Antibody-drug conjugates treatment of small cell lung cancer: advances in clinical research.

Small cell lung cancer (SCLC) is an extremely aggressive cancer with a relatively low median survival rate after diagnosis. Treatment options such as chemotherapy or combination immunotherapy have shown clinical benefits, but resistance and relapse can occur. Antibody-drug conjugates (ADCs), as a novel class of biopharmaceutical compounds, have broad application prospects in the treatment of SCLC. ADCs consist of monoclonal antibodies that specifically target cancer cells and are attached to cytotoxic drugs, allowing for targeted killing of cancer cells while sparing healthy tissues. Current clinical studies focus on Delta-like protein 3 (DLL3), CD56, Trophoblast cell surface antigen 2 (Trop-2), B7-H3, and SEZ6. Although toxicities exceeding expectations have been observed with Rova-T, drugs targeting TROP-2 (Sacituzumab Govitecan), B7-H3 (DS-7300), and SEZ6 (ABBV-011) have shown exciting clinical benefits. In this review, we collect the latest clinical evidence to describe the therapeutic efficacy and safety of ADCs in SCLC and discuss prospects and challenges.

Designing Mesoporous Prussian Blue@zinc Phosphate Nanoparticles with Hierarchical Pores for Varisized Guest Delivery and Photothermally-Augmented Chemo-Starvation Therapy.

Background: With the rapid development of nanotechnology, constructing a multifunctional nanoplatform that can deliver various therapeutic agents in different departments and respond to endogenous/exogenous stimuli for multimodal synergistic cancer therapy remains a major challenge to address the inherent limitations of chemotherapy. Methods: Herein, we synthesized hollow mesoporous Prussian Blue@zinc phosphate nanoparticles to load glucose oxidase (GOx) and DOX (designed as HMPB-GOx@ZnP-DOX NPs) in the non-identical pore structures of their HMPB core and ZnP shell, respectively, for photothermally augmented chemo-starvation therapy. Results: The ZnP shell coated on the HMPB core, in addition to providing space to load DOX for chemotherapy, could also serve as a gatekeeper to protect GOx from premature leakage and inactivation before reaching the tumor site because of its degradation characteristics under mild acidic conditions. Moreover, the loaded GOx can initiate starvation therapy by catalyzing glucose oxidation while causing an upgradation of acidity and H2O2 levels, which can also be used as forceful endogenous stimuli to trigger smart delivery systems for therapeutic applications. The decrease in pH can improve the pH-sensitivity of drug release, and O2 can be supplied by decomposing H2O2 through the catalase-like activity of HMPBs, which is beneficial for relieving the adverse conditions of anti-tumor activity. In addition, the inner HMPB also acts as a photothermal agent for photothermal therapy and the generated hyperthermia upon laser irradiation can serve as an external stimulus to further promote drug release and enzymatic activities of GOx, thereby enabling a synergetic photothermally enhanced chemo-starvation therapy effect. Importantly, these results indicate that HMPB-GOx@ZnP-DOX NPs can effectively inhibit tumor growth by 80.31% and exhibit no obvious systemic toxicity in mice. Conclusion: HMPB-GOx@ZnP-DOX NPs can be employed as potential theranostic agents that incorporate multiple therapeutic modes to efficiently inhibit tumors.

HER3 receptor and its role in the therapeutic management of metastatic breast cancer.

Metastatic breast cancer (mBC) poses a significant threat to women's health and is a major cause of malignant neoplasms in women. Human epidermal growth factor receptor (HER)3, an integral member of the ErbB/HER receptor tyrosine kinase family, is a crucial activator of the phosphoinositide-3 kinase/protein kinase B signaling pathway. HER3 overexpression significantly contributes to the development of resistance to drugs targeting other HER receptors, such as HER2 and epidermal growth factor receptors, and plays a crucial role in the onset and progression of mBC. Recently, numerous HER3-targeted therapeutic agents, such as monoclonal antibodies (mAbs), bispecific antibodies (bAbs), and antibody-drug conjugates (ADCs), have emerged. However, the efficacy of HER3-targeted mAbs and bAbs is limited when used individually, and their combination may result in toxic adverse effects. On the other hand, ADCs are cytotoxic to cancer cells and can bind to target cells through antibodies, which highlights their use in targeted HER3 therapy for mBC. This review provides an overview of recent advancements in HER3 research, historical initiatives, and innovative approaches in targeted HER3 therapy for metastatic breast cancer. Evaluating the advantages and disadvantages of current methods may yield valuable insights and lessons.

Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell.

Endothelial and skeletal muscle lineages arise from common embryonic progenitors. Despite their shared developmental origin, adult endothelial cells (ECs) and muscle stem cells (MuSCs; satellite cells) have been thought to possess distinct gene signatures and signaling pathways. Here, we shift this paradigm by uncovering how adult MuSC behavior is affected by the expression of a subset of EC transcripts. We used several computational analyses including single-cell RNA-seq (scRNA-seq) to show that MuSCs express low levels of canonical EC markers in mice. We demonstrate that MuSC survival is regulated by one such prototypic endothelial signaling pathway (VEGFA-FLT1). Using pharmacological and genetic gain- and loss-of-function studies, we identify the FLT1-AKT1 axis as the key effector underlying VEGFA-mediated regulation of MuSC survival. All together, our data support that the VEGFA-FLT1-AKT1 pathway promotes MuSC survival during muscle regeneration, and highlights how the minor expression of select transcripts is sufficient for affecting cell behavior.

Evaluation of the tumor-targeting specific imaging and killing effect of a CEA-targeting nanoparticle in colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is a prevalent digestive malignancy with significant global mortality and morbidity rates. Improving diagnostic capabilities for CRC and investigating novel therapeutic approaches are pressing clinical imperatives. Additionally, carcinoembryonic antigen (CEA) has emerged as a highly promising candidate for both colorectal tumor imaging and treatment. METHODS: A novel active CEA-targeting nanoparticle, CEA(Ab)-MSNs-ICG-Pt, was designed and synthesized, which served as a tumor-specific fluorescence agent to help in CRC near-infrared (NIR) fluorescence imaging. In cell studies, CEA(Ab)-MSNs-ICG-Pt exhibited specific targeting to RKO cells through specific antibody-antigen binding of CEA, resulting in distribution both within and around these cells. The tumor-targeting-specific imaging capabilities of the nanoparticle were determined through in vivo fluorescence imaging experiments. Furthermore, the efficacy of the nanoparticle in delivering chemotherapeutics and its killing effect were evaluated both in vitro and in vivo. RESULTS: The CEA(Ab)-MSNs-ICG-Pt nanoparticle, designed as a novel targeting agent for carcinoembryonic antigen (CEA), exhibited dual functionality as a targeting fluorescent agent. This CEA-targeting nanoparticle showed exceptional efficacy in eradicating CRC cells in comparison to individual treatment modalities. Furthermore, it exhibits exceptional biosafety and biocompatibility properties. CEA(Ab)-MSNs-ICG-Pt exhibits significant promise due to its ability to selectively target tumors through NIR fluorescence imaging and effectively eradicate CRC cells with minimal adverse effects in both laboratory and in vivo environments. CONCLUSION: The favorable characteristics of CEA(Ab)-MSNs-ICG-Pt offer opportunities for its application in chemotherapeutic interventions, tumor-specific NIR fluorescence imaging, and fluorescence-guided surgical procedures.

Treatment Advances in Lung Cancer with Leptomeningeal Metastasis.

Leptomeningeal metastasis (LM) is a serious and often fatal complication in patients with advanced lung cancer, resulting in significant neurological deficits, decreased quality of life, and a poor prognosis. This article summarizes current research advances in treating lung cancer with meningeal metastases, discusses clinical challenges, and explores treatment strategies. Through an extensive review of relevant clinical trial reports and screening of recent conference abstracts, we collected clinical data on treating patients with lung cancer with meningeal metastases to provide an overview of the current research progress. Exciting progress has been made by focusing on specific mutations within lung cancer, including the use of EGFR tyrosine kinase inhibitors or inhibitors for anaplastic lymphoma kinase gene rearrangement, such as osimertinib, alectinib, and lorlatinib. These targeted therapies have shown impressive results in penetrating the central nervous system (CNS). Regarding whole-brain radiotherapy, there is currently some controversy among investigators regarding its effect on survival. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated reliable clinical benefits due to their ability to retain anticancer activity in CNS metastases. Moreover, combination therapy shows promise in providing further treatment possibilities. Considerable progress has been made in the clinical research of lung cancer with LM. However, the sample size of prospective clinical trials investigating LM for lung cancer is still limited, with most reports being retrospective. Developing more effective management protocols for metastatic LM in lung cancer remains an ongoing challenge for the future.

Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression.

Immune cell infiltration in response to myocyte death regulates extracellular matrix remodeling and scar formation after myocardial infarction (MI). Caspase-recruitment domain family member 9 (CARD9) acts as an adapter that mediates the transduction of pro-inflammatory signaling cascades in innate immunity; however, its role in cardiac injury and repair post-MI remains unclear. We found that Card9 was one of the most upregulated Card genes in the ischemic myocardium of mice. CARD9 expression increased considerably 1 day post-MI and declined by day 7 post-MI. Moreover, CARD9 was mainly expressed in F4/80-positive macrophages. Card9 knockout (KO) led to left ventricular function improvement and infarct scar size reduction in mice 28 days post-MI. Additionally, Card9 KO suppressed cardiomyocyte apoptosis in the border region and attenuated matrix metalloproteinase (MMP) expression. RNA sequencing revealed that Card9 KO significantly suppressed lipocalin 2 (Lcn2) expression post-MI. Both LCN2 and the receptor solute carrier family 22 member 17 (SL22A17) were detected in macrophages. Subsequently, we demonstrated that Card9 overexpression increased LCN2 expression, while Card9 KO inhibited necrotic cell-induced LCN2 upregulation in macrophages, likely through NF-κB. Lcn2 KO showed beneficial effects post-MI, and recombinant LCN2 diminished the protective effects of Card9 KO in vivo. Lcn2 KO reduced MMP9 post-MI, and Lcn2 overexpression increased Mmp9 expression in macrophages. Slc22a17 knockdown in macrophages reduced MMP9 release with recombinant LCN2 treatment. In conclusion, our results demonstrate that macrophage CARD9 mediates the deterioration of cardiac function and adverse remodeling post-MI via LCN2.

PEG-grafted arsenic trioxide-loaded mesoporous silica nanoparticles endowed with pH-triggered delivery for liver cancer therapy.

Liver cancer (LC), one of the most common malignant primary tumors, presents a poor prognosis, high morbidity rate, and poor clinical outcomes. Despite conventional treatments have been applied prior to the deterioration, their clinical benefits were still limited. Arsenic trioxide (ATO), a toxic Chinese medicine, has been proven to efficiently inhibit the growth of LC both in vitro and in vivo. However, its therapeutic effects are hindered by poor pharmacokinetics and dose-limited toxicity. In this study, we developed a pH-responsive nanoplatform (PEG-MSN@ATO) consisting of mesoporous silica nanoparticles (MSN) that were modified with amino groups, loaded with ATO, and grafted with PEG to achieve the pH-triggered release and regulate CD8+ T cells and Treg cells in the tumor microenvironment (TME). PEG-MSN@ATO were characterized by uniform size, good loading efficiency, pH-responsive release features, decreased macrophage uptake, and enhanced dendritic cell activation in vitro. Furthermore, in vivo studies demonstrated that PEG-MSN@ATO enhanced the antitumor efficacy by inducing apoptosis and ROS production, inhibiting tumor cell proliferation and metastasis, and activating antitumor immunity within the TME. PEG-MSN@ATO also reduced the system toxicity of ATO by controlling the pH-trigger release in the tumor site. These results indicate that the PEG-MSN@ATO represents a promising drug delivery platform for reducing toxicity and enhancing the therapeutic efficacy of ATO against LC.

Caffeic acid, but not ferulic acid, inhibits macrophage pyroptosis by directly blocking gasdermin D activation.

Regulated pyroptosis is critical for pathogen elimination by inducing infected cell rupture and pro-inflammatory cytokines secretion, while overwhelmed pyroptosis contributes to organ dysfunction and pathological inflammatory response. Caffeic acid (CA) and ferulic acid (FA) are both well-known antioxidant and anti-inflammatory phenolic acids, which resemble in chemical structure. Here we found that CA, but not FA, protects macrophages from both Nigericin-induced canonical and cytosolic lipopolysaccharide (LPS)-induced non-canonical pyroptosis and alleviates LPS-induced mice sepsis. It significantly improved the survival of pyroptotic cells and LPS-challenged mice and blocked proinflammatory cytokine secretion. The anti-pyroptotic effect of CA is independent of its regulations in cellular lipid peroxidation, mitochondrial function, or pyroptosis-associated gene transcription. Instead, CA arrests pyroptosis by directly associating with gasdermin D (GSDMD) and blocking its processing, resulting in reduced N-GSDMD pore construction and less cellular content release. In LPS-induced septic mice, CA inhibits GSDMD activation in peritoneal macrophages and reduces the serum levels of interleukin-1ß and tumor necrosis factor-α as the known pyroptosis inhibitors, disulfiram and dimethyl fumarate. Collectively, these findings suggest that CA inhibits pyroptosis by targeting GSDMD and is a potential candidate for curbing the pyroptosis-associated disease.

Emodin ameliorates renal injury and fibrosis via regulating the miR-490-3p/HMGA2 axis.

Renal fibrosis is a major pathological feature of chronic kidney disease (CKD). While emodin is reported to elicit anti-fibrotic effects on renal injury, little is known about its effects on microRNA (miRNA)-modulated mechanisms in renal fibrosis. In this study, we established a unilateral ureteral obstruction (UUO) model and a transforming growth factor (TGF)-ß1-induced normal rat renal tubular epithelial cell line (NRK-52E) model to investigate the protective effects of emodin on renal fibrosis and its miRNA/target gene mechanisms. Dual-luciferase assay was performed to confirm the direct binding of miRNA and target genes in HEK293 cells. Results showed that oral administration of emodin significantly ameliorated the loss of body weight and the increase in physicochemical parameters, including serum uric acid, creatinine, and urea nitrogen in UUO mice. Inflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin (IL)-1ß, but not IL-6, were down-regulated by emodin administration. Emodin decreased the expression levels of TGF-ß1 and fibrotic-related proteins, including alpha-smooth muscle actin, Collagen IV, and Fibronectin, and increased the expression of E-cadherin. Furthermore, miR-490-3p was decreased in UUO mice and negatively correlated with increased expression of high migration protein A2 (HMGA2). We further confirmed HMGA2 was the target of miR-490-3p. Transfection of miR-490-3p mimics decreased, while transfection of miR-490-3p inhibitors increased fibrotic-related proteins and HMGA2 expression levels in TGF-ß1-induced NRK-52E cells. Furthermore, transfection of miR-490-3p mimics enhanced the anti-fibrotic effects of emodin, while transfection of miR-490-3p inhibitors abolished the protective effects of emodin. Thus, as a novel target of emodin that prevents renal fibrosis in the HMGA2-dependent signaling pathway, miR-490-3p has potential implications in CKD pathology.

Comparative study of aluminum speciation on brain-type creatine kinase: Enzyme kinetic, molecular docking, cellular experiment, and mouse model study.

Brain-type Creatine kinase (CK-BB), which has a high affinity for Aluminum (Al), and its abnormality is closely related to neurodegenerative diseases. In this study, the comparative effect of Al speciation on the bioactivity of CK-BB has been studied by the inhibition kinetics method, molecular docking, cellular experiment, and mouse model study. Results showed that the half-inhibitory concentration of AlCl3 was 0.67 mM, while Al(mal)3 was 3.81 mM. Fluorescence spectra showed that Al(mal)3 had a more substantial effect on the endogenous fluorescence of CK-BB than AlCl3. Molecular docking showed that AlCl3 was closer to the active site of CK-BB. C6 cells were used to explore the enzyme activity and intracellular distribution of CK-BB by AlCl3 or Al(mal)3. AlCl3 treatment may directly affect CK-BB activity and cause insufficient local ATP supply in cells which affected the formation of F-actin and cell morphology. The change in the hydrophobicity of CK-BB induced by Al(mal)3 affected the movement of CK-BB, which subsequently activated thecytochrome C (Cyt C)/Caspase 9/Caspase 3 pathway. Similar results have been found in vivo experiments. This study demonstrated that interaction between Al and CK-BB might be related to the process of Al-induced energy metabolism disorders, in which the Al speciation revealed differentiated toxicity mechanisms.

The relationship between serum lipid levels and colorectal serrated lesions: A systematic review and meta-analysis.

Objective: To clarify the relationship between colorectal serrated lesions and serum lipid levels, and provide a scientific basis for the identification and early clinical prevention and treatment of populations that are at risk for colorectal serrated lesions. Methods: Studies comparing serum lipid levels in patients with colorectal serrated lesions and controls were searched in PubMed, Embase, Web of Science, the Cochrane Library, China Biomedical Literature Database, CNKI, Wanfang Database, and VIP Database. Relevant literature was screened according to the inclusion and exclusion criteria. The mean and standard deviation of the serum lipid levels in patients and controls were extracted from the included literature. The combined weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated using Review Manager 5.0 software to evaluate the relationship between serum lipid levels and colorectal serrated lesions. Publication bias of the included studies was evaluated by the Egger test. Results: Twenty-three studies were included, comprising 2,063 patients and 63,909 controls. The serum high-density lipoprotein cholesterol (HDL-C) levels in the case group was significantly lower than in the control group (WMD = -0.122 mmol/L, 95% CI: 0.170-0.073). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and serum triglyceride levels in the case group were significantly higher than in the control group, and the WMDs were 0.180 mmol/L (95% CI: 0.061-0.299), 0.155 mmol/L (95% CI: 0.038-0.273), and 0.241 mmol/L (95% CI: 0.181-0.302), respectively. Conclusion: Colorectal serrated lesions may be related to blood lipid levels. Hyperlipidemia might be a risk factor for colorectal serrated lesions.

Cangma Huadu granules attenuate H1N1 virus-induced severe lung injury correlated with repressed apoptosis and altered gut microbiome.

Severe influenza A virus infection leads to overwhelming inflammatory responses and cellular apoptosis, which causes lung injury and contributes to high mortality and morbidity. The gut microbiome altered in response to the infection might influence the disease progression and the treatment outcome. Cangma Huadu (CMHD) granules, an in-hospital preparation of traditional Chinese medicine, have been shown to be favorable in the clinical treatment of influenza. However, the effects and mechanisms of CMHD granules on severe influenza pneumonia and its mechanisms are not well-known. In this study, a lethal influenza A (H1N1) A/Puerto Rico/8/34 virus (PR8)-infected mice model was established, and the 16S ribosomal RNA (16S rRNA) V3-V4 region sequencing of the intestinal microbiome was conducted. We revealed that the oral administration of CMHD granules protects mice against higher mortality, enhanced weight loss, overwhelmed interferon-γ concentration, lung viral titers, and severe lung pathological injury in PR8-infected mice. CMHD granules' administration downregulated the levels of interleukin (IL)-1ß, tumor necrosis factor-α, and malondialdehyde, while it upregulated the levels of IL-10, superoxide dismutase, and glutathione peroxidase. Subsequently, it decreased the protein ratio of B-cell lymphoma-2/Bcl-2-associated X and the expression of cleaved caspase-3. The diversity and compositions of the gut microbes were altered profoundly after the administration of CMHD granules in PR8-infected mice. A higher abundance of Bifidobacterium, Parasutterella, Bacteroides, and Faecalibaculum was observed in the CMHD group, and a higher abundance of Lactobacillus and Turicibacter was observed in the positive drug Ribavirin group. The linear discriminant analysis effect size also revealed a higher proportion of Bacteroides and Bifidobacterium_pseudolongum characterized in the CMHD group. These results demonstrated that CMHD granules are a promising strategy for managing severe influenza and attenuating severe lung damage via reducing viral titer, inflammatory responses, and oxidative stress. The mechanisms are involved in repressed Bcl-2-regulated apoptosis and altered composition and diversity of the gut microbiome.

Moxibustion attenuates neurogenic detrusor overactivity in spinal cord injury rats by inhibiting M2/ATP/P2X3 pathway.

PURPOSE: Activation of muscarinic receptors located in bladder sensory pathways is generally considered to be the primary contributor for driving the pathogenesis of neurogenic detrusor overactivity following spinal cord injury. The present study is undertaken to examine whether moxibustion improves neurogenic detrusor overactivity via modulating the abnormal muscarinic receptor pathway. MATERIALS AND METHODS: Female Sprague-Dawley rats were subjected to spinal cord injury with T9-10 spinal cord transection. Fourteen days later, animals were received moxibustion treatment for one week. Urodynamic parameters and pelvic afferents discharge were measured. Adenosine triphosphate (ATP) content in the voided cystometry fluid was determined. Expressions of M2, M3, and P2X3 receptors in the bladder mucosa were evaluated. RESULTS: Moxibustion treatment prevented the development of detrusor overactivity in spinal cord injury rats, with an increase in the intercontraction interval and micturition pressure threshold and a decrease in afferent activity during filling. The expression of M2 was markedly suppressed by moxibustion, accompanied by a reduction in the levels of ATP and P2X3. M2 receptor antagonist methoctramine hemihydrate had similar effects to moxibustion on bladder function and afferent activity, while the M2-preferential agonist oxotremorine methiodide abolished the beneficial effects of moxibustion. CONCLUSION: Moxibustion is a potential candidate for treating neurogenic bladder overactivity in a rat model of spinal cord injury, possibly through inhibiting the M2/ATP/P2X3 pathway.

Recent Developments in Mesoporous Silica Nanoparticles for Tumor Theranostic Applications.

Due to the advantages of adjustable pore size, easy surface modification, high biocompatibility, and so on, mesoporous silica nanoparticles (MSNs) have attracted significant attention. Moreover, they are widely used in the fields of biology and medical research, mostly focusing on drug and gene delivery and bioimaging. This review introduces several commonly used synthetic methods of MSNs and the latest progress of MSNs in tumor therapy and diagnosis, mainly including the study about modified MSNs as drug carriers and the application of MSNs in bioimaging. The deficiencies of MSNs' application and prospects for its future clinical transformation are also discussed.

Apigenin protects mice against 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestasis.

Cholestasis can induce liver fibrosis and cirrhosis. Apigenin has anti-oxidant and anti-inflammatory effects. Herein, we determined whether apigenin can protect mice against cholestasis. In vitro, apigenin protected TFK-1 cells (a human bile duct cancer cell line) against H2O2-induced ROS generation and inhibited transforming growth factor-ß-activated collagen type 1 alpha 1 and α-smooth muscle actin in LX2 cells (a human hepatic stellate cell line). In vivo, cholestatic mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) were treated with apigenin. Apigenin potently blocked DDC-induced gallbladder atrophy and associated liver injury, fibrosis and collagen accumulation. Moreover, apigenin relieved the DDC-caused abnormality of bile acid metabolism and restored the balance between bile secretion and excretion by regulating the farnesoid X receptor signaling pathway. Furthermore, apigenin reduced inflammation or oxidative stress in the liver by blocking the DDC-activated Toll-like receptor 4, nuclear factor κB and tumor necrosis factor α, or DDC-suppressed superoxidase dismutase 1/2, catalase and glutathione peroxidase. Taken together, apigenin improves DDC-induced cholestasis by reducing inflammation and oxidative damage and improving bile acid metabolism, indicating its potential application for cholestasis treatment.

NaoXinTong Capsule ameliorates memory deficit in APP/PS1 mice by regulating inflammatory cytokines.

Alzheimer's disease (AD) is the most common neurodegenerative disease in aging population. Neuroinflammation, hyperphosphorylated Tau (p-Tau) and the imbalance between production and clearance of ß-amyloid peptide (Aß) are the major causes for AD development. NaoXinTong Capsule (NXT), a traditional Chinese medicine, is wildly used for treatment of cardiovascular and cerebrovascular diseases. Hence, we used the double transgenic mice expressing chimeric human amyloid precursor protein and mutant human presenilin 1 (APP/PS1) and HT-22 cells to determine the neuroprotective effects of NXT in AD development and the involved mechanisms. The 3-month-old APP/PS1 mice were randomly divided into 3 groups and received following treatment: Control group, mice were fed normal chow; NXT groups, mice were fed normal chow containing NXT at a normal and a high dose, respectively. While the age-matched C57BL/6J mice fed normal chow were used as the normal control. The NXT treatment was lasted for 5 months. We found that NXT treatment improved spatial memory impairment and cognitive decline in APP/PS1 mice by decreasing p-Tau levels and Aß accumulation in the brain. Mechanistically, we observed that NXT inhibited neuron atrophy and apoptosis by downregulating inflammatory cytokines, interleukin 1ß (IL-1ß), IL-6 and tumor necrosis factor α (TNF-α), and inflammation mediators, nuclear factor κB (NF-κB) and toll-like receptor 4 (TLR4) in the brain. Consistently, NXT blocked l-glutamic acid-induced reactive oxygen species production, inflammation and apoptosis in HT-22 cells partially by inhibiting TLR4/NF-κB/IL-1ß signaling pathway. Our study demonstrates that NXT ameliorates AD by reducing p-Tau, Aß accumulation, inflammation and neuron apoptosis via regulation of TLR4-mediated inflammatory system. It also suggests the potential application of NXT for AD treatment.

LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-ß precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aß plaque accumulation by inhibiting ß-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aß accumulation by inhibiting ß-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

Erythrocyte Membrane-Coated Arsenic Trioxide-Loaded Sodium Alginate Nanoparticles for Tumor Therapy.

Arsenic trioxide (ATO) has a significant effect on the treatment of acute promyelocytic leukemia (APL) and advanced primary liver cancer, but it still faces severe side effects. Considering these problems, red blood cell membrane-camouflaged ATO-loaded sodium alginate nanoparticles (RBCM-SA-ATO-NPs, RSANs) were developed to relieve the toxicity of ATO while maintaining its efficacy. ATO-loaded sodium alginate nanoparticles (SA-ATO-NPs, SANs) were prepared by the ion crosslinking method, and then RBCM was extruded onto the surface to obtain RSANs. The average particle size of RSANs was found to be 163.2 nm with a complete shell-core bilayer structure, and the average encapsulation efficiency was 14.31%. Compared with SANs, RAW 264.7 macrophages reduced the phagocytosis of RSANs by 51%, and the in vitro cumulative release rate of RSANs was 95% at 84 h, which revealed a prominent sustained release. Furthermore, it demonstrated that RSANs had lower cytotoxicity as compared to normal 293 cells and exhibited anti-tumor effects on both NB4 cells and 7721 cells. In vivo studies further showed that ATO could cause mild lesions of main organs while RSANs could reduce the toxicity and improve the anti-tumor effects. In brief, the developed RSANs system provides a promising alternative for ATO treatment safely and effectively.

Inhibition of PTP1B Promotes M2 Polarization via MicroRNA-26a/MKP1 Signaling Pathway in Murine Macrophages.

Sepsis is a life-threatening condition that often occurs in the intensive care unit. The excessive activation of the host's immune system at early stages contributes to multiple organ damage. Mitogen-activated protein kinase phosphatase-1 (MKP1) exerts an important effect on the inflammatory process. In our recent bioinformatic analysis, we confirmed that the inhibition of protein tyrosine phosphatase-1B (PTP1B) significantly promoted the expression of MKP1 in murine macrophages. However, the underlying mechanism and its effect on macrophage polarization remain unclear. In this study, we show that the suppression of PTP1B induced upregulation of MKP1 in M1 macrophages. A RayBiotech mouse inflammation antibody assay further revealed that MKP1-knockdown promoted pro-inflammatory cytokine (IL-1ß, IL12p70, IL-17, IL-21, IL-23, and TNF-α) secretion but suppressed anti-proinflammatory cytokine (IL-10) production in M2 macrophages. Phospho-proteomics analysis further identified ERK1/2 and p38 as downstream molecules of MKP1. Moreover, we found that the inhibition of PTP1B lowered the expression of miR-26a, showing a negative correlation with MKP1 protein expression. Thus, we concluded that the inhibition of PTP1B contributes to M2 macrophage polarization via reducing mir-26a and afterwards enhancing MKP1 expression in murine macrophages.