Free-radical triggered formation of dioxins from 2-chlorophenol pyrolysis investigated by synchrotron radiation photoionization mass spectrometry.

Polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and polychlorinated naphthalenes (PCNs) are a category of highly toxic and environmentally persistent pollutants released particularly via thermal processes of chlorine-containing materials. However, the detailed reaction mechanism, especially the evolution of related radicals remains elusive for decades. Herein we have for the first time characterized the radicals and intermediates during pyrolysis of 2-chlorophenol resulting in PCDD/Fs and PCNs, using a flow tube reactor coupled with in-situ synchrotron radiation photoionization mass spectrometry (SR-PIMS). Transient species including 2-chlorophenoxy (C6H4ClO•), phenoxy (C6H5O•), chloro-cyclopentadienyl (•C5H4Cl), chloro-cyclopentadiene (C5H5Cl), fulvenone ketene (C6H4O) and o-benzyne (o-C6H4), were identified via m/z and photoionization efficiency profile. Potential energy surfaces of the early-stage mechanism and the associated rate constants and branching ratios were elucidated. Successively, the formation mechanisms of PCDD/Fs and PCNs from these transient intermediates at high temperatures were proposed which have experimentally validated and refined the previous mechanism. The results suggested that the combination of 2-chlorophenoxy radicals with another 2-chlorophenoxy, phenoxy, phenyl, or o-benzyne leads to the formation of PCDD/Fs, while PCNs are generated from the self-coupling of chloro-cyclopentadienyl.

Mechanisms and Efficacy of Chinese Herbal Medicines in Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men, the incidence of which gradually increases with age and leads to lower urinary tract symptoms (LUTS), which seriously affects the quality of life of patients. Chinese herbal medicines (CHMs) are widely used for the treatment of BPH in China and some other countries. To explore the molecular mechanisms of CHMs for BPH, we conducted a review based on peer-reviewed English-language publications in PubMed and Web of Science databases from inception to December 31, 2023. This article primarily reviewed 32 papers on the use of CHMs and its active compounds in the treatment of BPH, covering animal and cell experiments, and identified relevant mechanisms of action. The results suggest that the mechanisms of action of CHMs in treating BPH may involve the regulation of sex hormones, downregulation of cell growth factors, anti-inflammatory and antioxidative effects, inhibition of cell proliferation, and promotion of apoptosis. CHMs also exhibit α-blocker-like effects, with the potential to relax urethral smooth muscle and alleviate LUTS. Additionally, we also reviewed 4 clinical trials and meta-analyses of CHMs for the treatment of BPH patients, which provided initial evidence of the safety and effectiveness of CHMs treatment. CHMs treatment for BPH shows advantages as a multi-component, multi-target, and multi-pathway therapy, which can mitigate the severity of the disease, improve LUTS, and may become a reliable treatment option in the future.

Far-infrared radiation and its therapeutic parameters: A superior alternative for future regenerative medicine?

In future regenerative medicine, far-infrared radiation (FIR) may be an essential component of optical therapy. Many studies have confirmed or validated the efficacy and safety of FIR in various diseases, benefiting from new insights into FIR mechanisms and the excellent performance of many applications. However, the lack of consensus on the biological effects and therapeutic parameters of FIR limits its practical applications in the clinic. In this review, the definition, characteristics, and underlying principles of the FIR are systematically illustrated. We outline the therapeutic parameters of FIR, including the wavelength range, power density, irradiation time, and distance. In addition, the biological effects, potential molecular mechanisms, and preclinical and clinical applications of FIR are discussed. Furthermore, the future development and applications of FIR are described in this review. By applying optimal therapeutic parameters, FIR can influence various cells, animal models, and patients, eliciting diverse underlying mechanisms and offering therapeutic potential for many diseases. FIR could represent a superior alternative with broad prospects for application in future regenerative medicine.

Fulvenallenyl Radical (C7H5·)-Mediated Gas-Phase Synthesis of Bicyclic Aromatic C10H8 Isomers: Can Fulvenallenyl Efficiently React with Closed-Shell Hydrocarbons?

To understand the reactivity of resonantly stabilized radicals, often found in relevant concentrations in gaseous environments, it is important to determine their main reaction pathways. Here, it is investigated whether the fulvenallenyl radical (C7H5·) reacts preferentially with closed-shell molecules or radicals. Electronic structure calculations on the C10H9 potential energy surface accessed by the reactions of C7H5· with methylacetylene (CH3CCH) and allene (H2CCCH2) were combined with RRKM-ME calculations of temperature- and pressure-dependent rate constants using the automated EStokTP software suite and kinetic modeling to assess the reactivity of C7H5· with closed-shell unsaturated hydrocarbons. Experimentally, the reactions were attempted in a chemical microreactor heated to 998 ± 10 K by preparing fulvenallenyl radicals via pyrolysis of trichloromethylbenzene (C7H5Cl3) and seeding the radicals in methylacetylene or allene carrier gas, with product identification by means of photoionization mass spectrometry. The measured photoionization efficiency curve of m/z = 128 was assigned to a linear combination of the reference curves of two C10H8 isomers, azulene (minor) and naphthalene (major), presumably resulting from the C7H5· plus C3H4 reactions. However, the calculations demonstrated that these reactions are too slow, and kinetic modeling of processes in the reactor allowed us to conclude that the observation of naphthalene and azulene is due to the C7H5· plus C3H3· reaction, where propargyl is produced by direct hydrogen atom abstraction by chlorine (Cl) atoms from allene or methylacetylene and Cl stem from the pyrolysis of C7H5Cl3. Modeling results under the copyrolysis conditions of toluene and methylacetylene in high-temperature shock tube experiments confirmed the prevalence of the fulvenallenyl reaction with propargyl over its reactions with C3H4 even when the concentrations of allene and methylacetylene largely exceed that of propargyl. Overall, the reactions of fulvenallenyl with both allene and methylacetylene were found to be noncompetitive in the formation of naphthalene and azulene thus attesting the inefficiency of the fulvenallenyl radical reactions with the prototype closed-shell hydrocarbon species. In the meantime, the new reaction pathways revealed, including H-assisted isomerizations between C10H8 isomers and decomposition reactions of various C10H9 isomers, emerge as relevant and are recommended for inclusion in combustion kinetic models for naphthalene formation.

A novel signature based on twelve programmed cell death patterns to predict the prognosis of lung adenocarcinoma.

Programmed cell death (PCD) plays a pivotal role in tumor initiation and progression. However, the prognostic value and clinical characteristics of PCD-related genes (PRGs) remain unclear. We collected and analyzed genes associated with twelve PCD patterns, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, and oxeiptosis to construct a gene signature. Our analysis identified 215 differentially expressed PRGs out of 1254 in lung adenocarcinoma (LUAD) and normal lung tissues. Subsequently, we performed univariate Cox regression analysis and identified 58 prognostic PRGs. Based on LASSO Cox regression analysis, we constructed a risk score using the expression levels of seven genes: DAPK2, DDIT4, E2F2, GAPDH, MET, PIM2, and FOXF1. Patients with lower risk scores showed earlier stages of cancer, longer survival times, and better immune infiltrations and functions. Notably, we found that knockdown of DDIT4 significantly increased apoptosis and impaired the proliferation of human LUAD cell lines. Our study proposes a PRG-based prognostic signature that sheds light on the potential role of PCD-related genes in LUAD and provides valuable insights into future therapeutic strategies.

Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis.

The incidence of rheumatoid arthritis (RA) is increasing with age. DNA fragments is known to accumulate in certain autoimmune diseases, but the mechanistic relationship among ageing, DNA fragments and RA pathogenesis remain unexplored. Here we show that the accumulation of DNA fragments, increasing with age and regulated by the exonuclease TREX1, promotes abnormal activation of the immune system in an adjuvant-induced arthritis (AIA) rat model. Local overexpression of TREX1 suppresses synovial inflammation in rats, while conditional genomic deletion of TREX1 in AIA rats result in higher levels of circulating free (cf) DNA and hence abnormal immune activation, leading to more severe symptoms. The dysregulation of the heterodimeric transcription factor AP-1, formed by c-Jun and c-Fos, appear to regulate both TREX1 expression and SASP induction. Thus, our results confirm that DNA fragments are inflammatory mediators, and TREX1, downstream of AP-1, may serve as regulator of cellular immunity in health and in RA.

Sphingosine 1-phosphate receptor 1 regulates blood-brain barrier permeability in epileptic mice.

Destruction of the blood-brain barrier is a critical component of epilepsy pathology. Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity. However, its effect on blood-brain barrier permeability in epileptic mice remains unclear. In this study, we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice. S1P1 expression was increased in the hippocampus after status epilepticus, whereas tight junction protein expression was decreased in epileptic mice compared with controls. Intraperitoneal injection of SEW2871, a specific agonist of sphingosine-1-phosphate receptor 1, decreased the level of tight junction protein in the hippocampus of epileptic mice, increased blood-brain barrier leakage, and aggravated the severity of seizures compared with the control. W146, a specific antagonist of sphingosine-1-phosphate receptor 1, increased the level of tight junction protein, attenuated blood-brain barrier disruption, and reduced seizure severity compared with the control. Furthermore, sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1ß and tumor necrosis factor-α and caused astrocytosis. Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline, a neuroinflammation inhibitor. Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors. Additionally, specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage, seizure severity, and epilepsy-associated depression-like behaviors. Taken together, our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.

Down-regulating GRP78 reverses pirarubicin resistance of triple negative breast cancer by miR-495-3p mimics and involves the p-AKT/mTOR pathway.

Due to the lack of known therapeutic targets for triple-negative breast cancer (TNBC), chemotherapy is the only available pharmacological treatment. Pirarubicin (tetrahydropyranyl Adriamycin, THP) is the most commonly used anthracycline chemotherapy agent. However, TNBC has a high recurrence rate after chemotherapy, and the mechanisms of chemoresistance and recurrence are not entirely understood. To study the chemoresistance mechanisms, we first screened compounds on a pirarubicin-resistant cell line (MDA-MB-231R) derived from MDA-MB-231. The drug resistance index of MDA-MB-231R cells was approximately five times higher than that of MDA-MB-231 cells. MDA-MB-231R cells have higher GRP78 and lower miR-495-3p expression levels than MDA-MB-231 cells. Transfecting MDA-MB-231R cells with a siGRP78 plasmid reduced GRP78 expression, which restored pirarubicin sensitivity. Besides, transfecting MDA-MB-231R cells with miR-495-3p mimics increased miR-495-3p expression, which also reversed pirarubicin chemoresistance. Cell counting kit-8 (CCK-8), EdU, wound healing, and Transwell assays showed that the miR-495-3p mimics also inhibited cell proliferation and migration. Based on our results, miR-495-3p mimics could down-regulate GRP78 expression via the p-AKT/mTOR signaling pathway in TNBC cells. Remarkably, chemo-resistant and chemo-sensitive TNBC tissues had opposite trends in GRP78 and miR-495-3p expressions. The lower the GRP78 and the higher the miR-495-3p expression, the better prognosis in TNBC patients. Therefore, the mechanism of pirarubicin resistance might involve the miR-495-3p/GRP78/Akt axis, which would provide a possible strategy for treating TNBC.

Anaemia and cerebrospinal fluid biomarkers of Alzheimer's pathology in cognitively normal elders: the CABLE study.

BACKGROUND: Anaemia has been reported to be associated with cognitive decline and Alzheimer's disease (AD), but the associations between anaemia and cerebrospinal fluid (CSF) AD biomarkers are still unknown. This study aimed to investigate the associations between anaemia and CSF AD biomarkers. METHODS: Participants were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. The associations of anaemia and its severity with CSF AD biomarkers including ß-amyloid 1-42 (Aß42), total tau (t-tau) and phosphorylated tau (p-tau) were analysed by multiple linear regression models. Adjusted for age, gender, educational levels, APOE ε4 alleles, comorbidities (history of coronary heart disease, history of stroke, hypertension, diabetes mellitus, dyslipidaemia) and glomerular filtration rate. RESULTS: A total of 646 cognitively normal older adults, consisting of 117 anaemia patients and 529 non-anaemia individuals, were included in this study. Anaemia patients had lower levels of CSF Aß42 than individuals without anaemia (p = 0.035). Besides, participants with more severe anaemia had lower CSF Aß42 levels (p = 0.045). No significant association of anaemia with CSF t-tau and p-tau levels was found. CONCLUSION: Cross-sectionally, anaemia was associated with lower CSF Aß42 levels. These findings consolidated the causal close relationship between anaemia and AD.

Metabolic Insight Into the Neuroprotective Effect of Tao-He-Cheng-Qi (THCQ) Decoction on ICH Rats Using Untargeted Metabolomics.

Tao-He-Cheng-Qi decoction (THCQ) is an effective traditional Chinese medicine used to treat intracerebral hemorrhage (ICH). This study was performed to investigate the possible neuroprotective effect of THCQ decoction on secondary brain damage in rats with intracerebral hemorrhage and to elucidate the potential mechanism based on a metabolomics approach. Sprague-Dawley (SD) rats were randomly divided into five groups: the sham group, collagenase-induced ICH model group, THCQ low-dose (THCQ-L)-treated group, THCQ moderate-dose (THCQ-M)-treated group and THCQ high-dose (THCQ-H)-treated group. Following 3 days of treatment, behavioral changes and histopathological lesions in the brain were estimated. Untargeted metabolomics analysis with multivariate statistics was performed by using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-Q-Exactive Orbitrap MS). THCQ treatment at two dosages (5.64 and 11.27 g/kg·d) remarkably improved behavior (p < 0.05), brain water content (BMC) and hemorheology (p < 0.05) and improved brain nerve tissue pathology and inflammatory infiltration in ICH rats. Moreover, a metabolomic analysis demonstrated that the serum metabolic profiles of ICH patients were significantly different between the sham group and the ICH-induced model group. Twenty-seven biomarkers were identified that potentially predict the clinical benefits of THCQ decoction. Of these, 4 biomarkers were found to be THCQ-H group-specific, while others were shared between two clusters. These metabolites are mainly involved in amino acid metabolism and glutamate-mediated cell excitotoxicity, lipid metabolism-mediated oxidative stress, and mitochondrial dysfunction caused by energy metabolism disorders. In addition, a correlation analysis showed that the behavioral scores, brain water content and hemorheology were correlated with levels of serum metabolites derived from amino acid and lipid metabolism. In conclusion, the results indicate that THCQ decoction significantly attenuates ICH-induced secondary brain injury, which could be mediated by improving metabolic disorders in cerebral hemorrhage rats.

Serum Uric Acid May Aggravate Alzheimer's Disease Risk by Affecting Amyloidosis in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-ß [Aß], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aß1 - 42 (p = 0.019) and Aß1 - 42/Aß1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aß1 - 42 (p = 0.009) and t-Tau/Aß1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.

Social Networks and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: Although social networks are deemed as moderators of incident Alzheimer's disease (AD), few data are available on the mechanism relevant to AD pathology. OBJECTIVE: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). METHODS: We studied participants from the Chinese Alzheimer's disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-ß (Aß1-42 and Aß1-40) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were measured using self-reported questionnaires about social ties. Linear regression models were used. RESULTS: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aß1-42 and T-tau/Aß1-42 and high Aß1-42/Aß1-40). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (ß= -0.005, p < 0.001), Aß1-42/Aß1-40 (ß= 0.481, p = 0.001), and T-tau/Aß1-42 (ß= -0.047, p < 0.001) were noted in preclinical AD stage than controls. CONCLUSION: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations.

[Potential of Arbuscular Mycorrhizal Fungi, Biochar, and Combined Amendment on Sandy Soil Improvement Driven by Microbial Community].

Sandy soils are considered as a significant transition phase to desertification. The effective recovery of sandy soils is of great significance to mitigate the desertification process. Some studies have shown that arbuscular mycorrhizal (AM) fungi and biochar improved the sandy soil, but there have been very few studies regarding the combined effects of AM fungi and biochar amendments on sandy soil improvement. Additionally, the roles of the bacterial and fungal community during the process of sandy soil improvement remain unclear. A greenhouse pot experiment with four treatments, including a control (CK, no amendment), single AM fungi-assisted amendment (RI), single biochar amendment (BC), and combined amendment (BC_RI, biochar plus AM fungi), was set up. This study investigated the effects of different amendment methods on the Nitrariasi birica mycorrhizal colonization, biomass, nutrient (N, P, K, Ca, and Mg) content, soil organic carbon, soil nutrient (TN, TP, and TK) content, and soil water-stable aggregate composition. High throughput sequencing technology was used to investigate the roles of the bacterial and fungal communities during the process of sandy soil improvement. Combined with multiple analysis methods, the improvement mechanisms of different amendment methods were explored. The aim was to provide basic data and scientific basics for reasonably and effectively improving sandy soils. The results indicated that a significant mycorrhiza colonization was observed in the inoculation (RI and BC_RI) treatments, but there was no substantial difference in the mycorrhiza colonization with the RI and BC_RI. Compared with the CK, the shoot biomass and shoot element (N, K, Ca, and Mg) contents were significantly increased in the RI, and the shoot element (N, P, K, Ca, and Mg) contents were significantly increased in the BC and BC_RI; compared with the RI and BC, the root biomass and the root element (P, K, Ca, and Mg) contents were significantly increased in the BC_RI. Compared with the CK, the soil organic carbon contents were significantly increased in the BC and BC_RI, the soil TN contents were significantly increased by 152.54%, and the soil TP and TK contents were significantly decreased by 12.5% and 18.8%, respectively. The proportion of soil aggregates with particle sizes of 0.25-0.05 mm was the highest in each treatment, and the large particle size (>0.25 mm) soil aggregate was significantly increased in the BC_RI. Compared with the CK, the Sobs and Shannon indices of the bacterial/fungal community were significantly decreased in the RI and BC_RI. There was a difference in the microbial community compositions and abundance in the various treatments. The results of the RDA and network analysis were as follows:the effects of AM fungi, biochar, and combined amendment on the soil environment and microbial community structure were significant; in the different amendment treatments, the relationship of the microbial molecular ecological network was significantly changed, and the composition of the core species varied; compared with the RI, there was a higher network connection degree and a richer core species composition in the BC and BC_RI; moreover, the essential role of Rhizophagus intraradices was weaken and the core roles of the other microorganisms (especially bacterial species) were enhanced under the combined effects of biochar and AM fungi. The SEM results demonstrated that the application of AM fungi and biochar could directly affect the bacteria/fungi community structure, and further affect the plant growth and soil properties. The differences in the microbial community structure (especially the change in the microbial interaction) were the key driving factors that led to the difference in the soil improvement effectiveness. In summary, the effects of the different amendment methods on the improvement effectiveness of sandy soils varied. The microbial community played key roles in the process of sandy soil improvement, and there were potential advantages and applications in accelerating the ecological restoration of sandy soils under the combined AM fungi and biochar amendment.

[Traditional medicinal knowledge in Lancang-Mekong River:a case study in Lancang Lahu autonomous county].

Lancang Lahu autonomous county, where the Lancang-Mekong River flows by, was selected as the case site to investigate the traditional medicinal knowledge(TMK). A comparison of TMK between Lancang county and other places in the Lancang-Mekong sub-region was conducted. Research on TMK has been seldom reported although there are abundant medicinal resources in this sub-region. The key informant interview and other methods have been adopted in the field surveys in the past six years. The investigation revealed that there was rich TMK and various herbal medicine resources in Lancang county. A total of 220 folk prescriptions have been collected, which were normally simple with easy processing methods and usages, and most raw materials were freshly used. As for medicinal plants, 121 species in 67 families have been documented. Other findings included that TMK in Lancang county was remained at the level of medication based on experience only. The processing methods of herbal medicines were simple and the bioactive ingredients were not clear. Without text and cultural support for self-teaching, coupled with conservative inheritance, it resulted in massive losses of TMK. The folk doctors have accumulated their factions based on self-study or ancestral experience. There was different treatment experience among folk doctors, but the safety and effectiveness should be paid attention to. The folk doctors used various herbal medicines, but there was a lack of standards or specifications for quality control. Given the problems existing in inheritance and development, conservation strategies were proposed in the present study.

Syringaresinol Protects against Type 1 Diabetic Cardiomyopathy by Alleviating Inflammation Responses, Cardiac Fibrosis, and Oxidative Stress.

SCOPE: Syringaresinol (SYR) is a phenolic compound, which could be found in various cereals and medicinal plants. It exerts both anti-inflammatory and antioxidant pharmacological properties. However, little is known about the effect of SYR on modulating diabetic cardiomyopathy. The present study aimed to investigate the pharmacodynamic effect of SYR on diabetic cardiomyopathy and the underlying molecular mechanism. METHODS AND RESULTS: In STZ-induced type 1 diabetic mice, orally administration with SYR in every other day for 8 weeks significantly improves cardiac dysfunction and preventes cardiac hypertrophy and fibrosis. The macrophage infiltration and oxidative stress biomarkers are also suppressed by SYR without affecting hyperglycemia and body weight. In neonatal cardiomyocytes, high glucose-induced cell apoptosis and fibrosis are potently decreased by SYR, and the inflammatory response and oxidant stress are also alleviated by SYR incubation. Mechanistically, SYR may exert protective effects by restoring suppression of antioxidant kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-E2-related factor 2 (Nrf2) system and abnormal activation of transforming growth factor-ß (TGF-ß)/mothers against decapentaplegic homolog (Smad) signaling pathway in vitro and in vivo. CONCLUSION: The results indicated that SYR could be a potential therapeutic agent for the treatment of diabetic cardiomyopathy by inhibiting inflammation, fibrosis, and oxidative stress. The signaling pathway of Keap1/Nrf2 and TGF-ß/Smad could be used as therapeutic targets for diabetic complications.

A novel role of kynureninase in the growth control of breast cancer cells and its relationships with breast cancer.

Breast cancer is the most common malignancy among women worldwide. Kynureninase (KYNU) located in 2q22.2, which was associated with tryptophan utilization and metabolic diseases including cardiac, renal and limb defects syndrome 2. However, the role of KYNU in breast cancer (BC) development remains unclear. The expression of KYNU was examined by immunohistochemistry (IHC) in 137 primary BC tissues, and the correlation of KYNU expression with clinical pathological characteristics and the biomarkers (ER, PR, HER2, E-cad and Ki-67) was analysed. The role of KYNU in cancer cell proliferation, tumour growth and development was evaluated by MTT assay, soft agar colony formation assay and xenograft mouse models. Among 137 primary BC tissues, 46.7% (64/137) had high KYNU expression (IHC scores >4) while 53.3% (73/137) had low KYNU expression (IHC scores ≤4). The expression of KYNU was positively correlated with the expressions of ER (P = .002), PR (P = .007) and E-cad (P = .03), while negatively associated with tumour grade (P = .008), tumour stage (P < .001) and the expressions of HER2 (P = .04) and Ki-67 (P = .019). Overexpression of KYNU significantly inhibited cell proliferation in cell culture, colony formation in soft agar and xenograft BC development in NOD/SCID mice. Kynureninase suppresses BC cell proliferation, tumour growth and development. Kynureninase may function as a tumour suppressor in BC.

Long-Term Tracking of Cancer Cell Nucleus and Identification of Colorectal Cancer with an Aggregation-Induced Emission-Based Fluorescent Probe.

In clinical diagnosis and treatment, it is very important to distinguish cancer cells from normal cells. Nuclear-selective fluorescent probe that specifically target tumors can not only make the difference in assessing tumor margins during surgery and then facilitating accurate resection of the tumor, but also can provide crucial biomedical information of tumor progress if it can be used for long-term dynamic visualization of nucleus in cancer. Herein, a novel fluorescent probe 3 was designed and characterized to be of low-toxicity and water-solubility. The biological evaluation indicated that probe 3 prefers nucleic acids rather than accumulation in non-neuclear sites while superior to the commercial available agent DAPI (4',6-diamidino-2-phenylindole), in terms of its character of aggregation-induced emission (AIE), large Stokes shift (175 nm) and light stability. Further experiments demonstrated that probe 3 can not only differentiate SW480 and SW620 (cancer cells) from GES-1 (normal cells) with high contrast (dyed in nuclear of cancer cells and not in nuclear of normal cells), but also used for tracking cancer cell nuclear for long time. Furthermore, 3D reconstruction fluorescence imaging proved that probe 3 was able for identifying colorectal cancer tissues from para-carcinoma tissues by a strong contrast. Therefore, in precise surgery of colorectal cancer, probe 3 may be a promising-agent for guiding of intraoperation.

Graphene oxide@gold nanorods-based multiple-assisted electrochemiluminescence signal amplification strategy for sensitive detection of prostate specific antigen.

A novel and competitive electrochemiluminescence (ECL) aptasensor for prostate specific antigen (PSA) assay was constructed using gold nanorods functionalized graphene oxide (GO@AuNRs) multilabeled with glucose oxidase (GOD) and streptavidin (SA) toward luminol-based ECL system. A strong initial ECL signal was achieved by electrodeposited gold (DpAu) on the electrode because of gold nanoparticles (AuNPs) motivating the luminol ECL signal. The signal probes prepared by loading GOD and SA-biotin-DNA on GO@AuNRs were used for achieving multiple signal amplification. In the absence of PSA, the signal probes can be attached on the electrode by hybridization reaction between PSA aptamer and biotin-DNA. In this state, the GOD loaded on the probe could catalyze glucose to in situ produce H2O2 and then AuNRs catalyze H2O2 to generate abundant reactive oxygen species (ROSs) in luminol ECL reaction. Both the high-content GOD and AuNRs in the signal probe amplified the ECL signal in the ECL system. Moreover, the combination of SA with biotin-DNA further expands ECL intensity. The integration of such amplifying effects in this protocol endows the aptasensor with high sensitivity and good selectivity for PSA detection. This aptasensor exhibits a linear relation in the range of 0.5pgmL-1 to 5.0ngmL-1 with the detection limit of 0.17pgmL-1 (S/N = 3). Besides, the strategy was successfully applied in determination of human serum samples with recovery of 81.4-116.0%.

Ferrocene-graphene sheets for high-efficiency quenching of electrochemiluminescence from Au nanoparticles functionalized cadmium sulfide flower-like three dimensional assemblies and sensitive detection of prostate specific antigen.

A signal-switchable electrochemiluminescence (ECL) aptasensor was presented for sensitive prostate specific antigen (PSA) assay using ferrocene-graphene sheets (Fc-GNs) for high-efficiency quenching of ECL from Au nanoparticles functionalized cadmium sulfide flower-like three dimensional (3D) assemblies (Au-CdS flower-like 3D assemblies). Au-CdS flower-like 3D assemblies were synthesized and employed as luminophore, exhibiting strong and stable ECL intensity, and followed by assembling captured DNA (cDNA) and hybridizing it with half of base sequence of PSA aptamer on the Au-CdS flower-like 3D assemblies modified electrode. The remaining part of the non-complementary base of the aptamer could preferentially adsorb GN with the signal switched "off" state. While in the presence of the PSA, the binding of PSA with aptamer caused desorption of aptamer from the surface of Fc-GNs and was then released from electrode surface, thus allowing the ECL signal enhancement. With the transformation of luminescence signal from "off" to "on", the aptasensor displays high sensitivity for PSA detection with a linear range from 1pgmL-1 to 25ngmL-1 and a detection limit of 0.38pgmL-1S/N=3). Moreover, this developed method could be successfully applied to the determination of PSA in human serum samples with recoveries of 85.8-104.0%, suggesting great potential applications in biochemical analysis.

Simultaneous determination of four local anesthetics by CE with ECL and study on interaction between procainamide and human serum albumin.

A new method of capillary electrophoresis (CE) coupled with tris(2, 2'-bipyridyl) ruthenium(II) electrochemiluminescence (ECL) detection has been developed to detect four local anesthetics procainamide (PAH), tetracaine (TCH), proparacaine (PCH) and cinchocaine (CIN) simultaneously. An europium (III)-doped prussian blue analogue film (Eu-PB) modified platinum electrode was prepared and applied to improve the detection sensitivity. The parameters including additives, concentration and pH of the running buffer, separation voltage and detection potential that affect CE separation and ECL detection were optimized in detail. The four local anesthetics were baseline separated and detected within 10min under the optimized conditions. The detection limits (LOD) of PAH, TCH, PCH and CIN are 5.5×10(-8), 9.6×10(-8), 2.5×10(-8) and 3.5×10(-8)molL(-1) (S/N=3), respectively. RSDs of the migration time for four analytes range from 1.2% to 2.5% within intraday and from 2.4% to 4.9% in interday, RSDs of the peak area for four analytes are from 1.7% to 3.3% within intraday and from 2.2% to 5.6% in interday, respectively. The limits of quantitation (LOQ) (S/N=10) for PAH, TCH, PCH and CIN in human urine sample are 5.9×10(-7), 9.2×10(-7), 8.3×10(-7) and 5.0×10(-7)molL(-1), separately. The recoveries (n=3) of four analytes in human urine are from 87.6% to 107.7% with less than 5.9% in RSDs. The developed method was used to determine four local anesthetics in human urine samples and investigate the interaction between PAH and human serum albumin (HSA). The number of binding sites and the binding constant of PAH with HSA were calculated to be 1.03 and 2.4×10(4)Lmol(-1), respectively.