Levosimendan: A New Therapeutical Strategy in Patients with Renal Insufficiency.

Levosimendan, a Ca2 + sensitizer with positive inotropic effects, is primarily employed for the short-term treatment of acute decompensated heart failure (ADHF). Levosimendan exerts renal function protection through various mechanisms, including anti-apoptosis, anti-inflammatory, and antioxidant effects in vivo. Additionally, levosimendan may have a protective effect on individuals with heart failure and renal insufficiency, as well as on renal function impairment after cardiac surgery. However, the application of levosimendan in patients with severe renal dysfunction remains controversial. This article delves into the use of levosimendan in severe renal insufficiency, explores its impact on renal function, and provides a comprehensive overview of its impact on renal function after cardiac surgery.

ShengqingJiangzhuo capsule ameliorates diabetic nephropathy by improving Keap1/Nrf2 signaling pathway.

BACKGROUND: Diabetic nephropathy (DN) is a major contributor to end-stage renal failure, and lacking effective treatment options. Shengqing Jiangzhuo capsule (SQJZJN), a traditional Chinese medicine prescription with known efficacy in chronic kidney disease, has not been thoroughly investigated for its potential in DN protection. METHODS: Eight-week-old male C57BLKS/J db/db, C57BLKS/J db/m mice, and human glomerular mesangial cell (HMC) cells cultured with high glucose were used as experimental models in this study. RESULTS: The in vivo investigation showed that SQJZJN can significantly ameliorate renal pathological damage, reduce serum creatinine, and lower urinary microalbumin levels in db/db mice. In vitro, SQJZJN treatment mitigated advanced glycation end products (AGEs) and reactive oxygen species (ROS), leading to a reduction in renal cell apoptosis. Mechanistically, SQJZJN activated the Keap1/Nrf2/ARE pathway by promoting nuclear factor erythroid-derived 2-related factor 2 (Nrf2), γ-glutamylcysteine synthetase heavy subunit (γ-GCS), and Heme oxygenase-1 (HO-1) expressions, while decreasing Kelch-like ECH-associated protein 1 (KEAP1) expressions. CONCLUSION: These findings suggest that SQJZJN exerts a protective effect on DN, potentially through the activation of the Keap1/Nrf2/ARE pathway.

Comprehensive analysis of ETS1 expression and its prognostic value in clear cell renal cell carcinoma.

BACKGROUND: ETS1, a member of the large ETS domain family of transcription factors, plays a role in the progression of many types of carcinoma. ETS1 expression has been linked to a more favorable prognosis in renal cell carcinoma. The objective of this study was to assess the predictive significance of ETS1 in individuals suffering from clear cell renal cell carcinoma (ccRCC). METHODS: The correlation between ETS1 expression and ccRCC was analyzed. Data on ETS1 and clinical information for ccRCC patients were obtained from the Cancer Genome Atlas database and analyzed using R software. Then, we presented validation results using RT-qPCR (quantitative reverse transcription PCR). The receiver operator characteristic (ROC) curves were generated using the pROC software package to determine the cutoff values for ETS1. Additionally, the ImmuneScore, StromalScore, and ESTIMATEScore were calculated using the ESTIMATES algorithm. The connection between ccRCC and ETS1 was investigated using enrichment analysis based on Gene Oncology and the Kyoto Encyclopedia of Genes and Genomes. The tumor immunity estimation resource (TIMER) and the integrated repository portal for tumor-immune system interactions (TISIDB) databases were utilized to analyze the association between ETS1 expression and immune cell infiltration in ccRCC. The impact of ETS1 on the survival of ccRCC patients was evaluated using the PrognoScan database. We evaluated the Tumor Mutation Burden (TMB) value between the two sets of samples with high and low ETS1 expression, as well as the differences in gene mutations between the two groups. RESULTS: The mRNA expression of ETS1 in ccRCC was higher compared to normal tissues. Results showed a significant positive correlation between elevated ETS1 expression levels and improved overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS), with a P < 0.05. Furthermore, high ETS1 expression levels were closely linked to early tumor stage and prolonged survival time. TMB in the ETS1-high expression group was significantly less than that in the ETS1-low expression group. CONCLUSIONS: Downregulation of ETS1 expression correlated with poor prognosis and immune infiltration in ccRCC, further suggesting that ETS1 may be a biomarker for better prognosis in ccRCC patients.

Emodin alleviates CRS4-induced mitochondrial damage via activation of the PGC1α signaling.

Cardiorenal syndrome type 4 (CRS4), a progressive deterioration of cardiac function secondary to chronic kidney disease (CKD), is a leading cause of death in patients with CKD. In this study, we aimed to investigate the cardioprotective effect of emodin on CRS4. C57BL/6 mice with 5/6 nephrectomy and HL-1 cells stimulated with 5% CKD mouse serum were used for in vivo and in vitro experiments. To assess the cardioprotective potential of emodin, we employed a comprehensive array of methodologies, including echocardiography, tissue staining, immunofluorescence staining, biochemical detection, flow cytometry, real-time quantitative PCR, and western blot analysis. Our results showed that emodin exerted protective effects on the function and structure of the residual kidney. Emodin also reduced pathologic changes in the cardiac morphology and function of these mice. These effects may have been related to emodin-mediated suppression of reactive oxygen species production, reduction of mitochondrial oxidative damage, and increase of oxidative metabolism via restoration of PGC1α expression and that of its target genes. In contrast, inhibition of PGC1α expression significantly reversed emodin-mediated cardioprotection in vivo. In conclusion, emodin protects the heart from 5/6 nephrectomy-induced mitochondrial damage via activation of the PGC1α signaling. The findings obtained in our study can be used to develop effective therapeutic strategies for patients with CRS4.

Rational design of multimodal therapeutic nanosystems for effective inhibition of tumor growth and metastasis.

Simultaneous inhibition of both tumor growth and metastasis is the key to treating metastatic cancer, yet the development of effective drug delivery systems represents a great challenge since multimodal therapeutic agents must be rationally combined to overcome the biological mechanisms underpinning tumor cell proliferation and invasion. In this context, we report a hybrid therapeutic nanoscale platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. In our design, we first conjugated DOX via an acid-labile linker onto gold nanorods that were pre-modified with the tumor targeting peptide RGD and a positively charged, disulfide cross-linked short polyethylenimines (DSPEI), and then incorporated shRNA through electrostatic complexation with DSPEI. We show that this "all in one" nanotherapeutic system (RDG/shRNA@DOX) can be effectively internalized through RGD-mediated endocytosis, followed by stimuli-responsive intracellular co-release of DOX and shRNA. Our in vitro experiments suggest that this multimodal system can significantly inhibit cell proliferation, angiogenesis, and invasion of metastatic MDA-MB-435 cancer cells. Systemic administration of RDG/shRNA@DOX into a metastatic mouse model led to enhanced tumor accumulation, and, most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides important insight into the rational design of therapeutic systems for the effective treatment of metastatic carcinoma. STATEMENT OF SIGNIFICANCE: The key to successfully treat metastatic cancer is the simultaneous inhibition of both tumor growth and metastasis. This represents a great challenge for the design of drug delivery systems since multimodal therapeutic agents must be rationally combined to overcome the respective biological mechanisms underpinning tumor cell proliferation and invasion. Toward this end, we developed a hybrid nanomedicine platform that incorporates an anti-proliferative drug, doxorubicin (DOX), and an anti-NF-κB agent, p65-shRNA, for effective treatment of metastatic breast cancer. We showed that this multimodal system (RDG/shRNA@DOX) enhanced tumor accumulation, led to prolonged circulation, and most importantly, significant inhibition of in situ tumor growth and almost complete suppression of tumor metastasis. We believe this hybrid multimodal nanotherapeutic system provides significant insight into the rational design of therapeutic systems for the effective treatment of metastatic cancer.

Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells.

Previously, combination chemotherapy of doxorubicin (DOX) and quercetin (QUR) was developed to improve antitumor effects and reverse multidrug resistance and several biocompatible nanocarriers, such as liposomes and micelles, were validated for their targeted delivery. In this study, we report a near-infrared (NIR)-responsive drug delivery system based on DOX and QUR co-loaded gold nanocages (AuNCs) with biotin modification. The system was simply fabricated by filling the hollow interiors of AuNCs with tetradecanol (TD), a phase-change material with a melting point of 39°C, to control the drug release. The main cause of multidrug resistance (MDR) of DOX is the overexpression of P-glycoprotein (P-gp), which can be inhibited by QUR. Thus the combination chemotherapy of DOX and QUR may provide a promising strategy for MDR. The in vitro cytotoxicity of DOX and QUR at several fixed mass ratios was carried out and showed that the combination index (CI) was the smallest at the ratio of 1:0.2, indicating that the best synergistic effect was achieved. The resultant nanocomplex (abbreviated as BPQD-AuNCs) exhibited fast release (80% released in 20min) and strong cytotoxicity against MCF-7/ADR cells (IC50, 1.5µg/mL) under NIR irradiation. Additionally, BPQD-AuNCs were found to generate a large amount of reactive oxygen species (ROS), to inhibit P-gp expression and ATP activity. Taken together, the results show that BPQD-AuNC is a prospective nano-delivery system for overcoming multidrug-resistant cancer.

A new NIR-triggered doxorubicin and photosensitizer indocyanine green co-delivery system for enhanced multidrug resistant cancer treatment through simultaneous chemo/photothermal/photodynamic therapy.

It is a great challenge to combat multidrug resistant (MDR) cancer effectively. To address this issue, we developed a new near-infrared (NIR) triggered chemotherapeutic agent doxorubicin (DOX) and photosensitizer indocyanine green (ICG) co-release system by aid of NIR induced photothermal effect of gold nanocages (AuNCs) and temperature sensitive phase-change property of 1-tetradecanol at its melting point of 39°C, which could simultaneously exerted chemo/photothermal/photodynamic treatment on MDR human breast cancer MCF-7/ADR cells. This nano-sized system was constructed by filling the interior of AuNCs with DOX, ICG and 1-tetradecanol, and modifying the surface with biotinylated poly (ethylene glycol) via Au-S bonds, termed as DOX/ICG@biotin-PEG-AuNC-PCM. The DOX and ICG co-release from DOX/ICG@biotin-PEG-AuNC-PCM was much faster in PBS at 40°C or under 808nm NIR irradiation at 2.5W/cm2 than at 37°C (e.g. 67.27% or 80.31% vs. 5.57% of DOX, 76.08% vs. 3.83% of ICG for 20min). The flow cytometry and confocal laser scanning microscopy (CLSM) results showed, the AuNCs were taken up by MCF-7/ADR cells via endocytosis, thus enhancing DOX uptake; the biotin on AuNCs facilitated this endocytosis; NIR irradiation caused the heating of the AuNCs, triggering the DOX and ICG co-release and enhancing the distribution of DOX in nuclei, the released ICG generated ROS to take photodynamic therapy. Due to the above unique properties, DOX/ICG@biotin-PEG-AuNC-PCM exerted excellent anti-tumor effects under NIR irradiation, its IC50 against MCF-7/ADR cells was very low, only 0.48µg/mL, much smaller than that of free DOX (74.51µg/mL). STATEMENT OF SIGNIFICANCE: A new near-infrared (NIR) triggered chemotherapeutic agent doxorubicin (DOX) and photosensitizer indocyanine green (ICG) co-release system by aid of NIR induced photothermal effect of gold nanocages (AuNCs) and temperature sensitive phase-change property of 1-tetradecanol at its melting point of 39°C, was prepared, termed as DOX/ICG@biotin-PEG-AuNC-PCM, which could simultaneously exerted chemo/photothermal/photodynamic treatment on MDR human breast cancer MCF-7/ADR cells. DOX/ICG@biotin-PEG-AuNC-PCM exerted excellent anti-tumor effects under NIR irradiation, its IC50 against MCF-7/ADR cells was very low, only 0.48µg/mL, much smaller than that of free DOX (74.51µg/mL).

Photothermal gold nanocages filled with temperature sensitive tetradecanol and encapsulated with glutathione responsive polycurcumin for controlled DOX delivery to maximize anti-MDR tumor effects.

The design of an ideal drug delivery system with targeted recognition and minimized premature release, especially controlled and specific release that is triggered by endogenous and exogenous dual-stimuli, is a great challenge. A biotin receptor-targeted, near-infrared (NIR) irradiation and redox responsive nano-system has now been developed. The nano-system was constructed by filling the interior of Au nanocages with doxorubicin as a chemotherapy agent trapped in tetradecanol, followed by surface conjugation of biotinylated poly(ethylene glycol)-poly(curcumin-dithiodipropionic acid) (Biotin-PEG-PCDA) as a macromolecular chemosensitizer. Once the nano-system had been delivered into MCF-7/ADR cells by biotin receptor mediated recognition and endocytosis, drug release was triggered by degradation of PCDA via a glutathione induced redox reaction in combination with a solid-liquid change of tetradecanol by photothermal effects under NIR irradiation, which could minimize premature drug release and then maximize the therapeutic efficacy.

pH and near-infrared light dual-stimuli responsive drug delivery using DNA-conjugated gold nanorods for effective treatment of multidrug resistant cancer cells.

A thiolated pH-responsive DNA conjugated gold nanorod (GNR) was developed as a multifunctional nanocarrier for targeted, pH-and near infrared (NIR) radiation dual-stimuli triggered drug delivery. It was further passivated by a thiolated poly(ethylene glycol)-biotin to improve its cancer targeting ability by specific binding to cancer cell over-expressed biotin receptors. Doxorubicin (DOX), a widely used clinical anticancer drug, was conveniently loaded into nanocarrier by intercalating inside the double-stranded pH-responsive DNAs on the GNR surface to complete the construction of the multifunctional nanomedicine. The nanomedicine can rapidly and effectively release its DOX payload triggered by an acidic pH environment (pH~5) and/or applying an 808nm NIR laser radiation. Compared to free DOX, the biotin-modified nanomedicine displayed greatly increased cell uptake and significantly reduced drug efflux by model multidrug resistant (MDR) breast cancer cell lines (MCF-7/ADR). The application of NIR radiation further increased the DOX release and facilitated its nuclear accumulation. As a result, this new DNA-GNR based multifunctional nanomedicine exerted greatly increased potency (~67 fold) against the MDR cancer cells over free DOX.

Preparation and evaluation of lipid emulsified docetaxel-loaded nanoparticles.

OBJECTIVES: Lipid emulsified nanoparticles (LPNPs) have been developed to load anticancer drug docetaxel (DTX) in this work. METHODS: We evaluated DTX-loaded lipid emulsified nanoparticles (DTX-LPNPs) in vitro compared with the conventional nanoparticles (DTX-NPs). The newly developed formulation was compared with DTX-NPs in terms of physicochemical properties and in-vitro efficacy. KEY FINDINGS: These two formulations had similar physicochemical properties in our results. And it has been proven that phosphatidylethanolamine had higher emulsification efficiency (20-fold of polyvinyl alcohol) in the same preparation procedure. The in-vitro release of DTX from DTX-LPNPs showed burst release initially and then followed by a sustained release, which prolonged the half time. The cytotoxicity test indicated that the DTX-LPNPs were more effective against tumour growth, and the IC50 of Duopafei, DTX-NPs and DTX-LPNPs for the inhibition of human lung cancer A549 cells at 48 h (n = 3) were found to be 3.53 ± 0.43, 1.15 ± 0.06 and 0.55 ± 0.08 µm, respectively. The evaluation of the cellular uptake showed that DTX-LPNPs improved the drug delivery into cytoplasm compared with the commercial product Duopafei and DTX-NPs. CONCLUSIONS: DTX-LPNPs may be a promising formulation for cancer therapy.

Polycyclic aromatic hydrocarbons in soils from urban to rural areas in Nanjing: Concentration, source, spatial distribution, and potential human health risk.

Polycyclic aromatic hydrocarbons (PAHs) have become a major type of pollutant in urban areas and their degree of pollution and characteristics of spatial distribution differ between various regions. We conducted a comprehensive study about the concentration, source, spatial distribution, and health risk of 16 PAHs from urban to rural soils in Nanjing. The mean total concentrations of 16 PAHs (∑16PAHs) were 3330 ng g(-1) for urban soils, 1680 ng g(-1) for suburban soils, and 1060 ng g(-1) for rural soils. Five sources in urban, suburban, and rural areas of Nanjing were identified by positive matrix factorization. Their relative contributions of sources to the total soil PAH burden in descending order was coal combustion, vehicle emissions, biomass burning, coke tar, and oil in urban areas; in suburban areas the main sources of soil PAHs were gasoline engine and diesel engine, whereas in rural areas the main sources were creosote and biomass burning. The spatial distribution of soil PAH concentrations shows that old urban districts and commercial centers were the most contaminated of all areas in Nanjing. The distribution pattern of heavier PAHs was in accordance with ∑16PAHs, whereas lighter PAHs show some special characteristics. Health risk assessment based on toxic equivalency factors of benzo[a]pyrene indicated a low concentration of PAHs in most areas in Nanjing, but some sensitive sites should draw considerable attention. We conclude that urbanization has accelerated the accumulation of soil PAHs and increased the environmental risk for urban residents.