced cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is characterized by impaired learning and memory. 6 h duration isoflurane anesthesia is an important factor to induce POCD, and the dysfunction of ryanodine receptor (RyR) in the hippocampus may be involved in this process. We investigated the expression of RyR3 in the hippocampus of mice after 6-h duration isoflurane anesthesia, as well as the improvement of RyR receptor agonist caffeine on POCD mice, while attempting to identify the underlying molecular mechanism. MATERIALS: We constructed a POCD model using 8-week-old male C57BL/6J mice that were exposed to 6-h duration isoflurane. Prior to the three-day cognitive behavioral experiment, RyR agonist caffeine were injected. Fear conditioning and location memory tests were used in behavioral studies. We also exposed the mouse neuroblastoma cell line Neuro-2a (N2A) to 6-h duration isoflurane exposure to simulate the conditions of in vivo cognitive dysfunction. We administered ryanodine receptor agonist (caffeine) and inhibitor (ryanodine) to N2a cells. Following that, we performed a series of bioinformatics analysis to discover proteins that are involved in the development of cognitive dysfunction. Rt-PCR and Western blot were used to assess mRNA level and protein expression. RESULTS: 6-h duration isoflurane anesthesia induced cognitive dysfunction and increased RyR3 mRNA levels in hippocampus. The mRNA levels of RyR3 in cultured N2a cells after anesthesia were comparable to those in vivo, and the RyR agonist caffeine corrected the expression of some cognitive-related phenotypic proteins that were disturbed after anesthesia. Intraperitoneal injection of RyR agonist caffeine can improve cognitive function after isoflurane anesthesia in mice, and bioinformatics analyses suggest that CaMKⅣ may be involved in the molecular mechanism. CONCLUSION: Ryanodine receptor agonist caffeine may improve cognitive dysfunction in mice after isoflurane anesthesia.

Young obese patients may benefit from GnRH-a long protocol contributing to higher implantation rate and live birth rate of fresh IVF-ET cycles.

Introduction: Obesity has detrimental influences on women reproductive health. There is little experience in optimizing controlled ovarian hyperstimulation (COH) protocols to treat Chinese obese patients who are undergoing in vitro fertilization and embryo transfer (IVF-ET) therapy. Methods: The clinical outcome differences were retrospectively analyzed among obese patients who received gonadotrophin-releasing hormone agonist (GnRH-a), GnRH antagonist (GnRH-ant), micro dose GnRH-a (mGnRH-a) and GnRH-a long protocol in IVF-ET cycle at Chengdu Jinjiang Hospital for Women's and Children's Health from January 2014 to December 2019. Results: The transplantation rate of the GnRH-a long protocol group (59.1%) was higher than that of the GnRH-ant (25.9%) and mGnRH-a (36.7%) groups. The total live birth rate of the GnRH-a long protocol group (46.2%) was higher than that of the GnRH-a group (25.9%) and GnRH-ant group (40.3%). The total number of frozen embryos in the GnRH-ant group was higher than in the other groups (P < 0.05). After adjusting for confounding factors, the logistic regression analysis showed that the GnRH-a long protocol group had higher probabilities of biochemical pregnancy, clinical pregnancy, and live birth than the GnRH-a protocol group. The Gn dose in the mGnRH-a group was higher than the other three groups. Whether single or twin, there were similar neonatal outcomes among the four groups including premature birth rate, Apgar score, newborn weight, and length. Conclusion: For young obese patients undergoing IVF-ET, the GnRH-a long protocol for COH gives better pregnancy outcomes.

Identification of unique indolylcyanoethylenyl sulfonylanilines as novel structural scaffolds of potential antibacterial agents.

The increasing incidence of antibiotic resistance has forced the development of unique antimicrobials with novel multitargeting mechanisms to combat infectious diseases caused by multidrug-resistant pathogens. Structurally unique indolylcyanoethylenyl sulfonylanilines (ISs) were exploited as novel promising antibacterial agents to confront stubborn drug resistance. Some prepared ISs possessed favorable bacteriostatic action towards the tested bacteria. Especially, hydroxyethyl IS 14a exerted 8-fold more potent inhibitory efficacy against multidrug-resistant A. baumannii and E. coli 25922 with the low MIC of 0.5 µg/mL than norfloxacin, and showed low cell toxicity and rapid bactericidal property. Moreover, this compound also possessed obvious effect of eradicating bacterial biofilm, which could effectually relieve the development of drug resistance. A preliminary assessment of the antibacterial mechanism indicated that compound 14a could disintegrate membrane integrity leading to the leakage of intracellular protein, inactivation of lactate dehydrogenase and metabolism inhibition. Hydroxyethyl IS 14a mediated the accumulation of excess reactive oxygen species, which further contributed to reducing glutathione, resulting in oxidative damage to bacteria. Furthermore, IS 14a could intercalate into DNA to hinder the biological function of DNA. Quantum chemical study disclosed that IS 14a with the lowest energy gap was conducive to displaying high bioactivity. These findings demonstrated that hydroxyethyl IS 14a as a prospective antimicrobial candidate for combating A. baumannii and E. coli 25922 would be a promising starting point.

What makes a multidisciplinary medication review and deprescribing intervention for older people work well in primary care? A realist review and synthesis.

BACKGROUND: A third of older people take five or more regular medications (polypharmacy). Conducting medication reviews in primary care is key to identify and reduce/ stop inappropriate medications (deprescribing). Recent recommendations for effective deprescribing include shared-decision making and a multidisciplinary approach. Our aim was to understand when, why, and how interventions for medication review and deprescribing in primary care involving multidisciplinary teams (MDTs) work (or do not work) for older people. METHODS: A realist synthesis following the Realist And Meta-narrative Evidence Syntheses: Evolving Standards guidelines was completed. A scoping literature review informed the generation of an initial programme theory. Systematic searches of different databases were conducted, and documents screened for eligibility, with data extracted based on a Context, Mechanisms, Outcome (CMO) configuration to develop further our programme theory. Documents were appraised based on assessments of relevance and rigour. A Stakeholder consultation with 26 primary care health care professionals (HCPs), 10 patients and three informal carers was conducted to test and refine the programme theory. Data synthesis was underpinned by Normalisation Process Theory to identify key mechanisms to enhance the implementation of MDT medication review and deprescribing in primary care. FINDINGS: A total of 2821 abstracts and 175 full-text documents were assessed for eligibility, with 28 included. Analysis of documents alongside stakeholder consultation outlined 33 CMO configurations categorised under four themes: 1) HCPs roles, responsibilities and relationships; 2) HCPs training and education; 3) the format and process of the medication review 4) involvement and education of patients and informal carers. A number of key mechanisms were identified including clearly defined roles and good communication between MDT members, integration of pharmacists in the team, simulation-based training or team building training, targeting high-risk patients, using deprescribing tools and drawing on expertise of other HCPs (e.g., nurses and frailty practitioners), involving patents and carers in the process, starting with 'quick wins', offering deprescribing as 'drug holidays', and ensuring appropriate and tailored follow-up plans that allow continuity of care and management. CONCLUSION: We identified key mechanisms that could inform the design of future interventions and services that successfully embed deprescribing in primary care.

Video education improves patients' knowledge and satisfaction in treatment of solar lentigines with picosecond 755-nm alexandrite laser: A retrospective study.

Background: Picosecond lasers are widely used in dermatologic and cosmetic practice. In clinical practice, informed consent for laser treatments is critical to ensure patients' understanding of health information. Objectives: To evaluate whether video-based informed consent improves patient comprehension and satisfaction. Methods: The study was performed from August 1 to November 30, 2022. Solar lentigines patients who fulfilled the inclusion criteria were included. Before October 1, 2022, traditional informed consent methods were performed. In the subsequent 2 months, a video-based informed consent was used as an adjunct to traditional consenting methods. Finally, patient comprehension of relevant knowledge about laser treatment and client satisfaction were assessed. Results: A total of 106 patients were included. The mean number of correct answers in the comprehension assessment in the video-based informed consent group was significantly higher than that in the traditional informed consent group (4.4 ± 1.2 vs. 3.4 ± 1.1, p < 0.001). Compared to the traditional informed consent group, more correct answers in the video-based informed consent group were provided by older patients (3.9 ± 1.2 vs. 2.9 ± 1.1, p = 0.004) and patients with lower education levels (4.1 ± 1.1 vs. 3.0 ± 1.2, p < 0.001). The mean satisfaction score in the video-based informed consent group was significantly higher than that in the traditional informed consent (27.8 ± 5.7 vs. 24.3 ± 6.2, p = 0.003). Conclusion: Video-based informed consent helps patients learn clinical literacy more effectively and improves patient satisfaction, especially in those with lower education levels and older ages.

Inverse association between apolipoprotein C-II and cardiovascular mortality: role of lipoprotein lipase activity modulation.

AIMS: Apolipoprotein C-II (ApoC-II) is thought to activate lipoprotein lipase (LPL) and is therefore a possible target for treating hypertriglyceridemia. Its relationship with cardiovascular risk has not been investigated in large-scale epidemiologic studies, particularly allowing for apolipoprotein C-III (ApoC-III), an LPL antagonist. Furthermore, the exact mechanism of ApoC-II-mediated LPL activation is unclear. METHODS AND RESULTS: ApoC-II was measured in 3141 LURIC participants of which 590 died from cardiovascular diseases during a median (inter-quartile range) follow-up of 9.9 (8.7-10.7) years. Apolipoprotein C-II-mediated activation of the glycosylphosphatidylinositol high-density lipoprotein binding protein 1 (GPIHBP1)-LPL complex was studied using enzymatic activity assays with fluorometric lipase and very low-density lipoprotein (VLDL) substrates. The mean ApoC-II concentration was 4.5 (2.4) mg/dL. The relationship of ApoC-II quintiles with cardiovascular mortality exhibited a trend toward an inverse J-shape, with the highest risk in the first (lowest) quintile and lowest risk in the middle quintile. Compared with the first quintile, all other quintiles were associated with decreased cardiovascular mortality after multivariate adjustments including ApoC-III as a covariate (all P < 0.05). In experiments using fluorometric substrate-based lipase assays, there was a bell-shaped relationship for the effect of ApoC-II on GPIHBP1-LPL activity when exogenous ApoC-II was added. In ApoC-II-containing VLDL substrate-based lipase assays, GPIHBP1-LPL enzymatic activity was almost completely blocked by a neutralizing anti-ApoC-II antibody. CONCLUSION: The present epidemiologic data suggest that increasing low circulating ApoC-II levels may reduce cardiovascular risk. This conclusion is supported by the observation that optimal ApoC-II concentrations are required for maximal GPIHBP1-LPL enzymatic activity.

A Novel Ageladine A Derivative Acts as a STAT3 Inhibitor and Exhibits Potential Antitumor Effects.

The Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) signaling pathway controls multiple biological processes, including cell survival, proliferation, and differentiation. Abnormally activated STAT3 signaling promotes tumor cell growth, proliferation, and survival, as well as tumor invasion, angiogenesis, and immunosuppression. Hence, JAK/STAT3 signaling has been considered a promising target for antitumor therapy. In this study, a number of ageladine A derivative compounds were synthesized. The most effective of these was found to be compound 25. Our results indicated that compound 25 had the greatest inhibitory effect on the STAT3 luciferase gene reporter. Molecular docking results showed that compound 25 could dock into the STAT3 SH2 structural domain. Western blot assays demonstrated that compound 25 selectively inhibited the phosphorylation of STAT3 on the Tyr705 residue, thereby reducing STAT3 downstream gene expression without affecting the expression of the upstream proteins, p-STAT1 and p-STAT5. Compound 25 also suppressed the proliferation and migration of A549 and DU145 cells. Finally, in vivo research revealed that 10 mg/kg of compound 25 effectively inhibited the growth of A549 xenograft tumors with persistent STAT3 activation without causing significant weight loss. These results clearly indicate that compound 25 could be a potential antitumor agent by inhibiting STAT3 activation.

Metal-Organic Frameworks Facilitate Nucleic Acids for Multimode Synergistic Therapy of Breast Cancer.

Compared with traditional medical methods, gene therapy and photodynamic therapy are the new fields of cancer treatment, and they more accurately and effectively obtain preferable therapeutic effects. In this study, a chemotherapy drug-free nanotherapeutic system based on ZIF-90 encapsulated with Ce6-G3139 and Ce6-DNAzyme for gene and photodynamic therapies was constructed. Once entering the cancer cell, the therapy system will decompose and release Zn2+, Ce6-G3139, and Ce6-DNAzyme in the acidic environment. On the one hand, G3139 binds to the antiapoptotic gene BCL-2 in tumor cells and downregulates related proteins to inhibit tumor proliferation. On the other hand, Zn2+ produced by the decomposition of ZIF-90 can be used as a cofactor to activate the cleavage activity of DNAzyme to initiate gene therapy. Proliferation and metastasis of tumors were further inhibited by DNAzyme, targeting and cutting the gene of human early growth factor-1 (EGR-1). In addition, the photosensitizer Ce6 carried by the nucleic acid will produce cytotoxic ROS to kill cancer cells after irradiation. The results of this study demonstrated that the designed nanoplatform, which synergistically combines gene and photodynamic therapies, has shown great potential for cancer treatment.