SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia.

BACKGROUND: Astrogliosis and white matter lesions (WML) are key characteristics of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular mechanisms underlying VCID remain poorly understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its upstream kinases WNK (with no lysine) and SPAK (the STE20/SPS1-related proline/alanine-rich kinase) play a role in astrocytic intracellular Na+ overload, hypertrophy, and swelling. Therefore, in this study, we assessed the effect of SPAK inhibitor ZT-1a on pathogenesis and cognitive function in a mouse model of VCID induced by bilateral carotid artery stenosis (BCAS). METHODS: Following sham or BCAS surgery, mice were randomly assigned to receive either vehicle (DMSO) or SPAK inhibitor ZT-1a treatment regimen (days 14-35 post-surgery). Mice were then evaluated for cognitive functions by Morris water maze, WML by ex vivo MRI-DTI analysis, and astrogliosis/demyelination by immunofluorescence and immunoblotting. RESULTS: Compared to sham control mice, BCAS-Veh mice exhibited chronic cerebral hypoperfusion and memory impairments, accompanied by significant MRI DTI-detected WML and oligodendrocyte (OL) death. Increased activation of WNK-SPAK-NKCC1-signaling proteins was detected in white matter tissues and in C3d+ GFAP+ cytotoxic astrocytes but not in S100A10+ GFAP+ homeostatic astrocytes in BCAS-Veh mice. In contrast, ZT-1a-treated BCAS mice displayed reduced expression and phosphorylation of NKCC1, decreased astrogliosis, OL death, and WML, along with improved memory functions. CONCLUSION: BCAS-induced upregulation of WNK-SPAK-NKCC1 signaling contributes to white matter-reactive astrogliosis, OL death, and memory impairment. Pharmacological inhibition of the SPAK activity has therapeutic potential for alleviating pathogenesis and memory impairment in VCID.

Fragmentation Pattern-Based Screening Strategy Combining Diagnostic Ion and Neutral Loss Uncovered Novel para-Phenylenediamine Quinone Contaminants in the Environment.

Identifying transformed emerging contaminants in complex environmental compartments is a challenging but meaningful task. Substituted para-phenylenediamine quinones (PPD-quinones) are emerging contaminants originating from rubber antioxidants and have been proven to be toxic to the aquatic species, especially salmonids. The emergence of multiple PPD-quinones in various environmental matrices and evidence of their specific hazards underscore the need to understand their environmental occurrences. Here, we introduce a fragmentation pattern-based nontargeted screening strategy combining full MS/All ion fragmentation/neutral loss-ddMS2 scans to identify potential unknown PPD-quinones in different environmental matrices. Using diagnostic fragments of m/z 170.0600, 139.0502, and characteristic neutral losses of 199.0633, 138.0429 Da, six known and three novel PPD-quinones were recognized in air particulates, surface soil, and tire tissue. Their specific structures were confirmed, and their environmental concentration and composition profiles were clarified with self-synthesized standards. N-(1-methylheptyl)-N'-phenyl-1,4-benzenediamine quinone (8PPD-Q) and N,N'-di(1,3-dimethylbutyl)-p-phenylenediamine quinone (66PD-Q) were identified and quantified for the first time, with their median concentrations found to be 0.02-0.21 µg·g-1 in tire tissue, 0.40-2.76 pg·m-3 in air particles, and 0.23-1.02 ng·g-1 in surface soil. This work provides new evidence for the presence of unknown PPD-quinones in the environment, showcasing a potential strategy for screening emerging transformed contaminants in the environment.

Andrographolide attenuates sepsis-induced acute kidney injury by inhibiting ferroptosis through the Nrf2/FSP1 pathway.

Sepsis is a systemic inflammatory response syndrome caused by infection, which causes renal dysfunction known as sepsis-associated acute kidney injury (S-AKI). Ferroptosis is a form of lipid peroxidation dependent on iron and reactive oxygen species that differs from other forms of programmed cell death at the morphological and biochemical levels. Andrographolide (AG), a natural diterpenoid lactone compound extracted from Andrographis paniculata, has been shown to have therapeutic effects in kidney disease. In this study, we investigated the novel mechanism by which AG attenuates septic acute kidney injury by inhibiting ferroptosis in renal tubular epithelial cells (HK-2) through the Nrf2/FSP1 pathway. Cecum ligation and puncture (CLP)-induced septic rats and lipopolysaccharide (LPS)-induced HK-2 cells were used for in vivo and in vitro experiments. Firstly, in septic rats and HK-2 cells, AG effectively decreased the levels of kidney injury indicators, including blood creatinine, urea nitrogen, and markers of kidney injury such as neutrophil gelatinase-associated lipid transport protein and kidney injury molecule-1 (KIM-1). In addition, AG prevented ferroptotosis, by avoiding the accumulation of iron and lipid peroxidation, and an increase in SLC7A11 and GPX4 in AG-treated HK-2 cells. Furthermore, AG attenuated mitochondrial damage, including mitochondrial swelling, outer membrane rupture, and a reduction in mitochondrial cristae in LPS-treated HK-2 cells. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, significantly inhibited LPS-induced ferroptosis in HK-2 cells. Importantly, our results confirm that Nrf2/FSP1 is an important pathway for ferroptosis resistance. Nrf2 siRNA hindered the effect of AG in attenuating acute kidney injury and inhibiting ferroptosis. These findings demonstrate that Nrf2/FSP1-mediated HK-2 ferroptosis is associated with AG, alleviates septic acute kidney injury, and indicates a novel avenue for therapeutic interventions in the treatment of acute kidney injury in sepsis.

Numerical Study on Effect of Aggregate Moisture on Mixing Process.

During the concrete mixing process, the transition of aggregates from a dry to a moist state introduces a crucial dynamic that significantly influences particle interaction, consequently impacting mixing homogeneity. In this paper, based on the discrete element method, the effect of aggregate moisture on the mixing process of sand and stone was investigated. The interaction between dry particles was described by the Hertz-Mindlin model, while the interaction between wet particles was calculated by the linear cohesion model considering the liquid bridge force. Additionally, a functional relationship between the moisture content and the parameters of the linear cohesive contact model was established. The results show that the numerical method can be employed to simulate the mixing process. Notably, when the moisture content of pebbles ranges from 0% to 0.75% and that of sand ranges from 0% to 10.9%, the linear cohesion model is deemed suitable. The standard deviation of the mixing homogeneity of wet particles is lower than that of dry particles for short mixing time, indicating that a small amount of liquid enhances mixing homogeneity. However, moisture has no obvious effect on mixing homogeneity for a long mixing time. This nuanced understanding of the interplay between moisture, particle interactions, and mixing duration contributes valuable insights to optimize concrete mixing processes.

Microbiome and its relevance to indigenous inflammatory bowel diseases in China.

BACKGROUND: Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with an unknown etiology. Although dysbiosis is implicated in its pathogenesis, deep sequencing and oral microbiota study in Chinese IBD patients is absent. AIM: To explore the role of oral / intestinal microbiota in patients with IBD and the potential associations therein. METHODS: Clinical data, fecal and saliva samples were harvested from 80 patients with IBD (Crohn's disease, CD, n = 69; Ulcerative colitis, UC, n = 11) and 24 normal controls. Microbiomics (16S rRNA sequencing and 16S rRNA full-length sequencing) were used to detect and analyze the difference between IBD patients and normal control. RESULTS: Compared with normal controls, a higher abundance of the intestinal Shigella spp. (Shigella flexneri and Shigella sonnei, which were positively relate to the severity of IBD), lower abundance of intestinal probiotics (Prevotella, Faecalibacterium and Roseburia), and higher abundance of oral Neisseria were present in IBD patients with microbiome. The higher inflammation-related markers, impaired hepatic and renal function, and dyslipidaemia were present in patients with IBD. A higher intake of red meat and increased abundance of Clostridium in the gut were found in CD patients, while the elevated abundance of Ruminococcus in the gut was showed in UC ones. The bacterial composition of saliva and fecal samples was completely different, yet there was some correlation in the distribution of dominant probiotics. CONCLUSION: Enteric dysbacteriosis and the infections of pathogenic bacteria (Shigella) may associate with the occurrence or development of IBD.

UV-induced photodegradation of emerging para-phenylenediamine quinones in aqueous environment: Kinetics, products identification and toxicity assessments.

Substituted para-phenylenediamine quinones (PPD-quinones) are a class of emerging contaminants frequently detected in the aqueous environment. One of them, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q), was found to cause acute toxicities to aquatic species at extremely low environmental levels. The ubiquitousness and ecotoxicity of such pollutants underscore the importance of their transformation and elimination. In this work, we demonstrated effective removals of five PPD-quinones in aqueous environments under UV irradiation, with up to 94% of 6PPD-Q eliminated after a 40-min treatment. By applying high-resolution mass spectrometry (HRMS) non-targeted screening in combination with isotope labeling strategies, a total of 22 transformation products (TPs) were identified. Coupling with the time-based dynamic patterns, potential transformation mechanisms were identified as an •OH-induced photocatalysis reaction involving bond cleavage, hydroxylation, and oxidation. Computational toxicity assessment predicted lower aquatic toxicity of the TPs than their parent PPD-quinones. Our results in parallel evidenced an obvious reduction of PPD-quinones accompanied by the presence of their TPs in the effluent after UV disinfection in real municipal wastewater. This work builds a comprehensive understanding of the fate, transformation products, and related toxicological characteristics of emerging PPD-quinone contaminants in the aqueous environment.

Forefronts and hotspots evolution of the nanomaterial application in anti-tumor immunotherapy: a scientometric analysis.

BACKGROUND: Tumor immunotherapy can not only eliminate the primary lesion, but also produce long-term immune memory, effectively inhibiting tumor metastasis and recurrence. However, immunotherapy also showed plenty of limitations in clinical practice. In recent years, the combination of nanomaterials and immunotherapy has brought new light for completely eliminating tumors with its fabulous anti-tumor effects and negligible side effects. METHODS: The Core Collection of Web of Science (WOSCC) was used to retrieve and obtain relevant literatures on antitumor nano-immunotherapy since the establishment of the WOSCC. Bibliometrix, VOSviewer, CiteSpace, GraphPad Prism, and Excel were adopted to perform statistical analysis and visualization. The annual output, active institutions, core journals, main authors, keywords, major countries, key documents, and impact factor of the included journals were evaluated. RESULTS: A total of 443 related studies were enrolled from 2004 to 2022, and the annual growth rate of articles reached an astonishing 16.85%. The leading countries in terms of number of publications were China and the United States. Journal of Controlled Release, Biomaterials, Acta Biomaterialia, Theranostics, Advanced Materials, and ACS Nano were core journals publishing high-quality literature on the latest advances in the field. Articles focused on dendritic cells and drug delivery accounted for a large percentage in this field. Key words such as regulatory T cells, tumor microenvironment, immune checkpoint blockade, drug delivery, photodynamic therapy, photothermal therapy, tumor-associated macrophages were among the hottest themes with high maturity. Dendritic cells, vaccine, and T cells tend to become the popular and emerging research topics in the future. CONCLUSIONS: The combined treatment of nanomaterials and antitumor immunotherapy, namely antitumor nano-immunotherapy has been paid increasing attention. Antitumor nano-immunotherapy is undergoing a transition from simple to complex, from phenotype to mechanism.

PM2.5-induced DNA oxidative stress in A549 cells and regulating mechanisms by GST DNA methylation and Keap1/Nrf2 pathway.

Fine particulate matter (PM2.5) increases the risks of lung cancer. Epigenetics provides a new toxicology mechanism for the adverse health effects of PM2.5. However, the regulating mechanisms of PM2.5 exposure on candidate gene DNA methylation changes in the development of lung cancer remain unclear. Abnormal expression of the glutathione S transferase (GST) gene is associated with cancer. However, the relationship between PM2.5 and DNA methylation-mediated GST gene expression is not well understood. In this study, we performed GST DNA methylation analysis and GST-related gene expression in human A549 cells exposed to PM2.5 (0, 50, 100 µg/mL, from Taiyuan, China) for 24 h (n = 4). We found that PM2.5 may cause DNA oxidative damage to cells and the elevation of GSTP1 promotes cell resistance to reactive oxygen species (ROS). The Kelch-1ike ECH-associated protein l (Keap1)/nuclear factor NF-E2-related factor 2 (Nrf2) pathway activates the GSTP1. The decrease in the DNA methylation level of the GSTP1 gene enhances GSTP1 expression. GST DNA methylation is associated with reduced levels of 5-methylcytosine (5mC), DNA methyltransferase 1 (DNMT1), and histone deacetylases 3 (HDAC3). The GSTM1 was not sensitive to PM2.5 stimulation. Our findings suggest that PM2.5 activates GSTP1 to defend PM2.5-induced ROS and 8-hydroxy-deoxyguanosine (8-OHdG) formation through the Keap1/Nrf2 signaling pathway and GSTP1 DNA methylation.

Multi-omics analysis of attenuated variant reveals potential evaluation marker of host damaging for SARS-CoV-2 variants.

SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination. The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences. Molecular markers for evaluating the pathogenicity of new variants are therefore needed. By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels, six key molecules on the polyamine biosynthesis pathway including putrescine, SAM, dc-SAM, ODC1, SAMS, and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants. To validate our discovery, human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients. Using ODC1 as a proof-of-concept, differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system (RAS) and positively associated with ACE2 activity. Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern (VOCs) and was found to be correlated with each VOCs' pathogenic properties. Particularly, the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models. Our work, therefore, presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.

Systemic treatment with ubiquitin carboxy terminal hydrolase L1 TAT protein ameliorates axonal injury and reduces functional deficits after traumatic brain injury in mice.

Traumatic brain injury (TBI) is often associated with axonal injury that leads to significant motor and cognitive deficits. Ubiquitin carboxy terminal hydrolase L1 (UCHL1) is highly expressed in neurons and loss of its activity plays an important role in the pathogenesis of TBI. Fusion protein was constructed containing wild type (WT) UCHL1 and the HIV trans-activator of transcription capsid protein transduction domain (TAT-UCHL1) that facilitates transport of the protein into neurons after systemic administration. Additional mutant proteins bearing cysteine to alanine UCHL1 mutations at cysteine 152 (C152A TAT-UCHL1) that prevents nitric oxide and reactive lipid binding of C152, and at cysteine 220 (C220A TAT-UCHL1) that inhibits farnesylation of the C220 site were also constructed. WT, C152A, and C220A TAT-UCHL1 proteins administered to mice systemically after controlled cortical impact (CCI) were detectable in brain at 1 h, 4 h and 24 h after CCI by immunoblot. Mice treated with C152A or WT TAT-UCHL1 decreased axonal injury detected by NF200 immunohistochemistry 24 h after CCI, but C220A TAT-UCHL1 treatment had no significant effect. Further study indicated that WT TAT-UCHL1 treatment administered 24 h after CCI alleviated axonal injury as detected by SMI32 immunoreactivity 7 d after CCI, improved motor and cognitive deficits, reduced accumulation of total and K48-linked poly-Ub proteins, and attenuated the increase of the autophagy marker Beclin-1. These results suggest that UCHL1 activity contributes to the pathogenesis of white matter injury, and that restoration of UCHL1 activity by systemic treatment with WT TAT-UCHL1 after CCI may improve motor and cognitive deficits. These results also suggest that farnesylation of the C220 site may be required for the protective effects of UCHL1.

Stable isotope-assisted mass spectrometry reveals in vivo distribution, metabolism, and excretion of tire rubber-derived 6PPD-quinone in mice.

6PPD-quinone (6PPD-Q) has been identified as a ubiquitous contaminant in the surrounding locality, including air particles, roadside soils, dust, and water. Recently, the prevalence of 6PPD-Q in human urine has accentuated the urgency for investigating its biological fate. To address this, we conducted a stable isotope-assisted high-resolution mass spectrometry (HRMS) assay to unveil the distribution, metabolism, excretion, and toxicokinetic properties of this contaminant in a mouse model. Mice were fed with a single dose of deuterated 6PPD-Q-d5 at human-relevant exposure levels. Results indicated that 6PPD-Q was quickly assimilated and distributed into bloodstream and main organs of mice, with the concentrations reaching peaks under 1 h following administration. Notably, 6PPD-Q was primarily distributed in the adipose tissue, marked by a significant Cmax (p < 0.05), followed by the kidney, lung, testis, liver, spleen, heart, and muscle. In addition, our measurement demonstrated that 6PPD-Q can penetrate the blood-brain barrier of mice within 0.5 h after exposure. The half-lives (t1/2) of 6PPD-Q in serum, lung, kidney, and spleen of mice were measured at 12.7 ± 0.3 h, 20.7 ± 1.4 h, 21.6 ± 5.3 h, and 20.6 ± 2.8 h, respectively. Using HRMS combined with isotope tracing techniques, two novel hydroxylated metabolites of 6PPD-Q in the mice liver were identified for the first time, which provides new insights into its rapid elimination in-vivo. Meanwhile, fecal excretion was identified as the main excretory pathway for 6PPD-Q and its hydroxylated metabolites. Collectively, our findings extend the current knowledge on the biological fate and exposure status of 6PPD-Q in a mouse model, which has the potential to be extrapolated to humans.

Tumor suppressive function of IGF2BP1 in gastric cancer through decreasing MYC.

Gastric cancer is one of the most common causes of cancer-related death worldwide. The N6 -methyladenosine (m6 A) reader IGF2BP1 (insulin-like growth factor-2 mRNA binding protein 1) has been reported to promote cancer progression by stabilizing oncogenic mRNAs through its m6 A-binding activity in some tumors. However, the role of IGF2BP1 in gastric carcinogenesis remains unclear. In this study, we found that IGF2BP1 is significantly downregulated in tumor tissues from patients with gastric cancer. Lower expression of IGF2BP1 is associated with poor prognosis. Gastric cancer cell proliferation is suppressed by IGF2BP1 in an m6 A-dependent manner. Additionally, IGF2BP1 is able to significantly attenuate tumor growth of gastric cancer cells. Further m6 A sequencing and m6 A-RNA immunoprecipitation assays show that MYC (c-myc proto-oncogene) mRNA is a target transcript of IGF2BP1 in gastric cancer cells. IGF2BP1 inhibits gastric cancer cell proliferation by reducing the mRNA and protein expression of MYC. Mechanistically, IGF2BP1 promotes the degradation of MYC mRNA and inhibits its translation efficiency. Taken together, these data suggest that IGF2BP1 plays a tumor-suppressive role in gastric carcinogenesis by downregulating MYC in an m6 A-dependent manner, thereby making the IGF2BP1-MYC axis a potential target for gastric cancer treatment.

6PPD-quinone exposure induces neuronal mitochondrial dysfunction to exacerbate Lewy neurites formation induced by α-synuclein preformed fibrils seeding.

The emerging toxicant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q) is of wide concern due to its ubiquitous occurrence and high toxicity. Despite regular human exposure, limited evidence exists about its presence in the body and potential health risks. Herein, we analyzed cerebrospinal fluid (CSF) samples from Parkinson's disease (PD) patients and controls. The CSF levels of 6PPD-Q were twice as high in PD patients compared to controls. Immunostaining assays performed with primary dopaminergic neurons confirm that 6PPD-Q at environmentally relevant concentrations can exacerbate the formation of Lewy neurites induced by α-synuclein preformed fibrils (α-syn PFF). Assessment of cellular respiration reveals a considerable decrease in neuronal spare respiratory and ATP-linked respiration, potentially due to changes in mitochondrial membrane potential. Moreover, 6PPD-Q-induced mitochondrial impairment correlates with an upsurge in mitochondrial reactive oxygen species (mROS), and Mito-TEMPO-driven scavenging of mROS can lessen the amount of pathologic phospho-serine 129 α-synuclein. Untargeted metabolomics provides supporting evidence for the connection between 6PPD-Q exposure and changes in neuronal metabolite profiles. In-depth targeted metabolomics further unveils an overall reduction in glycolysis metabolite pool and fluctuations in the quantity of TCA cycle intermediates. Given its potentially harmful attributes, the presence of 6PPD-Q in human brain could potentially be a risk factor for PD.

Occurrence and Fate of Substituted p-Phenylenediamine-Derived Quinones in Hong Kong Wastewater Treatment Plants.

para-Phenylenediamine quinones (PPD-Qs) are a newly discovered class of transformation products derived from para-phenylenediamine (PPD) antioxidants. These compounds are prevalent in runoff, roadside soil, and particulate matter. One compound among these, N-1,3-dimethylbutyl-n'-phenyl-p-phenylenediamine quinone (6PPD-Q), was found to induce acute mortality of coho salmon, rainbow trout, and brook trout, with the median lethal concentrations even lower than its appearance in the surface and receiving water system. However, there was limited knowledge about the occurrence and fate of these emerging environmental contaminants in wastewater treatment plants (WWTPs), which is crucial for effective pollutant removal via municipal wastewater networks. In the current study, we performed a comprehensive investigation of a suite of PPD-Qs along with their parent compounds across the influent, effluent, and biosolids during each processing unit in four typical WWTPs in Hong Kong. The total concentrations of PPDs and PPD-Qs in the influent were determined to be 2.7-90 and 14-830 ng/L. In the effluent, their concentrations decreased to 0.59-40 and 2.8-140 ng/L, respectively. The median removal efficiency for PPD-Qs varied between 53.0 and 91.0% across the WWTPs, indicating that a considerable proportion of these contaminants may not be fully eliminated through the current processing technology. Mass flow analyses revealed that relatively higher levels of PPD-Qs were retained in the sewage sludge (20.0%) rather than in the wastewater (16.9%). In comparison to PPDs, PPD-Qs with higher half-lives exhibited higher release levels via effluent wastewater, which raises particular concerns about their environmental consequences to aquatic ecosystems.

A Novel Needle Mouse Model of Vascular Cognitive Impairment and Dementia.

Bilateral common carotid artery (CCA) stenosis (BCAS) is a useful model to mimic vascular cognitive impairment and dementia (VCID). However, current BCAS models have the disadvantages of high cost and incompatibility with magnetic resonance imaging (MRI) scanning because of metal implantation. We have established a new low-cost VCID model that better mimics human VCID and is compatible with live-animal MRI. The right and the left CCAs were temporarily ligated to 32- and 34-gauge needles with three ligations, respectively. After needle removal, CCA blood flow, cerebral blood flow, white matter injury (WMI) and cognitive function were measured. In male mice, needle removal led to ∼49.8% and ∼28.2% blood flow recovery in the right and left CCA, respectively. This model caused persistent and long-term cerebral hypoperfusion in both hemispheres (more severe in the left hemisphere), and WMI and cognitive dysfunction in ∼90% of mice, which is more reliable compared with other models. Importantly, these pathologic changes and cognitive impairments lasted for up to 24 weeks after surgery. The survival rate over 24 weeks was 81.6%. Female mice showed similar cognitive dysfunction, but a higher survival rate (91.6%) and relatively milder white matter injury. A novel, low-cost VCID model compatible with live-animal MRI with long-term outcomes was established.SIGNIFICANCE STATEMENT Bilateral common carotid artery (CCA) stenosis (BCAS) is an animal model mimicking carotid artery stenosis to study vascular cognitive impairment and dementia (VCID). However, current BCAS models have the disadvantages of high cost and incompatibility with magnetic resonance imaging (MRI) scanning due to metal implantation. We established a new asymmetric BCAS model by ligating the CCA to various needle gauges followed by an immediate needle removal. Needle removal led to moderate stenosis in the right CCA and severe stenosis in the left CCA. This needle model replicates the hallmarks of VCID well in ∼90% of mice, which is more reliable compared with other models, has ultra-low cost, and is compatible with MRI scanning in live animals. It will provide a new valuable tool and offer new insights for VCID research.

Validation of quercetin in the treatment of colon cancer with diabetes via network pharmacology, molecular dynamics simulations, and in vitro experiments.

This study built a prognostic model for CRC-diabetes and analyzed whether quercetin could be used for CRC-diabetes treatment through a network of pharmacology, molecular dynamics simulation, bioinformatics, and in vitro experiments. First, multivariate Cox proportional hazards regression was used to construct the prognosis modelof CRC-diabetes. Then, the intersection of quercetin target genes with CRC-diabetes genes was used to find the potential target for quercetin in the treatment of CRC-diabetes. Molecular docking and molecular dynamics simulations were used to screen the potential targets for quercetin in the treatment of CRC-diabetes. Finally, we verified the target and pathway of quercetin in the treatment of CRC-diabetes through in vitro experiments. Through molecular docking, seven proteins (HMOX1, ACE, MYC, MMP9, PLAU, MMP3, and MMP1) were selected as potential targets of quercetin. We conducted molecular dynamics simulations of quercetin and the above proteins, respectively, and found that the binding structure of quercetin with MMP9 and PLAU was relatively stable. Finally, according to the results of Western blot results, it was confirmed that quercetin could interact with MMP9. The experimental results show that quercetin may affect the JNK pathway, glycolysis, and epithelial-mesenchymal transition (EMT) to treat CRC-diabetes. Based on the TCGA, TTD, DrugBank, and other databases, a prediction model that can effectively predict the prognosis of colon cancer patients with diabetes was constructed. According to experiment results, quercetin can regulate the expression of MMP9. By acting on the JNK pathway, glycolysis, and EMT, it can treat colon cancer patients with diabetes.

An Alternative Thinking in Tumor Therapeutics: Living Yeast Armored with Silicate.

A hybrid platform, constructed via the surface "armoring" of living yeasts by a manganese silicate compound (MS@Yeast), is investigated for combinational cancer treatment. The intrinsic characteristics of living yeasts, in both acidophilic and anaerobic conditions, empower the hybrid platform with activated selected colonization in tumors. While silicate particles are delivered in a targeting manner, yeast fermentation occurs at the cancerous region, inducing both alcohol and CO2. The excessive content of alcohol causes the hemangiectasis of tumor tissue, facilitating the penetration of therapeutics into central tumors and subsequent endocytosis. The catalytic Mn2+ ions, released from silicate particles, react with CO2 to induce forceful oxidative stress in tumor cells, ablating the primary tumors. More interestingly, the debris of sacrificed tumor cells and yeasts triggers considerable antitumor immune responses, rejecting both rechallenged and metastatic tumors. The integration of biologically active microorganisms and functional materials, illustrated in this study, provides distinctive perspectives in the exploration of potential therapeutics for tackling cancer.

A real-word study: is normothermic intraoperative intraperitoneal chemotherapy impactful as we expect?

Background: Patients with gastric cancer have a poor prognosis. Currently, intraperitoneal chemotherapy has been considered a therapeutic option to improve prognosis due to its appealing theoretical rationales. But there is no consensus on the choice of chemotherapeutic agents used in intraperitoneal chemotherapy for gastric cancer. The real-world efficacy of applying intraoperative chemotherapy in gastric cancer still remains undefined. Methods: Patients with gastric cancer who underwent radical gastrectomy at the Gastrointestinal Department of The First Affiliated Hospital of Anhui Medical University between 2012 and 2019 were enrolled in this study. Patients were divided into two groups based on whether they received intraperitoneal chemotherapy. The t-test (mean of two samples) was conducted to compare the difference in measurement data between the two groups, and the chi-square test was used to compare the difference in count data. Kaplan-Meier method with log-rank test was performed to analyze the overall survival of patients. Kaplan-Meier method with log-rank test was also performed in various subgroups to respectively compare the survival of patients. Multivariate Cox analysis was performed to analyze the prognosis factors of these patients. Results: A total of 1253 patients were included in the final analysis, in which 861 patients received intraperitoneal chemotherapy and 352 not received intraperitoneal chemotherapy. The clinicopathological features of the participants in the two groups were comparable. There was no significant difference between the two groups in overall survival (P > 0.05). Consistently, no significant difference was found between the two groups in each subgroup (P > 0.05). The multivariate Cox analysis demonstrated that only age, BMI, pathological type, TNM stage, and differentiation grade were independent risk factors of survival. Conclusion: Intraoperative intraperitoneal chemotherapy usage did not improve survival in patients with gastric cancer undergoing radical gastrectomy.

High-throughput profiling of RNA modifications by ultra-performance liquid chromatography coupled to complementary mass spectrometry: Methods, quality control, and applications.

Although next-generation sequencing technology has been used to delineate RNA modifications in recent years, the paucity of appropriate converting reactions or specific antibodies impedes the accurate characterization and quantification of numerous RNA modifications, especially when these modifications demonstrate wide variations across developmental stages and cell types. In this study, we developed a high-throughput analytical platform coupling ultra-performance liquid chromatograph (UPLC) with complementary mass spectrometry (MS) to identify and quantify RNA modifications in both synthetic and biological samples. Sixty-four types of RNA modifications, including positional isomers and hypermodified ribonucleosides, were successfully monitored within a 16-min single run of UPLC-MS. Two independent methods to cross-validate the purity of RNA extracted from Caenorhabditis elegans (C. elegans) were developed using the coexisting C. elegans and Escherichia coli (E. coli) as a surveillance system. To test the validity of the method, we investigated the RNA modification landscape of three model organisms, C. elegans, E. coli, and Arabidopsis thaliana (A. thaliana). Both the identity and molarity of modified ribonucleosides markedly varied among the species. Moreover, our platform is not only useful for exploring the dynamics of RNA modifications in response to environmental cues (e.g., cold shock) but can also help with the identification of RNA-modifying enzymes in genetic studies. Cumulatively, our method presents a novel platform for the comprehensive analysis of RNA modifications, which will be of benefit to both analytical chemists involved in biomarker discovery and biologists conducting functional studies of RNA modifications.