Clinical Effect Observation of Apatinib Combined with 131I for Radioiodine-Refractory Differentiated Thyroid Cancer and Prognostic Significance Analysis of Macrophage Inflammatory Protein-1α After Treatment: A Cell Regulation Study

SUMMARY: The objective of this study was to observe the clinical efficacy of apatinib (AP) combined with 131I in the treatment of radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) and the prognostic significance of MIP-1α after treatment, and to provide reference and guidance for future treatment and disease assessment of RAIR-DTC. One hundred and six patients with RAIR- DTC admitted to our hospital from January 2019 to October 2020 were selected for the study. All the patients were treated with TC surgery with 131I at our hospital, and 58 of them were subsequently transferred to AP treatment, which was considered as the research group; the other 48 patients were transferred to thyroid stimulating hormone (TSH) suppression treatment, which was considered as the control group. The clinical efficacy of the research group was better than that of the control group (P 0.05). After treatment, Tg, TL, maximum diameter of C/B lymph nodes, number of lymph nodes and number of calcified spots were lower in the research group than in the control group (P < 0.05). ROC analysis revealed that the predictive sensitivity of MIP-1α for prognosis of 3-year RAIR-DTC death in the research group of patients was 84.63 % and the specificity was 72.16 %. AP combined with 131I is effective in the treatment of RAIR-DTC and is worth using in the clinical practice. In addition, elevated levels of MIP-1α predicted a poor prognosis for patients with RAIR-DTC.

El objetivo de este estudio fue observar la eficacia clínica de apatinib (AP) combinado con 131I en el tratamiento del cáncer de tiroides diferenciado refractario al yodo radiactivo (RAIR-DTC) y la importancia pronóstica de MIP-1α después del tratamiento, y proporcionar referencia y orientación para futuros tratamientos y enfermedades. Evaluación de RAIR- DTC. Se seleccionaron para el estudio 106 pacientes con RAIR- DTC ingresados en nuestro hospital desde enero de 2019 hasta octubre de 2020. Todos los pacientes fueron tratados con cirugía CT con 131I, y 58 de ellos fueron trasladados posteriormente a tratamiento AP, los que fueron considerados como grupo de investigación; los otros 48 pacientes fueron transferidos a tratamiento de supresión de la hormona estimulante de la tiroides (TSH), que se consideró como grupo de control. La eficacia clínica del grupo de investigación fue mejor que la del grupo de control (P 0,05). Después del tratamiento, Tg, TL, diámetro máximo de los linfonodos C/B, número linfonodos y número de manchas calcificadas fueron menores en el grupo de investigación que en el grupo de control (P <0,05). El análisis ROC reveló que la sensibilidad predictiva de MIP-1α para el pronóstico de muerte por RAIR-DTC a 3 años en el grupo de pacientes de investigación fue del 84,63 % y la especificidad fue del 72,16 %. AP combinado con 131I es eficaz en el tratamiento del RAIR-DTC y vale la pena utilizarlo en la práctica clínica. Además, los niveles elevados de MIP-1α predijeron un mal pronóstico para los pacientes con RAIR- DTC.

The association between the composite dietary antioxidant index and thyroid functionality among adults in the USA: NHANES 2007-2012.

Objective: Composite Dietary Antioxidant Index (CDAI) values serve as a summary of an individual's combined dietary antioxidant intake. Although specific antioxidants are known to reduce thyroid damage from oxidative stress, the relationship between the CDAI and thyroid function remains uncertain. The purpose of this study was thus to investigate this relationship in greater detail while focusing on a representative American adult population. Methods: A total of 6,860 subjects from the 2007-2012 NHANES cohort were included in this study. Associations between CDAI values and thyroid function were evaluated with weighted linear regression models and smoothed curve fitting. Subgroup analyses were also performed. Results: The weighted mean (SD) values for variables analyzed in this study included a CDAI of 0.13 (0.06), serum free T4 (FT4) levels of 0.80 (0.01) ng/dL, and serum total T4 (TT4) levels of 7.80 (0.03) ug/dL. Lower CDAI values were found to be associated with higher levels of FT4 and TT4 using both unadjusted and adjusted models that accounted for relevant confounders (adjusted model, FT4 ß = -0.003, p = 0.005; TT4 ß = -0.035, p < 0.001). This negative correlation persisted when CDAI was categorized into quartiles (FT4, p for trend = 0.014; TT4, p for trend = 0.003). Conclusion: These findings suggest that a diet rich in antioxidants, as reflected by higher CDAI scores, is associated with significant decreases in levels of free and total T4. Further analyses will be necessary to better clarify the underlying mechanisms behind these observations.

Associations among thyroid hormone levels and mean corpuscular volume in adults in the US: A cross-sectional examination of the NHANES 2007-2012 dataset.

Mean corpuscular volume (MCV) is an important indicator used to determine the etiology of anemia and is associated with a variety of diseases. However, the link between thyroid function and MCV has yet to be clarified. This study was thus developed to assess relationships between thyroid function and MCV in a population of adults in the US. Results from the National Health and Nutrition Examination Survey study performed from 2007 to 2012 were used to conduct a cross-sectional analysis. Key thyroid-related variables included in this analysis were thyroid-stimulating hormone, total thyroxine (TT4), free triiodothyronine (FT3), total triiodothyronine (TT3), free thyroxine (FT4), antithyroglobulin, thyroglobulin, and antithyroid peroxidase levels. Generalized linear regression models were employed when estimating associations between MCV quartiles and thyroid parameters in 8104 adults 18 + years of age. In these participants, the weighted mean (SD) MCV was 89.36 (0.16) fL, with thyroid-stimulating hormone levels of 1.86 (0.03) mIU/mL, FT3 levels of 3.20 (0.01) pg/mL, FT4 levels of 0.80 (0.01) ng/dL, TT3 levels of 115.09 (0.64) ng/dL, and TT4 levels of 7.81 (0.04) µg/dL. When analyses were not adjusted, higher MCV values were related to reduced serum levels of FT3, TT3, or TT4. Following adjustment for possible confounding variables, this significant negative correlation between MCV and levels of FT3, TT3, and TT4 remained, and subgroup analysis revealed that this negative correlation was present in the male group and in the age group >50 years, but not in the female group and in the age group less than or equal to 50 years. These results suggest a significant negative correlation between MCV and FT3, TT3, and TT4, and this negative correlation originated more from the male population and those older than 50 years of age. The underlying mechanisms warrant additional investigation.

The relationship between sleep duration and thyroid function in the adult US population: NHANES 2007-2012.

OBJECTIVE: Sleep disturbance is a common problem in the general population. Sleep deprivation or dysfunction can have profound health consequences. However, how sleep duration is associated with thyroid function remains unclear. This study was thus developed to examine the association between sleep duration and thyroid function in the US adult population. METHODS: A total of 8102 participants from the NHANES 2007-2012 dataset were included in this study. Weighted data analyses were conducted, and the link between sleep duration and thyroid function was probed using linear regression models with smoothed curve fitting. Stratified analyses were also performed. RESULTS: Weighted mean (standard deviation) values for study variables were as follows: sleep duration 6.85 (0.02) hours, thyroid-stimulating hormone (TSH) 1.86 (0.03) mIU/ml, serum free T3 3.20 (0. 01) pg/mL, serum free T4 0.80 (0.01) ng/dL, serum total T3 115.12 (0.64) ng/dL, serum total T4 7.81 (0.04) ug/dL, TPOAb 16.20 (1.53) IU/mL, TgAb 5.75 (0.73) IU/mL, and Tg 15.11 (0.46) ng/mL. In unadjusted analyses, increased sleep duration was associated with higher serum TSH levels and decreased FT3 levels. After adjustment for potential confounders, a significant negative relationship was detected between sleep duration and FT3 levels in participants with ≤7 hours of sleep. When sleep duration exceeded 7 hours, no significant changes in FT3 levels were observed after further increases in sleep duration. CONCLUSION: Increased sleep duration was related to decreased FT3 levels, primarily at short sleep durations, and this correlation was no longer evident when participants reached the recommended healthy sleep duration.

The relationship between dietary inflammatory index values and thyroid function in the US adult population: An analysis of the NHANES 2007-2012 cohort.

OBJECTIVE: Researchers have developed the Dietary Inflammatory Index (DII) as a tool to quantify the inflammatory potential of a given diet. Higher DII scores indicated a more proinflammatory diet. While inflammation is known to have a strong impact on thyroid function, the precise nature of the association between DII scores and thyroid function has yet to be clarified. This study was conducted with the goal of exploring this relationship in a representative population of adults from the United States. METHODS: For this study, we used data from the National Health and Nutrition Examination Survey (NHANES). Standardized questionnaires were used to collect demographic and dietary data from the participants, and laboratory tests were used to collect data on the participants' thyroid parameters and other relevant data. Linear regression models and smoothed curve fitting were used to assess the relationship between DII scores and thyroid function, with weighted data analyses and subgroup analyses being conducted as appropriate. RESULTS: In total, 7712 subjects were recruited from the NHANES 2007-2012 cohort. Their weighted mean age was 44.87 (0.47) years, mean DII score was 1.41 (0.05). Mean FT3 was 3.20 (0.01) pg/mL and mean TT4 was 7.81 (0.03) µg/dL. In adjusted analyses, higher DII values were related to increases in FT3 (ß = .007; p = .027) and TT4 (ß = .050; p = .005) levels. Subgroup analyses showed a negative correlation between FT3 levels and DII scores in a population with high urinary iodine concentrations. CONCLUSION: These data indicate that the consumption of a more proinflammatory diet, as evidenced by elevated DII scores, is correlated with significant increases in FT3 and TT4 levels. However, for people with high urinary iodine concentrations, a more proinflammatory diet was associated with lower FT3 levels. Additional research will be vital to clarify the mechanistic basis for these findings.

Nanocrystalline Cellulose Modulates Dysregulated Intestinal Barriers in Ulcerative Colitis.

Ulcerative colitis (UC) is a recurrent chronic inflammation of the colon with increasing incidence and prevalence, which could increase the risk of colorectal cancer. It is urgent to find an effective method with few side effects. Nanocrystalline cellulose (NCC), which is from plant fibers, has a good biocompatibility and high biosafety. Herein, we used NCC to treat UC and evaluated its treatment effect by the disease activity index, intestinal pathology, inflammatory cytokines, tight junction proteins, and mucins. We studied the impact of NCC on mucin expression and gut microbiota to discuss the therapeutic mechanism. NCC can effectively treat UC by regulating the MAPK pathway of mucin 2 and the relative abundance of Akkermansia and Odoribacter, which could not cause the body damage. NCC could not cause body damage compared to the medications, while it had a better effect on the regulation of MUC2 compared to the present drug substitutes. NCC is a practical alternative for the treatment of UC.

Ligand-Modified Gold Nanoparticles as Mitochondrial Modulators: Regulation of Intestinal Barrier and Therapy for Constipation.

Intestinal metabolism-related diseases, such as constipation, inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer, could be associated with the dysfunction of intestinal mitochondria. The mitochondria of intestinal epithelial cells are of great significance for promoting intestinal motility and maintaining intestinal metabolism. It is necessary for the prophylaxis and therapy of intestinal metabolism-related diseases to improve mitochondrial function. We investigated the effect of 4,6-diamino-2-pyrimidinethiol-modified gold nanoparticles (D-Au NPs) on intestinal mitochondria and studied the regulatory role of D-Au NPs on mitochondria metabolism-related disease. D-Au NPs improved the antioxidation capability of mitochondria, regulated the mitochondrial metabolism, and maintained intestinal cellular homeostasis via the activation of AMPK and regulation of PGC-1α with its downstream signaling (UCP2 and DRP1), enhancing the intestinal mechanical barrier. D-Au NPs improved the intestinal mitochondrial function to intervene in the emergence of constipation, which could help develop drugs to treat and prevent mitochondrial metabolism-related diseases. Our findings provided an in-depth understanding of the mitochondrial effects of Au NPs for improving human intestinal barriers.

Dysregulated ceRNA network modulated by copy number variation-driven lncRNAs in breast cancer: A comprehensive analysis.

Breast cancer is a malignancy harmful to physical and mental health in women, with quite high mortality. Copy number variations (CNVs) are vital factors affecting the progression of breast cancer. Detecting CNVs in breast cancer to predict the prognosis of patients has become a promising approach to accurate treatment in recent years. The differential analysis was performed on CNVs of long noncoding RNAs (lncRNAs) as well as the expression of lncRNAs, microRNAs (miRNAs) and mRNAs in normal tissue and breast tumor tissue based on The Cancer Genome Atlas (TCGA) database. The CNV-driven lncRNAs were identified by the Kruskal-Wallis test. Meanwhile, a competitive endogenous RNA (ceRNA) network regulated by CNV-driven lncRNA was constructed. As the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed, the mRNAs in the dysregulated ceRNA network were mainly enriched in the biological functions and signaling pathways, including the Focal Adhesion-PI3K-Akt-mTOR-signaling pathway, the neuronal system, metapathway biotransformation Phase I and II and blood circulation, etc. The relationship between the CNVs of five lncRNAs and their gene expression in the ceRNA network was analyzed via a chi-square test, which confirmed that except for LINC00243, the expression of four lncRNAs was notably correlated with the CNVs. The survival analysis revealed that only the copy number gain of LINC00536 was evidently related to the poor prognosis of patients. The CIBERSORT algorithm showed that five lncRNAs were correlated with the abundance of immune cell infiltration and immune checkpoints. In a word, by analyzing CNV-driven lncRNAs and the ceRNA network regulated by these lncRNAs, this study explored the mechanism of breast cancer and provided novel insights into new biomarkers.

Nanocrystalline Cellulose Cures Constipation via Gut Microbiota Metabolism.

Constipation can seriously affect the quality of life and increase the risk of colorectal cancer. The present strategies for constipation therapy have adverse effects, such as causing irreversible intestinal damage and affecting the absorption of nutrients. Nanocrystalline cellulose (NCC), which is from natural plants, has good biocompatibility and high safety. Herein, we used NCC to treat constipation assessed by the black stool, intestinal tissue sections, and serum biomarkers. We studied the effect of NCC on gut microbiota and discussed the correlation of gut microbiota and metabolites. We evaluated the long-term biosafety of NCC. NCC could effectively treat constipation through gut microbiota metabolism, which required a small dosage and did not affect the organs and intestines. NCC could be used as an alternative to medications and dietary fiber for constipation therapy.

Ultra-flat and long-lived plasmons in a strongly correlated oxide.

Plasmons in strongly correlated systems are attracting considerable attention due to their unconventional behavior caused by electronic correlation effects. Recently, flat plasmons with nearly dispersionless frequency-wave vector relations have drawn significant interest because of their intriguing physical origin and promising applications. However, these flat plasmons exist primarily in low-dimensional materials with limited wave vector magnitudes (q < ~0.7 Å-1). Here, we show that long-lived flat plasmons can propagate up to ~1.2 Å-1 in α-Ti2O3, a strongly correlated three-dimensional Mott-insulator, with an ultra-small energy fluctuation (<40 meV). The strong correlation effect renormalizes the electronic bands near Fermi level with a small bandwidth, which is responsible for the flat plasmons in α-Ti2O3. Moreover, these flat plasmons are not affected by Landau damping over a wide range of wave vectors (q < ~1.2 Å-1) due to symmetry constrains on the electron wavefunctions. Our work provides a strategy for exploring flat plasmons in strongly correlated systems, which in turn may give rise to novel plasmonic devices in which flat and long-lived plasmons are desirable.

DNMT1 facilitates growth of breast cancer by inducing MEG3 hyper-methylation.

BACKGROUND: To understand the effect of DNMT1-mediated MEG3 promoter methylation on breast cancer progression. METHODS: Expression of DNMT1, MEG3 and miR-494-3p was assayed by qRT-PCR and western blot. Methylation-specific PCR was used to examine MEG3 promoter methylation level. ChIP, RNA binding protein immunoprecipitation assay and dual-luciferase reporter gene assay were applied to verify interaction between DNMT1 and MEG3, miR-494-3p and MEG3 and OTUD4. CCK-8, wound healing and Transwell assays were used to detect biological functions of breast cancer cells. Tumor growth was observed by tumor xenograft model. RESULTS: DNMT1 and miR-494-3p were highly expressed while MEG3 and OTUD4 were lowly expressed in breast cancer cells. Knockdown of DNMT1 inhibited progression of breast cancer cells by enhance MEG3 expression through demethylation. MEG3 could downregulate miR-494-3p expression, and OTUD4 was a target of miR-494-3p. Upregulation of MEG3 and downregulation of miR-494-3p both inhibited malignant behavior of cells in vitro. In addition, high MEG3 expression restrained growth of breast cancer in vivo. CONCLUSION: Briefly, our results demonstrated that, DNMT1 induced methylation of MEG3 promoter, and played a key role in breast cancer growth throughmiR-494-3p/OTUD4 axis. These findings provide new insights into molecular therapeutic targets for breast cancer.

Impact of nanomaterials on the intestinal mucosal barrier and its application in treating intestinal diseases.

The intestinal mucosal barrier (IMB) is one of the important barriers to prevent harmful substances and pathogens from entering the body environment and to maintain intestinal homeostasis. The dysfunction of the IMB is associated with intestinal diseases and disorders. Nanomaterials have been widely used in medicine and as drug carriers due to their large specific surface area, strong adsorbability, and good biocompatibility. In this review, we comprehensively discuss the impact of typical nanomaterials on the IMB and summarize the treatment of intestinal diseases by using nanomaterials. The effects of nanomaterials on the IMB are mainly influenced by factors such as the dosage, size, morphology, and surface functional groups of nanomaterials. There is huge potential and a broad prospect for the application of nanomaterials in regulating the IMB for achieving an optimal therapeutic effect for antibiotics, oral vaccines, drug carriers, and so on.

Adsorptivity of cationic cellulose nanocrystals for phosphate and its application in hyperphosphatemia therapy.

Nanocellulose has gained much attention because of its excellent properties. Cationic cellulose nanocrystals (cCNC) shows good adsorptivity toward negative ions and molecules. Phosphate binders are most used to treat hyperphosphatemia and it is significant to develop its alternatives with high specific and low cost in the clinic. Herein, we prepared cCNC and characterized it by FTIR, TEM, dynamic light scattering, and viscosity method. We simulated the binding process of cationic cellulose for phosphate and used it as phosphate binder for hyperphosphatemia therapy to study the phosphate binding effect and evaluate the oral toxicity. Cationic cellulose improved the conditions of mice models and efficiently decreased the level of phosphate in the serum. cCNC had a better binding effect than cationic microcrystalline cellulose both in vitro and in vivo. cCNC could be used as alternatives to phosphate binder for therapy of chronic renal failure and hyperphosphatemia.

Evaluation of the impact of body mass index on venous thromboembolism risk factors.

In this paper, we investigate the interaction impacts of body mass index (BMI) on the other important risk factors for venous thromboembolism (VTE), using deep venous thrombosis (DVT) patient data from the International Warfarin Pharmacogenetics Consortium (IWPC). We apply eight machine learning techniques, including naive Bayes classifier (NB), support vector machine (SVM), elastic net regression (ENET), logistic regression (LR), lasso regression (LAR), multivariate adaptive regression splines (MARS), boosted regression tree (BRT) and random forest model (RF). The RF method is selected as the best model for classification. Out of 33 features considered in this study, we identify 12 variables as relatively important risk factors for VTE. Finally, we examine the interaction impacts of BMI on these important VTE risk factors. We conclude that the impacts of risk factors on VTE incidence are varying across different BMI groups, and the variations are different for different risk factors. Therefore the interaction impacts of BMI on the other risk factors have to be taken into account in order to better understand the incidence of VTE.

A review on nanocellulose as a lightweight filler of polyolefin composites.

Nanocellulose (NC) possesses low density, high aspect ratio, impressive mechanical properties, nanoscale dimensions, which shows huge potential applications as a reinforced filler. Polyolefin (PO), represented by polyethylene (PE) and polypropylene (PP), has been widely used in industries. Recently nanocellulose/polyolefin nanocomposites (NC/PO nanocomposites) have caught more attention from the application of automotive components, aerospace, furniture, building, home appliances, and sport. In this review, the surface modifications of nanocellulose and polyolefin are summarized respectively, such as surface adsorption modification, small molecule modification, and graft copolymerization modification. The common preparations of NC/PO nanocomposites are discussed, including the melting compounding, the solvent casting, and the in-situ polymerization. The lightweight, mechanical properties, and aging-resistant properties of NC/PO nanocomposites are highlighted. Finally, the potentials and challenges for industrial production development of NC/PO nanocomposites are discussed.

Gold Nanoparticles Cure Bacterial Infection with Benefit to Intestinal Microflora.

Antibiotics that are most used to cure bacterial infections in the clinic result in the imbalance of intestinal microflora, destroy the intestinal barrier, and induce bacterial resistance. There is an urgent need for antibacterial agent therapy for bacterial infections that does not destroy intestinal microflora. Herein, we applied 4,6-diamino-2-pyrimidinethiol (DAPT)-coated Au nanoparticles (D-Au NPs) for therapy of bacterial infection induced by Escherichia coli ( E. coli) in the gut. We cultured D-Au NPs and E. coli in an anaerobic atmosphere to evaluate their bactericidal effect. We studied the microflora, distribution of Au, and biomarkers in mice after a 28-day oral administration to analyze the effect of Au NPs on mice. D-Au NPs cured bacterial infections more effectively than levofloxacin without harming intestinal microflora. D-Au NPs showed great potential as alternatives to oral antibiotics.

Tribological Behavior of Titanium Alloy Treated by Nitriding and Surface Texturing Composite Technology.

This study experimentally investigated the effect of surface textures on the tribological mechanism of nitrided titanium alloy (Ti⁻6Al⁻4V). The titanium alloy samples were nitrided at various temperatures ranging from 750 to 950 °C for 10 h in a plasma nitriding furnace. Then, surface textures were fabricated on the polished titanium alloy and plasma nitrided samples by laser process system. The surface roughness, microhardness, and constitution of samples treated by single nitriding and samples treated by composite technology were characterized. The tribological properties of the samples were investigated on a CSM ball-on-disc tribometer. The results show that plasma nitriding effectively enhances the wear resistance of the substrate. The wear rate decreases first and then increases with the increase of nitriding temperature, and the wear rate reaches the minimum at 900 °C. However, the increase in roughness caused by nitriding treatment leads to an increase in the friction coefficient. It is found that surface textures can obviously reduce the friction coefficient of the nitrided titanium alloy. In addition, it can also reduce the wear rate of titanium alloys after nitriding at 900 and 950 °C. It can be concluded that the nitriding and surface texturing combined treatment can obviously reduce the friction coefficient and wear rate at the nitriding temperatures of 900 and 950 °C. This is attributed to the combined effect of high hardness of nitride layers and the function of micro-trap for wear debris of surface textures.

IL-6 is involved in malignancy and doxorubicin sensitivity of renal carcinoma cells.

Various survival factors such as the pleiotropic cytokine interleukin-6 (IL-6), a major mediator of inflammation and activator of signal transducer and activator of transcription 3 (STAT3), serve to block apoptosis in cancer cells. Our present study revealed that the expression of IL-6, while not other IL-2, IL-4, IL-8, or IL-10, was significantly elevated in resistance of renal carcinoma cells (RCC) when compared with human renal proximal tubule epithelial cell line HK-2. The inhibition of IL-6 by siRNA can suppress the proliferation, migration and invasion of RCC cells and increase the doxorubicin (Dox) sensitivity. While recombination IL-6 can attenuate the inhibition effects of Dox on proliferation of RCC cells. Further studies indicated that inhibition of IL-6 by siRNA can decrease the phosphorylation of STAT3 in RCC cells. Over expression of STAT3 increased the proliferation, migration and invasion of RCC cells and reversed si-IL-6 induced increase of Dox sensitivity of ACHN and A498 cells. In addition, IL-6 treatment can activate ERK1/2 via increasing its phosphorylation. PD98059, the ERK1/2 inhibitor, attenuated IL-6 induced proliferation and synergistically increased the Dox sensitivity of si-IL-6 transfected ACHN cells. Collectively, our data suggested that IL-6 plays an important role in malignancy and Dox sensitivity of RCC. The targeted inhibition of IL-6 signals might be a promising therapeutic strategy for the treatment of renal cancer.

A CuI/CuIII prototypical organometallic mechanism for the deactivation of an active pincer-like CuI catalyst in Ullmann-type couplings.

Unraveling the mechanistic details of copper-catalyzed arylation of nucleophiles (Ullmann-type couplings) is a very challenging task. It is a matter of intense debate whether it is a radical-based process or an organometallic redox-based process. The ancillary ligand choice in Ullmann-type couplings plays a key role in such transformations and can strongly influence the catalytic efficiency as well as the mechanism. Here, we show how a predesigned tridentate pincer-like catalyst undergoes a deactivation pathway through a CuI/CuIII prototypical mechanism as demonstrated by helium-tagging infrared photodissociation (IRPD) spectroscopy and DFT studies, lending a strong support to the existence of an aryl-CuIII species in the Ullmann couplings using this tridentate ligand.

Role of Protease-Activated Receptor 2 in Regulating Focal Segmental Glomerulosclerosis.

Background /Aims: The underlying mechanisms leading to focal segmental glomerulosclerosis (FSGS) are lacking. In this report, we examined the role of protease-activated receptors (PARs) subtype PAR2 and its downstream signals in regulating the pathophysiological process of FSGS. METHODS: Nephropathy was induced by intravenous injections of adriamycin (ADR) in rats to study FSGS. Western Blot analysis and ELISA were employed to determine the protein expression levels of PAR2 and its downstream signal pathways as well as the levels of PICs. RESULTS: In ADR rats, expression of PAR2, PKCε and PKA was amplified and this was accompanied with increases of pro-inflammatory cytokines (PICs) including IL-1ß, IL-6 and TNF-α. Inhibition of PAR2 signal by systemic administration of FSLLRY-NH2 (FSL) attenuated amplification of PICs. Notably, FSL further influenced key molecular mediators during development of FSGS. i.e., it specifically restored the impaired nephrin and attenuated the exaggerated transforming growth factor beta 1 (TGF-ß1), caspase-9 and desmin thereby improving worsened renal functions and glomerular injury. Consistent with this, in cultured podocytes FSL also largely restored downregulation of nephrin and attenuated amplifications of caspase-9 and desmin induced by TGF-ß1. CONCLUSIONS: Results of this study suggest that PAR2 plays an important role in mediating renal injury induced by glomerulosclerosis. Inhibition of PAR2 signal pathway has a protective effect on FSGS mainly via PIC and TGF-ß1 mechanisms. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of FSGS observed in patients.