Precise Synthesis of Optically Active and Thermo-degradable Poly(trifluoromethyl methylene) with Circularly Polarized Luminescence.

Developing high performance and environment-friendly fluoropolymers is greatly desired. In this work, we found that 2-diazo-1,1,1-trifluoroethane can be polymerized by air-stable alkyne-palladium(II) catalysts following a living polymerization mechanism, affording a fluoropolymer, poly(trifluoromethyl methylene) in high yield with controlled molar mass and low dispersity. This polymer bears trifluoromethyl on every main chain atom and thus has good resistance to chemical corrosion, high hydrophobicity, and excellent dielectric constant with low dielectric loss. Due to the steric hindrance between the trifluoromethyl pendants, the synthetic poly(trifluoromethyl methylene) can twist into a stable helix. The one-handed preferred helices synthesized using chiral PdII -catalysts exhibit high optical activity and circularly polarized luminescence. Remarkably, such polymer can be completely degraded to (E)-1,1,1,4,4,4-hexafluorobut-2-ene at high temperatures (>280 °C). Additionally, taking advantage of the living chain end, the polymer can be further modified.

Controlled Synthesis of Cyclic-Helical Polymers with Circularly Polarized Luminescence.

Cyclic polymers attract attention because of their endless structure and unique properties, which differ from the linear analogs. However, the synthesis of cyclic polymers is difficult and prohibits their functions and applications. In this study, we reported chiral cyclic PdII -catalysts that initiate a living ring-expansion polymerization of isocyanides, yielding a single-handed cyclic-helical poly(phenyl isocyanide), with predictable molecular weight (Mn ) and low dispersity (Mw /Mn ), in good yield. Using this method, cyclic bottlebrush polymers were prepared via the grafting-onto strategy. The cyclic topology was confirmed using various spectroscopic data and atomic force microscope observation. Moreover, the cyclic polymer brushes, comprising of a one-handed helical backbone, showed interesting photoluminescence and circularly-polarized luminescence.

Precise fabrication of porous polymer frameworks using rigid polyisocyanides as building blocks: from structural regulation to efficient iodine capture.

Porous materials have recently attracted much attention owing to their fascinating structures and broad applications. Moreover, exploring novel porous polymers affording the efficient capture of iodine is of significant interest. In contrast to the reported porous polymers fabricated with small molecular blocks, we herein report the preparation of porous polymer frameworks using rigid polyisocyanides as building blocks. First, tetrahedral four-arm star polyisocyanides with predictable molecular weight and low dispersity were synthesized; the chain-ends of the rigid polyisocyanide blocks were then crosslinked, yielding well-defined porous organic frameworks with a designed pore size and narrow distribution. Polymers of appropriate pore size were observed to efficiently capture radioactive iodine in both aqueous and vapor phases. More than 98% of iodine could be captured within 1 minute from a saturated aqueous solution (capacity of up to 3.2 g g-1), and an adsorption capacity of up to 574 wt% of iodine in vapor was measured within 4 hours. Moreover, the polymers could be recovered and recycled for iodine capture for at least six times, while maintaining high performance.

Self-Assembly of a Bilayer 2D Supramolecular Organic Framework in Water.

Accurate control of the layer number of orderly stacked 2D polymers has been an unsettled challenge in self-assembly. Herein we describe the fabrication of a bilayer 2D supramolecular organic framework from a monolayer 2D supramolecular organic framework in water by utilizing the cooperative coordination of a rod-like bipyridine ligands to zinc porphyrin subunits of the monolayer network. The monolayer supramolecular framework is prepared from the co-assembly of an octacationic zinc porphyrin monomer and cucurbit[8]uril (CB[8]) in water through CB[8]-encapsulation-promoted dimerization of 4-phenylpyridiunium subunits that the zinc porphyrin monomer bear. The bilayer 2D supramolecular organic framework exhibits structural regularity in both solution and the solid state, which is characterized by synchrotron small-angle X-ray scattering and high-resolution transmission electron microscopic techniques. Atomic force microscopic imaging confirms that the bilayer character of the 2D supramolecular organic framework can be realized selectively on the micrometer scale.

Relationship Between Gene Polymorphism of Methylenetetrahydrofolate Reductase C677T and Left Ventricular Hypertrophy in Chinese Patients with Chronic Kidney Disease.

OBJECTIVE: This study aimed to investigate the relationship between the gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T and left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD). METHODS: A total of 763 Chinese patients with CKD undergoing genetic testing were included in the study. The association between the gene polymorphism of MTHFR C677T and echocardiographic parameters was analyzed through univariate and multivariate analyses. RESULTS: We found a remarkably positive association between MTHFR C677T gene polymorphism and LVH indexes, including interventricular septal thickness (F = 3.8; P = .022), left ventricular posterior wall thickness (F = 3.0; P = .052), left ventricular mass (F = 3.9; P = .022), and left ventricular mass index (F = 2.6; P = .075). After adjusting for the potential confounders linking the polymorphism,we found that the positive association between the polymorphism and LVH indexes still existed in patients with CKD in some multiple linear regression models (P <.05). CONCLUSION: MTHFR C677T gene polymorphism may be a genetic susceptibility marker for the development of LVH in patients with CKD.

Precise Synthesis of π-Conjugated Block Copolymers and Polymerization-Induced Chiral Self-Assembly toward Helical Nanofibers with Circularly Polarized Luminescence.

Precise synthesis and efficient self-assembly of semiconducting polymers are of great interest. Herein, we report the controlled synthesis of π-conjugated poly(phenyl isocyanide)-b-poly(phenyleneethylene) (PPI-b-PPE) copolymers via chain extension of ethynyl 4-iodobenzene initiated by Pd(II)-terminated helical poly(phenyl isocyanide) (PPI). The in-situ-generated block copolymers self-assembled into various supramolecular architectures depending on the PPE length. The helical PPI segment induced the block copolymers with an appropriate PPE length self-assemble into helical nanofibers with a controlled size and defined helicity. Interestingly, the chiral assemblies of the block copolymers exhibit intense optical activity and emit clear circularly polarized luminescence.

Selective Synthesis of Single-Handed Helical Polymers from Achiral Monomer and a Mechanism Study on Helix-Sense-Selective Polymerization.

Inspired by the exquisite helices in Nature, fabrication of helical materials with controlled handedness has attracted considerable attention. Herein, we report on precis synthesis of single left- and right-handed helical polyisocyanides through living polymerization of achiral monomers using chiral palladium catalysts under helix-sense-selective manner. Mechanism study revealed that the yielded helices with opposite handedness showed different activity of the living chain end. The helix with unfavored handedness was self-terminated, while the one with favored handedness showed high activity and could undergo chain propagation to form a high molecular weight polymer with maintained single-handed helicity.

Crystallization-Driven Asymmetric Helical Assembly of Conjugated Block Copolymers and the Aggregation Induced White-light Emission and Circularly Polarized Luminescence.

Controlling the self-assembly morphology of π-conjugated block copolymer is of great interesting. Herein, amphiphilic poly(3-hexylthiophene)-block-poly(phenyl isocyanide)s (P3HT-b-PPI) copolymers composed of π-conjugated P3HT and optically active helical PPI segments were readily prepared. Taking advantage of the crystallizable nature of P3HT and the chirality of the helical PPI segment, crystallization-driven asymmetric self-assembly (CDASA) of the block copolymers lead to the formation of single-handed helical nanofibers with controlled length, narrow dispersity, and well-defined helicity. During the self-assembly process, the chirality of helical PPI was transferred to the supramolecular assemblies, giving the helical assemblies large optical activity. The single-handed helical assemblies of the block copolymers exhibited interesting white-light emission and circularly polarized luminescence (CPL). The handedness and dissymmetric factor of the induced CPL can be finely tuned through the variation on the helicity and length of the helical nanofibers.

Controlled Synthesis of Shell Cross-Linked Helical Poly(phenylborate isocyanide) Nanoparticles with H2O2/Redox Dual Responsiveness and Their Application in Antitumor Drug Delivery.

To mimic the helical structure and function of biopolymers, shell cross-linked nanoparticle (P4) composed of left-handed helical poly(phenylborate isocyanide) in core and hydrophilic polyisocyanide in shell was prepared. The phenylborate in the core and the disulfide bonds in the cross-linkage render the nanoparticle with excellent dual stimuli-responsiveness to glutathione (GSH) and H2O2. Nevertheless, it has good stability in normal physiological conditions. Because of the helicity and borate pendants of the core, such nanoparticle has high capacity for anticancer drug loading, for example, the loading capacity of doxorubicin (DOX) was up to 68%. Moreover, the DOX-loaded DOX@P4 showed excellent tumor cell penetration potency and fast drug release. More than 78% of murine breast cancer cell (4T1) can be killed within 48 h, supporting this material with great potential in antitumor drug nanocarriers.

Kidney injury molecule-1 expression predicts structural damage and outcome in histological acute tubular injury.

BACKGROUND: A few studies have shown that urinary kidney injury molecule-1 (uKIM-1) levels are increased in acute kidney injury (AKI); however, the correlation between uKIM-1 and histological tubular injury, which is considered to be the gold standard for evaluating renal damage and predicting prognosis, is still unclear. We performed this study to determine whether the predicted value of uKIM-1 is correlated with renal KIM-1 (tKIM-1) expression and tissue damage in AKI patients. METHODS: This retrospective study recruited 14 healthy individuals and 27 biopsy-proven acute tubular injury (ATI) patients. uKIM-1 and plasma KIM-1 (sKIM-1) levels were measured by ELISA, and tKIM-1 expression was evaluated by immunohistochemistry. RESULTS: Elevated levels of urinary, plasma, and renal KIM-1 were found in ATI patients. The uKIM-1 concentration was positively correlated with tKIM-1 expression and reflected the severity of renal histological injury. The outcome of ATI was associated with uKIM-1 expression: the ATI patients with higher uKIM-1 levels had an increased potential for an incomplete recovery of renal function during follow-up. Additionally, the level of KIM-1, regardless of source, was negatively related to the eGFR, and ROC curve analysis revealed that the ROC-AUC was 0.923 (p = 0.000) for the diagnosis of ATI based on a combination of high uKIM-1 and sKIM-1 levels. CONCLUSION: The uKIM-1 level corresponds with the severity of renal histological damage and can be a potential reliable predictor of adverse renal outcomes in ATI patients. Moreover, combining uKIM-1 and sKIM-1 can increase the sensitivity and specificity of the diagnosis of severe ATI.

Fast Living Polymerization and Helix-Sense-Selective Polymerization of Diazoacetates Using Air-Stable Palladium(II) Catalysts.

In this work, air-stable palladium(II) catalysts bearing bidentate phosphine ligands were designed and prepared, which could initiate fast and living polymerizations of various diazoacetate monomers under mild conditions. The polymerization afforded the desired polymers in high yields with controlled molecular weights ( Mns) and narrow molecular weight distributions ( Mw/ Mns). The Mns of the isolated polymers were linearly correlated to the initial feed ratios of monomer to catalyst, confirming the living/controlled manner of the polymerizations. The Mn also increased linearly with the monomer conversion, and all of the isolated polymers showed narrow Mw/ Mns. The polymerization was relatively fast and could be accomplished within several minutes. Such fast living polymerization method can be applied to a wide range of diazoacetate monomers in various organic solvents at room temperature in air. Taking advantage of the living nature, we facilely prepared a series of block copolymers through chain extension reactions. The amphiphilic block copolymers synthesized by this method exhibited interesting self-assembly properties. Moreover, polymerization of achiral bulky diazoacetate by Pd(II) catalysts bearing a chiral bidentate phosphine ligand leads to the formation of polymers with high optical activity due to the formation of the predominantly one-handed helix of the main chain. The helix sense of the polymers was determined by the chirality of the Pd(II) catalysts.

Synthesis of Redox-Responsive Core Cross-Linked Micelles Carrying Optically Active Helical Poly(phenyl isocyanide) Arms and Their Applications in Drug Delivery.

In this manuscript, we designed and synthesized three core cross-linked micelles (M-5L, P-5L, and P-5D) with redox-responsive disulfide bonds in the core and carrying optically active helical polyisocyanide arms. Their arms were different in the helicity of the main chain and the chirality of the side groups. These micelles showed excellent redox-responsiveness to reducing agent. However, because of the different chiralities of the arms, the three micelles exhibited different performances in drug delivery and controlled release. The M-5L micelle carrying left-handed helical arms showed better therapeutic effect than the other two due to the rapid cell membrane permeability.

A Facile Synthetic Route to Amphiphilic Poly(Meta-Phenylene Ethynylene) and Poly(Meta-Phenylene Ethynylene)-Block-Polyisocyanide Using a Single Catalyst.

An optically active, amphiphilic meta-phenylene ethynylene (m-PE) bearing a chiral amide pendant was designed and synthesized. Living polymerization of m-PE using alkyne-Pd(II) as the initiator afforded well-defined poly(meta-phenylene ethynylene) (m-PPE). These m-PPEs were found to have a stable helical conformation in THF, 1,4-dioxane, and CH3CN and showed split Cotton effects over the range of 245⁻400 nm. The positive first Cotton effect was observed at a wavelength of approximately 308 nm, and the negative second Cotton effect was observed at a wavelength of approximately 289 nm. The m-PPEs exhibited helical conformational changes in different mixed solvents and showed effective solvent-dependent helix inversion in CHCl3/THF solutions. The sign of the Cotton effect of m-PPE was inverted at 25 °C by varying the mixing ratio of THF and CHCl3. Finally, amphiphilic poly(meta-phenylene ethynylene)-block-polyisocyanide containing hydrophilic PPE and hydrophobic PPI segments were facilely prepared using Pd(II)-terminated m-PPE as the macroinitiator. This block copolymer can self-assemble into well-defined spherical nanostructures in a selective THF/CH3OH solution. This efficient polymerization will open up enormous opportunities for the preparation of functional amphiphilic block copolymers in a wide variety of fields.

Oxidative stress in 5/6 nephrectomized rat model: effect of alpha-lipoic acid.

Alpha-lipoic acid (ALA) is a powerful antioxidant, and its effect in ameliorating complications of diabetes mellitus has been widely documented. The aim of this study was to investigate the role of ALA in the disease progression of remnant kidneys (RK). Systolic blood pressure (SBp), hemoglobin, renal function, kidney malondialdehyde (MDA), glutathione (GSH), vitamin E (Vit E) concentrations, p65 nuclear factor (NF)-κB activity, and macrophage infiltration were analyzed in sham and RK rats supplemented with ALA (100 mg/kg body weight, i.p., every other day) or vehicle for 12 weeks. RK rats exhibited increases in SBp, kidney MDA concentration, p65 NF-κB activity, and macrophage infiltration, which were prominent in weeks 4 and 8 and decreased at week 12. RK rats also showed anemia, microalbuminuria, and decreased renal function and kidney GSH and Vit E concentrations. These changes were all attenuated by 8 weeks of ALA treatment compared to RK vehicle group. But the continued ALA treatment after week 8 reversed the beneficial effect on SBp, kidney MDA concentration, p65 NF-κB activity, macrophage infiltration, anemia, microalbuminuria, and renal function, while the beneficial effect was maintained if the treatment was discontinued after week 8. Furthermore, ALA increased albuminuria and kidney MDA concentration in sham animals. In conclusion, ALA administration attenuates oxidative stress, inflammation, and hypertension and delayed the deterioration of kidney function in RK rats with enhanced oxidative stress, while in healthy animals or RK rats with a well-balanced redox state, ALA may act as a pro-oxidant, contributing to renal dysfunction.

The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration.

BACKGROUND: Chronic hypoxia in the kidney has been suggested as a final common pathway in the progression of chronic kidney disease (CKD) leading to eventual kidney failure. Hypoxia-inducible factor (HIF) activation might offer a promising approach to the protection of hypoxic tissues, but the effect of HIF activation on CKD is still controversial. In this study, we investigated whether HIF activation had a beneficial or deleterious effect on CKD in the rat remnant kidney (RK) model. METHODS: One week after a subtotal nephrectomy, rats were randomized and each received special administration of prolyl hydroxylases (PHD) inhibitor L-mimosine (L-Mim) as follows: in the early long-time L-Mim treatment group they were administered L-Mim at Weeks 2-12; in the advanced medium-term L-Mim treatment group they were administered L-Mim at Weeks 4-12 and in the end-stage L-Mim treatment group they were administered L-Mim at Weeks 8-12. RESULTS: Compared with the control group, renal dysfunction and increased collagen III deposition, α-smooth muscle actin expression and ED-1-positive macrophage infiltration in tubulointerstitium were exacerbated by early long-term L-Mim treatment and improved by advanced medium-term L-Mim treatment. End-stage L-Mim treatment had no effect on RK rats. Furthermore, early long-term L-Mim treatment activated HIF-1α, connective tissue growth factor (CTGF) and phospho-Smad3 prominently throughout the time course and activated HIF-2α, vascular endothelial growth factor (VEGF) and erythropoietin (EPO) slightly at the end stage, while advanced medium-term L-Mim treatment activated HIF-2α, VEGF and EPO significantly and had no effect on HIF-1α, CTGF and phospho-Smad3. CONCLUSION: HIF-α activation by PHD inhibitor L-Mim has dual roles in the development of CKD in the rat RK model depending on the timing of the administration and possibly the activated isoform of HIF-α.

The relationship between the level of serum creatinine, modified diet and renal disease formula, Cockcroft-Gault formula, and renal tubulointerstitial lesion.

OBJECTIVE: This study investigated the relationship between the levels of serum creatinine (SCr), the estimated glomerular filtration rate (eGFR), and the degree of tubulointerstitial injury. METHODS: A total of 511 patients of Zhongshan hospital in China were hospitalized due to physical abnormalities and diagnosed with kidney disease by renal biopsy. The clinical and pathological data were retrospectively analyzed. The level of SCr was determined in all patients, and the eGFR was calculated with modification of diet in renal disease and Cockcroft-Gault formulae, whereas the renal histopathology was quantified according to the Katafuchi semi-quantitative standards. RESULTS: With the aggravation of tubulointerstitial injury, SCr level increased and eGFR decreased gradually. The degree of tubulointerstitial lesion showed a positive correlation with SCr level and negative correlation with Cockcroft-Gault formula and modification of diet in renal disease (r = 0.627, -0.649, -0.626; p < 0.001). When the SCr was in the normal range, above 90% of the patients had various degrees of tubulointerstitial damage and 12.2% of the patients had moderate-to-severe tubulointerstitial lesions. The correlation between SCr level and tubulointerstitial damage became weak. CONCLUSIONS: The morphologic changes of tubulointerstitium are closely linked with renal function, but incompletely parallel. SCr in the abnormal range could be used to diagnose tubulointerstitial injury well. However, when the level of SCr was in the so-called normal range, eGFR by the modification of diet in renal disease or Cockcroft-Gault formula may be preferred to assess renal tubulointerstitial injury.

Transient hypoxia-inducible factor activation in rat renal ablation and reduced fibrosis with L-mimosine.

AIM: Hypoxia-inducible factor (HIF) activity during the course of chronic kidney disease (CKD) development is poorly defined, and the effect of HIF activation on CKD is still controversial. The purpose of the present study was to characterize HIF expression during the course of CKD development, and to investigate the effect of HIF activation on CKD by using prolyl hydroxylase (PHD) inhibitor L-mimosine. METHODS: Rats with remnant kidneys (RK) were killed at week 1, 2, 4, 6, 8, 12 after subtotal nephrectomy. An additional group of RK rats was treated with L-mimosine to study the effect of HIF-α activation. RESULTS: Tubulointerstitial hypoxia in the remnant kidney began at week 1 and continued, albeit attenuated, until week 12, the last time point examined. The nuclear expression of HIF-1α and HIF-2α, as well as typical HIF target genes VEGF (vascular endothelial growth factor), HO-1 (heme oxygenase-1), GLUT-1 (glucose transporter-1) and EPO (erythropoietin), were all upregulated in the early stage of RK when renal function was stable, and returned to the basal level later, accompanied by impaired renal function and interstitial fibrosis. L-mimosine administered from week 5 to week 12 led to accumulation of HIF-1α and HIF-2α proteins, increased expression of VEGF, HO-1 and GLUT-1, and improved renal function. Furthermore, fibrosis markers α-smooth muscle actin (α-SMA) and Collagen III, as well as peritubular capillary rarefaction index, were all significantly decreased after L-mimosine treatment. CONCLUSION: There was a transient HIF-α activation in the remnant kidney of rats at the early stage following subtotal nephrectomy. L-mimosine administered in later stages re-activated HIF-α and reduced tubulointerstitial fibrosis.

Diverse effects of ischemic pretreatments on the long-term renal damage induced by ischemia-reperfusion.

BACKGROUND/AIMS: The role of ischemic pretreatment in long-term changes after renal ischemia-reperfusion (I/R) injury remains unknown. In this study, we mainly aimed to investigate the effect of ischemic pretreatments with different durations on the development of tubulointerstitial fibrosis and functional impairment following acute renal I/R. METHODS: We established a rat model of renal warm I/R, clamping both pedicles for 40 min followed by reperfusion; the experiment was followed up for 10 weeks. Prior ischemia (10, 20, 30 min) was induced 8 days before the 40-min ischemia. To assess tissue fibrosis, we performed morphometric analysis, Masson's trichrome and Sirius red staining. We also analyzed the expression of alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta(1) (TGF-beta(1)) and phospho-Smad2. RESULTS: Patchy tubulointerstitial fibrosis was found 5 and 10 weeks later in rats subjected to I/R alone or pretreated with 10-min ischemia. Tubulointerstitial fibrosis deteriorated further and renal dysfunction occurred in rats pretreated with 30-min ischemia accompanied by increased expression of alpha-SMA, TGF-beta(1), and phospho-Smad2 at 5 weeks. In contrast, the above abnormalities were significantly attenuated in rats pretreated with 20-min ischemia. CONCLUSION: Severe I/R injury may cause tubulointerstitial fibrosis in the long term, and different ischemic pretreatments have diverse effects on renal fibrosis.

Immunosuppressive effects of demethylzeylasteral in a rat kidney transplantation model.

In this study, we examined the immunosuppressive activity of demethylzeylasteral (T-96), isolated from the traditional Chinese herbal medicine, Tripterygium wilfordii Hook f. Its immunosuppressive effect was investigated using mouse splenocytes in vitro, and in an in vivo rat kidney transplant model. T-96 inhibited mouse splenocyte proliferation in a dose dependent manner. In the rat kidney transplant study, rats were randomly divided into eight groups following kidney transplantation, and different doses of T-96 or cyclosporin A (CsA) were administered to each group. T-96 alone at doses of 10 or 20 mg/kg/day significantly prolonged the survival of kidney-transplanted rats, compared with transplanted but untreated control rats. A combination of T-96 and prednisone also significantly prolonged survival: 10 mg/kg/day T-96 with 10 mg/kg/day prednisone increased the survival time to 31.8+/-6.5 days. Moreover, the combination of T-96 and prednisone was also effective in suppressing rejection of rat transplanted kidneys. These results demonstrate the strong immunosuppressive activity of T-96 and suggest a possible clinical use for T-96 as an immunosuppressive agent in the fields of organ transplantation and autoimmune disorders.