Application of Proteomics and Machine Learning Methods to Study the Pathogenesis of Diabetic Nephropathy and Screen Urinary Biomarkers.

Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide, causing significant health problems. Early diagnosis of the disease is quite inadequate. To screen urine biomarkers of DN and explore its potential mechanism, this study collected urine from 87 patients with type 2 diabetes mellitus (which will be classified into normal albuminuria, microalbuminuria, and macroalbuminuria groups) and 38 healthy subjects. Twelve individuals from each group were then randomly selected as the screening cohort for proteomics analysis and the rest as the validation cohort. The results showed that humoral immune response, complement activation, complement and coagulation cascades, renin-angiotensin system, and cell adhesion molecules were closely related to the progression of DN. Five overlapping proteins (KLK1, CSPG4, PLAU, SERPINA3, and ALB) were identified as potential biomarkers by machine learning methods. Among them, KLK1 and CSPG4 were positively correlated with the urinary albumin to creatinine ratio (UACR), and SERPINA3 was negatively correlated with the UACR, which were validated by enzyme-linked immunosorbent assay (ELISA). This study provides new insights into disease mechanisms and biomarkers for early diagnosis of DN.

Synergistic effects of Co-pyrolysis on the immobilization and transformation of lead (Pb), chromium (Cr), nickel (Ni), and fluorine (F) in phosphogypsum-biomass mixtures.

Co-pyrolysis of biomass with phosphogypsum (PG) presents an effective strategy for facilitating the recycling of PG resources. However, it is crucial to note the environmental threats arising from the presence of Pb, Cr, Ni, and F in PG. This study investigated the effect of immobilization and transformation of four elements during co-pyrolysis with biomass and its components. The co-pyrolysis experiments were carried out in a tube furnace with a mixture of PG and corn stover (CS), cellulose (C), lignin (L), glucose (G). Co-pyrolysis occurred at varying temperatures (600 °C, 700 °C, 800 °C, and 900 °C) and different addition ratios (10%, 15%, and 20%). The results indicated that an increase in co-pyrolysis temperature was more conducive to the immobilization and transformation of harmful elements in PG, demonstrating significant efficacy in controlling F. Additionally, the addition of biomass components exerts a significant impact on inhibiting product toxicity, with small molecules such as glucose playing a prominent role in this process. The mechanism underlying the control of harmful elements during co-pyrolysis of PG and biomass was characterized by three main aspects. Firstly, biomass components have the potential to melt-encapsulate the harmful elements in PG, leading to precipitation. Secondly, the pyrolysis gas produced during the co-pyrolysis process contributes to the formation of a rich pore structure in the product. Finally, this process aids in transforming hazardous substances into less harmful forms and stabilizing these elements. The findings of this study are instrumental in optimizing the biomass and PG blend to mitigate the environmental impact of their co-pyrolysis products.

Preconception Counseling for a Patient With a Mechanical Tricuspid Valve.

A 37-year-old woman with mechanical tricuspid valve thrombosis presented for preconception consultation. Multimodality imaging confirmed a malfunctioning bileaflet mechanical tricuspid valve with both leaflets fixed and open. This case highlights the key discussions held by the multidisciplinary pregnancy heart team.

Maleimide functionalized polycaprolactone micelles for glutathione quenching and doxorubicin delivery.

High glutathione production is known to be one of the defense mechanisms by which many cancer cells survive elevated oxidative stress. By explicitly targeting glutathione in these cancer cells and diminishing its levels, oxidative stress can be intensified, ultimately triggering apoptosis or programmed cell death. Herein, we developed a novel approach by creating maleimide-functionalized polycaprolactone polymers, specifically using 2,3-diiodomaleimide functionality to reduce the level of glutathione in cancer cells. Polycaprolactone was chosen to conjugate the 2,3-diiodomaleimide functionality due to its biodegradable and biocompatible properties. The amphiphilic block copolymer was synthesized using PEG as a macroinitiator to make corresponding polymeric micelles. The resulting 2,3-diiodomaleimide-conjugated polycaprolactone micelles effectively quenched glutathione, even at low concentrations (0.01 mg mL-1). Furthermore, we loaded these micelles with the anticancer drug doxorubicin (DOX), which exhibited pH-dependent drug release. We obtained a loading capacity (LC) of 3.5% for the micelles, one of the highest LC reported among functional PCL-based micelles. Moreover, the enhanced LC doesn't affect their release profile. Cytotoxicity experiments demonstrated that empty and DOX-loaded micelles inhibited cancer cell growth, with the DOX-loaded micelles displaying the highest cytotoxicity. The ability of the polymer to quench intracellular GSH was also confirmed. This approach of attaching maleimide to polycaprolactone polymers shows promise in depleting elevated glutathione levels in cancer cells, potentially improving cancer treatment efficacy.

Effect of aromatic substituents on thermoresponsive functional polycaprolactone micellar carriers for doxorubicin delivery.

Amphiphilic functional polycaprolactone (PCL) diblock copolymers are excellent candidates for micellar drug delivery. The functional groups on the backbone significantly affect the properties of PCL. A systematic investigation of the effect of aromatic substituents on the self-assembly of γ-functionalized PCLs and the delivery of doxorubicin (DOX) is presented in this work. Three thermoresponsive amphiphilic diblock copolymers with poly(γ-benzyloxy-ε-caprolactone) (PBnCL), poly(γ-phenyl- ε-caprolactone) (PPhCL), poly(γ-(4-ethoxyphenyl)-ε-caprolactone) (PEtOPhCL), respectively, as hydrophobic block and γ-tri(ethylene glycol) functionalized PCL (PME3CL) as hydrophilic block were prepared through ring-opening polymerization (ROP). The thermoresponsivity, thermodynamic stability, micelle size, morphology, DOX-loading, and release profile were determined. The LCST values of amphiphilic diblock copolymers PME3CL-b-PBnCL, PME3CL-b-PPhCL, and PME3CL-b-PEtOPhCL are 74.2°C, 43.3°C, and 37.3°C, respectively. All three copolymers formed spherical micelles in phosphate-buffered saline (PBS, 1×, pH = 7.4) at low concentrations ranging from 8.7 × 10-4 g/L to 8.9 × 10-4 g/L. PME3CL-b-PBnCL micelles showed the highest DOX loading capacity of 3.01 ± 0.18 (wt%) and the lowest drug release, while PME3CL-b-PEtOPhCL micelles exhibited the lowest DOX loading capacity of 1.95 ± 0.05 (wt%) and the highest drug release. Cytotoxicity and cellular uptake of all three micelles were assessed in vitro using MDA-MB-231 breast cancer cells. All three empty micelles did not show significant toxicity to the cells at concentrations high up to 0.5 mg/mL. All three DOX-loaded micelles were uptaken into the cells, and DOX was internalized into the nucleus of the cells.