Healthcare Costs Across Diabetic Kidney Disease Stages: A Veterans Affairs Study.

Background: In the United States, diabetic kidney disease (DKD) affects about one-third of individuals with type 2 diabetes, causing significant economic burdens on the health care system and affecting patients' quality of life. Objective: The aim of the study was to quantify the burden of care in patients at different stages of DKD and to monitor shifts in healthcare costs throughout these stages. Methods: This study used data from the Veterans Affairs National database, focusing on US veterans diagnosed with DKD between January 2016 and March 2022. Aggregated all-cause health care costs per month were summarized using descriptive statistics. We used a generalized linear model to calculate the cost of DKD patent care based on the stages, dialysis phase, and kidney replacement therapy. Results: The cohort of 685,288 patients with DKD was predominantly male (96.51%), White (74.42%), and non-Hispanic (93.54%). The mean (SD) per-patient per-month costs were $1,597 ($3,178), $1,772 ($4,269), $2,857 ($13,072), $3,722 ($12,134), $5,505 ($14,639), and $6,999 ($16,901) for stages 1, 2, 3a, 3b, 4 and 5 respectively. The average monthly expenditure for patients receiving long-term dialysis was $12,299. Costs peaked sharply during the first month of kidney replacement therapy at $38,359 but subsequently decreased to $6,636 after 1 year. Conclusions: The economic implications of DKD are profound, emphasizing the need for efficient early detection and disease management strategies. Preventing patients from progressing to advanced DKD stage will minimize the economic repercussions of DKD and will assist health care systems in optimizing resource allocation.

Diabetic kidney disease (DKD) places a substantial burden on health care systems in the United States. In part of our effort to close the knowledge gap around the disease burden, care cost analysis for the patients with DKD was performed for US veterans. Along with stage progression, overall care costs per-patient per-month drastically increases from $1,597 (stage 1) to $6,999 (stage 5). Monthly costs exceeded $10,000 once veterans started to receive long-term dialysis. The quantitative summary will help health care systems efficiently allocate resources across various disease sectors.

Epitranscriptomic regulation of lipid oxidation and liver fibrosis via ENPP1 mRNA m6A modification.

BACKGROUND: Dysregulated lipid oxidation occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the molecular mechanism of lipid oxidation is not well appreciated in liver fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. METHODS: We investigated the causes and consequences of lipid oxidation in liver fibrosis using cultured cells, animal models, and clinical samples. RESULTS: Increased ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) expression caused increased lipid oxidation, resulting in the proliferation and migration of hepatic stellate cells (HSCs) that lead to liver fibrosis, whereas fibroblast-specific ENPP1 knockout reversing these results. Elevated ENPP1 and N6-methyladenosine (m6A) levels were associated with high expression of Wilms tumor 1 associated protein (WTAP). Mechanistically, WTAP-mediated m6A methylation of the 3'UTR of ENPP1 mRNA and induces its translation dependent of YTH domain family proteins 1 (YTHDF1). Additionally, ENPP1 could interact with hypoxia inducible lipid droplet associated (HILPDA) directly; overexpression of ENPP1 further recruits HILPDA-mediated lipid oxidation, thereby promotes HSCs proliferation and migration, while inhibition of ENPP1 expression produced the opposite effect. Clinically, increased expression of WTAP, YTHDF1, ENPP1, and HILPDA, and increased m6A mRNA content, enhanced lipid oxidation, and increased collagen deposition in human liver fibrosis tissues. CONCLUSIONS: We describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis.

Reversible Molecule Interactions Enable Ultrastretchable and Recyclable Ionogels for Wearable Piezoionic Sensors.

Ionogel-based piezoionic sensors feel motions and strains like human skin relying on reversible ion migrations under external mechanical stimulus and are of great importance to artificial intelligence. However, conventional ion-conductive polymers behave with degraded electrical and mechanical properties after thousands of strain cycles, and the discarded materials and devices become electronic wastes as well. Here, we develop ultrastretchable ionogels with superior electrical properties via the mediation of metal-organic frameworks, whose properties are attributed to reversible molecule interactions inside the material system. Ionogels present excellent mechanical properties with breaking elongation as high as 850%, exceeding most previously reported similar materials, and the high conductivity enables further application in sensor devices. In addition, our ionogels display superior recyclability because of the reversible physical and chemical interactions inside material molecules, which are eco-friendly to the environment. As a result, the ionogel-based piezoionic sensors deliver high sensitivity, flexibility, cyclic stability, and signal reliability, which are of great significance to wearable applications in human-motion detections such as throat vibration, facial expression, joint mobility, and finger movement. Our study paves the way for ultrastretchable and eco-friendly ionogel design for flexible electrochemical devices.

A flexible rotator-expanded molecular framework integrated strategy for improving microviscosity sensitivity of molecular rotor probes.

A novel approach was proposed to enhance the microviscosity sensitivity of molecular rotor probes by integrating flexible rotators and expanded molecular frameworks, addressing the crucial challenge of weakening microviscosity sensitivity in dilute solutions of macromolecules.

Aggregation-induced emission-active supramolecular polymers: from controlled preparation to applications.

Supramolecular polymers are typical self-assemblies, in which repeating monomer units are bonded together with dynamic and reversible noncovalent interactions. Supramolecular polymers can combine the advantages of polymer science and supramolecular chemistry. Aggregation-induced emission (AIE) means that a molecule remains faintly emissive in the dispersed state but intensively luminescent in a highly aggregated state. AIE has brought new opportunities and further development potential to the field of polymeric chemistry. The integration of AIE luminogens with supramolecular interactions can provide new vitality for supramolecular polymers. Therefore, it is essential for scientists to understand the preparation and applications of AIE-active supramolecular polymers. This review focuses on the recent advanced progress in the preparation of AIE-active supramolecular polymers. In addition, we summarize the newly developed supramolecular polymers with an AIE nature and their applications in chemical sensing, and in vitro and in vivo imaging, as well as the visualization of their structure and properties. Finally, the development trends and challenges of AIE-active supramolecular polymers are prospected.

Development of Ampelopsis Radix Ethanolic Extract Loaded Phytosomes for Improved Efficacy in Colorectal Cancer: in vitro and in vivo Assessment Study.

The aim of present work was to develop and evaluate Ampelopsis Radix ethanolic extract loaded phytosomes for improved efficacy in colorectal cancer. Ampelopsis Radix ethanolic extract was prepared by Soxhlet extraction process followed by development of phytosomes using lipids and other excipients. The phytosomes were evaluated for surface morphology, particle size analysis, zeta potential, encapsulation efficiency, drug loading, in vitro drug release, Cytotoxicity assay, cellular uptake studies were performed on HCT-116 and SW480 cell lines. In vivo antitumor activity was performed. The phytosomes were found spherical shape with smooth surface characteristics. The drug loading was observed between 29.27 to 42.10 % while particle size of 85 to 130 nm was found. Phytosomes showed desired release pattern which is required for cancer treatment. Phytosomes showed maximum antiproliferative activity on cell lines over the period of 24 hours and showed highest internalization within both types of cell lines. The survival rate of animals in phytosomes treated group was found to be 100% proving the safety and efficacy. Phytosomes showed highest antitumor activity as compared to other formulations. Study confirms the potential use Ampelopsis Radix ethanolic extract loaded phytosomes for improved efficacy in colorectal cancer.

State-of-the-art strategies to enhance the mechanical properties of microneedles.

Microneedles (MNs) have gained increasing attention in the biomedical field, owing to their notable advantages over injectable and transdermal preparations. The mechanical properties of MNs are the key to determine whether MNs can puncture the skin for efficient drug delivery and therapeutic purposes. However, there is still lacking of a systemic summary on how to improve the mechanical properties of MNs. Herein, this review mainly analyzes the key factors affecting the mechanical properties of MNs from the theoretical point of view and puts forward improvement approaches. First, we analyzed the major stresses exerted on the MNs during skin puncture and described general methods to evaluate the mechanical properties of MNs. We then provided detail examples to elucidate how the physicochemical properties of single polymer, formulation compositions, and geometric parameters affected the mechanical properties of MNs. Overall, the mechanical strength of MNs can be enhanced by tuning the crosslinking density, crystallinity degree, and molecular weight of single polymer, introducing polysaccharides and nano-microparticles as reinforcers to form complex with polymer, and optimizing the geometric parameters of MNs. Therefore, this review will provide critical guidance on how to fabricate MNs with robust mechanical strength for successful transdermal drug delivery.

Gelatin/Dopamine/Zinc-Doped Ceria/Curcumin nanocomposite hydrogels for repair of chronic refractory wounds.

Chronic wound healing is a common clinical challenge, characterized by bacterial infection, protracted inflammatory response, oxidative stress, and insufficient neovascularization. Nanozymes have emerged as a promising solution for treating skin wounds due to their antioxidant, antibacterial, and angiogenic properties. In recent years, combining nanozymes with hydrogels to jointly promote wound healing has attracted increasing research interest. However, most of the current nanocomposite hydrogels are still not effective in simultaneously controlling inflammatory, oxidative stress and bacterial invasion in wound healing. Improving the therapeutic functional diversity and efficacy of nanocomposite hydrogels remains a problem that needs to be addressed. In this study, we prepared nanocomposite hydrogels (GelMD-Cur@ZHMCe) by combining methylacrylated gelatin modified with dopamine (GelMD) with Zinc-doped hollow mesoporous cerium oxide nanoparticles loaded with curcumin (Cur@ZHMCe). The resulting hydrogels exhibited excellent water absorption, adhesion, and biocompatibility. In vitro and in vivo studies have demonstrated that GelMD-Cur@ZHMCe has excellent antioxidant, antibacterial, anti-inflammatory and vasculature-promoting properties, which enable it to rapidly promote wound repair. The wound healing rate of the rat total skin defect infection model treated with GelMD-Cur@ZHMCe reached 98.5±4.9 % after 14 days of treatment. It was demonstrated that this multifunctional nanocomposite hydrogel provides a promising therapeutic strategy for skin repair.

Trends in Bundled Outpatient Behavioral Health Services in VA-Direct Versus VA-Purchased Care.

The Veterans Health Administration (VA) increasingly purchases community-based care (CC) to improve healthcare access, including behavioral health. In 2018, VA introduced standardized episodes of care (SEOCs) to guide authorization and purchase of CC services for specific indications in a defined timeframe without bundling payment. In this retrospective cross-sectional study, we describe trends in VA and CC behavioral healthcare utilization using the VA Outpatient Psychiatry SEOC definition. Counts of Outpatient Psychiatry SEOC-allowable service and procedure codes during fiscal years 2016-2019 were organized according to four SEOC-defined service types (evaluation and management, laboratory services, psychiatry services, transitional care) and measured as percentages of all included codes. Trends comparing behavioral healthcare utilization between Veterans using any CC versus VA only were analyzed using a linear mixed effects model. We identified nearly 3 million Veterans who registered 60 million qualifying service and procedure codes, with overall utilization increasing 77.8% in CC versus 5.2% in VA. Veterans receiving any CC comprised 3.9% of the cohort and 4.7% of all utilization. When examining service type as a percent of all Outpatient Psychiatry SEOC-allowable care among Veterans using CC, psychiatry services increased 12.2%, while transitional care decreased 8.8%. In regression analysis, shifts in service type utilization reflected descriptive results but with attenuated effect sizes. In sum, Outpatient Psychiatry SEOC-allowable service utilization grew, and service type composition changed, significantly more in CC than in VA. The role of SEOCs and their incentives may be important when evaluating future behavioral healthcare quality and value in bundled services.

The C5AR1/TNFSF13B axis alleviates osteoarthritis by activating the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway to inhibit ferroptosis.

Chondrocyte ferroptosis induces the occurrence of osteoarthritis (OA). As a key gene of OA, C5a receptor 1 (C5AR1) is related to ferroptosis. Here, we investigated whether C5AR1 interferes with chondrocyte ferroptosis during OA occurrence. C5AR1 was downregulated in PA-treated chondrocytes. Overexpression of C5AR1 increased the cell viability and decreased ferroptosis in chondrocytes. Moreover, Tumor necrosis factor superfamily member 13B (TNFSF13B) was downregulated in PA-treated chondrocytes, and knockdown of TNFSF13B eliminated the inhibitory effect of C5AR1 on ferroptosis in chondrocytes. More importantly, the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway inhibitor LY294002 reversed the inhibition of C5AR1 or TNFSF13B on ferroptosis in chondrocytes. Finally, we found that C5AR1 alleviated joint tissue lesions and ferroptosis in rats and inhibited the progression of OA in the rat OA model constructed by anterior cruciate ligament transection (ACLT), which was reversed by interfering with TNFSF13B. This study shows that C5AR1 reduces the progression of OA by upregulating TNFSF13B to activate the PI3K/Akt/GSK3ß/Nrf2/HO-1 pathway and thereby inhibiting chondrocyte sensitivity to ferroptosis, indicating that C5AR1 may be a potential therapeutic target for ferroptosis-related diseases.

Rosiglitazone and trametinib exhibit potent anti-tumor activity in a mouse model of muscle invasive bladder cancer.

Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.

Severe Hypothermia Induces Ferroptosis in Cerebral Cortical Nerve Cells.

Abnormal shifts in global climate, leading to extreme weather, significantly threaten the safety of individuals involved in outdoor activities. Hypothermia-induced coma or death frequently occurs in clinical and forensic settings. Despite this, the precise mechanism of central nervous system injury due to hypothermia remains unclear, hindering the development of targeted clinical treatments and specific forensic diagnostic indicators. The GEO database was searched to identify datasets related to hypothermia. Post-bioinformatics analyses, DEGs, and ferroptosis-related DEGs (FerrDEGs) were intersected. GSEA was then conducted to elucidate the functions of the Ferr-related genes. Animal experiments conducted in this study demonstrated that hypothermia, compared to the control treatment, can induce significant alterations in iron death-related genes such as PPARG, SCD, ADIPOQ, SAT1, EGR1, and HMOX1 in cerebral cortex nerve cells. These changes lead to iron ion accumulation, lipid peroxidation, and marked expression of iron death-related proteins. The application of the iron death inhibitor Ferrostatin-1 (Fer-1) effectively modulates the expression of these genes, reduces lipid peroxidation, and improves the expression of iron death-related proteins. Severe hypothermia disrupts the metabolism of cerebral cortex nerve cells, causing significant alterations in ferroptosis-related genes. These genetic changes promote ferroptosis through multiple pathways.

Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.

During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub). We identify regions within the DNMT3A1 amino terminus that bind H2AK119Ub and the nucleosome acidic patch. This bidentate interaction is required for effective DNMT3A1 engagement with H2AK119Ub-modified chromatin in cells. Further, aberrant redistribution of DNMT3A1 to Polycomb target genes recapitulates the cancer-associated DNA hypermethylation signature and inhibits their transcriptional activation during cell differentiation. This effect is rescued by disruption of the DNMT3A1-acidic patch interaction. Together, our analyses reveal a binding interface critical for mediating promoter CpG island DNA hypermethylation, a major molecular hallmark of cancer.

m6A epitranscriptomic and epigenetic crosstalk in liver fibrosis: Special emphasis on DNA methylation and non-coding RNAs.

Liver fibrosis is a pathological process caused by a variety of chronic liver diseases. Currently, therapeutic options for liver fibrosis are very limited, highlighting the urgent need to explore new treatment approaches. Epigenetic modifications and epitranscriptomic modifications, as reversible regulatory mechanisms, are involved in the development of liver fibrosis. In recent years, researches in epitranscriptomics and epigenetics have opened new perspectives for understanding the pathogenesis of liver fibrosis. Exploring the epigenetic mechanisms of liver fibrosis may provide valuable insights into the development of new therapies for chronic liver diseases. This review primarily focus on the regulatory mechanisms of N6-methyladenosine (m6A) modification, non-coding RNA, and DNA methylation in organ fibrosis. It discusses the interactions between m6A modification and DNA methylation, as well as between m6A modification and non-coding RNA, providing a reference for understanding the interplay between epitranscriptomics and epigenetics.

Phosphorylation of USP27X by PIM2 promotes glycolysis and breast cancer progression via deubiquitylation of MYC.

Aberrant cell proliferation is a hallmark of cancer, including breast cancer. Here, we show that USP27X is required for cell proliferation and tumorigenesis in breast cancer. We identify a PIM2-USP27X regulator of MYC signaling axis whose activity is an important contributor to the tumor biology of breast cancer. PIM2 phosphorylates USP27X, and promotes its deubiquitylation activity for MYC, which promotes its protein stability and leads to increase HK2-mediated aerobic glycolysis in breast cancer. Moreover, the PIM2-USP27X-MYC axis is also validated in PIM2-knockout mice. Taken together, these findings show a PIM2-USP27X-MYC signaling axis as a new potential target for breast cancer treatment.

Ultrasensitive Self-Powered Flexible Crystalline ß-Ga2O3-Based Photodetector Obtained through Lattice Symmetry and Band Alignment Engineering.

Due to its portable and self-powered characteristics, the construction of Ga2O3-based semiconductor flexible devices that can improve the adaptability in various complex environments have drawn great attention in recent decades. However, conventional Ga2O3-based flexible heterojunctions are based on either amorphous or poor crystalline Ga2O3 materials, which severely limit the performance of the corresponding devices. Here, through lattice-symmetry and energy-band alignment engineering, we construct a high-quality crystalline flexible NiO/ß-Ga2O3 p-n self-powered photodetector. Owing to its suitable energy-band alignment structure, the device shows a high photo-to-dark current ratio (1.71 × 105) and a large detection sensitivity (6.36 × 1014 Jones) under zero bias, which is superior than most Ga2O3 self-powered photodetectors even for those based on rigid substrates. Moreover, the fabricated photodetectors further show excellent mechanical stability and robustness in bending conditions, demonstrating their potential practical applications in flexible optoelectronic devices. These findings provide insights into the manipulation of crystal lattice and energy band engineering in flexible self-powered photodetectors and also offer guideline for designing other Ga2O3-based flexible electronic devices.

Antidepressant advantage of Chaihushugan san in female mice: A novel signaling mechanism in hippocampus.

ETHNOPHARMACOLOGICAL RELEVANCY: Chaihushugan san (CSS), a classic formula for soothing the liver and relieving depression, has been identified to produce rapid antidepressant-like effects in female mice. However, the gender predominance and underlying mechanisms of CSS's antidepressant remain unclear. AIM OF THE STUDY: In this study, we focused on unraveling the gender predominance of CSS in antidepressant and the specific neuronal mechanisms that mediate this predominance. METHODS AND MATERIALS: Tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT) were used to evaluate depressive phenotypes or antidepressant-like effects of CSS in female and male chronic unpredictable mild stress (CUMS) mice model. RNA-sequencing was used to screen specific target for CSS antidepressant gender dominance. RT-PCR and elisa were used to detect the expressions of specific molecule, hormones, and inflammatory factors in the hippocampus. hippocampal viral overactivation and pharmacological blockade were used to detect the correlation between CSS antidepressant gender dominance and related targets. RESULTS: In the present study, both female and male mice displayed depressive phenotypes including significant increasing immobility time in TST and reducing sucrose preference ratio in SPT after exposing CUMS for 3 weeks. However, acute administration of CSS (2, 4 g/kg) improved the depressive phenotypes only in female mice or not male mice at 2 h later. Moreover, the expressions of TC2N were increased only in female mice after exposing CUMS for 3 weeks, which were also reversed by CSS after a single administration 2 h later, but no alterations in male mice. The hippocampal expressions of estrogen receptor ß (Erß), pro-inflammatory factors (IL-1ß and TNF-α) and anti-inflammatory factors (IL-10, TGF-ß and IL-1Rα) were all abnormal in female CUMS mice model, which were all normalized by CSS. Furthermore, overactivation of hippocampal TC2N by AAV-TC2N+/+ blocked the antidepressant-like effects of CSS and the up-regulation of hippocampal Erß in female mice. However, inhibition of Erß blunted the antidepressant-like effects of CSS and CSS's suppression of pro-inflammatory factors (IL-1ß and TNF-α), which had no any effect on hippocampal TC2N and anti-inflammatory factors (IL-10 and TGF-ß). CONCLUSIONS: The study revealed that CSS had antidepressant superiority in female mice depending on inhibiting hippocampal TC2N and then activating Erß, further inhibiting the release of pro-inflammatory factors to produce antidepressant effects, which provided a basis for the guidance of CSS in clinical application, new ideas and targets for the development of drugs for depression with gender differences.

Manipulating AIE ligands into layers of pillar-layered MOFs for enhanced emission.

Four pillar-layered AIEgen-based MOFs exhibit higher thermal stability, tunable emission colors and improved QYs compared with that of non-pillar-layered AIEgen-based MOFs by confining the AIE ligands into layers. These results reveal that rationally manipulating AIE ligands into layers of pillar-layered MOFs is an effective strategy for the design and construction of tunable luminescent MOF systems.

Aggregation-induced emission micelle-based sensing array for discrimination of long-chain fatty acids.

A sensing array based on aggregation-induced emission micelles was proposed for efficient discrimination of three typical long-chain fatty acids (lauric, palmitic, and stearic acids) and their mixtures.

Cancer-associated fibroblasts-secreted exosomal miR-92a-3p promotes tumor growth and stemness in hepatocellular carcinoma through activation of Wnt/ß-catenin signaling pathway by suppressing AXIN1.

Cancer-associated fibroblasts (CAFs) are a major cellular component in the tumor microenvironment and have been shown to exhibit protumorigenic effects in hepatocellular carcinoma (HCC). This study aimed to delve into the mechanisms underlying the tumor-promoting effects of CAFs in HCC. Small RNA sequencing was conducted to screen differential expressed microRNAs in exosomes derived from CAFs and normal fibroblasts (NFs). The miR-92a-3p expression was then measured using reverse transcriptase quantitative real-time PCR in CAFs, NFs, CAFs-derived exosomes (CAFs-Exo), and NF-derived exosomes (NFs-Exo). Compared to NFs or NF-Exo, CAFs and CAFs-Exo significantly promoted HCC cell proliferation, migration, and stemness. Additionally, compared to NFs or NF-Exo, miR-92a-3p level was notably higher in CAFs and CAFs-Exo, respectively. Exosomal miR-92a-3p was found to enhance HCC cell proliferation, migration, and stemness. Meanwhile, AXIN1 was targeted by miR-92a-3p. Exosomal miR-92a-3p could activate ß-catenin/CD44 signaling in HCC cells by inhibiting AXIN1 messenger RNA. Furthermore, in vivo studies verified that exosomal miR-92a-3p notably promoted tumor growth and stemness through targeting AXIN1/ß-catenin axis. Collectively, CAFs secreted exosomal miR-92a-3p was capable of promoting growth and stemness in HCC through activation of Wnt/ß-catenin signaling pathway by suppressing AXIN1. Therefore, targeting CAFs-derived miR-92a-3p may be a potential strategy for treating HCC.