Role of NF-κB signaling pathway in H2O2-induced oxidative stress of hiPSCs.

The balance between oxidation and antioxidation is crucial for the development of embryo. It is harmful to the early embryonic development if embryonic stem cells (ESCs) encounter the serious oxidative stress in vivo. Induced pluripotent stem cells (iPSCs) are very similar to ESCs and are the important cell source to replace ESCs for research and therapy. Studies show that iPSCs have better resistant ability to oxidative stress, but the involved mechanism remains unclear. In this study, we predicted that the NF-κB pathway might be involved in H2O2-induced developmental damage by network toxicology analysis. Then, the oxidative stress model was established with different concentrations of H2O2 to investigate the mechanism of NF-κB pathway in oxidative stress of human induced pluripotent stem cells (hiPSCs). The results showed as follows: With the increase of H2O2 concentration, the ROS level gradually went up leading to an increasing damage degree of hiPSCs; however, the MDA content was obviously high only in the 400 µM H2O2 group; the activities of some antioxidant indexes such as SOD2 and T-AOC were significantly upregulated in the 100 µM group, while most of antioxidant indexes showed downregulated tendency to different degrees with the increase of H2O2 concentration. The expression levels of P65, P50, IκB, SOD2, and FHC mRNA were upregulated in most H2O2-treated groups, showing a dose-dependent relationship. In subsequent experiments, the inhibitor of IκB-α phosphorylation, Bay11-7082, reversed the upregulation of P65, IκB, and FHC mRNA expression induced by 400 µM H2O2. The protein levels of P65, p-P65, P50, p-P50, IκB, p-IκB, SOD2, and FHC were upregulated in most H2O2-treated groups. However, the upregulation induced by 400 µM H2O2 could be reversed by BAY 11-7082, except for IκB and SOD2. In conclusion, H2O2 could promote the expressions and phosphorylations of NF-κB that could upregulate the expressions of its downstream antioxidant genes to minimize the damage of hiPSCs caused by oxidative stress. These results contribute to a fundamental understanding of the antioxidant mechanism of iPSCs and will further facilitate the application of iPSCs, as well as provide a reference for controlling the oxidative stress encountered in the early development stage of embryo.

Heteryunine A, an amidated tryptophan-catechin-spiroketal hybrid with antifibrotic activity from Heterosmilax yunnanensis.

An unprecedented spiro-C-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA).

Neohesperidin alleviates the inhibitory effect of bisphenol A on the myogenic differentiation of umbilical cord mesenchymal stem cells via the IGF1R/AKT1/RHOA signaling pathway.

Bisphenol A (BPA), a typical environmental endocrine disruptor, has raised concerns among researchers due to its toxicological effects. Whether neohesperidin (NEO) can intervene in the toxic effects of BPA remains unknown. This study aims to investigate the effects and mechanisms of NEO on the myogenic differentiation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) exposed to BPA. Sheep UC-MSCs were isolated, characterized, and induced to myogenic differentiation. BPA decreased cell viability, cell migration, and the expressions of myogenic marker genes, leading to myogenic differentiation inhibition, which were reversed by NEO. Network pharmacology suggested the IGF1R/AKT1/RHOA pathway as potential targets of BPA and NEO regulating muscle development. Western blot results showed that NEO could reverse the down-regulation of the pathway proteins induced by BPA, and counteract the effects of picropodophyllin (PPP) or MK-2206 dihydrochloride (MK-2206) in the myogenic differentiation of sheep UC-MSCs. Additionally, the expression levels of (p-) IGF1R, AKT1, and RHOA were positively correlated. Taken together, the mechanisms of NEO resistance to BPA involved the IGF1R/AKT1/RHOA signaling pathway. These findings provide a scientific basis for alleviating BPA toxicity, preventing and treating muscular dysplasia, and promoting muscle damage repair.

Rhodamine and related substances in food: Recent updates on pretreatment and analysis methods.

Rhodamine, a colorant prohibited in various consumer products due to its demonstrated carcinogenic, mutagenic, and toxic properties, necessitates the development of a straightforward, efficient, sensitive, environmentally friendly, and cost-effective analytical method. This review provides an overview of recent advancements in the pretreatment and determination techniques for rhodamine across diverse sample matrices since 2017. Sample preparation methods encompass both commonly used pretreatment techniques such as filtration, centrifugation, solvent extraction, and cloud point extraction, as well as innovative approaches including solid phase extraction, dispersive liquid-liquid microextraction, hollow fiber liquid phase microextraction, magnetic solid phase extraction, and matrix solid phase dispersion. The analytical techniques encompass high performance liquid chromatography, surface-enhanced Raman scattering, and sensor-based methods. Furthermore, a comprehensive examination is conducted to offer insights for future research on rhodamine regarding the advantages, disadvantages, and advancements in various pretreatment and determination methodologies.

PVA/PANI-DBSA Nanomesh Tactile Sensor for Force Feedback.

Touch serves as an important medium for human-environment interaction. The piezoresistive tactile sensor has attracted much attention due to its convenient technology, simple principle, and convenient signal acquisition and analysis. In this paper, conductive beads-on-string polyvinyl alcohol (PVA)/polyaniline doped with dodecyl benzene sulfonic acid (PANI-DBSA) nanofibers were fabricated via the electrospinning technique. Due to the special nanostructure of PVA-coated PANI-DBSA, the tactile sensor presented a wide measuring range of 12 Pa-121 kPa and appreciable sensitivity of 8.576 kPa-1 at 12 Pa~484 Pa. In addition, the response time and recovery time of the sensor were approximately 500 ms, demonstrating promising prospects in the field of tactile sensing for active upper limb prostheses.

Early identification of macrophage activation syndrome secondary to systemic lupus erythematosus with machine learning.

OBJECTIVE: The macrophage activation syndrome (MAS) secondary to systemic lupus erythematosus (SLE) is a severe and life-threatening complication. Early diagnosis of MAS is particularly challenging. In this study, machine learning models and diagnostic scoring card were developed to aid in clinical decision-making using clinical characteristics. METHODS: We retrospectively collected clinical data from 188 patients with either SLE or the MAS secondary to SLE. 13 significant clinical predictor variables were filtered out using the Least Absolute Shrinkage and Selection Operator (LASSO). These variables were subsequently utilized as inputs in five machine learning models. The performance of the models was evaluated using the area under the receiver operating characteristic curve (ROC-AUC), F1 score, and F2 score. To enhance clinical usability, we developed a diagnostic scoring card based on logistic regression (LR) analysis and Chi-Square binning, establishing probability thresholds and stratification for the card. Additionally, this study collected data from four other domestic hospitals for external validation. RESULTS: Among all the machine learning models, the LR model demonstrates the highest level of performance in internal validation, achieving a ROC-AUC of 0.998, an F1 score of 0.96, and an F2 score of 0.952. The score card we constructed identifies the probability threshold at a score of 49, achieving a ROC-AUC of 0.994 and an F2 score of 0.936. The score results were categorized into five groups based on diagnostic probability: extremely low (below 5%), low (5-25%), normal (25-75%), high (75-95%), and extremely high (above 95%). During external validation, the performance evaluation revealed that the Support Vector Machine (SVM) model outperformed other models with an AUC value of 0.947, and the scorecard model has an AUC of 0.915. Additionally, we have established an online assessment system for early identification of MAS secondary to SLE. CONCLUSION: Machine learning models can significantly improve the diagnostic accuracy of MAS secondary to SLE, and the diagnostic scorecard model can facilitate personalized probabilistic predictions of disease occurrence in clinical environments.

Atypical phenotypes and novel OCRL variations in southern Chinese patients with Lowe syndrome.

BACKGROUND: Lowe syndrome is characterized by the presence of congenital cataracts, psychomotor retardation, and dysfunctional proximal renal tubules. This study presents a case of an atypical phenotype, investigates the genetic characteristics of eight children diagnosed with Lowe syndrome in southern China, and performs functional analysis of the novel variants. METHODS: Whole-exome sequencing was conducted on eight individuals diagnosed with Lowe syndrome from three medical institutions in southern China. Retrospective collection and analysis of clinical and genetic data were performed, and functional analysis was conducted on the five novel variants. RESULTS: In our cohort, the clinical symptoms of the eight Lowe syndrome individuals varied. One patient was diagnosed with Lowe syndrome but did not present with congenital cataracts. Common features among all patients included cognitive impairment, short stature, and low molecular weight proteinuria. Eight variations in the OCRL gene were identified, encompassing three previously reported and five novel variations. Among the novel variations, three nonsense mutations were determined to be pathogenic, and two patients harboring novel missense variations of uncertain significance exhibited severe typical phenotypes. Furthermore, all novel variants were associated with altered protein expression levels and impacted primary cilia formation. CONCLUSION: This study describes the first case of an atypical Lowe syndrome patient without congenital cataracts in China and performs a functional analysis of novel variants in the OCRL gene, thereby expanding the understanding of the clinical manifestations and genetic diversity associated with Lowe syndrome.

Advances in research on autophagy mechanisms in resistance to endometrial cancer treatment.

Administering medication is a crucial strategy in improving the prognosis for advanced endometrial cancer. However, the rise of drug resistance often leads to the resurgence of cancer or less-than-ideal treatment outcomes. Prior studies have shown that autophagy plays a dual role in the development and progression of endometrial cancer, closely associated with drug resistance. As a result, concentrating on autophagy and its combination with medical treatments might be a novel approach to improve the prognosis for endometrial cancer. This study explores the impact of autophagy on drug resistance in endometrial cancer, investigates its core mechanisms, and scrutinizes relevant treatments aimed at autophagy, aiming to illuminate the issue of treatment resistance in advanced endometrial cancer.

Epithelial and mesenchymal phenotypes determine the dynamics of circulating breast tumor cells in microfluidic capillaries under chemotherapy-induced stress.

Circulating tumor cells (CTCs) with different epithelial and mesenchymal phenotypes play distinct roles in the metastatic cascade. However, the influence of their phenotypic traits and chemotherapy on their transit and retention within capillaries remains unclear. To explore this, we developed a microfluidic device comprising 216 microchannels of different widths from 5 to 16 µm to mimic capillaries. This platform allowed us to study the behaviors of human breast cancer epithelial MCF-7 and mesenchymal MDA-MB-231 cells through microchannels under chemotherapy-induced stress. Our results revealed that when the cell diameter to microchannel width ratio exceeded 1.2, MCF-7 cells exhibited higher transit percentages than MDA-MB-231 cells under a flow rate of 0.13 mm/s. Tamoxifen (250 nM) reduced the transit percentage of MCF-7 cells, whereas 100 nM paclitaxel decreased transit percentages for both cell types. These differential responses were partially due to altered cell stiffness following drug treatments. When cells were entrapped at microchannel entrances, tamoxifen, paclitaxel, and high-flow stress (0.5 mm/s) induced a reduction in mitochondrial membrane potential (MMP) in MCF-7 cells. Tamoxifen treatment also elevated reactive oxygen species (ROS) levels in MCF-7 cells. Conversely, MMP and ROS levels in entrapped MDA-MB-231 cells remained unaffected. Consequently, the viability and proliferation of entrapped MCF-7 cells declined under these chemical and physical stress conditions. Our findings emphasize that phenotypically distinct CTCs may undergo selective filtration and exhibit varied responses to chemotherapy in capillaries, thereby impacting cancer metastasis outcomes. This highlights the importance of considering both cell phenotype and drug response to improve treatment strategies.

Naringenin inhibits APAP-induced acute liver injury through activating PPARA-dependent signaling pathway.

Acute liver injury (ALI) refers to the damage to the liver cells of patients due to drugs, food, and diseases. In this work, we used a network pharmacology approach to analyze the relevant targets and pathways of the active ingredients in Citri Reticulatae Pericarpium (CRP) for the treatment of ALI and conducted systematic validation through in vivo and in vitro experiments. The network pharmacologic results predicted that naringenin (NIN) was the main active component of CRP in the treatment of ALI. GO functional annotation and KEGG pathway enrichment showed that its mechanism may be related to the regulation of PPARA signaling pathway, PPARG signaling pathway, AKT1 signaling pathway, MAPK3 signaling pathway and other signaling pathways. The results of in vivo experiments showed that (NIN) could reduce the liver lesions, liver adipose lesions, hepatocyte injury and apoptosis in mice with APAP-induced ALI, and reduce the oxidative stress damage of mouse liver cells and the inflammation-related factors to regulate ALI. In vitro experiments showed that NIN could inhibit the proliferation, oxidative stress and inflammation of APAP-induced LO2 cells, promote APAP-induced apoptosis of LO2 cells, and regulate the expression of apoptotic genes in acute liver injury. Further studies showed that NIN inhibited APAP-induced ALI mainly by regulating the PPARA-dependent signaling pathway. In conclusion, this study provides a preliminary theoretical basis for the screening of active compounds in CRP for the prevention and treatment of ALI.

Knowledge, Attitudes, and Practices Among Patients with Systemic Lupus Erythematosus Toward Disease Management and Biologic Therapy.

Background: This study aims to investigate the knowledge, attitudes, and practices (KAP) among patients with systemic lupus erythematosus (SLE) toward disease management and biologic therapy. Methods: This cross-sectional study was conducted between April 20, 2023, and May 5, 2023, among patients with SLE at Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology. A self-designed questionnaire was developed to collect demographic information of SLE patients and assess their KAP. Results: A total of 463 SLE patients participated. The mean scores for knowledge, attitudes, and practices were 8.52 ± 2.36 (possible range: 0-11), 39.40 ± 3.38 (possible range: 11-55), and 27.10 ± 6.29 (possible range: 8-40), respectively. The path analysis demonstrated a significant and positive association between knowledge and attitudes, as indicated by a path coefficient of 0.455 (p < 0.001), and a significant and positive relationship between knowledge and practices, with a path coefficient of 0.709 (p < 0.001). Conclusion: Patients with SLE exhibited insufficient knowledge, negative attitudes, and poor practices.

Regulating bacterial biofilms in food and biomedicine: unraveling mechanisms and Innovating strategies.

Bacterial biofilm has brought a lot of intractable problems in food and biomedicine areas. Conventional biofilm control mainly focuses on inactivation and removal of biofilm. However, with robust construction and enhanced resistance, the established biofilm is extremely difficult to eradicate. According to the mechanism of biofilm development, biofilm formation can be modulated by intervening in the key factors and regulatory systems. Therefore, regulation of biofilm formation has been proposed as an alternative way for effective biofilm control. This review aims to provide insights into the regulation of biofilm formation in food and biomedicine. The underlying mechanisms for early-stage biofilm establishment are summarized based on the key factors and correlated regulatory networks. Recent developments and applications of novel regulatory strategies such as anti/pro-biofilm agents, nanomaterials, functionalized surface materials and physical strategies are also discussed. The current review indicates that these innovative methods have contributed to effective biofilm control in a smart, safe and eco-friendly way. However, standard methodology for regulating biofilm formation in practical use is still missing. As biofilm formation in real-world systems could be far more complicated, further studies and interdisciplinary collaboration are still needed for simulation and experiments in the industry and other open systems.

Fourteen new 2-benzylbenzofuran glycosides with cardioprotective activity from Heterosmilax yunnanensis.

Fourteen new 2-benzylbenzofuran O-glycosides (1-13, 15) and one new key precursor, diarylacetone (14) were isolated from the roots of Heterosmilax yunnanensis Gagnep, which all have characteristic 2,3,4-O-trisubstituted benzyl. Their structures were elucidated by 1D and 2D NMR, HRESIMS, UV and IR. The isolated compounds were assessed for their cardioprotective activities and compounds 1, 3 and 6 could significantly improve cardiomyocytes viability. Moreover, the mechanistic study revealed that these three compounds could significantly decrease intracellular ROS levels and maintain mitochondrial homeostasis upon hypoxia inducement. Consequently, 1, 3 and 6 might serve as potential lead compounds to prevent myocardial ischemia.

[Systemic lupus erythematosus associated macrophage activation syndrome with neuropsychiatric symptoms: A report of 2 cases].

Systemic lupus erythematosus (SLE) associated macrophage activation syndrome (MAS) is clinically severe, with a high mortality rate and rare neuropsychiatric symptoms. In the course of diagnosis and treatment, it is necessary to actively determine whether the neuropsychiatric symptoms in patients are caused by neuropsychiatric systemic lupus erythematosus (NPSLE) or macrophage activation syndrome. This paper retrospectively analyzed the clinical data of 2 cases of SLE associated MAS with neuropsychiatric lesions, Case 1: A 30-year-old female had obvious alopecia in 2019, accompanied by emaciation, fatigue and dry mouth. In March 2021, she felt weak legs and fell down, followed by fever and chills without obvious causes. After completing relevant examinations, she was diagnosed with SLE and given symptomatic treatments such as hormones and anti-infection, but the patient still had fever. The relevant examinations showed moderate anemia, elevated ferritin, elevated triglycerides, decreased NK cell activity, and a perforin positivity rate of 4.27%, which led to the diagnosis of "pre-hemophagocytic syndrome (HPS)". In May 2021, the patient showed mental trance and babble, and was diagnosed with "SLE-associated MAS"after completing relevant examinations. After treatment with methylprednisolone, anti-infection and psychotropic drugs, the patient's temperature was normal and mental symptoms improved. Case 2: A 30-year-old female patient developed butterfly erythema on both sides of the nose on her face and several erythema on her neck in June 2019, accompanied by alopecia, oral ulcers, and fever. She was diagnosed with "SLE" after completing relevant examinations, and her condition was relieved after treatment with methylprednisolone and human immunoglobulin. In October 2019, the patient showed apathy, no lethargy, and fever again, accompanied by dizziness and vomiting. The relevant examination indicated moderate anemia, decreased NK cell activity, elevated triglycerides, and elevated ferritin. The patient was considered to be diagnosed with "SLE, NPSLE, and SLE-associated MAS". After treatment with hormones, human immunoglobulin, anti-infection, rituximab (Mabthera), the patient's condition improved and was discharged from the hospital. After discharge, the patient regularly took methylprednisolone tablets (Medrol), and her psychiatric symptoms were still intermittent. In November 2019, she developed symptoms of fever, mania, and delirium, and later turned to an apathetic state, and was given methylprednisolone intravenous drip and olanzapine tablets (Zyprexa) orally. After the mental symptoms improved, she was treated with rituximab (Mabthera). Later, due to repeated infections, she was replaced with Belizumab (Benlysta), and she was recovered from her psychiatric anomalies in March 2021. Through the analysis of clinical symptoms, imaging examination, laboratory examination, treatment course and effect, it is speculated that the neuropsychiatric symptoms of case 1 are more likely to be caused by MAS, and that of case 2 is more likely to be caused by SLE. At present, there is no direct laboratory basis for the identification of the two neuropsychiatric symptoms. The etiology of neuropsychiatric symptoms can be determined by clinical manifestations, imaging manifestations, cerebrospinal fluid detection, and the patient's response to treatment. Early diagnosis is of great significance for guiding clinical treatment, monitoring the condition and judging the prognosis. The good prognosis of the two cases in this paper is closely related to the early diagnosis, treatment and intervention of the disease.

Effects of Schlemm's Canal Suture Implantation Surgery and Pilocarpine Eye Drops on Trabecular Meshwork Pulsatile Motion.

The trabecular meshwork is an important structure in the outflow pathway of aqueous humor, and its movement ability directly affects the resistance of aqueous humor outflow, thereby affecting the steady state of intraocular pressure (IOP). (1) Objective: The purpose of this study was to preliminarily estimate the effects of pilocarpine eye drops and trabeculotomy tunneling trabeculoplasty (3T) on trabecular meshwork (TM) pulsatile motion via phase-sensitive optical coherence tomography (Phs-OCT). (2) Method: In a prospective single-arm study, we mainly recruited patients with primary open-angle glaucoma who did not have a history of glaucoma surgery, and mainly excluded angle closure glaucoma and other diseases that may cause visual field damage. The maximum velocity (MV) and cumulative displacement (CDisp) of the TM were quantified via Phs-OCT. All subjects underwent Phs-OCT examinations before and after the use of pilocarpine eye drops. Then, all subjects received 3T surgery and examinations of IOP at baseline, 1 day, 1 week, 1 month, 3 months, and 6 months post-surgery. Phaco-OCT examinations were performed at 3 and 6 months post-surgery, and the measurements were compared and analyzed. (3) Results: The MV of TM before and after the use of pilocarpine eye drops was 21.32 ± 2.63 µm/s and 17.00 ± 2.43 µm/s. The CDisp of TM before and after the use of pilocarpine eye drops was 0.204 ± 0.034 µm and 0.184 ± 0.035 µm. After the use of pilocarpine eye drops, both the MV and CDisp significantly decreased compared to those before use (p < 0.001 and 0.013, respectively). The IOP decreased from baseline at 22.16 ± 5.23 mmHg to 15.85 ± 3.71 mmHg after 3 months post-surgery and from 16.33 ± 2.51 mmHg at 6 months post-surgery, showing statistically significant differences (p < 0.001). The use of glaucoma medication decreased from baseline at 3.63 ± 0.65 to 1.17 ± 1.75 at 3 months and 1.00 ± 1.51 at 6 months post-surgery; the differences were statistically significant (p < 0.001). Additionally, there was no statistically significant difference in the MV between 3 and 6 months after surgery compared to baseline (p = 0.404 and 0.139, respectively). Further, there was no statistically significant difference in the CDisp between 3 and 6 months after surgery compared to baseline (p = 0.560 and 0.576, respectively) (4) Conclusions: After the preliminary study, we found that pilocarpine eye drops can attenuate TM pulsatile motion, and that 3T surgery may reduce IOP without affecting the pulsatile motion status of the TM.

Application of E-coach chronic disease management model in rehabilitation management of patients with arteriosclerosis obliterans.

OBJECTIVE: To explore the effect of a health (E)-coach chronic disease management model on the rehabilitation behaviour management of patients with arteriosclerosis obliterans (ASO). METHODS: The E-coach chronic disease management model was constructed based on a literature review and expert interviews. The effect of the E-coach model on patients with ASO during hospitalisation was analysed by comparing the compliance rates of blood glucose control, blood pressure control, drug compliance, ankle-brachial index, 6-min walking test (6MWT) and pain-free walking distance (PFWD) scores between the E-coach and control groups. RESULTS: In total, 212 patients with ASO were included in this study. After the intervention, the blood pressure compliance rate (44.8% vs. 65.7%) and blood glucose compliance rate (48.6% vs. 66.8%) were higher in the E-coach group than in the control group (p < 0.05). After intervention, compared with the control group, the patients in the E-coach group had better drug compliance (6.8 ± 1.9 vs. 7.9 ± 1.0), and the difference was statistically significant (p < 0.05). The scores for the 6MWT (329.19 ± 5.58 vs. 353.00 ± 9.76; 412.65 ± 12.59 vs. 499.16 ± 18.43) and PFWD (219.15 ± 11.96 vs. 225.36 ± 16.13; 331.62 ± 51.36 vs. 369.42 ± 75.71) tests were significantly higher in the E-coach group than in the control group at 1 and 6 months after intervention (p < 0.05). CONCLUSION: The E-coach chronic disease management model can effectively improve the control rates of blood glucose and blood pressure and the behaviour management of patients with ASO and is thus worthy of clinical reference.

A Nucleus-Targeting WT1 Antagonistic Peptide Encapsulated in Polymeric Nanomicelles Combats Refractory Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is recognized as a classic clonal myeloproliferative disorder. Given the limited treatment options for CML patients in the accelerated phase (AP) and blast phase (BP), there is an evident need to develop new therapeutic strategies. This has the potential to improve outcomes for individuals in the advanced stages of CML. A promising therapeutic target is Wilms' tumor 1 (WT1), which is highly expressed in BP-CML cells and plays a crucial role in CML progression. In this study, a chemically synthesized nucleus-targeting WT1 antagonistic peptide termed WIP2W was identified. The therapeutic implications of both the peptide and its micellar formulation, M-WIP2W, were evaluated in WT1+ BP-CML cell lines and in mice. The findings indicate that WIP2W can bind specifically to the WT1 protein, inducing cell cycle arrest and notable cytotoxicity in WT1+ BP-CML cells. Moreover, subcutaneous injections of M-WIP2W were observed to significantly enhance intra-tumoral accumulation and to effectively inhibit tumor growth. Thus, WIP2W stands out as a potent and selective WT1 inhibitor, and the M-WIP2W nanoformulation appears promising for the therapeutic treatment of refractory CML as well as other WT1-overexpressing malignant cancers.

Non-steroidal anti-inflammatory drugs (NSAIDs) in the environment: Recent updates on the occurrence, fate, hazards and removal technologies.

Non-steroidal Anti-inflammatory Drugs (NSAIDs) are extensively utilized pharmaceuticals worldwide. However, owing to the improper discharge and disposal practices, they have emerged as significant contaminants that are widely distributed in water, soils, and sewage sediments. This ubiquity poses a substantial threat to the ecosystem and human health. Consequently, it is imperative to develop rapid, cost-effective, efficient and reliable approaches for containing these substance in order to mitigate the deleterious impact of NSAIDs. This research provides a comprehensive review of the occurrence, fate, and hazards associated with NSAIDs in the general environment. Additionally, various removal technologies, including advanced oxidation processes, biodegradation, and adsorption, were systematically summarized. The study also presents a comparative analysis of the benefits and drawbacks of different removal technologies while interpreting challenges related to NSAIDs' removal and proposing strategies for future development.

Safety and Effectiveness of Baricitinib in Chinese Patients with Moderate-to-Severe Rheumatoid Arthritis: 24-Week Results from a Post-Marketing Safety Study.

INTRODUCTION: Baricitinib, a JAK1/JAK2 inhibitor, is approved for treatment of moderate-to-severe rheumatoid arthritis (RA) in China. This single-arm, prospective, multi-center, post-marketing safety study (PMSS) evaluated the safety and effectiveness of baricitinib in Chinese patients. METHODS: This study included adult patients with moderate-to-severe active RA who received baricitinib over periods of approximately 12 and 24 weeks. The primary endpoint was safety, defined as week 12 adverse event (AE)/serious AE incidence. Secondary endpoints were week 24 safety and effectiveness (disease activity score with 28 joints/C-reactive protein [DAS28-CRP] and simplified/Clinical Disease Activity Index [SDAI/CDAI]). RESULTS: Safety analyses included 667 patients (female, 82.3%; mean age, 53.3 years; mean RA duration, 86.9 months); 106/667 (15.9%) were 65-74 years old and 19/667 (2.8%) were ≥ 75 years old; 87.0% received baricitinib 2 mg QD. Total exposure was 262.1 patient-years (PY). At week 12, AEs had occurred in 214 (32.1%; exposure-adjusted incidence rate [EAIR], 172.5 per 100 PY) patients (serious AEs: 22 [3.3%; EAIR, 15.0]). At week 24, AEs had occurred in 250 (37.5%; EAIR, 125.9) patients (serious AEs: 28 [4.2%; EAIR, 10.9]). Two patients (0.3%) died (of pneumonia and unknown cause); EAIR for death, 0.77. Serious infection occurred in 1.2% of patients (EAIR, 3.1). Hepatotoxicity occurred in 3.4% of patients (EAIR, 9.0). No patients met potential Hy's law laboratory criteria (alanine/aspartate aminotransferases ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN). Malignancy occurred in one patient. No patients experienced venous thromboembolism (VTE) or major adverse cardiovascular events (MACE). At week 24, 52.4%, 27.5%, and 27.6% of patients achieved remission per DAS28-CRP, SDAI, and CDAI, respectively. CONCLUSIONS: This PMSS investigated the safety and effectiveness of baricitinib in clinical practice in China. No VTE/MACE or new safety signals were reported and there was promising effectiveness, supporting the use of baricitinib in Chinese patients with moderate-to-severe active RA. TRIAL REGISTRATION: EU PAS Register: EUPAS34213.

Supermolecular nanovehicles co-delivering TLR7/8-agonist and anti-CD47 siRNA for enhanced tumor immunotherapy.

Cancer immunotherapy is the most promising method for tumor therapy in recent years, among which the macrophages play a critical role in the antitumor immune response. However, tumor-associated macrophages (TAMs) usually display the tumor-promoting M2 phenotype rather than the tumor-killing M1 phenotype. Moreover, the over-expressed CD47 on tumor cells severely hinders the function of macrophages by blocking the CD47/SIRPα pathway. Herein, a nano-assembly system of CHTR/siRNA was constructed through the host-guest interaction of a hyperbranched amino-functionalized ß-cyclodextrin and immune agonist imiquimod (R848), while CD47 siRNA was loaded inside through electrostatic interaction. The Toll-like receptor (TLR) 7/8 agonist R848 can "re-educate" macrophages from the protumoral M2 phenotype to antitumoral M1 phenotype, while CD47 siRNA can down-regulate the "don't eat me" CD47 signal on the surface of cancer cells and enhance the phagocytosis of cancer cells by macrophages. Through the dual regulation of TAMs, the immunosuppressive tumor microenvironment was relieved, and the host-guest drug-carrying system resulted in synergistic immunotherapy effect on tumors and inhibited tumor growth. The facile self-assembly of nanodrug offers a new strategy in co-delivery of multiple therapeutic agents for cascade cancer immunotherapy.