Sonoinduced Tumor Therapy and Metastasis Inhibition by a Ruthenium Complex with Dual Action: Superoxide Anion Sensitization and Ligand Fracture.

Photoresponsive ruthenium(II) complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology, as well as for antimicrobial applications. However, the limited penetration power of photons prevents the treatment of deep-seated lesions. In this study, we introduce a sonoresponsive ruthenium complex capable of generating superoxide anion (O2•-) via type I process and initiating a ligand fracture process upon ultrasound triggering. Attaching hydroxyflavone (HF) as an "electron reservoir" to the octahedral-polypyridyl-ruthenium complex resulted in decreased highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps and triplet-state metal to ligand charge transfer (3MLCT) state energy (0.89 eV). This modification enhanced the generation of O2•- under therapeutic ultrasound irradiation at a frequency of 1 MHz. The produced O2•- rapidly induced an intramolecular cascade reaction and HF ligand fracture. As a proof-of-concept, we engineered the Ru complex into a metallopolymer platform (PolyRuHF), which could be activated by low-power ultrasound (1.5 W cm-2, 1.0 MHz, 50% duty cycle) within a centimeter range of tissue. This activation led to O2•- generation and the release of cytotoxic ruthenium complexes. Consequently, PolyRuHF induced cellular apoptosis and ferroptosis by causing mitochondrial dysfunction and excessive toxic lipid peroxidation. Furthermore, PolyRuHF effectively inhibited subcutaneous and orthotopic breast tumors and prevented lung metastasis by downregulating metastasis-related proteins in mice. This study introduces the first sonoresponsive ruthenium complex for sonodynamic therapy/sonoactivated chemotherapy, offering new avenues for deep tumor treatment.

ESRRA modulation by empagliflozin mitigates diabetic tubular injury via mitochondrial restoration.

BACKGROUND: The protection of the diabetic kidney by Empagliflozin (EMPA) is attributed to its interaction with the sodium glucose cotransporter 2 located on proximal tubular epithelial cells (PTECs). Estrogen-related receptor α (ESRRA), known for its high expression in PTECs and association with mitochondrial biogenesis, plays a crucial role in this process. This study aimed to explore the impact of ESRRA on mitochondrial mass in diabetic tubular injury and elucidate the mechanism underlying the protective effects of EMPA. METHODS: Mitochondrial changes in PTECs of 16-week-old diabetic mice were assessed using transmission electron microscopy (TEM) and RNA-sequences. In vivo, EMPA administration was carried out in db/db mice for 8 weeks, while in vitro experiments involved modifying ESRRA expression in HK2 cells using pcDNA-ESRRA or EMPA. RESULTS: Evaluation through TEM revealed reduced mitochondrial mass and swollen mitochondria in PTECs, whereas no significant changes were observed under light microscopy. Analysis of RNA-sequences identified 110 downregulated genes, including Esrra, associated with mitochondrial function. Notably, ESRRA overexpression rescued the loss of mitochondrial mass induced by high glucose (HG) in HK2 cells. EMPA treatment ameliorated the ultrastructural alterations and mitigated the downregulation of ESRRA both in db/db mice and HG-treated HK2 cells. CONCLUSION: The diminished expression of ESRRA is implicated in the decline of mitochondrial mass in PTECs during the early stages of diabetes, highlighting it as a key target of EMPA for preventing the progression of diabetic kidney injury.

Blockade of STARD3-mediated cholesterol transport alleviates diabetes-induced podocyte injury by reducing mitochondrial cholesterol accumulation.

AIMS: Steroidogenic acute regulatory (StAR)-related lipid transfer domain-3 (STARD3) is a sterol-binding protein that facilitates cholesterol transport between cellular organelles. Cholesterol accumulation in podocytes directly contributes to the pathogenesis of albuminuria and renal injury under the condition of diabetic kidney disease (DKD). The aim of this study is to determine the role of STARD3 on the intracellular distribution of cholesterol within podocytes. METHODS: In vivo and in vitro models of diabetes were performed. The protein levels of STARD3, Niemann-Pick disease type C1 (NPC1), and Niemann-Pick disease type C2 (NPC2) were respectively detected by western blot analysis, immunohistochemistry, and immunofluorescence. Filipin staining was used to evaluate the subcellular localization of cholesterol in podocytes. Mitochondrial damage was evaluated using JC-1 (CBIC2) and ROS (reactive oxygen species) assays. KEY FINDINGS: Upregulation of STARD3 under diabetes and hyperglycemia increases cholesterol transport from the late endosomal/lysosomal (LE/LY) to mitochondria, leading to mitochondrial cholesterol accumulation and cell injury in podocytes. Conversely, downregulating STARD3 expression attenuated mitochondrial cholesterol accumulation, and improved mitochondrial homeostasis. SIGNIFICANCE: STARD3 may govern intracellular cholesterol transport in podocytes, subsequently leading to regulation of mitochondrial metabolism. Therefore, targeting STARD3 emerges as a potential therapeutic strategy to mitigate diabetes-induced mitochondrial cholesterol accumulation and associated injury in podocytes.

Effect of ionic groups on the morphology and transport properties in a novel perfluorinated ionomer containing sulfonic and phosphonic acid groups: a molecular dynamics study.

Combining the phosphonic acid group with the sulfonic acid group in PEMs has been shown to be an effective strategy for improving the fuel cell performance. However, the interplay of two different ionic groups and the resulting effect on the membrane properties have not been fully elucidated. Here, we used classical molecular dynamics simulation to investigate the morphologies, transport properties and effects of ionic groups in a novel perfluorinated PEM containing two ionic groups (PFSA-PFPA) in comparison to the corresponding homopolymers. Phase separations between hydrophilic and hydrophobic domains are confirmed in these PEMs and result from the evolution of water clusters formed around the ionic groups. The combination of both ionic groups brings a complicated morphological feature in PFSA-PFPA, with near-cylindrical aqueous domains of large length scales interconnected by tortuous domains of small sizes. And we found that the self-diffusion coefficients of water molecules are strongly related to morphologies, with the water transport in PFSA-PFPA lying between two analogous homopolymers. At the molecular level, we found that the sulfonic and phosphonic acid groups have distinct effects on the coordination behaviors and the dynamics of water molecules and hydronium ions. Strong electrostatic interactions lead to compact coordination structures and sluggish dynamics of hydronium ions around phosphonic acid groups, which determine the morphological evolution and transport properties in PFSA-PFPA. Our study affords insights into the relationship between molecular characteristics and transport properties bridged by phase-separated morphologies in a novel PEM containing both sulfonic acid and phosphonic acid groups, which deepens the understanding of the interplay between two ionic groups and may inspire the rational design of high-performance PEMs.

Bi2Te3-Based Thermoelectric Modules for Efficient and Reliable Low-Grade Heat Recovery.

Bismuth-telluride-based alloy has long been considered as the most promising candidate for low-grade waste heat power generation. However, optimizing the thermoelectric performance of n-type Bi2Te3 is more challenging than that of p-type counterparts due to its greater sensitivity to texture, and thus limits the advancement of thermoelectric modules. Herein, the thermoelectric performance of n-type Bi2Te3 is enhanced by incorporating a small amount of CuGaTe2, resulting in a peak ZT of 1.25 and a distinguished average ZT of 1.02 (300-500 K). The decomposed Cu+ strengthens interlayer interaction, while Ga+ optimizes carrier concentration within an appropriate range. Simultaneously, the emerged numerous defects, such as small-angle grain boundaries, twin boundaries, and dislocations, significantly suppresses the lattice thermal conductivity. Based on the size optimization by finite element modelling, the constructed thermoelectric module yields a high conversion efficiency of 6.9% and output power density of 0.31 W cm-2 under a temperature gradient of 200 K. Even more crucially, the efficiency and output power little loss after subjecting the module to 40 thermal cycles lasting for 6 days. This study demonstrates the efficient and reliable Bi2Te3-based thermoelectric modules for broad applications in low-grade heat harvest.

STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury.

Recently, innate immunity and inflammation were recognized as the key factors for acute kidney injury (AKI) caused by sepsis, which is closely related to high mortality. Stimulator of interferon genes (STING) has emerged as a critical component of innate immune and inflammatory responses. However, the role of STING in the pathogenesis of septic AKI remains unclear. This study demonstrated that the STING was significantly activated in tubular cells induced by lipopolysaccharide (LPS) in vivo and in vitro. Tubule-specific STING knockout attenuated LPS-induced renal dysfunction and pathological changes. Mechanistically, the STING pathway promotes NOD-like receptor protein 3 (NLRP3) activation. STING triggers endoplasmic reticulum (ER) stress to induce mitochondrial reactive oxygen species (mtROS) overproduction, enhancing thioredoxin-interacting protein activation and association with NLRP3. Eventually, the NLRP3 inflammasome leads to tubular cell inflammation and pyroptosis. This study revealed the STING-regulated network and further identified the STING/ER stress/mtROS/NLRP3 inflammasome axis as an emerging pathway contributing to tubular damage in LPS-induced AKI. Hence, targeting STING may be a promising therapeutic strategy for preventing septic AKI.

CALPHAD accelerated design of advanced full-Zintl thermoelectric device.

Since thermoelectric materials have different physical and chemical properties, the design of contact layers requires dedicated efforts, and the welding temperatures are distinctly different. Therefore, a general interface design and connection technology can greatly facilitate the development of thermoelectric devices. Herein, we proposed a screening strategy for the contact materials based on the calculation of phase diagram method, and Mg2Ni has been identified as a matched contact layer for n-type Mg3Sb2-based materials. And this screening strategy can be effectively applied to other thermoelectric materials. By adopting the low-temperature sintering silver nanoparticles technology, the Zintl phase thermoelectric device can be fabricated at low temperature but operate at medium temperature. The single-leg n-type Mg3.15Co0.05SbBi0.99Se0.01 device achieves an efficiency of ~13.3%, and a high efficiency of ~11% at the temperature difference of 430 K has been realized for the Zintl phase thermoelectric device comprised together with p-type Yb0.9Mg0.9Zn1.198Ag0.002Sb2. Additionally, the thermal aging and thermal cycle experiments proved the long-term reliability of the Mg2Ni/Mg3.15Co0.05SbBi0.99Se0.01 interface and the nano-silver sintering joints. Our work paves an effective avenue for the development of advanced devices for thermoelectric power generation.

Thickened Perirenal Fat Predicts Poor Renal Outcome in Patients with Immunoglobulin A Nephropathy: A Population-Based Retrospective Cohort Study.

Introduction: Perirenal fat is a pad that fills the retroperitoneal space outside the kidney, which affects kidney function in various ways. However, the association between perirenal fat and IgA nephropathy (IgAN) has not yet been elucidated. This study aimed to investigate the role of perirenal fat in predicting IgAN progression. Methods: A total of 473 patients with biopsy-proven IgAN and follow-up information were recruited, and perirenal fat thickness (PFT) was measured using color Doppler ultrasonography at renal biopsy. Patients were divided into two groups according to the median PFT: the low-PFT group (PFT ≤1.34 cm, n = 239) and the high PFT group (PFT >1.35 cm, n = 234). A total of 473 healthy participants were included in the control group. Basic clinical characteristics were assessed at the time of renal biopsy, and the relationship between PFT and combined endpoints was analyzed. The renal composite endpoints were defined as a two-fold increase in blood creatinine level, end-stage renal disease (dialysis over 3 months). Kaplan-Meier survival analysis was used to explore the role of PFT in the progression of IgAN. Three clinicopathological models of multivariate Cox regression analysis were established to evaluate the association between PFT and renal prognosis in patients with IgAN. Results: Compared to healthy subjects, patients with IgAN showed significantly higher PFT. After a median follow-up of 50 months, 75 of 473 patients (15.9%) with IgAN reached renal composite endpoints. Among those, 13 of 239 patients (5.4%) were in the low PFT group, and 62 of 234 patients (26.5%) were in the high PFT group (p < 0.001). The results of three Cox regression models (including demographics, pathological and clinical indicators, and PFT) demonstrated that a higher PFT was significantly associated with a higher risk of reaching renal composite endpoints in patients with IgAN. Conclusion: This study indicated a positive relationship between PFT at renal biopsy and renal progression in patients with IgAN, suggesting that perirenal fat might act as a marker of poor prognosis in patients with IgAN.

Improved Thermoelectric Performance of p-Type PbTe by Entropy Engineering and Temperature-Dependent Precipitates.

Entropy engineering is aneffective scheme to reduce the thermal conductivity of thermoelectric materials, but it inevitably deteriorates the carrier mobility. Here, we report the optimization of thermoelectric performance of PbTe by combining entropy engineering and nanoprecipitates. In the continuously tuned compounds of Pb0.98Na0.02Te(1-2x)SxSex, we show that the x = 0.05 sample exhibits an exceptionally low thermal conductivity relative to its configuration entropy. By introducing Mn doping, the produced temperature-dependent nanoprecipitates of MnSe cause the high-temperature thermal conductivity to be further reduced. A very low lattice thermal conductivity of 0.38 W m-1 K-1 is achieved at 825 K. Meanwhile, the carrier mobility of the samples is only slightly influenced, owing to the well-controlled configuration entropy and the size of nanoprecipitates. Finally, a high peak zT of ∼2.1 at 825 K is obtained in the Pb0.9Na0.04Mn0.06Te0.9S0.05Se0.05 alloy.