Self-Assembling P38 Peptide Inhibitor Nanoparticles Ameliorate the Transition from Acute to Chronic Kidney Disease by Suppressing Ferroptosis.

Accumulating evidence highlights p38 as a crucial factor highly activated during the process of acute kidney injury (AKI), but the application of p38 inhibitor in AKI is quite limited due to the low efficiency and poor kidney-targeting ability. Herein, a novel self-assembling peptide nanoparticle with specific p38-inhibiting activity is constructed, which linked mitogen-activated protein kinase kinase 3b (MKK3b), the functional domain of p38, with the cell-penetrating TAT sequence, ultimately self-assembling into TAT-MKK3b nanoparticles (TMNPs) through tyrosinase oxidation. Subsequent in vitro and in vivo studies demonstrated that TMNPs preferably accumulated in the renal tubular epithelial cells (RTECs) through forming protein coronas by binding to albumin, and strongly improved the reduced renal function of ischemia-reperfusion injury (IRI)-induced AKI and its transition to chronic kidney disease (CKD). Mechanically, TMNPs inhibited ferroptosis via its solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis-inducing capacity and synergistic potent antioxidant property in AKI. The findings indicated that the multifunctional TMNPs exhibited renal targeting, ROS-scavenging, and ferroptosis-mitigating capabilities, which may serve as a promising therapeutic agent for the treatment of AKI and its progression to CKD.

Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition.

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which are involved in RTEC injury and kidney fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed in RTECs, is well known as an anti-aging hormone wielding versatile functions, and its membrane form predominantly acts as a co-receptor for fibroblast growth factor 23. Here, we discovered a connection between membrane αKlotho and intracellular LDs in RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that membrane αKlotho deficiency in RTECs, as seen in αKlotho homozygous mutated (kl/kl) mice or in mice with ischemia-reperfusion injury (IRI)-induced AKI, inhibited FA mobilization from LDs by impairing adipose triglyceride lipase (ATGL)-mediated lipolysis and lipophagy. This resulted in LD accumulation and FA underutilization. IRI-induced alterations were more striking in αKlotho deficiency. Mechanistically, membrane αKlotho deficiency promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting in ubiquitin-mediated degradation of ATGL which is a common molecular basis for lipolysis and lipophagy. Overexpression of αKlotho rescued FA mobilization by preventing ATGL ubiquitination, thereby lessening LD accumulation and fibrosis after AKI. This suggests that membrane αKlotho is indispensable for the maintenance of lipid homeostasis in RTECs. Thus, our study identified αKlotho as a critical regulator of lipid turnover and homeostasis in AKI, providing a viable strategy for preventing tubular injury and the AKI-to-chronic kidney disease transition.

Geometry-invariant texture retrieval using a dual-output pulse-coupled neural network.

This letter proposes a novel dual-output pulse coupled neural network model (DPCNN). The new model is applied to obtain a more stable texture description in the face of the geometric transformation. Time series, which are computed from output binary images of DPCNN, are employed as translation-, rotation-, scale-, and distortion-invariant texture features. In the experiments, DPCNN has been well tested by using Brodatz's album and the VisTex database. Several existing models are compared with the proposed DPCNN model. The experimental results, based on different testing data sets for images with different translations, orientations, scales, and affine transformations, show that our proposed model outperforms existing models in geometry-invariant texture retrieval. Furthermore, the robustness of DPCNN to noisy data is examined in the experiments.

Integrated care for severely disabled long-term care facility residents: is it better?

The demands of long-term care facilities (LTCFs) residents are complex which usually require a range of professionals and caregivers to provide treatment and care. To reduce this fragmentation of care, integrated care models are developed in modern health care system, and a gradual change from traditional LTCF care to integrated care has occurred in many countries. Although integrated care is assumed to improve the quality of care, evidences supporting these effects are insufficient. We recruited 7 private LTCF (74 residents) in northern Taipei and randomized them into integrated care model (N=42, mean age=82.8+/-8.0 years, 54.8% males) and traditional model (N=32, 81.7+/-8.8 years, 43.8% males). Integrated care model group was provided an actively working interdisciplinary team in addition to traditional nursing and personal care in traditional model group. Physical function, nutritional status and several quality indicators (unplanned feeding tube replacement, unplanned urinary catheter replacement, pneumonia, urinary tract infection and so on) were compared with both groups. Overall, LTCF residents in the integrated care model group showed significant improvement in serum levels of albumin (3.78+/-0.32 vs. 3.60+/-0.45, p=0.004) and hemoglobin (12.62+/-1.58 vs. 12.03+/-1.24, p=0.004) during the study period. Among selected quality indicators, subjects in integrated care model group were similar to traditional model group except that integrated care model group had a significantly reduced unplanned feeding tube replacement rate. In conclusion, the clinical effectiveness of integrated care model among severly disabled LTCF residents is minimal and a further cost-effectiveness study is needed to promote optimal quality of care in this setting.