Colorectal cancer (CRC) is a major global malignant tumor with high morbidity and mortality, and current clinical therapies have limited curative effects and obvious adverse reactions. Genistein, a key bioactive isoflavone derived from soybeans, has shown prominent anti-tumor activity, whereas its exact molecular mechanism against CRC remains unclear. This study evaluated the anti-CRC effects of genistein using in vitro cell experiments and a nude mouse xenograft model, focusing on the LINC00355/miR-150/SGK1 axis and its downstream EGFR/PI3K/AKT and MAPK signaling pathways to explore the underlying regulatory mechanism. The results revealed that genistein dose-dependently inhibited CRC cell proliferation without obvious cytotoxicity to normal colon cells. It also induced cell cycle arrest and cancer cell apoptosis, and suppressed tumor migration and invasion. Mechanistically, genistein inhibited the activation of downstream oncogenic pathways by regulating the expression of the target molecular axis. In vivo assays further confirmed that genistein effectively repressed tumor growth with good safety. This study provides reliable experimental evidence for the development of genistein as a potential adjuvant therapeutic agent for CRC treatment.

The therapeutic efficacy of ischemic stroke (IS) treatment is severely limited by insufficient accumulation of therapeutic agents within ischemic lesions and persistent secondary injury after ischemia–reperfusion. Herein, we report a cRGD-functionalized exosome-based nanoplatform that enhances ischemic lesion-associated accumulation and antioxidative neuroprotection for the treatment of IS. Neural stem cell-derived exosomes were functionalized with cyclic RGD peptides (cRGD) and subsequently loaded with Mn₃O₄ nanoparticles to construct a hybrid nanosystem (cRGD-Exo@Mn₃O₄). The engineered exosomes preserve intrinsic brain tropism, while cRGD modification promotes preferential accumulation in ischemic regions, potentially through interaction with αvβ3 integrin that is upregulated in ischemic lesions. The incorporated Mn₃O₄ nanoparticles confer robust reactive oxygen species (ROS) scavenging capability, thereby mitigating oxidative stress in ischemic microenvironments. In vitro and in vivo studies demonstrate that cRGD-Exo@Mn₃O₄ exhibits enhanced accumulation in ischemic regions compared with non-modified counterparts. The nanosystem effectively attenuates oxidative stress and neuroinflammation, leading to reduced infarct volume, alleviation of cerebral edema, and improved neurological function in MCAO/R mice. Mechanistically, transcriptomic analysis suggests that the therapeutic effects are associated with modulation of inflammation-and cell death-related pathways, including suppression of the RIPK1/RIPK3/MLKL signaling cascade. Collectively, this study presents a rationally designed exosome-based nanoplatform integrating ischemic lesion-associated accumulation with ROS-scavenging capability.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes joint swelling and pain, often leading to disability. Despite advances in nonsteroidal anti-inflammatory drugs and anticytokine biologics, their use remains limited due to the complexity of cytokine interactions, long-term drug dependence, and side effects. Recent studies emphasize the crucial role of miRNA in regulating inflammation, but their degradation and poor druggability hinder clinical application. This study identified that miRNA-709-z, derived from anti-inflammatory exosomes, exhibited strong anti-inflammatory effects. To overcome delivery challenges, an ionizable lipidoid incorporating a benzene ring, MO12, was synthesized and employed to formulate lipid nanoparticles (LNPs) for targeted delivery of miRNA-709-z to the ankle joint. MO12-LNPs not only significantly improved the cellular uptake and stability of miRNA-709-z but also enhanced its accumulation in the inflamed ankle joints of collagen-induced arthritis (CIA) mice. Treatment with MO12-LNP@miRNA-709-z effectively alleviated ankle inflammation in this model. Further studies revealed that MO12-LNP@miRNA-709-z reduced proinflammatory cytokines, inhibited synovial inflammation, and protected cartilage, preventing joint damage. This study not only developed an efficient miRNA delivery system but also demonstrated the potential of miRNA-based cytokine silencing in clinical RA treatment.

The organophosphorus pesticide chlorpyrifos (CPF) is widely utilized in agriculture to protect crops from pests and diseases. Concerns regarding its extensive use have emerged due to the substance's persistence, bioaccumulation, endocrine disruption, and associated toxicity, which may lead to various adverse reactions. In this study, 32 male C57BL/6 J mice were orally administered varying doses of CPF over a period of two weeks. Metabolic perturbations resulting from subacute exposure to CPF were assessed using LC-MS/MS-based untargeted metabolomics, alongside biochemical analysis and histopathological techniques. The 16S rRNA gene sequencing method was employed to evaluate changes in the gut microbial community within the cecal contents of mice exposed to CPF. In vivo studies have shown that CPF exposure induced dose-dependent damage and dysregulation of the intestinal microbiota in mouse colonic tissues. This was characterized by significant alterations in the gut microbiota, increased intestinal permeability and elevated levels of lipopolysaccharides. These changes may have compromised intestinal barrier function and facilitated the transfer of intestinal microbial metabolites and endotoxins to the liver, subsequently leading to liver injury. Collectively, this study elucidates a potential mechanism by which CPF triggers liver injury through alterations in the intestinal microbial community and increased intestinal permeability. These findings not only enhance our understanding of the toxicological effects of CPF but also contribute to the assessment of health risks associated with CPF exposure.

The TLR4/NLRP3 inflammasome pathway drives lung cancer cell proliferation, migration, and invasiveness. However, no in vivo treatments targeting this pathway in lung cancer exist. Resveratrol, an anti-inflammatory compound, inhibits the NLRP3 inflammasome but requires high doses due to its hydrophobicity and instability. This study aimed to enhance the therapeutic efficacy of resveratrol by encapsulating it in liposomes to effectively target the TLR4/NLRP3 inflammasome pathway in lung cancer. In this study, the efficacy of resveratrol liposome was tested in vitro through cell proliferation and migration assays and gene expression analysis. In vivo effects were evaluated in a lung cancer mouse model using histological and molecular techniques. Resveratrol liposome significantly inhibited lung cancer cell proliferation and migration, and induced apoptosis in orthotopic lung cancer models. Additionally, by suppressing TLR4/NLRP3 inflammasome-related genes, resveratrol liposomes diminished levels of IL-1β and IL-18 both locally at tumor sites and systemically, thus modulating the tumor immune microenvironment by decreasing MDSCs and increasing CD4+ and CD8+ T cells. In conclusion, resveratrol liposome alleviates lung cancer progression by targeting the TLR4/NLRP3 inflammasome pathway and enhancing anti-tumor immune responses, highlighting its potential as a promising therapeutic strategy for lung cancer treatment.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline and behavioral impairments, typically manifesting in the elderly and presenile population. With the rapid global aging trend, early diagnosis and treatment of AD have become increasingly urgent research priorities. The primary pathological features of AD include excessive accumulation of β-amyloid (Aβ) plaques, the formation of neurofibrillary tangles, and neuronal loss. Conventional diagnostic techniques, such as positron emission tomography-computed tomography (PET-CT) and cerebrospinal fluid (CSF) analysis, are limited by their high cost and invasiveness. As a result, there is growing interest in developing blood-based biomarker assays for AD detection. Electrochemical biosensors offer notable advantages in this context, including high sensitivity, low cost, and minimally invasive sampling. However, due to the extremely low concentrations of AD-related biomarkers in blood, signal amplification is necessary. The incorporation of nanomaterials significantly enhances the sensitivity and performance of the electrochemical biosensors. This Perspective highlights the application of various nanomaterial-enhanced electrochemical biosensors in the early diagnosis and disease monitoring of AD, underscoring their potential in advancing AD prevention, diagnosis, and therapeutic strategies.

Ischemic stroke is one of the leading causes of disability and mortality worldwide, posing a significant threat to human health. Neural stem cells possess the remarkable capabilities of self-renewal and differentiation into diverse neural cell types, endowing them with significant potential for the restoration of damaged neural tissues and functions. Exosomes, which carry a multitude of bioactive substances, serve as crucial tools for intercellular communication. Neural stem cell-derived exosomes are capable of engaging in the modulation of various physiological functions, presenting a highly promising novel approach for the treatment of ischemic stroke. This paper elaborates on the pathophysiological mechanisms of ischemic stroke, the engineering strategies for exosomes, and the prospects and limitations of neural stem cell transplantation therapies. It systematically reviews the potential roles of neural stem cell-derived exosomes in the treatment of ischemic stroke. Studies have shown that neural stem cell-derived exosomes can contribute to brain targeting, promote neural regeneration and angiogenesis, suppress neuroinflammation, and enhance the integrity of the blood-brain barrier in the treatment of ischemic stroke. However, their efficacy is constrained by insufficient targeting precision and limited cargo content. To improve the therapeutic efficacy of neural stem cell-derived exosomes, strategies such as surface modification and cargo loading can be employed. These include attaching targeting peptides, proteins, and antibodies to the exosome surface via chemical modification and genetic engineering, as well as loading small-molecule drugs and nanomaterials. Furthermore, accelerating the clinical translation of exosomes requires strict adherence to Good Manufacturing Practices. Neural stem cell-derived exosomes hold substantial potential in the treatment of ischemic stroke, which is expected to promote the development of the field of neural regeneration and bring new hope for more central nervous system diseases.

INTRODUCTION:Mendelian randomization (MR) is an innovative epidemiological research method. In order to summarize and clarify the research status of MR related to cardiovascular disease (CVD) and point out the possible future development direction, we conducted a comprehensive and multidimensional bibliometric analysis of the literature published in this field from 2003 to 2024. METHODS:We analyzed 1,870 articles published between 2003 and 2024 from the Web of Science Core Collection (WoSCC) using VOSviewer, R software, bibliometric online analysis tool, and CiteSpace software. RESULTS:CVD-related MR research demonstrated an overall upward trend, with the USA leading in terms of publication output, followed by the UK and China. The most prolific institution in this field was the University of Bristol, and Smith GD, who had the highest number of publications (n = 103), was also affiliated with this institution. The European Heart Journal (36 publications, 5,023 citations) was the most cited journal. Related topics of frontiers will still focus on MR, coronary heart disease, heart failure, C-reactive protein, cholesterol, and body mass index. CONCLUSIONS:As the scope of MR studies continues to expand, especially the number of measurable features continues to increase, the need for rigorous methods and critical interpretation of MR findings becomes increasingly apparent. However, this ease of use can compromise the reliability of study results due to methodological flaws and publication bias, thereby affecting the perceived significance of the results. Nonetheless, with the emergence of large genetic datasets supporting two-sample MR, resources such as MR-Base and PhenoScanner, MR remains a powerful method for identifying potential pathogenic features in cardiometabolic and other diseases. In addition, it plays a crucial role in prioritizing drug targets for entry into clinical trials.

Ischemic stroke, often modeled by middle cerebral artery occlusion and reperfusion (MCAO/R), involves severe neuroinflammation and lipid metabolic dysregulation that exacerbate neuronal damage. To address these dual pathological processes, we engineered a hybrid nanoplatform (Exo-Lip) by fusing neural stem cell-derived exosomes (Exo) with liposomes loaded with Yulangsan polysaccharide (Lip). Exosomes provide blood-brain barrier (BBB) permeability and intrinsic anti-inflammatory activity, while liposomes confer antioxidant and immunoregulatory effects. The resulting Exo-Lip exhibited improved colloidal stability and synergistic therapeutic potential. In MCAO/R mice, Exo-Lip markedly attenuated neuroinflammation by decreasing TNF-α and IL-6 while upregulating IL-10 and TGF-β. It restored lipid metabolism, alleviated oxidative stress, and preserved membrane integrity. TTC staining revealed a reduced infarct volume, and behavioral testing confirmed the recovery of motor and cognitive functions. Histological analyses further demonstrated neuronal survival and structural preservation. Transcriptomic profiling revealed that Exo-Lip modulated gene networks associated with inflammation and lipid regulation, including activation of the AKT/Nrf2/HO-1 signaling pathway. Collectively, these findings suggest that Exo-Lip represents a multifunctional, biomimetic nanotherapeutic capable of targeting both inflammatory and metabolic pathways in ischemic stroke. This work highlights a precision nanomedicine strategy with translational potential for central nervous system disorders.

OBJECTIVE:The role of gamma-aminobutyric acid-ergic (GABAergic) neuron impairment in Alzheimer's disease (AD), and if and how transplantation of healthy GABAergic neurons can improve AD, remain unknown. METHODS:Human-derived medial ganglionic eminence progenitors (hiMGEs) differentiated from programmed induced neural precursor cells (hiNPCs) were injected into the dentate gyrus region of the hippocampus (HIP). RESULTS:We showed that grafts migrate to the whole brain and form functional synaptic connections in amyloid precursor protein gene/ presenilin-1 (APP/PS1) chimeric mice. Following transplantation of hiMGEs, behavioral deficits and AD-related pathology were alleviated and defective neurons were repaired. Notably, exosomes secreted from hiMGEs, which are rich in anti-inflammatory miRNA, inhibited astrocyte activation invitro and in vivo, and the mechanism was related to regulation of CD4+ Th1 cells mediated tumor necrosis factor (TNF) pathway. INTERPRETATION:Taken together, these findings support the hypothesis that hiMGEs transplantation is an alternative treatment for neuronal loss in AD and demonstrate that exosomes with anti-inflammatory activity derived from hiMGEs are important factors for graft survival. ANN NEUROL 2024;96:488-507.

INTRODUCTION:Distinguishing between malignant pleural effusion (MPE) and benign pleural effusion (BPE) poses a challenge in clinical practice. We aimed to construct and validate a combined model integrating radiomic features and clinical factors using computerized tomography (CT) images to differentiate between MPE and BPE. METHODS:A retrospective inclusion of 315 patients with pleural effusion (PE) was conducted in this study (training cohort: n = 220; test cohort: n = 95). Radiomic features were extracted from CT images, and the dimensionality reduction and selection processes were carried out to obtain the optimal radiomic features. Logistic regression (LR), support vector machine (SVM), and random forest were employed to construct radiomic models. LR analyses were utilized to identify independent clinical risk factors to develop a clinical model. The combined model was created by integrating the optimal radiomic features with the independent clinical predictive factors. The discriminative ability of each model was assessed by receiver operating characteristic curves, calibration curves, and decision curve analysis (DCA). RESULTS:Out of the total 1,834 radiomic features extracted, 15 optimal radiomic features explicitly related to MPE were picked to develop the radiomic model. Among the radiomic models, the SVM model demonstrated the highest predictive performance [area under the curve (AUC), training cohort: 0.876, test cohort: 0.774]. Six clinically independent predictive factors, including age, effusion laterality, procalcitonin, carcinoembryonic antigen, carbohydrate antigen 125 (CA125), and neuron-specific enolase (NSE), were selected for constructing the clinical model. The combined model (AUC: 0.932, 0.870) exhibited superior discriminative performance in the training and test cohorts compared to the clinical model (AUC: 0.850, 0.820) and the radiomic model (AUC: 0.876, 0.774). The calibration curves and DCA further confirmed the practicality of the combined model. CONCLUSION:This study presented the development and validation of a combined model for distinguishing MPE and BPE. The combined model was a powerful tool for assisting in the clinical diagnosis of PE patients.

Abstract Background Alzheimer’s disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms. Main content Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron–glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics. Conclusion Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.

An electrochemical biosensor based on dual-amplified nucleic acid mode and biocatalytic silver deposition was constructed using catalytic hairpin assembly-hybrid chain reaction (CHA-HCR). The electrochemical detection of silver on the electrode by linear sweep voltammetry (LSV) can be utilized to quantitatively measure miR-205-5p since the amount of silver deposited on the electrode is proportional to the target nucleic acid. The current response values exhibit strong linearity with the logarithm of miR-205-5p concentrations ranging from 0.1 pM to 10 μM, and the detection limit is 28 fM. A consistent trend was found in the results of the qRT-PCR and electrochemical biosensor techniques, which were employed to determine the total RNA recovered from cells, respectively. Moreover, the constructed sensor was used to assess miR-205-5p on various cell counts, and the outcomes demonstrated the excellent analytical efficiency of the proposed strategy. The recoveries ranged from 97.85

BACKGROUND:Our previous study found that hyperbaric oxygen (HBO) attenuated cognitive impairment in mice induced by cerebral ischemia-reperfusion injury (CIRI). However, its mechanism of action is not fully understood. In this study, we aimed to establish a rat model of cerebral ischemia-reperfusion, explore the possible role of ferroptosis in the pathogenesis of CIRI, and observe the effect of HBO on ferroptosis-mediated CIRI.METHODS:Sprague Dawley (SD) rats were randomly divided into control, model, Ferrostatin-1 (Fer-1), HBO and Fer-1+ HBO groups. Morris water maze, myelin basic protein (MBP) and β-tubulin immunoreactivity were assessed to evaluate the neuroprotective effects of HBO on cerebral ischemia reperfusion injury. Ferroptosis were examined to investigate the mechanism underlying the effects of HBO.RESULTS:Our result showed that Fer-1 and HBO improved learning and memory ability in the navigation trail and probe trail of the Morris water maze and increased MBP and β-tubulin immunoreactivity of the cortex in the model rats. The levels of ferritin, malondialdehyde (MDA) and glutathione (GSH) in the serum were also reversed by Fer-1 and HBO treatment. Mitochondrial cristae dissolution and vacuolization were observed in the model group by transmission electron microscopy and these conditions were improved in the Fer-1 and HBO groups. Furthermore, Fer-1 and HBO treatment reversed Prostaglandin-Endoperoxide Synthase 2 (PTGS2), Iron Responsive Element Binding Protein 2 (IREB2), acyl-CoA synthetase long chain family member 4 (ACSL4) and Solute Carrier Family 7 Member 11 (SLC7A11) mRNA levels and Transferrin Receptor 1 (TFR1), ferritin light chain (FTL), ferritin heavy chain 1 (FTH1), glutathione peroxidase 4 (GPX4), Nuclear factor E2-related factor 2 (Nrf2), lysophosphatidylcholine acyltransferase 3 (LPCAT3), c-Jun N-terminal kinase (JNK), phosphorylated c-Jun N-terminal kinase (P-JNK) phosphorylated Extracellular signal-regulated protein kinase (P-ERK) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) protein levels. The above changes were more pronounced in Fer-1+ HBOGroup.DISCUSSION:The results of the present study indicated that HBO improves cerebral ischemia-reperfusion injury in rats, which may be related to inhibition of ferroptosis. This also means that ferroptosis may become a new target of HBO against CIRI.

BACKGROUND:Environmental exposure to dicofol (DCF), one of common organochlorine pesticides (OCPs) widely used for controlling agricultural pests, elicits a potential risk for human health due to its toxicity. However, potential physiological hazards of oral DCF exposure remain largely unknown.METHODS:Mice were exposed to relatively chronic and subacute DCF at different doses (5, 20 and 100 mg/kg) by gavage for 2 weeks. 1H NMR-based metabolomics was used to explore alterations of metabolic profiling induced by DCF exposure. Targeted metabolomics was subsequently employed to investigate the dose-dependent effects of oral DCF exposure on lipid metabolism and the gut microbiota-derived metabolites of mice. 16S rRNA gene sequencing was further employed to evaluate the changes of gut community of mice exposed to DCF.RESULTS:Oral exposure to DCF dose-dependently induced liver injury, manifested by hepatic lipogenesis, inflammation and liver dysfunction of mice. Typically, DCF exposure disrupted host fatty acids metabolism that were confirmed by marked alteration in the levels of related genes. DCF exposure also dose-dependently caused dysbiosis of the gut bacteria and its metabolites including altered microbial composition accompanied by inhibition of bacterial fermentation.CONCLUSION:These results provide metabolic evidence that DCF exposure dose-dependently induces liver lipidosis and disruption of the gut microbiota in mice, which enrich our views of molecular mechanism of DCF hepatoxicity.

Objective:The incidence of cardiogenic shock cases treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support has been on the rise. Acute kidney injury (AKI) is a significant complication of cardiogenic shock and a frequent serious complication in patients requiring ECMO-supported therapy. AKI is strongly associated with unfavorable patient prognosis. However, there is a paucity of data on the influence of AKI on the prognosis of patients with acute myocardial infarction complicated by cardiogenic shock (AMI-CS) who are receiving ECMO support, particularly with regard to long-term outcomes.Methods:This retrospective observational study included 103 patients in the People's Hospital of Guangxi Zhuang Autonomous Region from January 2017 and June 2022. AKI was defined according to Kidney Disease Improving Global Outcome (KDIGO) criteria. Cox regression and logistic regression were used to identify risk factors.Results:In this study, the incidence of AKI was 63.11%, with AKI stage 1, 2, and 3 accounting for 21.36%, 12.62%, and 29.13%, respectively. Patients with severe AKI had significantly higher in-hospital mortality (43.33% vs 27.40%, P < 0.001), 30-day mortality (60.00% vs 31.51%, P = 0.001), and 1-year mortality (63.67% vs 34.25%, P<0.001) than those without severe AKI. Furthermore, severe AKI significantly increased the risk of one-year mortality (HR 10.816, CI 3.118-37.512, P<0.001). Baseline serum creatinine, baseline platelet, and active cardiopulmonary resuscitation were independent predictors of one-year mortality. In addition, baseline white blood cell count, baseline aspartate aminotransferase, baseline alanine aminotransferase (ALT), baseline serum creatinine, preoperative lactate, and postoperative mean arterial pressure were independent risk factors of severe AKI during hospitalization.Conclusion:In patients with AMI-CS receiving ECMO support, AKI is highly prevalent. Development of severe AKI significantly increased the risk of one-year mortality.

The CLU rs11136000C mutation (CLUC) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLUC leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLUC AD. Examination of grafted CLUC medial ganglionic eminence progenitors (CLUC hiMGEs) revealed increased GAD65/67 and a high frequency of spontaneous releasing events. CLUC hiMGEs also impaired cognition in chimeric mice and caused AD-related pathologies. The expression of GABA A receptor, subunit alpha 2 (Gabrα2) was higher in chimeric mice. Interestingly, cognitive impairment in chimeric mice was reversed by treatment with pentylenetetrazole, which is a GABA A receptor inhibitor. Taken together, these findings shed light on the pathogenesis of CLUC AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder.