Bilirubin ameliorates osteoarthritis via activating Nrf2/HO-1 pathway and suppressing NF-κB signalling.

Osteoarthritis (OA) is a chronic degenerative joint disease that affects worldwide. Oxidative stress plays a critical role in the chronic inflammation and OA progression. Scavenging overproduced reactive oxygen species (ROS) could be rational strategy for OA treatment. Bilirubin (BR) is a potent endogenous antioxidant that can scavenge various ROS and also exhibit anti-inflammatory effects. However, whether BR could exert protection on chondrocytes for OA treatment has not yet been elucidated. Here, chondrocytes were exposed to hydrogen peroxide with or without BR treatment. The cell viability was assessed, and the intracellular ROS, inflammation cytokines were monitored to indicate the state of chondrocytes. In addition, BR was also tested on LPS-treated Raw264.7 cells to test the anti-inflammation property. An in vitro bimimic OA microenvironment was constructed by LPS-treated Raw264.7 and chondrocytes, and BR also exert certain protection for chondrocytes by activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. An ACLT-induced OA model was constructed to test the in vivo therapeutic efficacy of BR. Compared to the clinical used HA, BR significantly reduced cartilage degeneration and delayed OA progression. Overall, our data shows that BR has a protective effect on chondrocytes and can delay OA progression caused by oxidative stress.

Multifunctional iron-apigenin nanocomplex conducting photothermal therapy and triggering augmented immune response for triple negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to its low sensitivity to many chemotherapeutic drugs and a relatively low overall survival rate in clinical practice. Photothermal therapy has recently garnered substantial interest in cancer treatment, owing to its swift therapeutic effectiveness and minimal impact on normal cells. Metal-polyphenol nanostructures have recently garnered significant attention as photothermal transduction agents due to their facile preparation and favorable photothermal properties. In this study, we employed a coordinated approach involving Fe3+ and apigenin, a polyphenol compound, to construct the nanostructure (nFeAPG), with the assistance of ß-CD and DSPE-PEG facilitating the formation of the complex nanostructure. In vitro research demonstrated that the formed nFeAPG could induce cell death by elevating intracellular oxidative stress, inhibiting antioxidative system, and promoting apoptosis and ferroptosis, and near infrared spectrum irradiation further strengthen the therapeutic outcome. In 4T1 tumor bearing mice, nFeAPG could effectively accumulate into tumor site and exhibit commendable control over tumor growth. Futher analysis demonstrated that nFeAPG ameliorated the suppressed immune microenvironment by augmenting the response of DC cells and T cells. This study underscores that nFeAPG encompasses a multifaceted capacity to combat TNBC, holding promise as a compelling therapeutic strategy for TNBC treatment.

Ultraviolet B radiation-induced JPH203-loaded keratinocyte extracellular vesicles exert etiological interventions for psoriasis therapy.

Psoriasis is a multifactorial immuno-inflammatory skin disease, characterized by keratinocyte hyperproliferation and aberrant immune activation. Although the pathogenesis is complex, the interactions among inflammation, Th17-mediated immune activation, and keratinocyte hyperplasia are considered to play a crucial role in the occurrence and development of psoriasis. Therefore, pharmacological interventions on the "inflammation-Th17-keratinocyte" vicious cycle may be a potential strategy for psoriasis treatment. In this study, JPH203 (a specific inhibitor of LAT1, which engulfs leucine to activate mTOR signaling)-loaded, ultraviolet B (UVB) radiation-induced, keratinocyte-derived extracellular vesicles (J@EV) were prepared for psoriasis therapy. The EVs led to increased interleukin 1 receptor antagonist (IL-1RA) content due to UVB irradiation, therefore not only acting as a carrier for JPH203 but also functioning through inhibiting the IL-1-mediated inflammation cascade. J@EV effectively restrained the proliferation of inflamed keratinocytes via suppressing mTOR-signaling and NF-κB pathway in vitro. In an imiquimod-induced psoriatic model, J@EV significantly ameliorated the related symptoms as well as suppressed the over-activated immune reaction, evidenced by the decreased keratinocyte hyperplasia, Th17 expansion, and IL17 release. This study shows that J@EV exerts therapeutic efficacy for psoriasis by suppressing LAT1-mTOR involved keratinocyte hyperproliferation and Th17 expansion, as well as inhibiting IL-1-NF-κB mediated inflammation, representing a novel and promising strategy for psoriasis therapy.

Salidroside alleviates diet-induced obesity and insulin resistance by activating Nrf2/ARE pathway and enhancing the thermogenesis of adipose tissues.

Recent reports suggest that salidroside protects cardiomyocytes from oxidative injury and stimulates glucose uptake by skeletal muscle cells. Despite these findings, the therapeutic potential of salidroside in the treatment of obesity and insulin resistance remains uncertain and requires further investigation. In the present study, the treatment effect of salidroside on the onset and development of the obese phenotype and insulin resistance as well as the underlying mechanisms was investigated using long-term high-fat diet-induced obese mice supplemented with salidroside. We used biochemical kits to determine serum biochemical parameters (including triacylglycerol, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting glucose, and insulin). The results show that salidroside-supplemented animals showed better glucose tolerance and insulin sensitivity, decreased blood lipids, and weight gain (p < .05). Protein expression of p-Nrf2 and Nrf2 was analyzed by western blotting, and the mRNA levels of thermogenic-related genes (Ucp1, Pgc1a, Prdm16, and Cidea) were detected by quantitative RT-PCR. The results show an improvement in lipid peroxidation and Nrf2/ARE signaling, as well as an increased expression of the Ucp1, Pgc1a, Prdm16, and Cidea (p < .05). Our evidence suggests that salidroside alleviates diet-induced obesity and insulin resistance potentially by activating Nrf2/ARE pathway and enhancing the thermogenesis of adipose tissues. This induction represents a potential technique for the management of comorbidities related to obesity and its prevention.

ATB0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy.

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0,+) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0,+) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.

A Biomimetic Nanoparticle Exerting Protection against Acute Liver Failure by Suppressing CYP2E1 Activity and Scavenging Excessive ROS.

Acute liver failure (ALF) is a severe liver disease caused by many reasons. One of them is the overdosed acetaminophen (APAP), which is metabolized into N-acetyl-p-benzoquinone imine (NAPQI), an excessive toxic metabolite, by CYP2E1, resulting in excessive reactive oxygen species (ROS), exhausted glutathione (GSH), and thereafter hepatocyte necrosis. N-acetylcysteine is the Food and Drug Administration-approved drug for detoxification of APAP, but it has limited clinical application due to the short therapeutic time window and concentration-related adverse effects. In this study, a carrier-free and bilirubin dotted nanoparticle (B/BG@N) is developed, which is formed using bilirubin and 18ß-Glycyrrhetinic acid, and bovine serum albumin (BSA) is then adsorbed to mimic the in vivo behavior of the conjugated bilirubin for hitchhiking. The results demonstrate that B/BG@N can effectively reduce the production of NAPQI as well as exhibit antioxidant effects against intracellular oxidative stress via regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signal axis and reducing the production of inflammatory factors. In vivo study shows that B/BG@N can effectively improve the clinical symptom of the mice model. This study suggests that B/BG@N own increases circulation half-life, improves accumulation in the liver, and dual detoxification, providing a promising strategy for clinical ALF treatment.

Expert consensus statement on therapeutic drug monitoring and individualization of linezolid.

Linezolid is an oxazolidinone antibacterial drug, and its therapeutic drug monitoring and individualized treatment have been challenged since its approval. With the in-depth clinical research of linezolid, we have changed our attitude toward its therapeutic drug monitoring and our view of individualized treatment. On the basis of summarizing the existing clinical studies, and based on the practical experience of each expert in their respective professional fields, we have formed this expert consensus. Our team of specialists is a multidisciplinary team that includes pharmacotherapists, clinical pharmacology specialists, critical care medicine specialists, respiratory specialists, infectious disease specialists, emergency medicine specialists and more. We are committed to the safe and effective use of linezolid in patients in need, and the promotion of its therapeutic drug monitoring.

Dual Targeting EGFR and STAT3 With Erlotinib and Alantolactone Co-Loaded PLGA Nanoparticles for Pancreatic Cancer Treatment.

Pancreatic cancer (PC) is one of the most common malignancies and also a leading cause of cancer-related mortality worldwide. Many studies have shown that epidermal growth factor receptor (EGFR) is highly expressed in PC, which provides a potential target for PC treatment. However, EGFR inhibitors use alone was proven ineffective in clinical trials, due to the persistence of cellular feedback mechanisms which foster therapeutic resistance to single targeting of EGFR. Specifically, the signal transducer and activator of transcription 3 (STAT3) is over-activated when receiving an EGFR inhibitor and is believed to be highly involved in the failure and resistance of EGFR inhibitor treatment. Therein, we hypothesized that dual inhibition of EGFR and STAT3 strategy could address the STAT3 induced resistance during EGFR inhibitor treatment. To this end, we tried to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles to co-load Alantolactone (ALA, a novel STAT3 inhibitor) and Erlotinib (ERL, an EGFR inhibitor) for pancreatic cancer to test our guess. The loading ratio of ALA and ERL was firstly optimized in vitro to achieve a combined cancer-killing effect. Then, the ALA- and ERL-co-loaded nanoparticles (AE@NPs) were successfully prepared and characterized, and the related anticancer effects and cellular uptake of AE@NPs were studied. We also further detailly explored the underlying mechanisms. The results suggested that AE@NPs with uniform particle size and high drug load could induce significant pancreatic cancer cell apoptosis and display an ideal anticancer effect. Mechanism studies showed that AE@NPs inhibited the phosphorylation of both EGFR and STAT3, indicating the dual suppression of these two signaling pathways. Additionally, AE@NPs could also activate the ROS-p38 axis, which is not observed in the single drug treatments. Collectively, the AE@NPs prepared in this study possess great potential for pancreatic cancer treatment by dual suppressing of EGFR and STAT3 pathways and activating ROS-responsive p38 MAPK pathway.

ATB0,+-targeted delivery of triptolide prodrugs for safer and more effective pancreatic cancer therapy.

Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and distribution found in animal studies. In this study, we designed and synthesized three amino acids (tryptophan, valine, and lysine) based TP prodrugs to target ATB0,+ which are highly expressed in pancreatic cancer cells for more effective pancreatic cancer therapy. The stability, uptake profiles, uptake mechanism, and cancer-killing ability were studied in vitro. All three prodrugs showed increased uptake and enhanced cytotoxicity in pancreatic cancer cells, but not in normal pancreatic cells. The difference in killing effect on normal and cancer cells was attributed to pancreatic cancer over-expressed ATB0,+-mediated uptake. Specifically, tryptophan-conjugated TP prodrug (TP-Trp) showed the highest uptake and the best cancer cell killing effect, considered as the best candidate. The present study provided the proof-of-concept of exploiting TP prodrug to target ATB0,+ for pancreatic cancer-selective delivery and treatment.

Physical exercise promotes proliferation and differentiation of endogenous neural stem cells via ERK in rats with cerebral infarction.

Physical exercise is beneficial for the functional recovery of neurons after stroke. It has been suggested that exercise regulates proliferation and differentiation of endogenous neural stem cells (NSCs); however, the underlying molecular mechanisms are still largely unknown. In the present study, the aim was to investigate whether physical exercise activates the extracellular signal­regulated kinase (ERK) signaling pathway to promote proliferation and differentiation of NSCs in rats with cerebral infarction, thereby improving neurological function. Following middle cerebral artery occlusion, rats underwent physical exercise and neurological behavior was analyzed at various time points. Immunofluorescence staining was performed to detect proliferation and differentiation of NSCs, and western blotting was used to analyze cyclin­dependent kinase 4 (CDK4), Cyclin D1, retinoblastoma protein (p­Rb), P­16, phosphorylated (p)­ERK1/2 and c­Fos expression. The results indicated that physical exercise promoted proliferation and differentiation of NSCs, and led to improved neural function. In addition, the expression levels of CDK4, Cyclin D1, p­Rb, p­ERK1/2 and c­Fos were upregulated, whereas the expression of P­16 was downregulated following exercise. U0126, an inhibitor of ERK signaling, reversed the beneficial effects of exercise. Therefore, it may be hypothesized that physical exercise enhances proliferation and differentiation of endogenous NSCs in the hippocampus of rats with cerebral infarction via the ERK signaling pathway.

Injectable micellar supramolecular hydrogel for delivery of hydrophobic anticancer drugs.

In this paper, an injectable micellar supramolecular hydrogel composed of α-cyclodextrin (α-CD) and monomethoxy poly(ethylene glycol)-b-poly(ε-caplactone) (MPEG5000-PCL5000) micelles was developed by a simple method for hydrophobic anticancer drug delivery. By mixing α-CD aqueous solution and MPEG5000-PCL5000 micelles, an injectable micellar supramolecular hydrogel could be formed under mild condition due to the inclusion complexation between α-CD and MPEG segment of MPEG5000-PCL5000 micelles. The resultant supramolecular hydrogel was thereafter characterized by X-ray diffraction (XRD) and Scanning electron microscopy (SEM). The effect of α-CD amount on the gelation time, mechanical strength and thixotropic property was studied by a rheometer. Payload of hydrophobic paclitaxel (PTX) to supramolecular hydrogel was achieved by encapsulation of PTX into MPEG5000-PCL5000 micelles prior mixing with α-CD aqueous solution. In vitro release study showed that the release behavior of PTX from hydrogel could be modulated by change the α-CD amount in hydrogel. Furthermore, such supramolecular hydrogel could enhance the biological activity of encapsulated PTX compared to free PTX, as indicated by in vitro cytotoxicity assay. All these results indicated that the developed micellar supramolecular hydrogel might be a promising injectable drug delivery system for anticancer therapy.

Construction and application of biotin-poloxamer conjugate micelles for chemotherapeutics.

Biotin was conjugated on poloxamer to prepare biotin-poloxamer (BP) conjugate micelles for chemotherapeutics. Epirubicin (EPI) was encapsulated in BP micelles. The EPI-loaded BP micelles were characterized in terms of size, ζ-potential, morphology, drug loading, drug encapsulation and drug release. Marrow leukemic HL-60 cells were used for evaluating the in vitro cytotoxicity of EPI-loaded BP micelles. Nude mice were axillainoculated subcutaneously HL-60 cells to establish tumour model for investigating the inhibition effects of EPI-loaded BP micelles. From the results, the sizes of these nanoparticles were about 100 nm. Fluorescence microscope observation supported the enhanced cellular uptake of the micelles. The order of the inhibition on tumour volume growth was: EPI-loaded BP micelles >EPI-loaded MATP micelles >EPI-loaded poloxamer micelles >EPI. BP micelles showed significant antitumour activity and low toxicity, compared with the non-targeted micelles. With the advantage of EPR effect and tumour-targeting potential, BP conjugate micelles might be developed as a new system for chemotherapeutics.

Preparation and antitumor activity of bFGF-mediated active targeting doxorubicin microbubbles.

Characterization and antitumor activity of basic fibroblast growth factor-mediated active targeting doxorubicin microbubbles (bFGF-DOX-MB) were investigated. Pluronic F68 with chemical conjugation of doxorubicin (DOX-P) and peptide KRTGQYKLC-conjugated DSPE-PEG2000 were prepared. bFGF-DOX-MB had a normal distribution of particle size, with average particle size of 2.7 µm. Using A549 mouse model, bFGF-DOX-MB combined ultrasound showed the best inhibition effect on tumor volume growth among all the test groups. Similar conclusion was obtained from experimental measurements of tumor weight change and blood cell count. From the results, chemotherapeutic drug inhibition on tumor growth could be enhanced by local ultrasound combined with active targeting bFGF-DOX-MB, which might provide a potential application for ultrasound-mediated chemotherapy.