Pharmacokinetics, Mass Balance, and Biotransformation of [14C]tinengotinib, A Novel Multi-target Kinase Inhibitor, in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [14C]tinengotinib following a single oral dose in healthy subjects. METHODS: Six healthy male subjects received a single oral dose of [14C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism. RESULTS: Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (Tmax) of 1.0-4.0 h post-dose and a long terminal half-life (t½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration-time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4. CONCLUSIONS: Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent. REGISTRATION: ChinadrugTrials.org.cn identifier: CTR20212852.

Pentachlorophenol impairs the antimicrobic capability of blood clam via undermining humoral immunity and disrupting humoral-cellular crosstalk.

Due to past massive usage and persistent nature, pentachlorophenol (PCP) residues are prevalent in environments, posing a potential threat to various organisms such as sessile filter-feeding bivalves. Although humoral immunity and its crosstalk with cellular one are crucial for the maintaining of robust antimicrobic capability, little is known about the impacts of PCP on these critical processes in bivalve mollusks. In this study, pathogenic bacterial challenge and plasma antimicrobic capability assays were carried out to assess the toxic effects of PCP on the immunity of a common bivalve species, blood clam (Tegillarca granosa). Moreover, the impacts of PCP-exposure on the capabilities of pathogen recognition, hemocyte recruitment, and pathogen degradation were analyzed as well. Furthermore, the activation status of downstream immune-related signalling pathways upon PCP exposure was also assessed. Data obtained illustrated that 28-day treatment with environmentally realistic levels of PCP resulted in evident declines in the survival rates of blood clam upon Vibrio challenge along with markedly weakened plasma antimicrobic capability. Additionally, the levels of lectin and peptidoglycan-recognition proteins (PGRPs) in plasma as well as the expression of pattern recognition receptors (PRRs) in hemocytes were found to be significantly inhibited by PCP-exposure. Moreover, along with the downregulation of immune-related signalling pathway, markedly fewer chemokines (interleukin 8 (IL-8), IL-17, and tumor necrosis factor α (TNF-α)) in plasma and significantly suppressed chemotactic activity of hemocytes were also observed in PCP-exposed blood clams. Furthermore, compared to that of the control, blood clams treated with PCP had markedly lower levels of antimicrobic active substances, lysozyme (LZM) and antimicrobial peptides (AMP), in their plasma. In general, the results of this study suggest that PCP exposure could significantly impair the antimicrobic capability of blood clam via undermining humoral immunity and disrupting humoral-cellular crosstalk.

Quality deterioration of mashed potatoes during the freeze-thaw cycle: From the perspective of moisture and microstructure.

This study aimed to simulate cold chain sales temperatures to predict the effects of temperature fluctuations on the physicochemical properties, moisture distribution, microstructure, and flavor of mashed potatoes. The results showed a decline in the hardness and chewability of mashed potatoes alongside the migration of water from bound water states to weakly bound states under freeze-thaw cycles (FTC) conditions. Microstructural analysis indicated that the adhesive forces between proteins and starch granules were weakened, and the structure of mashed potatoes particles was destroyed following FTC. The oxidation and degradation of fat induced by FTC increased the content of key compounds such as octanal and nonanal, thereby contributing to an overall deterioration in the flavor of mashed potatoes. This study elucidates the effects of FTC on water migration, microstructure, and flavor characteristics of mashed potatoes, thereby providing a theoretical foundation for improving the quality of prefabricated frozen mashed potatoes dishes.

Studies on immunological characteristics and transcriptomic analysis of Litopenaeus vannamei low salt-tolerance family.

Litopenaeus vannamei is a widely distributed euryhaline aquatic animal, affected by low salinity, which can impact its disease resistance and immunity. However, there is a limited understanding of the adaptation mechanisms of L. vannamei with different genetic backgrounds to low salinity. Therefore, the present study aimed to compare the immunity characteristics and transcriptomics of L. vannamei low salt-tolerant (FG I/J) and low salt-sensitive (control) families. Also, the disease resistance and immune parameters (including [THC], hemolymph cell viability, lysozyme activity [LZM], phenoloxidase content [PO], interleukin-6 [IL-6], and tumor necrosis factor-alpha [TNF-α]) of the FG I/J and control families of L. vannamei under low salinity (5‰) and ambient salinity (24‰) were examined. Additionally, hepatopancreas transcriptomics of the FG I/J and control families were analyzed at a salinity of 5‰. The results showed that the FG I/J family had higher disease resistance to Vibrio parahaemolyticus and stronger immunological capacity than the control family. Transcriptomic analysis showed significantly enriched energy metabolism and immune regulation pathways. Therefore, we speculated that energy metabolism provides sufficient energy for immunological modulation in the FG I/J family to deal with long-term low-salt stress and achieve high growth and survival rates.

The value of fetal left ventricular global longitudinal strain in predicting neonatal complications in pregnant women with hypertensive disorders.

BACKGROUND: Pregnancy-induced hypertension remains one of the important types of diseases that affect maternal and infant outcomes; prenatal and perinatal ultrasound examination is an important tool for evaluating fetal development. So, this study aimed to explore the clinical value of applying fetal heart quantification (fetal HQ) measuring left ventricular global longitudinal strain (LVGLS) and left ventricular ejection fraction (LVEF) in mid-to-late fetuses to predict neonatal complications in patients with gestational hypertension. METHODS: A retrospective summary of 146 pregnant women with gestational hypertension diagnosed from August 2020 to October 2023 into JinHua Maternal and Child Health Care Hospital was performed. Fetal HQ measured the fetal global spherical index (GSI), left and right ventricular spherical index (SI), left and right ventricular fractional shortening (FS), LVGLS and RVGLS, LVEF, and fractional area change (FAC) of the left and right ventricles. They were divided into complication group and non-complication group based on whether fetal complications occurred 28 days after birth. Multivariate logistic regression was used to screen risk factors to neonatal complications. RESULTS: The 146 neonates were divided into 39 of the complication group and 107 of the non-complication group. Compared with the latter group, pregnant women in the former group had a higher incidence of preeclampsia and eclampsia, increased mean systolic and diastolic blood pressure, significantly lower estimated fetal weight (EFW), left ventricular 24-segment SI, LVGLS, LVEF, and left ventricular FAC values (p < .05). Logistic regression showed higher of LVGLS (adjusted OR = 2.281, p < .001) was risk factors for neonatal complications, while higher LVEF (adjusted OR = 0.600, p < .001) and left ventricular FAC (adjusted OR = 0.784, p = .035) were protective factors. Spearman's correlation analysis showed a significant negative correlation between LVGLS and LVEF (r = -0.368, p < .001). Receiver operating curves (ROCs) showed the area under the curve (AUC) for predicting overall neonatal complications was 0.880 for LVGLS and 0.878 for LVEF (p < .001). CONCLUSIONS: Fetal HQ for fetal LVGLS and LVEF in mid-to-late pregnancy with gestational hypertension helps to assess the overall neonatal complications risk.

Mussel-inspired Bifunctional Coating for Long-Term Stability of Oral Implants.

Peri-implantitis and osseointegration failure present considerable challenges to the prolonged stability of oral implants. To address these issues, there is an escalating demand for a resilient implant surface coating that seamlessly integrates antimicrobial features to combat bacteria-induced peri-implantitis, and osteogenic properties to promote bone formation. In the present study, a bio-inspired poly(amidoamine) dendrimer (DA-PAMAM-NH2) is synthesized by utilizing a mussel protein (DA) known for its strong adherence to various materials. Conjugating DA with PAMAM-NH2, inherently endowed with antibacterial and osteogenic properties, results in a robust and multifunctional coating. Robust adhesion between DA-PAMAM-NH2 and the titanium alloy surface is identified using confocal laser scanning microscopy (CLSM) and attenuated total reflectance-infrared (ATR-IR) spectroscopy. Following a four-week immersion of the coated titanium alloy surface in simulated body fluid (SBF), the antimicrobial activity and superior osteogenesis of the DA-PAMAM-NH2-coated surface remain stable. In contrast, the bifunctional effects of the PAMAM-NH2-coated surface diminish after the same immersion period. In vivo animal experiments validate the enduring antimicrobial and osteogenic properties of DA-PAMAM-NH2-coated titanium alloy implants, significantly enhancing the long-term stability of the implants. This innovative coating holds promise for addressing the multifaceted challenges associated with peri-implantitis and osseointegration failure in titanium-based implants. STATEMENT OF SIGNIFICANCE: Prolonged stability of oral implants remains a clinically-significant challenge. Peri-implantitis and osseointegration failure are two important contributors to the poor stability of oral implants. The present study developed a mussel-bioinspired poly(amidoamine) dendrimer (DA-PAMAM-NH2) for a resilient implant surface coating that seamlessly integrates antimicrobial features to combat bacteria-induced peri-implantitis, and osteogenic properties to promote bone formation to extend the longevity of oral implants.

Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH.

The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.

Pollutant degradation and hydrogen production of landfill leachate membrane concentrates via aqueous phase reforming.

Membrane filtration is a mainstream method for landfill leachate treatment, leaving the landfill leachate membrane concentrates (LLMCs) a high-toxicity residue. Conventional LLMCs disposal technology shows specific challenges due to the low biodegradability, high inorganic salts, and high heavy metal ions content of LLMCs. Therefore, it is necessary to degrade LLMCs with a more suitable technology. In this study, a special method was proposed to convert some organic chemicals into valuable compounds by aqueous phase reforming (APR). Ni-based catalysts (Ni//La2O3, Ni/CeO2, Ni/MgO, and Ni/Al2O3) were prepared to investigate the effect of different supports on the APR of LLMCs. APR performed outstanding characteristics in the decrease of chemical oxygen demand (COD) and total organic carbon (TOC), the degradation of macromolecules, and the removal of heavy metal ions in the aqueous phase. In addition, H2 was generated which is beneficial for energy compensating during the APR process. The best-performing catalyst (Ni/Al2O3) was selected to investigate the effects of reaction temperature, reaction time, and catalyst addition on product distribution. The optimal H2 selectivity (44.71%) and H2 production (11.63 mmol/g COD) were obtained at 250 °C with 2 g Ni/Al2O3 usage for 1 h. This paper provided a new perspective on the disposal of LLMCs, which will degrade pollutants efficiently.

Global disease burden attributable to kidney dysfunction, 1990-2019: A health inequality and trend analysis based on the global burden of disease study.

OBJECTIVE: This study aimed to evaluate the burden of kidney dysfunction (KD), assess socioeconomic inequalities, and project trends in the future. METHODS: Data on deaths, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) were from Global Burden of Disease Study 2019. The Joinpoint regression model was utilized to analyze the temporal trend by the annual percentage change (APC). The slope index and concentration index were employed to evaluate cross-country disparities. The future trend was predicted using an age-period-cohort analysis. RESULTS: In the past three decades, the death numbers of KD increased from 1,571,720 to 3,161,552, DALYs from 42,090,331 to 76,486,945, YLDs from 5,003,267 to 11,282,484, and YLLs from 37,087,065 to 65,204,461, respectively. The age-standardized rate (ASR) of deaths, DALYs, and YLLs exhibited a declining trend. The ASR of YLDs increased until 2017, then decreased. The slope index and concentration index for DALYs increased from 248.1 to 351.9 and from 40.70 to 57.8. In the future, the ASR of deaths, DALYs, YLDs, and YLLs will remain stable, while their numbers will continue to rise, except for YLLs. CONCLUSIONS: The disease burden of KD remained serious. Tailored interventions should be developed based on national contexts.

Olfactory toxicity of tetrabromobisphenol A to the goldfish Carassius auratus.

Tetrabromobisphenol A (TBBPA) is one of the most extensively used brominated flame retardants and its increasing use in consumer products has raised concerns about its ecotoxicity. Given the ubiquity of TBBPA in aquatic environments, it is inevitable that these chemicals will enter the olfactory chambers of fish via water currents. Nevertheless, the olfactory toxicity of TBBPA to aquatic organisms and the underlying toxic mechanisms have yet to be elucidated. Therefore, we investigated the olfactory toxicity of TBBPA in the goldfish Carassius auratus, a model organism widely used in sensory biology. Results showed that exposure to TBBPA resulted in abnormal olfactory-mediated behaviors and diminished electro-olfactogram (EOG) responses, indicating reduced olfactory acuity. To uncover the underlying mechanisms of action, we examined the structural integrity of the olfactory epithelium (OE), expression levels of olfactory G protein-coupled receptors (GPCRs), enzymatic activities of ion transporters, and fluctuations in neurotransmitters. Additionally, comparative transcriptomic analysis was employed to investigate the molecular mechanisms further. Our study demonstrates for the first time that TBBPA at environmentally relevant levels can adversely affect the olfactory sensitivity of aquatic organisms by interfering with the transmission of aqueous stimuli to olfactory receptors, impeding the binding of odorants to their receptors, disrupting the olfactory signal transduction pathway, and ultimately affecting the generation of action potentials.

Application of eculizumab, a terminal complement inhibitor, in the management of atypical hemolytic uremic syndrome in a 14-month-old Chinese pediatric patient: a case report.

Eculizumab, a recombined humanized monoclonal antibody which possesses high affinity for the complement protein C5, is a therapeutic agent utilized in the treatment of atypical hemolytic uremic syndrome (aHUS) by inhibiting the terminal complement complex C5b-9. In a pediatric patient with aHUS of 14 months, the administration of eculizumab therapy was accompanied by the inclusion of meningococcal vaccine as part of the national immunization program. Notably, no other antibiotics were administered prior to or during the course of eculizumab treatment. Moreover, there were no occurrences of infusion reactions or meningococcal infections observed throughout the course of treatment. Due to the presence of anti-factor H antibodies and insufficient recovery, glucocorticoids and eculizumab were administered at week 0 and week 1, followed by the initiation of mycophenolate mofetil (MMF) at a dosage of 250 mg (approximately 548 mg/m2) per day starting from Day 10. Due to the recovered of complement antibody after 8 doses of eculizumab, the therapeutic interval was extended from once every 3 weeks to once a month since 9th administration. We experienced and successfully treated a rare case of aHUS with eculizumab in a 14-month-old Chinese pediatric patient.

Enhanced Electromagnetic Interference Shielding Properties of CNT/Carbon Composites by Designing a Hierarchical Porous Structure.

With the widespread use of electronic devices, electromagnetic interference (EMI) has become an increasingly severe issue, adversely affecting device performance and human health. Carbon nanotubes (CNTs) are recognized for their electrical conductivity, flexibility, and stability, making them promising candidates for EMI shielding applications. This research developed hierarchical porous-structured CNT/carbon composites for enhancing electromagnetic interference (EMI) shielding properties. Featuring a CNT film with nano-scale pores and an amorphous carbon layer with micro-scale pores, the CNT/carbon composites are strategically arranged to promote the penetration of EM waves into the composite's interior and facilitate multiple reflections, thereby improving the EMI shielding performance. An impressive EMI shielding effectiveness of 61.4 dB was achieved by the CNT/carbon composites, marking a significant improvement over the 36.5 dB measured for the pristine CNT film. Owing to the micro pores in the amorphous carbon layer, a notable reduction in the reflection shielding efficiency (SER) but, concurrently, a substantial increase in the absorption shielding efficiency (SEA) compared with the pristine CNT film was realized in the composites. This study successfully validated the effectiveness of the hierarchical porous structure in enhancing the EMI shielding performance, providing a promising new strategy for the development of lightweight, flexible, and efficient EMI shielding materials.

Liposomal Nanomaterials: A Rising Star in Glioma Treatment.

Glioma is a primary malignant tumor in the central nervous system. In recent years, the treatment of glioma has developed rapidly, but the overall survival of glioma patients has not significantly improved. Due to the presence of the blood-brain barrier and intracranial tumor barrier, many drugs with good effects to cure glioma in vitro cannot be accurately transported to the corresponding lesions. In order to enable anti-tumor drugs to overcome the barriers and target glioma, nanodrug delivery systems have emerged recently. It is gratifying that liposomes, as a multifunctional nanodrug delivery carrier, which can be compatible with hydrophilic and hydrophobic drugs, easily functionalized by various targeted ligands, biodegradable, and hypoimmunogenic in vivo, has become a quality choice to solve the intractable problem of glioma medication. Therefore, we focused on the liposome nanodrug delivery system, and summarized its current research progress in glioma. Hopefully, this review may provide new ideas for the research and development of liposome-based nanomaterials for the clinical treatment of glioma.

Activation of CD14+ Monocytes via the IFN-γ Signaling Pathway Is Associated with Immune-Related Adverse Events in Hepatocellular Carcinoma Patients Receiving PD-1 Inhibition Combination Therapy.

(1) Background: Immune-related adverse events (irAEs) are a series of unique organ-specific inflammatory toxicities observed in patients with hepatocellular carcinoma (HCC) undergoing PD-1 inhibition combination therapy. The specific underlying mechanisms remain unclear. (2) Methods: We recruited 71 patients with HCC undergoing PD-1 inhibition combination therapy. These patients were then divided into two groups based on irAE occurrence: 34 had irAEs and 37 did not. Using Olink proteomics, we analyzed the aberrant inflammation-related proteins (IRPs) in these patient groups. For single-cell RNA sequencing (scRNA-seq) analysis, we collected peripheral blood mononuclear cells (PBMCs) from two representative patients at the pretreatment, irAE occurrence, and resolution stages. (3) Results: Our study revealed distinct plasma protein signatures in HCC patients experiencing irAEs after PD-1 inhibition combination therapy. We clarified the relationship between monocyte activation and irAEs, identified a strongly associated CD14-MC-CCL3 monocyte subset, and explored the role of the IFN-γ signaling pathway in monocyte activation during irAEs. (4) Conclusions: The activation of monocytes induced by the IFN-γ signaling pathway is an important mechanism underlying the occurrence of irAEs in HCC patients receiving PD-1 inhibition combination therapy.

The Global Burden of Disease Attributable to Child and Maternal Malnutrition: 1990-2019.

OBJECTIVE: With this study, we aimed to estimate the disease burden attributable to child and maternal malnutrition (CMM) throughout the world between 1990 and 2019. METHODS: The number, age-standardized rate, population attributable fraction of deaths, disability-adjusted life-years, years of life lost, and years lived with disability associated with CMM were estimated using the Global Burden of Disease Study 2019 by age, sex, year, location, and sociodemographic index at the global level. The slope index of inequality and concentration index were employed to measure socioeconomic-related health inequalities across countries. RESULTS: The number (million) of global deaths, disability-adjusted life-years, and years of life lost related to CMM were 2.9, 294.8, and 250.5 in 2019, showing decreases of 60.8, 57.4, and 60.7% since 1990. However, the number of years lived with CMM-related disability increased from 36.0 in 1990 to 44.3 in 2019. Additionally, the age-standardized rates of these 4 indicators showed varying degrees of decline. The global burden of CMM-related conditions differed with age and sex. The burden was the heaviest in western sub-Saharan Africa, especially in Chad. In terms of diseases, neonatal disorders represented the most significant burden attributed to CMM. Additionally, the CMM burden was more concentrated in regions with low sociodemographic indices, shown by the slope index of inequality and concentration index. CONCLUSIONS: The findings of this study highlight the ongoing global burden of CMM, particularly in terms of years lived with disability. Population-wide actions targeting the effective treatment and relief of CMM may reduce the CMM-related disease burden.

An Integrated Strategy Based on 10-DAB Extraction and In Situ Whole-Cell Biotransformation of Renewable Taxus Needles to Produce Baccatin III.

Baccatin III is a crucial precursor in the biosynthesis pathway of paclitaxel. Its main sources are extraction from Taxus or chemical synthesis using 10-deacetylbaccatin III (10-DAB) as substrate. However, these preparation approaches exhibit serious limitations, including the low content of baccatin III in Taxus and the complicated steps of chemical synthesis. Heterologous expression of 10-deacetylbaccatin III-10-O-acetyltransferase (TcDBAT) in microbial strains for biotransformation of 10-DAB is a promising alternative strategy for baccatin III production. Here, the promotion effects of glycerol supply and slightly acidic conditions with a low-temperature on the catalysis of recombinant TcDBAT strain were clarified using 10-DAB as substrate. Taxus needles is renewable and the content of 10-DAB is relatively high, it can be used as an effective source of the catalytic substrate 10-DAB. Baccatin III was synthesized by integrating the extraction of 10-DAB from renewable Taxus needles and in situ whole-cell catalysis in this study. 40 g/L needles were converted into 20.66 mg/L baccatin III by optimizing and establishing a whole-cell catalytic bioprocess. The method used in this study can shorten the production process of Taxus extraction for baccatin III synthesis and provide a reliable strategy for the efficient production of baccatin III by recombinant strains and the improvement of resource utilization rate of Taxus needles.

Micro/nanoplastics impair the feeding of goldfish by disrupting the complicated peripheral and central regulation of appetite.

The ubiquitous presence of plastic particles in water bodies poses a potential threat to aquatic species. Although numerous adverse effects of microplastics (MPs) and nanoplastics (NPs) have been documented, their effects on fish feeding, one of the most important behaviors of animals, are far from being fully understood. In this study, the effects of MPs and NPs (at environmentally realistic levels) on fish food consumption and feeding behavior were assessed using goldfish (Carassius auratus) and polystyrene (PS) particles as representatives. In addition, to reveal the potential mechanisms, the effects of MPs and NPs on peripheral and central regulation of appetite were evaluated by examining appetite-regulation related intestinal, serous, and hypothalamic parameters. The results obtained indicated that the 28-day MP- and NP-exposure significantly impaired goldfish feeding by disrupting peripheral and central appetite regulation. Based on differences observed in their effects on the abovementioned behavioral, histological, and physiological parameters, MPs and NPs may interfere with appetite regulation in a size-dependent manner. Blocking the gastrointestinal tract and causing histopathological and functional damage to inner organs may be the main routes through which MPs and NPs disrupt appetite regulation. Our findings suggested that plastic particles exposure may have far-reaching effects on fish species through impaired feeding, which warrants further attention.

Immunoglobulin Superfamily Containing Leucine-Rich Repeat (ISLR) Serves as a Redox Sensor That Modulates Antioxidant Capacity by Suppressing Pyruvate Kinase Isozyme M2 Activity.

Cells defend against oxidative stress by enhancing antioxidant capacity, including stress-activated metabolic alterations, but the underlying intracellular signaling mechanisms remain unclear. This paper reports that immunoglobulin superfamily containing leucine-rich repeat (ISLR) functions as a redox sensor that responds to reactive oxygen species (ROS) stimulation and modulates the antioxidant capacity by suppressing pyruvate kinase isozyme M2 (PKM2) activity. Following oxidative stress, ISLR perceives ROS stimulation through its cysteine residue 19, and rapidly degrades in the autophagy-lysosome pathway. The downregulated ISLR enhances the antioxidant capacity by promoting the tetramerization of PKM2, and then enhancing the pyruvate kinase activity, PKM2-mediated glycolysis is crucial to the ISLR-mediated antioxidant capacity. In addition, our results demonstrated that, in triple-negative breast cancer, cisplatin treatment reduced the level of ISLR, and PKM2 inhibition sensitizes tumors to cisplatin by enhancing ROS production; and argued that PKM2 inhibition can synergize with cisplatin to limit tumor growth. Our results demonstrate a molecular mechanism by which cells respond to oxidative stress and modulate the redox balance.

Spatial distribution and influencing factors of CDC health resources in China: a study based on panel data from 2016-2021.

Background: Measuring the development of Chinese centers for disease control and prevention only by analyzing human resources for health seems incomplete. Moreover, previous studies have focused more on the quantitative changes in healthcare resources and ignored its determinants. Therefore, this study aimed to analyze the allocation of healthcare resources in Chinese centers for disease control and prevention from the perspective of population and spatial distribution, and to further explore the characteristics and influencing factors of the spatial distribution of healthcare resources. Methods: Disease control personnel density, disease control and prevention centers density, and health expenditures density were used to represent human, physical, and financial resources for health, respectively. First, health resources were analyzed descriptively. Then, spatial autocorrelation was used to analyze the spatial distribution characteristics of healthcare resources. Finally, we used spatial econometric modeling to explore the influencing factors of healthcare resources. Results: The global Moran index for disease control and prevention centers density decreased from 1.3164 to 0.2662 (p < 0.01), while the global Moran index for disease control personnel density increased from 0.4782 to 0.5067 (p < 0.01), while the global Moran index for health expenditures density was statistically significant only in 2016 (p < 0.1). All three types of healthcare resources showed spatial aggregation. Population density and urbanization have a negative impact on the disease control and prevention centers density. There are direct and indirect effects of disease control personnel density and health expenditures density. Population density and urbanization had significant negative effects on local disease control personnel density. Urbanization has an indirect effect on health expenditures density. Conclusion: There were obvious differences in the spatial distribution of healthcare resources in Chinese centers for disease control and prevention. Social, economic and policy factors can affect healthcare resources. The government should consider the rational allocation of healthcare resources at the macro level.

Associations between digital literacy, health literacy, and digital health behaviors among rural residents: evidence from Zhejiang, China.

OBJECTIVE: Within the digital society, the limited proficiency in digital health behaviors among rural residents has emerged as a significant factor intensifying health disparities between urban and rural areas. Addressing this issue, enhancing the digital literacy and health literacy of rural residents stands out as a crucial strategy. This study aims to investigate the relationship between digital literacy, health literacy, and the digital health behaviors of rural residents. METHODS: Initially, we developed measurement instruments aimed at assessing the levels of digital literacy and health literacy among rural residents. Subsequently, leveraging micro survey data, we conducted assessments on the digital literacy and health literacy of 968 residents in five administrative villages in Zhejiang Province, China. Building upon this foundation, we employed Probit and Poisson models to empirically scrutinize the influence of digital literacy, health literacy, and their interaction on the manifestation of digital health behaviors within the rural population. This analysis was conducted from a dual perspective, evaluating the participation of digital health behaviors among rural residents and the diversity to which they participate in such behaviors. RESULTS: Digital literacy exhibited a notably positive influence on both the participation and diversity of digital health behaviors among rural residents. While health literacy did not emerge as a predictor for the occurrence of digital health behavior, it exerted a substantial positive impact on the diversity of digital health behaviors in the rural population. There were significant interaction effects between digital literacy and health literacy concerning the participation and diversity of digital health behaviors among rural residents. These findings remained robust even after implementing the instrumental variable method to address endogeneity issues. Furthermore, the outcomes of robust analysis and heterogeneity analysis further fortify the steadfastness of the aforementioned conclusions. CONCLUSION: The findings suggest that policymakers should implement targeted measures aimed at enhancing digital literacy and health literacy among rural residents. This approach is crucial for improving rural residents' access to digital health services, thereby mitigating urban-rural health inequality.