Dual-Targeting Macrophages and Hepatic Stellate Cells by Modified Albumin Nanoparticles for Liver Cirrhosis Treatment.

Hepatic cirrhosis has become a global public health concern with high mortality and currently lacks effective clinical treatment methods. Activation of hepatic stellate cells (HSCs) and the large number of macrophages infiltrating into the liver play a critical role in the development of liver cirrhosis. This study developed a novel modified nanoparticle system (SRF-CS-PSA NPs) in which Sorafenib (SRF) was encapsulated by palmitic acid-modified albumin (PSA) and further modified with chondroitin sulfate (CS). These modifications enabled the SRF-CS-PSA NPs to effectively target hepatic stellate cells (HSCs) and macrophages. SRF-CS-PSA NPs showed uniform particle size distribution of approximately 120 nm and high loading efficiency of up to 99.5% and can be taken up by HSCs and macrophages via CD44 and SR-A receptors, respectively. In a mouse model of liver cirrhosis, SRF-CS-PSA NPs demonstrated superior targeting and inhibition of HSCs and macrophages, effectively reversing the process of liver cirrhosis. Overall, our study demonstrates the potential of SRF-CS-PSA NPs as a targeted therapy for liver cirrhosis, with promising clinical applications.

Combined Amphiphilic Silybin Meglumine Nanosuspension Effective Against Hepatic Fibrosis in Mice Model.

Introduction: Silybin (SLB) as an effective hepatoprotective phytomedicine has been limited by its hydrophobicity, poor bioavailability and accumulation at lesion sites. Additionally, present drug loading methods are impeded by their low drug loading capacity, potential hazard of materials and poor therapeutic effects. Consequently, there is a pressing need to devise an innovative approach for preparing nanosuspensions loaded with both SLB and Silybin Meglumine salt (SLB-M), as well as to investigate the therapeutic effects of SLB nanosuspensions against hepatic fibrosis. Methods: The SLB nanosuspension (NS-SLB) was prepared and further modified with a hyaluronic acid-cholesterol conjugate (NS-SLB-HC) to improve the CD44 targeting proficiency of NS-SLB. To validate the accumulation of CD44 and ensure minimal cytotoxicity, cellular uptake and cytotoxicity assessments were carried out for the nanosuspensions. Western blotting was employed to evaluate the anti-hepatic fibrosis efficacy in LX-2 cells by inhibiting the secretion of collagen I. Hepatic fibrosis mouse models were used to further confirm the effectiveness of NS-SLB and NS-SLB-HC against hepatic fibrosis in vivo. Results: Uniform nanosuspensions were prepared through self-assembly, achieving high drug loading rates of 89.44% and 60.67%, respectively. Both SLB nanosuspensions showed minimal cytotoxicity in cellular environments and mitigated hepatic fibrosis in vitro. NS-SLB-HC was demonstrated to target activated hepatic stellate cells by receptor-ligand interaction between HA and CD44. They can reverse hepatic fibrosis in vivo by downregulating TGF-ß and inhibiting the secretion of α-SMA and collagen I. Conclusion: Designed as a medical excipient analogue, SLB-M was aimed to establish an innovative nanosuspension preparation method, characterized by high drug loading capacity and a notable impact against hepatic fibrosis.

A sustained-release phospholipid-based phase separation gel loaded with berberine for treating rheumatoid arthritis.

Berberine (BBR) has a long history of use in the treatment of Rheumatoid arthritis (RA) and is considered one of the most promising natural product for the treatment of RA. However, oral administration of berberine has low bioavailability and requires frequent administration, resulting in poor patient compliance. In this study, we developed a BBR-loaded phospholipid-based phase separation gel (BBR-PPSG) to achieve sustained drug release and long-term therapeutic effect. The stability of BBR-PPSG was verified and it was found that it can be stored for a long time. The pharmacokinetic study on rats and rabbits showed that BBR-PPSG not only achieved 1-month of sustained release, but also significantly increased the area under the curve (AUC) by nearly 9-fold and prolonged the half-life (t1/2) by 10-fold. By constructing rat and rabbit models of RA, we also proved that BBR-PPSG administration once a month effectively alleviated joint swelling, and significantly reduce TNF-α levels in AIA rats and OIA rabbits. Histopathological analysis of rabbit joint sections revealed that after intra-articular injection of BBR-PPSG, the synovial cell layer remained intact, while in the model group, the synovial cells were significantly reduced and exhibited necrosis. MicroCT data analysis showed that the values of Tb.N and Tb. Sp in the BBR-PPSG group were significantly better than those in the model group (p < 0.05). This study addressed the limitations of frequent administration of BBR by developing a phospholipid-based phase separation gel system for berberine delivery, achieving long-term sustained release. The BBR-PPSG demonstrated good biocompatibility, simple preparation and excellent stability, thus holding potential as a novel pharmaceutical formulation for RA treatment.

De Novo Design of Reversibly pH-Switchable NIR-II Aggregation-Induced Emission Luminogens for Efficient Phototheranostics of Patient-Derived Tumor Xenografts.

Phototheranostics has received sustained attention due to its great potential in revolutionizing conventional strategies of cancer treatment. However, trapped by the complexity, poor reproducibility, insufficient phototheranostic outputs, and inevitable damage to normal tissue of most multicomponent phototheranostic systems, its clinical translation has been severely hindered. Therefore, the exploration of "one for all" smart phototheranostic agents with versatile functionalities remains an appealing yet enormously challenging task. Herein, a reversibly pH-switchable and near-infrared second photosensitizer featuring aggregation-induced emission was tactfully designed by molecular engineering for precise tumor-targeting fluorescence imaging-guided phototherapy. Thanks to the strong intramolecular charge transfer, enhanced highly efficient intersystem crossing, and sufficient intramolecular motion, the developed agent DTTVBI was endowed with boosted type-I superoxide anion radical generation and excellent photothermal performance under 808 nm laser irradiation. More importantly, DTTVBI nanoparticles with high biocompatibility exhibit remarkably enhanced type-I photodynamic/photothermal therapy in the tumor region, thus offering significant antitumor effects both in vitro and in the patient-derived tumor xenograft model of colon cancer. This work sheds new light on the development of superior versatile phototheranostics for cancer therapy.

Efficacy of laser therapy combined with topical antifungal agents for onychomycosis: a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: Onychomycosis is a common fungal infection of the nail. Laser and topical antifungal agent combination therapy is an emerging treatment for onychomycosis. The objective of this study was to systematically evaluate the efficacy and safety of laser and topical antifungal agent combination therapy for onychomycosis. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang and VIP databases were searched from inception to November 2021. Randomised controlled trials (RCTs) on laser therapy combined with topical antifungal agents for onychomycosis were included. The Cochrane Collaboration tool was used to assess the risk of bias, and Revman 5.3 software was used in the meta-analysis. RESULTS: Twelve studies involving 869 patients were included in this meta-analysis. The results showed that compared with topical antifungal agents alone, laser and topical antifungal agent combination therapy was superior in terms of the complete cure rate (RR 6.04,95% CI (2.17, 16.85), P = 0.0006), mycological cure rate (RR 1.27, 95% CI (1.10, 1.48), P = 0.001), clinical effective rate (RR 1.38, 95% CI (1.20, 1.57), P < 0.00001) and patient satisfaction rate (RR 1.47,95% CI (1.17, 1.84), P = 0.0009).The subgroup analysis of outcome indicators, including mycological cure rate and clinical effective rate, demonstrated that both carbon dioxide (CO2) laser therapy combined with topical antifungal therapy and 1064-nm neodymium-doped:yttrium aluminium garnet (Nd:YAG) laser therapy combined with topical antifungal therapy showed better results than topical antifungal therapy alone. No adverse events were identified except for three studies reporting transient burning sensation without treatment and mild to moderate pain, both of which were well tolerated. CONCLUSION: The present study indicated that laser and topical antifungal agent combination therapy is effective for onychomycosis. However, more large-scale and well-designed RCTs are warranted.

Toxic arsenic in marketed aquatic products from coastal cities in China: Occurrence, human dietary exposure risk, and coexposure risk with mercury and selenium.

To improve the accuracy of dietary risk assessment of arsenic (As) from aquatic products, toxic As species (As(III), As(V), monomethylarsonic acid [MMA], and dimethylarsinic acid [DMA]) and total As were analyzed in 124 marketed aquatic products from eight coastal cities in China. Distribution characteristics of Toxic As (the sum of the four toxic As species) in the samples and associated risk of human dietary exposure were emphatically investigated. The impact of cooccurrence of As and other chemical elements in the aquatic products was assessed based on our former results of mercury (Hg) and selenium (Se). Toxic As contents (maximum value 0.358 mg kg-1 wet weight) in the samples accounted for at most 14.1% of total As. DMA was the major component (mean proportion 50.8% for shellfish, 100% for fish) of Toxic As in aquatic products. Shellfish contained more Toxic As than fish did. Mean estimated daily intakes of Toxic As for the residents with aquatic product consumption rates of 46.1-235 g day-1 ranged from 0.034 to 0.290 µg kg-1 day-1. Potential health risk was indicated among those who greatly consumed aquatic products, as their target hazard quotient (THQ) and target cancer risk (TR) values exceeded safety thresholds (1 for THQ, 10-4 for TR). DMA and MMA exposure contributed to 3.42-7.72% of the THQToxic As. Positive correlations between concentrations of As and Hg (Fish: r = 0.47, p < 0.01; Shellfish: r = 0.60, p < 0.01), as well as between that of As and Se (Fish: r = 0.69, p < 0.01; Shellfish: r = 0.37, p < 0.01) were found in the samples. It requires attentions urgently that As and Hg coexposure through aquatic product consumption rose the sum THQ of Toxic As and methylmercury (MeHg) to approximately two to eight times as high as the THQToxic As.

Total mercury, methylmercury, and selenium in aquatic products from coastal cities of China: Distribution characteristics and risk assessment.

This study analyzed total mercury (THg), methylmercury (MeHg) and selenium (Se) in 114 aquatic product samples (representing 39 species) from eight coastal cities of China. The THg and MeHg levels in different parts of the same sample species were in the order of muscle ≥ skin/shell > roe, whereas Se levels were much higher in roe. Concentrations of THg, MeHg, and Se in the muscles were between 2.27-154, 0.36-135, and 57.8-1.20 × 103 ng g-1 wet weight (ww), respectively. Although significant differences in analyte concentrations were not observed among cities, they existed among three species; marine fish, freshwater fish, and shellfish. Shellfish had generally lower Hg content (mean: 20.2 ng g-1 ww THg, 6.71 ng g-1 ww MeHg, and 30.9% MeHg/THg ratio); however it had higher Se content (528 ng g-1 ww) than the other types of fish (mean: 33.3 ng g-1 ww THg, 28.2 ng g-1 ww MeHg, and 79.2% MeHg/THg ratio, 257 ng g-1 ww Se). In addition to species, the individual growth and HgSe interaction influenced Hg distribution. Evident correlations were observed between several individual body features and Hg content, and between Se and THg concentrations (p < 0.05). The greater correlation coefficient between two elements for fish indicated stronger HgSe antagonism through HgSe compound formation in fish. Relatively low THg daily intakes (mean 0.013-0.080 µg kg-1 day-1) and MeHg daily intakes (0.006-0.065 µg kg-1 day-1) along with Se:Hg molar ratios >1 and positive HBVSe values suggest that aquatic products from these sites will not pose immediate health problems to consumers. Fish was the dominating contributor for MeHg intake whereas shellfish was the dominating contributor for Se intake. To safeguard against mercury exposure, residents in these areas can appropriately increase shellfish intake (especially bivalves), rather than exclusively consuming marine fish.