Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment.

Opsonization Inveigles Macrophages Engulfing Carrier-Free Bilirubin/JPH203 Nanoparticles to Suppress Inflammation for Osteoarthritis Therapy.

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.

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

Background Hepatic resection of Klatskin tumors usually requires postoperative intensive care unit (ICU) admission because of its high morbidity and mortality. Identifying surgical patients who will benefit most from ICU admission is important because of scarce resources but remains difficult. Sarcopenia is characterised by the loss of skeletal muscle mass and is associated with poor surgical outcomes. Methods We retrospectively analysed th.e relationship between preoperative sarcopenia and postoperative ICU admission and length of ICU stay (LOS-I) in patients who underwent hepatic resection for Klatskin tumors. Using preoperative computed tomography scans, the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra was measured and normalised to the patient’s height. Using these values, the optimal cut-off for diagnosing sarcopenia was determined using receiver operating characteristic curve analysis for each sex. Results Of 330 patients, 150 (45.5%) were diagnosed with sarcopenia. Patients with preoperative sarcopenia presented significantly more frequently to the ICU (77.3% vs. 47.9%, p < 0.001) and had longer total LOS-I (2.45 vs 0.89 days, p < 0.001). Moreover, patients with sarcopenia showed a significantly higher postoperative length of hospital stay, severe complication rate, and in-hospital mortality. Conclusions Sarcopenia correlated with poor postoperative outcomes, especially with the increased requirement of postoperative ICU admission and prolonged LOS-I after hepatic resection in patients with Klatskin tumors.

/pdf/effect-of-sarcopenia-on-postoperative-icu-admission-and-1wlx8jrx.pdf

Effect of sarcopenia on postoperative ICU admission and length of stay after hepatic resection for Klatskin tumor

Bilirubin Nanoparticles Alleviate Sepsis-Induced Acute Lung Injury by Protecting Pulmonary Endothelia Glycocalyx and Reducing Inflammation

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. 

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

Psoriasis is an immune‐mediated chronic inflammatory skin disorder characterized by epidermal hyperplasia and infiltration of inflammatory cells. Even though the pathogenesis remains unclear, T helper 17 (Th17) cells‐mediated inflammation and keratinocyte‐involved proliferation are considered to play key roles during the occurrence and the development of psoriasis. Therefore, suppressing the infiltration/function of Th17 and the abnormal hyperplasia of keratinocytes can be a rational strategy for ameliorating and treating psoriasis. In this study, a self‐assembly nanoparticle (BVn) is developed with bilirubin (an endogenous antioxidant) and V9302 (a blocker of ASCT2, an amino acid transporter mediating glutamine influx for providing energy and activating mammalian target of rapamycin [mTOR] pathway) to intervene the local metabolism and alleviate oxidative stress for psoriasis treatment. BVn effectively suppresses inflammatory keratinocyte proliferation and scavenges excess reactive oxygen species (ROS). In the in vivo psoriasis mouse model, BVn shows increased permeation and delayed retention in the psoriatic lesion and reverses the psoriasis‐related symptoms, evidenced by the normalized keratinocyte condition and decreased Th17 infiltration/activation. Mechanism study indicates that BVn not only cut off the energy supply but also suppressed cell proliferation or lymph cell expansion by deactivating mTOR pathway, besides alleviated oxidative stress. BVn‐based glutamine metabolism modulation strategy offers a promising strategy for psoriasis therapy.

Glutamine‐Based Metabolism Normalization and Oxidative Stress Alleviation by Self‐Assembled Bilirubin/V9302 Nanoparticles for Psoriasis Treatment

OBJECTIVE To integrate intrinsic surgical risk into the paediatric preoperative risk prediction score (PRPS) model to construct a more comprehensive risk scoring system (modified PRPS) and improve the prediction accuracy of postoperative intensive care unit (ICU) admission in paediatric patients. DESIGN This was a retrospective study conducted between 1 January and 30 December 2016. Data on age, American Society of Anaesthesiology physical status (ASA-PS), oxygen saturation, prematurity, non-fasted status, severity of surgery and immediate transfer to the ICU after surgery were collected. The modified PRPS was developed by logistic regression in the derivation cohort; it was tested and compared with the paediatric PRPS and ASA-PS by the Hosmer-Lemeshow test, the receiver operating characteristic (ROC) curve and Kappa analysis in the validation cohort. SETTING Hospital-based study in China. PARTICIPANTS Paediatric patients (≤14 years) who underwent surgery under general anaesthesia were included, and those who needed reoperation due to surgical complications or stayed in the ICU preoperatively were excluded. MAIN OUTCOME MEASURE ICU admission rate, defined as any patients' direct disposition from the operating room to the ICU immediately after the surgery. RESULTS A total of 9261 paediatric patients were included in this study, with 418 patients admitted to the ICU. In the validation cohort, the modified PRPS model fit the test data well (deciles of risk goodness-of-fit χ2=6.84, p=0.077). The area under the ROC curve of the modified PRPS, paediatric PRPS and ASA-PS were 0.963, 0.941 and 0.870, respectively (p<0.05), and the Kappa values were 0.620, 0.286 and 0.267. Analyses in the cohort indicated that the modified PRPS was superior to the paediatric PRPS and ASA-PS. CONCLUSIONS The modified PRPS integrating intrinsic surgical risk shows better prediction accuracy than the previous PRPS.

https://bmjopen.bmj.com/content/bmjopen/10/3/e036008.full.pdf

Modified paediatric preoperative risk prediction score to predict postoperative ICU admission in children: a retrospective cohort study.

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Glutamine‐Based Metabolism Normalization and Oxidative Stress Alleviation by Self‐Assembled Bilirubin/V9302 Nanoparticles for Psoriasis Treatment

Modified paediatric preoperative risk prediction score to predict postoperative ICU admission in children: a retrospective cohort study.