Ferroptosis, a programmed cell death modality discovered and defined in the last decade, is primarily induced by iron-dependent lipid peroxidation. At present, it has been found that ferroptosis is involved in various physiological functions such as immune regulation, growth and development, aging, and tumor suppression. Especially its role in tumor biology has attracted extensive attention and research. Breast cancer is one of the most common female tumors, characterized by high heterogeneity and complex genetic background. Triple negative breast cancer (TNBC) is a special type of breast cancer, which lacks conventional breast cancer treatment targets and is prone to drug resistance to existing chemotherapy drugs and has a low cure rate after progression and metastasis. There is an urgent need to find new targets or develop new drugs. With the increase of studies on promoting ferroptosis in breast cancer, it has gradually attracted attention as a treatment strategy for breast cancer. Some studies have found that certain compounds and natural products can act on TNBC, promote their ferroptosis, inhibit cancer cells proliferation, enhance sensitivity to radiotherapy, and improve resistance to chemotherapy drugs. To promote the study of ferroptosis in TNBC, this article summarized and reviewed the compounds and natural products that induce ferroptosis in TNBC and their mechanisms of action. We started with the exploration of the pathways of ferroptosis, with particular attention to the System X_c^--cystine-GPX4 pathway and iron metabolism. Then, a series of compounds, including sulfasalazine (SAS), metformin, and statins, were described in terms of how they interact with cells to deplete glutathione (GSH), thereby inhibiting the activity of glutathione peroxidase 4 (GPX4) and preventing the production of lipid peroxidases. The disruption of the cellular defense against oxidative stress ultimately results in the death of TNBC cells. We have also our focus to the realm of natural products, exploring the therapeutic potential of traditional Chinese medicine extracts for TNBC. These herbal extracts exhibit multi-target effects and good safety, and have shown promising capabilities in inducing ferroptosis in TNBC cells. We believe that further exploration and characterization of these natural compounds could lead to the development of a new generation of cancer therapeutics. In addition to traditional chemotherapy, we discussed the role of drug delivery systems in enhancing the efficacy and reducing the toxicity of ferroptosis inducers. Nanoparticles such as exosomes and metal-organic frameworks (MOFs) can improve the solubility and bioavailability of these compounds, thereby expanding their therapeutic potential while minimizing systemic side effects. Although preclinical data on ferroptosis inducers are relatively robust, their translation into clinical practice remains in its early stages. We also emphasize the urgent need for more in-depth and comprehensive research to understand the complex mechanisms of ferroptosis in TNBC. This is crucial for the rational design and development of clinical trials, as well as for leveraging ferroptosis to improve patient outcomes. Hoping the above summarize and review could provide references for the research and development of lead compounds for the treatment for TNBC.

Objective: To investigate the environmental contamination of norovirus in nurseries and primary/secondary schools, so as to provide a scientific basis for effective prevention and control measures. Methods: A total of 483 external environmental samples were collected from 34 cluster outbreaks of norovirus gastroenteritis in kindergartens and primary/secondary schools in Linhai City from 2021 to 2024. Pathogen detection was conducted using a rapid nucleic acid extraction kit and realtime fluorescence RT-PCR, and the results were analyzed using the χ2 test or Fishers exact test. Results: Among the collected external environmental samples, the total positive rate of surface contamination was 13.66%. The positive rates in kindergartens and primary/secondary schools were 12.20% and 15.82%, respectively. In kindergartens, the five surfaces with the highest detection rates were desks/chairs (23.33%), toilet stool troughs (20.69%), urinal troughs (12.00%), washbasins/sinks (11.11%), and toilet mops (9.38%). In primary/secondary schools, the top five were toilet stool troughs (38.30%), urinal troughs (23.53%), toilet door handles (13.04%), toilet mops (12.50%), and drinking cups (11.11%). The difference in positive detection rates among different external environments in primary/secondary schools was statistically significant (Fishers exact probability test, P<0.01). The positive detection rate in sanitary toilets was higher than that in classroom environments (χ2=17.38), while the positive detection rate in classroom environments of kindergartens was higher than that in primary/secondary schools (χ2=5.42)(P<0.05). Conclusions Norovirus exhibits a high contamination rate in nurseries and schools, particularly in restroom areas. Strengthening sanitation and disinfection in highrisk environments, and improving hygiene awareness among children and staff, are essential for the effective prevent and control of norovirus.

ObjectiveTo investigate the protective effect and mechanism of Shaoyaotang （SYD） on the lipopolysaccharide （LPS）-induced damage of tight junction proteins in the human colorectal adenocarcinoma （Caco-2） cell model of inflammation via the Ras homolog gene family member A （RhoA）/Rho-associated coiled-coil forming protein kinase （ROCK） pathway. MethodsCaco-2 cells were grouped as follows： Blank， model （LPS， 10 mg·L^-1）， SYD-containing serum （10%， 15%， and 20%）， and inhibitor （Fasudil， 25 μmol·L^-1）. After 24 hours of intervention， the cell viability in each group was examined by the cell-counting kit 8 （CCK-8） method. Enzyme-linked immunosorbent assay was employed to determine the levels of endothelin-1 （ET-1）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-6 （IL-6）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot were employed to determine the mRNA and protein levels， respectively， of RhoA， ROCK2， claudin-5， and zonula occludens-1 （ZO-1） in cells of each group. ResultsCompared with the blank group， the model group showcased a marked reduction in the cell viability （P<0.01）， elevations in the levels of ET-1， TNF-α， IL-1β， and IL-6 （P<0.01）， declines in both mRNA and protein levels of ZO-1 and claudin-5 （P<0.01）， and rises in mRNA and protein levels of RhoA and ROCK2 （P<0.01）. Compared with the model group， the Shaoyaotang-containing serum （10%， 15%， and 20%） groups had enhanced cell viability （P<0.01）， lowered levels of ET-1， TNF-α， IL-1β， and IL-6 （P<0.01）， up-regulated mRNA and protein levels of ZO-1 and claudin-5 （P<0.05， P<0.01）， and down-regulated mRNA and protein levels of RhoA and ROCK2 （P<0.01）. Moreover， the inhibitor group and the 15% and 20% Shaoyaotang-containing serum groups had lower levels of ET-1， TNF-α， IL-1β， and IL-6 （P<0.05， P<0.01）， higher mRNA and protein levels of ZO-1 and claudin-5 （P<0.05， P<0.01）， and lower mRNA and protein levels of RhoA and ROCK2 （P<0.05， P<0.01） than the 10% Shaoyaotang-containing serum group. ConclusionThe Shaoyaotang-containing serum can lower the levels of LPS-induced increases in levels of inflammatory cytokines and endothelin to ameliorate the damage of tight junction proteins of the Caco-2 cell model of inflammation by regulating the expression of proteins in the RhoA/ROCK pathway.

ObjectiveTo investigate the protective effect and mechanism of Shaoyaotang （SYD） on the lipopolysaccharide （LPS）-induced damage of tight junction proteins in the human colorectal adenocarcinoma （Caco-2） cell model of inflammation via the Ras homolog gene family member A （RhoA）/Rho-associated coiled-coil forming protein kinase （ROCK） pathway. MethodsCaco-2 cells were grouped as follows： Blank， model （LPS， 10 mg·L^-1）， SYD-containing serum （10%， 15%， and 20%）， and inhibitor （Fasudil， 25 μmol·L^-1）. After 24 hours of intervention， the cell viability in each group was examined by the cell-counting kit 8 （CCK-8） method. Enzyme-linked immunosorbent assay was employed to determine the levels of endothelin-1 （ET-1）， tumor necrosis factor-α （TNF-α）， interleukin-1β （IL-1β）， and interleukin-6 （IL-6）. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot were employed to determine the mRNA and protein levels， respectively， of RhoA， ROCK2， claudin-5， and zonula occludens-1 （ZO-1） in cells of each group. ResultsCompared with the blank group， the model group showcased a marked reduction in the cell viability （P<0.01）， elevations in the levels of ET-1， TNF-α， IL-1β， and IL-6 （P<0.01）， declines in both mRNA and protein levels of ZO-1 and claudin-5 （P<0.01）， and rises in mRNA and protein levels of RhoA and ROCK2 （P<0.01）. Compared with the model group， the Shaoyaotang-containing serum （10%， 15%， and 20%） groups had enhanced cell viability （P<0.01）， lowered levels of ET-1， TNF-α， IL-1β， and IL-6 （P<0.01）， up-regulated mRNA and protein levels of ZO-1 and claudin-5 （P<0.05， P<0.01）， and down-regulated mRNA and protein levels of RhoA and ROCK2 （P<0.01）. Moreover， the inhibitor group and the 15% and 20% Shaoyaotang-containing serum groups had lower levels of ET-1， TNF-α， IL-1β， and IL-6 （P<0.05， P<0.01）， higher mRNA and protein levels of ZO-1 and claudin-5 （P<0.05， P<0.01）， and lower mRNA and protein levels of RhoA and ROCK2 （P<0.05， P<0.01） than the 10% Shaoyaotang-containing serum group. ConclusionThe Shaoyaotang-containing serum can lower the levels of LPS-induced increases in levels of inflammatory cytokines and endothelin to ameliorate the damage of tight junction proteins of the Caco-2 cell model of inflammation by regulating the expression of proteins in the RhoA/ROCK pathway.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

BACKGROUND: Renal osteodystrophy (ROD) is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder (CKD-MBD) that is characterized by aberrant bone mineralization and remodeling. ROD increases the risk of fracture and mortality in CKD patients. The underlying mechanisms of ROD remain elusive, partially due to the absence of an appropriate animal model. To address this gap, we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing (RNA-seq). METHODS: Eight-week-old male C57BL/6J mice were randomly allocated into three groups: control group ( n = 5), adenine and high-phosphate (HP) diet group ( n = 20), and the optimized adenine-containing diet group ( n = 20) for 12 weeks. We assessed the skeletal characteristics of model mice through blood biochemistry, microcomputed tomography (micro-CT), and bone histomorphometry. RNA-seq was utilized to profile gene expression changes of ROD. We elucidated the functions of differentially expressed genes (DEGs) using gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). DEGs were validated via quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: By the fifth week, adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group, precluding further model development. Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels, accompanied by pronounced hyperparathyroidism and hyperphosphatemia. The femur bone mineral density (BMD) of the model mice was lower than that of control mice, with substantial bone loss and cortical porosity. ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers. Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice. Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway. The significant upregulation of alkaline ceramidase 1 ( Acer1 ), alkaline ceramidase 2 ( Acer2 ), prosaposin-like 1 ( Psapl1 ), adenosine A1 receptor ( Adora1 ), and sphingosine-1-phosphate receptor 5 ( S1pr5 ) were successfully validated in mouse femurs by qRT-PCR. CONCLUSIONS Optimized adenine diet mouse model may be a valuable proxy for studying ROD. RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis, thereby providing new avenues for therapeutic intervention.
Animals ; Mice ; Chronic Kidney Disease-Mineral and Bone Disorder/genetics* ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Sphingolipids/metabolism* ; Transcriptome/genetics* ; Signal Transduction/genetics* ; X-Ray Microtomography ; Adenine

ObjectiveTo establish an adjusted Serfling regression model to estimate the excess cases and the excess epidemic period of hand-foot-mouth disease (HFMD) in Beijing from 2011 to 2019, so as to provide data support and decision-making basis for HFMD prevention and control. MethodsThe weekly number of HFMD cases in Beijing from 2011 to 2019 was utilized for adjusted the Serfling regression model. Then the adjusted model was used to fit the baseline and epidemic threshold of HFMD in Beijing from 2011 to 2019, calculating the excess cases and determining the excess epidemic period. ResultsA total of 279 306 cases of HFMD were reported in Beijing from 2011 to 2019, with the climax of the disease occurring in summer and autumn. After adjusting the fitting R² of the Serfling regression model to 0.773, a total of 10 excess epidemic periods totaling 92 weeks were estimated, mainly occurring in summer. The highest number of excess cases during an excess epidemic period was found in 2014 (1 272 cases, 95%CI: 990‒1 554), accounting for 65.04% of the actual cases (95%CI: 50.62%‒79.46%). ConclusionThe adjusted Serfling regression model fits well and can be utilized for early warning of HFMD and estimating the disease burden caused by HFMD.

OBJECTIVE: To explore the improvement effect of electroacupuncture (EA) based on Xingnao Kaiqiao acupuncture (acupuncture for regaining consciousness and opening orifices) on cognitive impairment in mice with Parkinson's disease (PD), and to explore its regulatory mechanisms on the kinesin family member 5A (KIF5A)/mitochondrial Rho GTPase 1 (Miro1) pathway and mitophagy in prefrontal cortical neurons. METHODS: A total of 70 male C57BL/6J mice of clean grade were randomly divided into a normal group (12 mice), a sham operation group (12 mice), and a model pre-screening group (46 mice). Unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle was adopted to establish the PD model in the model pre-screening group. Twenty-four mice after successful modeling were randomly selected and divided into a model group and an EA group, 12 mice in each one. In the EA group, acupuncture was applied at "Shuigou" (GV26) and bilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6), ipsilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6) were connected to EA respectively, with disperse-dense wave, 5 Hz/20 Hz in frequency, 0.5 mA in current intensity, 20 min a time, 6 times a week for 30 days. Cognitive function was assessed by Y-maze and Morris water maze tests; morphology of prefrontal cortex was observed by H.E. staining; reactive oxygen species (ROS) level in prefrontal cortex was detected by fluorescence probe method; mitochondrial morphology and autophagosome ultrastructure were observed by transmission electron microscopy; the mRNA expression of tyrosine hydroxylase (TH) was detected by quantitative real-time PCR; the protein expression of TH, KIF5A, Miro1, p62, Parkin and PTEN induced kinase 1 (PINK1) was detected by Western blot. RESULTS: Compared with the sham operation group, both the model group and the EA group exhibited increased rotation number of per minute (P<0.001). Compared with the sham operation group, in the model group, the novel arm exploration time of Y-maze test was shortened (P<0.001), the escape latency of Morris water maze test was prolonged (P<0.05) and the platform crossing number of Morris water maze test was reduced (P<0.01); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was increased (P<0.001), and mitochondrial autophagosomes could be observed; in the prefrontal cortex, the relative expression of ROS was increased (P<0.001), the protein and mRNA expression of TH was decreased (P<0.001), the protein expression of Miro1, PINK1, Parkin was increased (P<0.001, P<0.01), the protein expression of KIF5A and p62 was decreased (P<0.001). Compared with the model group, in the EA group, the novel arm exploration time of Y-maze test was prolonged (P<0.01), the escape latency of Morris water maze test was shortened (P<0.05) and the platform crossing number of Morris water maze test was increased (P<0.05); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was decreased (P<0.001), and the number of mitochondrial autophagosomes reduced and the mitochondrial morphology was improved; in the prefrontal cortex, the relative expression of ROS was decreased (P<0.01), the protein and mRNA expression of TH was increased (P<0.001, P<0.01), the protein expression of Miro1, PINK1, Parkin was decreased (P<0.001, P<0.01, P<0.05), the protein expression of KIF5A and p62 was increased (P<0.01, P<0.05). CONCLUSION Xingnao Kaiqiao electroacupuncture effectively alleviates cognitive impairment and damage of neuronal function in PD mice, its mechanism may be related to the regulation of KIF5A/Miro1 pathway, hence reducing the mitophagy in prefrontal cortical neurons.
Animals ; Electroacupuncture ; Male ; Mice ; Parkinson Disease/physiopathology* ; Cognitive Dysfunction/psychology* ; Kinesins/genetics* ; Humans ; Mitophagy ; Mice, Inbred C57BL ; rho GTP-Binding Proteins/genetics* ; Mitochondria/genetics* ; Prefrontal Cortex/metabolism*

Neuronal reprogramming is an innovative technique for converting non-neuronal somatic cells into neurons that can be used to replace lost or damaged neurons, providing a potential effective therapeutic strategy for central nervous system (CNS) injuries or diseases. Transcription factors have been used to induce neuronal reprogramming, while their reprogramming efficiency is relatively low, and the introduction of exogenous genes may result in host gene instability or induce gene mutation. Therefore, their future clinical application may be hindered by these safety concerns. Compared with transcription factors, small-molecule compounds have unique advantages in the field of neuronal reprogramming, which can overcome many limitations of traditional transcription factor-induced neuronal reprogramming. Here, we review the recent progress in the research of small-molecule compound-mediated neuronal reprogramming and its application in CNS regeneration and repair.
Humans ; Cellular Reprogramming/drug effects* ; Neurons/cytology* ; Animals ; Transcription Factors ; Small Molecule Libraries/pharmacology* ; Nerve Regeneration

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual developmental disorder (IDD), are highly prevalent and lack effective treatments, posing significant health challenges. These disorders are frequently comorbid with disruptions in sleep rhythms, and sleep-related indicators are often used to assess disease severity and treatment efficacy. Recent evidence has highlighted the crucial roles of circadian rhythm disturbances and circadian clock gene mutations in the pathogenesis of NDDs. This review focuses on the mechanisms by which circadian rhythm disruptions and circadian clock gene mutations contribute to cognitive, behavioral, and emotional disorders associated with NDDs, particularly through the dysregulation of dopamine system. Additionally, we discussed the potential of targeting the circadian system as novel therapeutic strategies for the treatment of NDDs.
Humans ; Neurodevelopmental Disorders/genetics* ; Attention Deficit Disorder with Hyperactivity/genetics* ; Circadian Rhythm/genetics* ; Autism Spectrum Disorder/genetics* ; Mutation ; Intellectual Disability/genetics* ; Circadian Clocks/physiology* ; Dopamine/metabolism*