LATS1 Inhibitor and Zinc Supplement Synergistically Ameliorates Contrast-induced Acute Kidney Injury: Induction of Metallothionein-1 and Suppression of Tubular Ferroptosis.

Contrast-induced acute kidney injury (CI-AKI) is a prevalent cause of renal dysfunction among hospitalized patients, yet the precise pathogenesis and effective therapeutic strategies remain elusive. In this study, we investigated the role of tubular ferroptosis in both experimental CI-AKI models and in primary tubular epithelial cells (PTECs) treated with ioversol. Using whole exome sequencing, we identified metallothioneins (MTs) as being among the most significantly downregulated genes following ioversol exposure. Our findings reveal that overexpression of Mt1 mitigates, whereas suppression of Mt-1 exacerbates, ioversol-induced tubular ferroptosis. Interestingly, the level of MTF1 (metal regulatory transcription factor 1), a principal regulator of Mt1, was found to increase in response to ioversol treatment. We further elucidated that ioversol activates LATS1 (Large tumor suppressor homolog 1), a kinase that promotes the phosphorylation and nuclear translocation of MTF1, thereby inhibiting its transcriptional activity for Mt1. Both genetic and pharmacological inhibition of LATS1 reversed the ioversol-induced suppression of Mt-1. From a therapeutic perspective, the LATS1 inhibitor TDI-011536, in combination with zinc acetate, was administered to a rodent model of CI-AKI. Our data indicate that this combination synergistically upregulates Mt1 expression and provides protection against contrast media-induced tubular ferroptosis. In summary, our study demonstrates that the reduction of Mt-1 contributes to tubular ferroptosis associated with CI-AKI. We show that contrast media activate LATS1, which in turn suppresses the transcriptional activity of MTF1 for Mt1. Herein, the combination of zinc acetate and a LATS1 inhibitor emerges as a potential therapeutic approach for the treatment of CI-AKI.

Investigating the Mechanical Performance of Bionic Wings Based on the Flapping Kinematics of Beetle Hindwings.

The beetle, of the order Coleoptera, possesses outstanding flight capabilities. After completing flight, they can fold their hindwings under the elytra and swiftly unfold them again when they take off. This sophisticated hindwing structure is a result of biological evolution, showcasing the strong environmental adaptability of this species. The beetle's hindwings can provide biomimetic inspiration for the design of flapping-wing micro air vehicles (FWMAVs). In this study, the Asian ladybird (Harmonia axyridis Pallas) was chosen as the bionic research object. Various kinematic parameters of its flapping flight were analyzed, including the flight characteristics of the hindwings, wing tip motion trajectories, and aerodynamic characteristics. Based on these results, a flapping kinematic model of the Asian ladybird was established. Then, three bionic deployable wing models were designed and their structural mechanical properties were analyzed. The results show that the structure of wing vein bars determined the mechanical properties of the bionic wing. This study can provide a theoretical basis and technical reference for further bionic wing design.

National Population Growth Rate, Its Components, and Subnational Contributions: A Research Note.

A population's current growth rate is determined jointly by changes in fertility, mortality, and migration. This overall growth rate is also the average of age-specific growth rates, which can be decomposed into the result of historical changes in fertility, mortality, and migration. However, doing so requires more than 100 years of historical data, meaning that such analyses are possible only in a select few populations. In this research note, we propose an adapted version of the variable-r model to measure contributions to the population growth rate for countries with shorter demographic series. In addition, we extend this model to explore the contribution of subnational changes to the national population growth rate. Our results demonstrate that the age-specific growth rates obtained from short historical series, say 25 years, closely match those of the longer series. These abbreviated age-specific growth rates closely resemble the growth rate at birth of their respective cohorts, which is the major determinant of population growth, except at older ages where mortality becomes the main explanatory element. Exploring subnational populations, we find considerable heterogeneity in the age profile of the components of growth and find that the most populous regions tend to have an outsized impact on national-level growth.

A trinity strategy enabled by iodine-loaded nitrogen-boron-doped carbon protective layer for dendrite-free zinc-ion batteries.

Although aqueous zinc ion batteries (AZIBs) have the merits of environmental friendliness, high safety and theoretical capacity, the slow kinetics associated with zinc deposition and unavoidable interfacial corrosion have seriously affected the commercialization of aqueous zinc ion batteries. In this work, an ingenious "trinity" design is proposed by applying a porous hydrophilic carbon-loaded iodine coating to the zinc metal surface (INBC@Zn), which simultaneously acts as an artificial protective layer, electrolyte additive and anode curvature regulator, so as to reduce the nucleation overpotential of Zn and promote the preferential deposition of (002) planes to some extent. With this synergistic effect, INBC@Zn exhibits high reversibility and strong side reaction inhibition. As a result, INBC@Zn shows high symmetric cycling stability up to 4500 h at 1 mA cm-2. An ultra-long cycle stability of 1500 cycles with high Coulombic efficiency (99.8 %) is achieved in the asymmetric cell. In addition, the INBC@Zn//NVO full cells exhibit impressive capacity retention (96 % after 1000 cycles at 3 A/g). Importantly, the designed pouch cell demonstrates stable performance and shows certain prospects for application. This work provides a facile and instructive approach toward the development of high-performance AZIBs.

Decomposition of Differentials in Health Expectancies From Multistate Life Tables: A Research Note.

Multistate modeling is a commonly used method to compute healthy life expectancy. However, there is currently no analytical method to decompose the components of differentials in summary measures calculated from multistate models. In this research note, we propose a derivative-based method to decompose the differentials in population-based health expectancies estimated via a multistate model into two main components: the proportion resulting from differences in initial health structure and the proportion resulting from differences in health transitions. We illustrate the method using data on activities of daily living from the U.S. Health and Retirement Study to decompose the sex differential in disability-free life expectancy (HLE) among older Americans. Our results suggest that the sex gap in HLE results primarily from differences in transition rates between disability states rather than from the initial health distribution of female and male populations. The methods introduced here will enable researchers, including those working in fields other than health, to decompose the relative contribution of initial population structure and transition probabilities to differences in state-specific life expectancies from multistate models.

Disability and morbidity among US birth cohorts, 1998-2018: A multidimensional test of dynamic equilibrium theory.

A substantial body of prior research has explored patterns of disability-free and morbidity-free life expectancy among older populations. However, these distinct facets of later-life health are almost always studied in isolation, even though they are very likely to be related. Using data from the US Health and Retirement Study and a multistate life table approach, this paper explores the interactions between disability, morbidity, and mortality by sex and education among four successive US birth cohorts, born from 1914 to 1923 to 1944-1953 and compared in the periods 1998-2008 and 2008-2018. We find little compression of disability but a marked expansion of morbidity across cohorts. However, disability-free life expectancy (DFLE) among those living with chronic morbidities has increased, even though at the population-level DFLE is largely unchanged. Broadly, these patterns suggest that successive cohorts of older populations in the US are experiencing a dynamic equilibrium, where the link between chronic morbidities and disability has weakened over successive cohorts. Investigating patterns by educational attainment, we find marked disparities where the least educated individuals not only live significantly fewer years free of disabilities or chronic morbidities but also have experienced an expansion in morbidity and disability. Our findings suggest that the future trajectory of disability-free life expectancy in the US is increasingly contingent on efforts to improve disease management and control the severe consequences of chronic morbidities.

2, 2-dimethylthiazolidine hydrochloride protects against experimental contrast-induced acute kidney injury via inhibition of tubular ferroptosis.

Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of AKI acquired in hospital, lacking of effective interventions. In the study, we identified the renal beneficial role of 2, 2-dimethylthiazolidine hydrochloride (DMTD), a safer compound which is readily hydrolyzed to cysteamine, in the rodent model of CI-AKI. Our data showed that administration of DMTD attenuated the impaired renal function and tubular injury induced by the contrast agent. Levels of MDA, 4-hydroxynonenal, ferrous iron and morphological signs showed that contrast agent induced ferroptosis, which could be inhibited in the DMTD group. In vitro, DMTD suppressed ferroptosis induced by ioversol in the cultured tubular cells. Treatment of DMTD upregulated glutathione (GSH) and glutathione peroxidase 4 (GPX4). Moreover, we found that DMTD promoted the ubiquitin-mediated proteasomal degradation of Keap1, and thus increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, increase of the ubiquitylation degradation of Keap1 mediates the upregulated effect of DMTD on Nrf2. Consequently, activated Nrf2/Slc7a11 results in the increase of GSH and GPX4, and therefore leads to the inhibition of ferroptosis. Herein, we imply DMTD as a potential therapeutic agent for the treatment of CI-AKI.

Biotransformation to synthesize the methylated derivatives of baicalein using engineered Escherichia coli.

Oroxylin A and negletein are flavonoid compounds existing in plants, with excellent pharmacological activities such as anti-inflammatory, anti-viropexis, and anti-cancer. Nevertheless, the natural abundance of these compounds in plants is extremely low. Here, a biotransformation pathway was developed in engineered strains to synthesize oroxylin A and negletein from baicalin by using the crude extract of Scutellaria baicalensis as the substrate. Briefly, the precursor baicalin in this crude extract was hydrolyzed by a ß-glucuronidase to form the intermediate baicalein, then O-methyltransferases utilize this intermediate to synthesize oroxylin A and negletein. Through screening strains and carbon sources, regulating intercellular S-adenosyl L-methionine synthesis, and optimizing culture conditions, the titers of the target products increased gradually, with 188.0 mg/L for oroxylin A and 222.7 mg/L for negletein finally. The study illustrates a convenient method to synthesize oroxylin A and negletein from a low-cost substrate, paving the way for the mass acquisition and further bioactivities development and utilization of these rare and high-value compounds.

PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma.

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal's effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

The contribution of survival to changes in the net reproduction rate.

The net reproduction rate (NRR) is an alternative fertility measure to the more common total fertility rate (TFR) and accounts for the mortality context of the population studied. This study is the first to compare NRR trends in high- and low-income countries and to decompose NRR changes over time into fertility and survival components. The results show that changes in the NRR have been driven mostly by changes in fertility. Yet improvements in survival have also played an important role in explaining changes in the NRR over the last century and represent a substantial component of change in some low-income countries today. Furthermore, the decomposition of the survival component by age indicates that the survival effect on population reproduction is concentrated mostly in infancy, although the HIV/AIDS epidemic altered this age profile in some populations. The findings highlight the importance of mortality's effect on reproduction in specific periods and contexts.

KDM6B regulates M2 polarization of macrophages by modulating the stability of nuclear ß-catenin.

Accumulating evidences suggest that the epigenetic regulation plays a pivotal role in establishing phenotype and function of tumor associated macrophages (TAMs). KDM6B is an epigenetic enzyme responsible for the H3K27me3 and reported to influence macrophage polarization. However, the underlying mechanism remains to be determined. Here, we demonstrated that inhibition of KDM6B in TAMs increased M2 polarization induced by coculture of breast cancer cells. Furthermore, we identified that KDM6B downregulation activated ß-catenin/c-Myc signaling, and thus promoted the M2-like phenotype. KDM6B accelerated the intranuclear ubiquitination degradation of ß-catenin, which depended on its demethylase activity. Therapeutically, our data showed that activated vitamin D analog paricalcitol upregulated the expression of KDM6B and decreased the M2 polarization, consequently protected against tumor progress in the xenograft mouse model of breast cancer. Taken together, our data reveal that epigenetic regulator KDM6B prevents M2 polarization via promoting the intranuclear degradation of ß-catenin. Active vitamin D analog induces KDM6B and suppresses tumor progress, suggesting a novel therapeutic potential of epigenetic modulation for the tumor treatment.

Gallic acid ameliorates calcium oxalate crystal-induced renal injury via upregulation of Nrf2/HO-1 in the mouse model of stone formation.

BACKGROUND: High prevalence and reoccurrence rate of nephrolithiasis bring about serious socioeconomic and healthcare burden, necessitating the need of effective therapeutic agents. Previous study revealed that gallic acid (GAL) alters the nucleation pathway of calcium oxalate (CaOx). On the other hand, it appears protective role against oxidative injury. Whether GAL could protect against crystal-induced lesion in vivo, and its underlying mechanism is yet unsolved. PURPOSE: This study aims to investigate the protective effects of GAL on the crystal-induced renal injury and its underlying mechanism in the mouse model of stone formation induced by glyoxylic acid. STUDY DESIGN AND METHODS: The mouse model of stone formation was established via successive intraperitoneal injection of glyoxylate. Proximal tubular epithelial cell line HK-2 treated with calcium oxalate monohydrate (COM) was used as in vitro model. The protective role of GAL on nephrolithiasis was tested by determination of tubular injury, crystal deposition and adhesion, levels of inflammatory cytokines, macrophage infiltration and the redox status of kidney. In vitro, effect of GAL on the ROS level and oxidative tubular injury induced by COM were detected, as well as major antioxidant pathway Nrf2/HO-1. RESULTS: Administration of GAL alleviates the renal deposition and adhesion of CaOx stone. Meanwhile, GAL ameliorates the inflammation and renal tubular injury. Level of intracellular ROS, osteopontin and CD44 are reduced, either in the mouse model of stone formation or in the COM-treated HK-2 cells after treatment of GAL. Mechanistically, GAL activates Nrf2/HO-1 pathway in HK-2 cells. Silencing Nrf2 abrogates the protective effect of GAL on the oxidative injury and adhesion of COM in HK-2 cells. CONCLUSION: Taken together, our study demonstrates the protective effect of GAL on the deposition of kidney stone and consequent tubular injury. Induction of the antioxidant pathway Nrf2/HO-1 was found to decrease the level of ROS and oxidative injury, thus implying that GAL could be a potential therapeutic agent for the treatment of nephrolithiasis.

YAP1-TEAD1 mediates the perineural invasion of prostate cancer cells induced by cancer-associated fibroblasts.

Perineural invasion (PNI) driven by the tumor microenvironment (TME) has emerged as a key pattern of metastasis of prostate cancer (PCa), while its underlying mechanism is still elusive. Here, we identified increased CAFs and YAP1 expression levels in patients with metastatic PCa. In the cultured PCa cell line LNCaP, co-culture with cancer-associated fibroblasts (CAFs) could upregulate YAP1 protein expression. Either ectopic overexpression of YAP1 or co-culture with CAFs could promote the infiltration of LNCaPs towards dorsal root ganglia (DRG). This effect could be blocked using an YAP1 inhibitor. In vivo, overexpression of YAP1 could increase PNI in a mouse model of sciatic nerve tumor invasion. Mechanistically, TEAD1 binds to the NGF promotor and YAP1/TEAD1 activates its transcription and consequently increases NGF secretion. In turn, PCa cells treated with CM from CAFs or stable YAP1 overexpression can stimulate DRG to secrete CCL2. The epithelial-to-mesenchymal transition (EMT) of PCa cells is thus activated via CCL2/CCR2. Overall, our data demonstrate that CAFs can activate YAP1/TEAD1 signaling and increase the secretion of NGF, therefore promoting PCa PNI. In addition, EMT induced by PNI suggests a feedback loop is present between neurons and PCa cells.

ARPC1A is regulated by STAT3 to inhibit ferroptosis and promote prostate cancer progression.

The aim of this study was to investigate the biological function and molecular mechanism of ARPC1A (actin related protein 2/3 complex subunit 1A) in prostate cancer progression. RT-qPCR and IHC results showed that the level of ARPC1A in prostate cancer tissues was significantly higher than that in adjacent tissues. The results of TCGA (the cancer genome atlas) database analysis showed that high expression of ARPC1A indicates poor prognosis in prostate cancer patients. In vitro functional experiments confirmed that downregulation of ARPC1A expression resulted in decreased cell viability and invasive ability of prostate cancer cells, as ARPC1A knockdown promoted ferroptosis. The transcriptional regulation mechanism of STAT3 (signal transduction and activators of transcription 3) on ARPC1A was elucidated by Co-IP, ChIP and luciferase reporter assays. In vivo experiments also supported the in vitro results. We propose that reduced ARPC1A expression inhibits prostate cancer cell viability and invasion in a ferroptotic manner. The ARPC1A level may serve as an independent predictor of prognosis in prostate cancer patients.

Dioscin Alleviates Cardiac Dysfunction in Acute Myocardial Infarction via Rescuing Mitochondrial Malfunction.

Myocardial infarction is one of the most severe heart diseases, leading to sudden death. Currently, angiography and stenting are widely performed in clinics, yet more effective treatment is still needed. Herein, we presented that dioscin, a natural product, showed protective effect on infarcted hearts via mitochondrial maintenance. Upon dioscin treatment, cardiac dysfunction was alleviated, and remodeling is prevented. Mechanistically, disocin maintains mitochondria function through the maintenance of Kreb's cycle, and suppresion of ROS accumulation. In this way, by targeting mitochondrial dysfunction, dioscin is a potential drug for infarcted hearts.

The Components of Change in Population Growth Rates.

The demographic balance equation relates the population growth rate with crude rates of fertility, mortality, and net migration. All these rates refer to changes occurring between two time points, say, t and t + h. However, this fundamental balance equation overlooks the contribution of historical fertility, mortality, and migration in explaining these population counts. Because of this, the balance equation only partially explains a change in growth rate between time t and t + h as it does not include the contribution of historical population trends in shaping the population at time t. The overall population growth rate can also be expressed as the weighted average of age-specific growth rates. In this article, we develop a method to decompose the historical drivers of current population growth by recursively employing the variable-r method on the population's average age-specific growth rates. We illustrate our method by identifying the unique contributions of survival progress, migration change, and fertility decline for current population growth in Denmark, England and Wales, France, and the United States. Our results show that survival progress is mainly having an effect on population growth at older ages, although accounting for indirect historical effects illuminates additional contributions at younger ages. Migration is particularly important in Denmark and England and Wales. Finally, we find that across all populations studied, historical fertility decline plays the largest role in shaping recent reductions in population growth rates.

Dioscin Attenuates Myocardial Ischemic/Reperfusion-Induced Cardiac Dysfunction through Suppression of Reactive Oxygen Species.

Myocardial ischemic/reperfusion (MI/R) is a leading cause of cardiovascular disease with high morbidity and mortality. However, the mechanisms underlying pathological reperfusion remain obscure. In this study, we found that dioscin, a natural product, could be a potential candidate for treating MI/R through modulating cardiac dysfunction. Mechanistically, our work revealed that dioscin could suppress the production of reactive oxygen species (ROS) via repressing the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2) and enhancing the expression of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx). These findings indicate that dioscin may be a potential candidate for therapeutic interventions in MI/R injury.

Aptamer-conjugated mesoporous polydopamine for docetaxel targeted delivery and synergistic photothermal therapy of prostate cancer.

OBJECTIVES: It is imperative to develop efficient strategies on the treatment of prostate cancer. Here, we constructed multifunctional nanoparticles, namely AS1411@MPDA-DTX (AMD) for targeted and synergistic chemotherapy/photothermal therapy of prostate cancer. MATERIALS AND METHODS: Mesoporous polydopamine (MPDA) nanoparticles were prepared by a one-pot synthesis method, DTX was loaded through incubation, and AS1411 aptamer was modified onto MPDA by the covalent reaction. The prepared nanoparticles were characterized by ultra-micro spectrophotometer, Fourier transform infrared spectra, transmission electron microscope, and so on. The targeting ability was detected by selective uptake and cell killing. The mechanism of AMD-mediated synergistic therapy was detected by Western blot and immunofluorescence. RESULTS: The prepared nanoparticles can be easily synthesized and possessed excellent water solubility, stability, and controlled drug release ability, preferentially in acidic context. Based on in vitro and in vivo results, the nanoparticles can efficiently target prostate cancer cells, promote DTX internalization, and enhance the antitumor effects of chemo-photothermal therapy strategies under the NIR laser irradiation. CONCLUSIONS: As a multifunctional nanoplatform, AS1411@MPDA-DTX could efficiently target prostate cancer cells, promote DTX internalization, and synergistically enhance the antiprostate cancer efficiency by combining with NIR irradiation.