Detection of copper ions in an aqueous solution by a dual-peak long period fiber grating functionalized with a polypyrrole-chitosan composite.

A dual-peak long period fiber grating (DP-LPFG) sensor functionalized by polypyrrole-chitosan composite was proposed for sensitive detection of Cu2+ ions in aqueous solution. The nitrogen atom on the polypyrrole ring and the amino group on the chitosan chain in the complex matrix can chelate the Cu2+ ions. Thus, the refractive index of the overlay changed and further modulated the transmission spectrum of DP-LPFG. After special design, the double peaks can move in opposite directions with the increase of Cu2+ ion concentration, thereby greatly improving detection sensitivity. The linear sensitivity of the fabricated sensor was measured to be 9.12 and 2.14 nm/ppm (0.61 and 0.14 nm/µM) for concentrations of 0.1-0.5 (1.5 µM-7.5 µM) and 0.5-2 ppm (7.5 µM-30 µM), respectively. In addition, the Langmuir isothermal model was used to evaluate the overall response of the sensor to Cu2+ ions quantitatively, and the detection limit was determined to be 0.05 ppb (0.75 nM). This ingenious sensor offers a new solution for sensitive detection of heavy metal ions in environmental water.

The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, we report that esterification of the 5'-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5'-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.

Efficient peroxymonosulfate activation by N-rich pyridyl-iron phthalocyanine derivative for the elimination of pharmaceutical contaminants under solar irradiation.

It is of great significance for improving electron transmission performance by changing of the outer ring structure of iron phthalocyanine. Herein, 4 (pyridine-2, 3-yl) iron phthalocyanine (FepyPc), as N-rich pyridyl-iron phthalocyanine derivative, was introduced to degrade pharmaceutical contaminants. The catalytic degradation of organic pollutants with FepyPc was studied by activating peroxymonosulfate (PMS) at room temperature. The results clarified that the removal rate of carbamazepine (CBZ) was close to 100% within 60 min and the calculated apparent rate constant was about 2 times larger than FePc, which proved that FepyPc had superior performance. Four active species were identified for the degradation of CBZ, including superoxide radical (•O2-), singlet oxygen (1O2), sulfate radical (SO4•-) and hydroxyl radical (•OH). In addition, the possible reaction mechanism was inferred in FepyPc/PMS/sunlight system for CBZ removal. Finally, the CBZ degradation pathway was proposed by using ultra-performance liquid chromatography and high definition mass spectrometry (UPLC/HDMS). This research provided a meaningful and efficient method for the elimination of pharmaceutical contaminants.

Heat/pH-boosted release of 5-fluorouracil and albumin-bound paclitaxel from Cu-doped layered double hydroxide nanomedicine for synergistical chemo-photo-therapy of breast cancer.

Considerable attention has been devoted to nanomedicine development for breast cancer therapy, while the therapeutic efficiency is far from satisfactory owing to non-specific biodistribution-caused side effects and limitation of single modal treatment. In this study, we have developed a novel nanomedicine for efficient combination breast cancer therapy. This nanomedicine was based on copper-doped layered double hydroxide (Cu-LDH) nanoparticles loaded with two FDA-approved anticancer drugs, i.e. 5-fluorouracil (5-FU) and albumin-bound paclitaxel (nAb-PTX) with complementary chemotherapeutic actions. The 5-FU/Cu-LDH@nAb-PTX nanomedicine showed pH-sensitive heat-facilitated therapeutic on-demand release and demonstrated the moderate-to-strong synergy of photothermal therapy and chemotherapy in inducing apoptosis of breast cancer cells (4 T1). This nanomedicine had a high colloidal stability in saline and serum, and efficiently accumulated in the tumor tissue. Remarkably, this nanomedicine nearly eliminated 4 T1 tumors in vivo after a two-course treatment under mild 808 nm laser irradiation (0.75 W/cm2, 3 min) at very low doses of 5-FU and nAb-PTX (0.25 and 0.50 mg/kg, 8-50 times less than that used in other nanoformulations), without observable side effects. Therefore, this research provides a novel approach to designing multifunctional nanomedicines for on-demand release of chemotherapeutics to cost-effectively treat breast cancer with minimal side effects in future clinic applications.

Enhancing Tumor Accumulation and Cellular Uptake of Layered Double Hydroxide Nanoparticles by Coating/Detaching pH-Triggered Charge-Convertible Polymers.

Layered double hydroxide (LDH) nanoparticles are extensively explored as multifunctional nanocarriers due to their versatility in both the host layer and the interlayer anion. In this study, we report modification of positively charged Cu-containing LDH nanoparticles with a pH-responsive charge-changeable polymer to improve the particle colloidal stability in blood circulation, reduce the nonspecific uptake by normal cells in organs, and subsequently facilitate tumor accumulation and uptake by tumor cells in the acidic tumor microenvironment. In vitro experimental results demonstrate that this promising charge-convertible polymer-LDH nanocarrier well reduces the capture by macrophages in the physiologic medium (pH 7.4) but facilitates the uptake by tumor cells due to detaching of the coated polymer layer in the weakly acidic condition (pH 6.8). Cu-containing LDH nanoparticles also show pH-responsive magnetic resonance imaging (MRI) contrast capacity (i.e., r 1 relaxivity). In vivo MRI further confirms effective tumor accumulation of the charge-convertible nanohybrids, with ∼4.8% of the injected dose accumulated at 24 h postintravenous injection, proving the potential as a versatile delivery nanocarrier to enhance the antitumor treatment.

High-valent iron-oxo species on pyridine-containing MWCNTs generated in a solar-induced H2O2 activation system for the removal of antimicrobials.

The overuse of antimicrobials has resulted in serious damage to the ecosystem and human health. Therefore, the development of an efficient, stable, and reusable catalyst to eliminate antimicrobials under mild conditions is highly desired. Drawing inspiration from the metabolism of drugs by the enzymes in the human body, such as heme catalase, we developed a simulated enzyme catalyst, perchloride iron phthalocyanine (FePcCl16), immobilized on pyridine-modified multiwalled carbon nanotubes (FePcCl16-Py-MWCNTs). In the catalyst, FePcCl16 worked as the active site, and the axial fifth ligand, 4-aminopyridine, was introduced to cleave H2O2 heterolytically. Inspired by the reaction mechanism of heme catalase and H2O2, the catalytic system was designed based on FePcCl16-Py-MWCNTs for oxidizing 4-chloro-3,5-dimethylphenol (PCMX) by H2O2 activation. The results showed that the catalytic activity of the system was significantly increased under simulated solar light irradiation, which can promote electron transfer for heterolytic cleavage of H2O2. The enzyme-like catalyst achieved much higher catalytic activity than the Fenton reaction when the pH was close to neutral. It turned out that the main active species was high-valent iron-oxo (Fe(Ⅳ) = O) rather than hydroxyl radial (•OH) or superoxide radical (•O2-), different from most mechanisms. Ultraperformance liquid chromatography-high-definition mass spectrometry showed that the substrate was degraded to small molecule acids by Fe(Ⅳ) = O active species and further mineralization indicated by total organic carbon. The catalytic system exhibited highly efficient, stable, recyclable catalytic performance under mild conditions and did not cause secondary pollution to the environment. This study of a simulated enzyme catalytic system offers important insight into sewage treatment.

Charge Reversion Simultaneously Enhances Tumor Accumulation and Cell Uptake of Layered Double Hydroxide Nanohybrids for Effective Imaging and Therapy.

Nanotheranostics have been actively sought in precision nanomedicine in recent years. However, insufficient tumor accumulation and limited cell uptake often impede the nanotheranostic efficacy. Herein, pH-sensitive charge-reversible polymer-coated layered double hydroxide (LDH) nanohybrids are devised to possess long circulation in blood but reserve surface charges in the weakly acidic tumor tissue to re-expose therapeutic LDH nanoparticles for enhanced tumor accumulation and cell uptake. In vitro experimental data demonstrate that charge-reversible nanohybrids mitigate the cell uptake in physiological conditions (pH 7.4), but remarkably facilitate internalization by tumor cells after charge reversion in the weakly acidic environment (pH 6.8). More significantly, about 6.0% of injected charge-reversible nanohybrids accumulate in the tumor tissue at 24 h post injection, far higher than the average accumulation (0.7%) reported elsewhere for nanoparticles. This high tumor accumulation clearly shows the tumor tissues in T1 -weighted magnetic resonance imaging. As a consequence, >95% inhibition of tumor growth in the B16F0-bearing mouse model is achieved via only one treatment combining RNAi and photothermal therapy under very mild irradiation (808 nm laser, 0.3 W cm-2 for 180 s). The current research thus demonstrates a new strategy to functionalize nanoparticles and simultaneously enhance their tumor accumulation and cell internalization for effective cancer theranostics.

Enhanced Prevention of Breast Tumor Metastasis by Nanoparticle-Delivered Vitamin E in Combination with Interferon-Gamma.

Preventing cancer metastasis is one of the remaining challenges in cancer therapy. As an efficient natural product, alpha-tocopheryl succinate (α-TOS), the most effective form of vitamin E, holds great anticancer potential. To improve its efficacy and bioavailability, lipid-coated calcium carbonate/phosphate (LCCP) nanoparticles (NPs) with folic acid and PEG modification are synthesized for efficient delivery of α-TOS to 4T1 cancer cells. The optimized LCCP-FA NPs (NP-TOS15) show an α-TOS loading efficiency of around 60%, and enhanced uptake by 4T1 metastatic cancer cells. Consequently, NP-TOS15 significantly enhance the anticancer effect in combination with interferon-gamma (IFN-γ) in terms of apoptosis facilitation and migration inhibition. Importantly, NP-TOS15 upregulate the anticancer immunity via downregulating program death ligand 1 (PD-L1) expression that is initially induced by IFN-γ, and remarkably prevent the lung metastasis, particularly in combination with IFN-γ. Further investigation reveals that this combination therapy also modulates the cytotoxic lymphocyte infiltration into the tumor microenvironment for tumor elimination. Taken together, the NP delivery of α-TOS in combination with IFN-γ provides an applicable strategy for cancer therapy.

An Albumin-binding Polypeptide Both Targets Cytotoxic T Lymphocyte Vaccines to Lymph Nodes and Boosts Vaccine Presentation by Dendritic Cells.

Rationale: Albumin-binding carriers have been shown to target cytotoxic T lymphocyte (CTL) vaccines to lymph nodes (LNs) and improve the efficacy of the vaccines. However, it was not clear whether the improved efficacy is solely due to the LN targeting, which prompted this study. Methods: First, we generated a fusion protein consisting of an albumin-binding domain (ABD) and an immune-tolerant elastin-like polypeptide (iTEP). Then, we examined the binding between this fusion protein, termed ABD-iTEP, and mouse serum albumin (MSA). Next, we evaluated the accumulation of ABD-iTEP in LNs and dendritic cells (DCs) in the LNs. We also analyzed antigen presentation and in vitro T cell activation of vaccines that were delivered by ABD-iTEP and investigated possible underlying mechanisms of the presentation and activation results. Last, we measured CTL responses induced by ABD-iTEP-delivered vaccines in vivo. Results: ABD-iTEP bound with MSA strongly with an affinity of 1.41 nM. This albumin-binding carrier, ABD-iTEP, accumulated in LNs 3-fold more than iTEP, a control carrier that did not bind with albumin. ABD-iTEP also resulted in 4-fold more accumulation in DCs in the LNs than iTEP. Most importantly, ABD-iTEP drastically enhanced the antigen presentation of its vaccine payloads and the T cell activation induced by its payloads. The enhancement was dependent on the formation of the complex between MSA and ABD-iTEP. Meanwhile, the MSA/ABD-iTEP complex was found to have increased stability in acidic subcellular compartments and increased cytosolic accumulation in DCs, which might explain the enhanced vaccine presentation resulting from the complex. Finally, when ABD-iTEP was used to deliver CTL vaccines derived from both self- and non-self-antigens, it boosted the vaccine-induced responses by 2-fold in either case. Conclusion: ABD-iTEP not only targets vaccines to LNs but also promotes the presentation of the vaccines by DCs. Albumin-binding carriers have more than one mechanism to boost the efficacy of CTL vaccines.

Engineering of a self-adjuvanted iTEP-delivered CTL vaccine.

Cytotoxic T lymphocyte (CTL) epitope peptide-based vaccines are widely used in cancer and infectious disease therapy. We previously generated an immune-tolerant elastin-like polypeptides (iTEPs)-based carrier to deliver a peptide CTL vaccine and enhance the efficiency of the vaccine. To further optimize the vaccine carrier, we intended to potentiate its function by designing an iTEP-based carrier that was able to deliver adjuvant and a vaccine epitope as one molecule. Thus, we fused a 9-mer H100, a peptide derived from the high-mobility group box 1 protein (HMGB1) that could induce activation of dendritic cells (DCs), with an iTEP polymer to generate a new iTEP polymer named H100-iTEP. The H100-iTEP still kept the feature of reversible phase transition of iTEPs and should be able to be used as a polymer carrier to deliver peptide vaccines. The expression levels of CD80/CD86 on DCs were assessed using flow cytometry. The iTEP fusion-stimulated IL-6 secretion by DCs was measured with ELISA. Activation of antigen-specific CD8+ T cells induced by iTEP fusions was examined through a B3Z hybridoma cell activation assay. In vivo CTL activation promoted by iTEP fusions was detected by an IFN-γ-based ELISPOT assay. The iTEP fused with H100 could induce maturation of DCs in vitro as evidenced by increased CD80 and CD86 expression. The iTEP fusion also promoted activation of DCs by increasing secretion of a proinflammatory cytokine IL-6. The N-terminus or C-terminus fusion of H100 to iTEP had a similar effect and a reduced form of cysteine in iTEP fusions was required for DC stimulation. iTEP fusions potentiated a co-administrated CTL vaccine by increasing an antigen-specific CTL response in vitro and in vivo. When the H100-iTEP was fused to a CTL epitope to generate a one-molecule vaccine, this self-adjuvanted vaccine elicited a stronger antigen-specific CTL response than a vaccine adjuvanted by Incomplete Freund's Adjuvant. Thus, we have successfully generated a functional, one-molecule iTEP-based self-adjuvanted vaccine.

A Comparison Study of iTEP Nanoparticle-Based CTL Vaccine Carriers Revealed a Surprise Relationship between the Stability and Efficiency of the Carriers.

Vaccine carriers have been shown to enhance cytotoxic T lymphocyte (CTL) epitope peptide vaccines by addressing intrinsic limitations of the vaccines. We have previously developed an immune-tolerant elastin-like polypeptide (iTEP)-based nanoparticle (NP) as an effective and unique CTL vaccine carrier. The NP is unique for its humoral immune tolerance, flexible structure, and ability to deliver CTL vaccines as polypeptide fusions. Here, we aimed to improve the NP by increasing its stability since we found it was not stable. We thus generated a more stable iTEP NP (ST-NP) and used it to deliver a CTL peptide vaccine, SIINFEKL. However, we surprisingly found that the ST-NP had a lower efficiency than the previously developed, marginally stable iTEP NP (MS-NP) in terms of promoting vaccine presentation and vaccine-induced CTL responses. On the other hand, dendritic cells (DCs) showed preferential uptake of the ST-NP but not the MS-NP. To develop an iTEP vaccine carrier that outperforms both the MS-NP and the ST-NP, we devised an iTEP NP that has a changeable stability responsive to a cytosolic, reductive environment, termed reductive environment-dependent NP or RED-NP. The RED-NP showed an intermediate ability to promote vaccine presentation and T cell responses in vitro between the MS-NP and the ST-NP. However, the RED-NP induced the strongest CTL responses in vivo among all three NPs. In conclusion, iTEP NPs that have a dynamically changeable stability are most effective to deliver and enhance CTL peptide vaccines. The work also demonstrated the versatile nature of iTEP vaccine carriers.

Catalytic degradation of recalcitrant pollutants by Fenton-like process using polyacrylonitrile-supported iron (II) phthalocyanine nanofibers: Intermediates and pathway.

Iron (II) phthalocyanine (FePc) molecules were isolated in polyacrylonitrile (PAN) nanofibers by electrospinning to prevent the formation of dimers and oligomers. Carbamazepine (CBZ) and Rhodamine B (RhB) degradation was investigated during a Fenton-like process with FePc/PAN nanofibers. Classical quenching tests with isopropanol and electron paramagnetic resonance tests with 5,5-dimethyl-pyrroline-oxide as spin-trapping agent were performed to determine the formation of active species during hydrogen peroxide (H2O2) decomposition by FePc/PAN nanofibers. After eight recycles for CBZ degradation over the FePc/PAN nanofibers/H2O2 system, the removal ratios of CBZ remained at 99%. Seven by-products of RhB and twelve intermediates of CBZ were identified using ultra-performance liquid chromatography and high-resolution mass spectrometry. Pathways of CBZ and RhB degradation were proposed based on the identified intermediates. As the reaction proceeded, all CBZ and RhB aromatic nucleus intermediates decreased and were transformed to small acids, but also to potentially toxic epoxide-containing intermediates and acridine, because of the powerful oxidation ability of •OH in the catalytic system.

Violacein anticancer activity is enhanced under hypoxia.

Current cancer treatments of solid tumours such as chemotherapy and radiotherapy, have yet to produce effective therapeutic results due to non-specific targeting. This has led to many complications, such as toxicities in cancer patients. The ability of natural compounds in inducing programmed cell death (apoptosis), a process dysregulated in cancer cells, has been extensively studied in recent studies. This study assessed the anti-proliferative activity of violacein in a number of human cancer cell lines under normal and hypoxic conditions. Furthermore, we investigated its effects in a tumour­bearing subcutaneous mouse model. We also examined the ability of a tumour­targeting Salmonella strain to produce violacein for local delivery within the tumour microenvironment. The results showed that hypoxia significantly increased the cytotoxic effects of violacein. The most significant reduction in the IC50 was in the HT29 (12.6-fold) and HCT116 (4.8-fold) colon cancer cell lines, HN5 head and neck squamous carcinoma cell line (6.5-fold), and MCF-7 breast ductal carcinoma cell line (4-fold). Among the cell lines tested for active caspase-3/7 activity, violacein only increased caspase-3/7 activity in the A549 non-small lung cancer cell line. In vivo efficacy of violacein showed that HN5 tumour­bearing mice had regressed tumours during the treatment period and survival increased. The results also showed that transfer of the violacein biosynthetic cluster into the oncolytic strain VNP20009 of Salmonella resulted in the production of active violacein, suggesting targeted delivery of violacein by VNP20009. Taken together, our study has shown that hypoxia synergises the effects of violacein and the results from the in vivo administration of violacein require further investigation of violacein as an anticancer chemotherapeutic.

The critical roles of miR-21 in anti-cancer effects of curcumin.

Curcumin is a well-known phytochemical that has various anti-cancer effects. Although it has been demonstrated that curcumin can inhibit multiple signalling pathways, the exact mechanisms for its demonstrated anti-cancer effects are not fully understood. Recent studies have revealed that curcumin may affect cancer initiation and progression through regulating microRNAs (miRs). In this review, we focus on the roles of microRNA-21 (miR-21) in the anti-cancer effects of curcumin and regulatory mechanisms for the effects of curcumin on miR-21. MiR-21 mediates various effects of curcumin on cancer cells including proliferation, apoptosis, metastasis and anti-cancer drug resistance. Several downstream pathways of miR-21 have been identified including phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), programmed cell death protein 4 (PDCD4) and NF-κB pathways. Curcumin decreases miR-21 levels through both increasing miR-21 exosome exclusion from the cells and inhibiting the transcription of the miR-21 gene in the cells by binding to its promoter.

[Case-control study on clinical effects of arthroscopic single-versus double-bundle ACLs reconstructions].

OBJECTIVE: To compare the clinical results of arthroscopic single and double-bundle ACLs reconstructions. METHODS: From January 2009 to May 2010,45 patients with anterior cruciate ligament tear were divided into two groups. In the first group,the anterior cruciate ligament were anatomical reconstructed with double-bundle semitendinous tendon, and in the second group the anterior cruciate ligaments were anatomical reconstrucated with single bundle semitendinous tendon. There were 22 patients (15 males and 7 females) in double-bundle group, with an average age of (27.04 +/- 3.68) years; 18 patients (13 males and 5 females) in single bundle group, with an average age of (28.16 +/- 4.76) years. Therapeutic effects between two groups were compared according to the IKDC, Lysholm scoring standards and Lachman test, knee pivot shift test, KT-1000. RESULTS: Twenty-two patients in double-bundle group and 18 patients in single-bundle group were followed-up, and the mean duration was 12 months. The IKDC score of patients in single-bundle group improved from preoperative 41.40 +/- 6.30 to postoperatively 95.70 +/- 3.10, Lysholm score increased from preoperative 47.20 +/- 6.30 to postoperative 94.20 +/- 2.40. And the IKDC score of patients in double-bundle group improved from preoperative 40.90 +/- 6.10 to postoperative 96.10 +/-3.40, Lysholm score increased from preoperative 48.10 +/- 6.50 to postoperative 95.10 +/- 2.49. There was no statistically significant difference between the two groups. The Lachman test was positive in 2 patients (1 patient in double-bundle group and 1 patient in single-bundle group); and pivot shift test was positive in 2 patients (1 patient in double-bundle group and 1 patient in single-bundle group). KT-1000 of patients in double-bundle group was (1.5 +/- 1.2) mm, and (1.9 +/- 1.5) mm in single-bundle group, there were no statistically significant differences between the two groups. CONCLUSION: Arthroscopic single-bundle reconstruction and double-bundle anterior cruciate ligament reconstruction have no significant differences in clinical effects.

[Comparison of the relativity of MRI appearance of cartilage injuries and postoperative effect of arthroscope on articular cartilage disease of knee].

OBJECTIVE: To analyze the indication of arthroscope by examining the correlations between cartilage injury degree confirmed by MRI and postoperative effect. METHODS: From Aug. 2005 to April 2008, 87 cases with knee osteoarthritis were treated by arthroscopes including 44 males and 43 females,aged from 16 to 67 years (means 46.3 years). Arthrodial cartilage of knee was graded by ICRS MR, and the therapeutic effect was evaluated by Lysholm scoring. RESULTS: All 87 knees of 87 cases were followed-up for from 12 to 30 months (averaged 23 months). The cartilage injury degree of knees was graded as follows: grade 4 in 30 cases, grade 3 in 23 cases, grade 2 in 20 cases, grade 1 in 12 cases, grade 0 in 2 cases, means grade (2.770 +/- 1.138). Postoperative Lysholm score was from 59 to 100, means (95.170 +/- 7.556). Coefficient correlation (r) = -0.152, P = 0.159 > 0.05. Although the results had no correlations between cartilage injury degree and Lysholm score, negative correlation tendency existed. CONCLUSION: The patients with higher grade of knee cartilage injury degree confirmed by MRI (1.5T) have worse effect after operation, the grade is not a gold standard as a operation indication in arthroscopic procedure.

[Transformation of bar gene to tetraploid of Isatis indigotica].

The transgenic tetraploid of Isatis indigotica mediated by Agrobacterium tumefaciens was obtained. To transfer the plant binary expression vector pCAMBIA 3300 carrying bar gene, the Agrobacterium tumefaciens strain EHA 105 was used as engineering bacterium. The results of PCR indicated that the bar gene had been transferred into and merged with the genome of Isatis indigotica. This study will make foundation for improvement of other characters of this species with genetic engineering.