In this work, we developed a new antibody-targeted and redox-responsive drug delivery system "MSNs-CAIX" by binding the anti-carbonic anhydrase IX antibody (A-CAIX Ab) on the surface of mesoporous ...silica nanoparticles (MSNs) via disulfide linkages. The design of the composite particles "MSNs-CAIX" involved the synthesis and surface functionalization with thiol groups, 2,2'-dipyridyl disulfide and CAIX antibody. In vitro, CAIX capping the doxorubicin hydrochloric (DOX)-loaded nanoparticles (DOX@MSNs-CAIX) exhibited effectively redox-responsive release in the presence of glutathione (GSH) owing to the cleavage of the disulfide bond. Compared with CAIX negative Mef cells (mouse embryo fibroblast), remarkably more DOX@MSNs-CAIX was internalized into CAIX positive 4T1 cells (mouse breast cancer cells) by receptor-mediation. Tumor targeting in vivo studies clearly demonstrated DOX@MSNs-CAIX accumulated in tumors and induced more tumor cells apoptosis in 4T1 tumor-bearing mice. With great potential, this drug delivery system is a promising candidate for targeted and redox-responsive cancer therapy.
YAP (yes-associated protein), a key transcriptional co-factor that is negatively regulated by the Hippo pathway, is crucial for the development and size control of multiple organs, including the ...liver. However, its role in the brain remains unclear. Here, we provide evidence for YAP regulation of mouse neocortical astrocytic differentiation and proliferation. YAP was undetectable in neurons, but selectively expressed in neural stem cells (NSCs) and astrocytes. YAP in NSCs was required for neocortical astrocytic differentiation, with no apparent role in self-renewal or neural differentiation. However, YAP in astrocytes was necessary for astrocytic proliferation. Yap (Yap1) knockout, Yap(nestin) conditional knockout and Yap(GFAP) conditional knockout mice displayed fewer neocortical astrocytes and impaired astrocytic proliferation and, consequently, death of neocortical neurons. Mechanistically, YAP was activated by BMP2, and the active/nuclear YAP was crucial for BMP2 induction and stabilization of SMAD1 and astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued the astrocytic differentiation deficit in response to BMP2. Taken together, these results identify a novel function of YAP in neocortical astrocytic differentiation and proliferation, and reveal a BMP2-YAP-SMAD1 pathway underlying astrocytic differentiation in the developing mouse neocortex.
Zeaxanthin and lutein have a wide range of pharmacological applications. In this study, we conducted systematic experimental research to optimize antioxidant extraction based on detection, ...extraction, process amplification, and purification. An ultrasonic-assisted method was used to extract zeaxanthin and lutein with high efficiency from corn gluten meal. Firstly, the effects of solid-liquid ratio, extraction temperature, and ultrasonic extraction time on the extraction of zeaxanthin were investigated in single-factor experiments. The optimization extraction parameters of zeaxanthin and lutein with ethanol solvent were obtained using the response surface methodology (RSM) as follows: liquid-solid ratio of 7.9:1, extraction temperature of 56 °C, and extraction time of 45 min. The total content of zeaxanthin and lutein was 0.501%. The optimum extraction experimental parameters were verified by process amplification, and we confirmed that the parameters of the extraction process optimized using the RSM design are reliable and precise. Zeaxanthin and lutein from crude extract of corn gluten were separated and purified using silica gel column chromatography with the purity of zeaxanthin increasing from 0.28% to 31.5% (about 110 times) and lutein from 0.25% to 16.3% (about 65 times), which could be used for large-scale industrial production of carotenoids.
Diabetic peripheral neuropathy (DPN) is a major complication of diabetes. This study aimed to investigate the therapeutic effects and molecular mechanisms of Compound Qiying Granules (CQYG) for DPN.
...Rats and RSC96 cells of DPN models were established to evaluate the therapeutic effects of CQYG. Then the morphology and apoptotic changes of sciatic nerves were detected. Further, tandem mass tag based quantitative proteomics technology was used to identify differentially expressed proteins (DEPs) and the underlying molecular mechanisms. Protein expression of key signaling pathways was also detected.
CQYG treatment significantly improved blood glucose and oxidative stress levels, and further reduced nerve fiber myelination lesions, denervation, and apoptosis in DPN rats. Further, 2176 DEPs were found in CQYG treated DPN rats. Enrichment analysis showed that protein processing in the endoplasmic reticulum (ER), and apoptosis were all inhibited after CQYG treatment. Next, CQYG treatment reduced inflammatory factor expression, mitochondrial damage, and apoptosis in RSC96 cells which induced by high glucose. Transmission electron microscopy results found that CQYG treatment improved the morphology of nerve myelin, mitochondria, and ER. CQYG treatment decreased ER stress and apoptosis pathway proteins that were highly expressed in DPN models. In addition, we also predicted the potential targets of CQYG in DEPs.
CQYG exerts neuroprotective effects in experimental diabetic neuropathy through anti-ER stress and anti-apoptosis.
There is insufficient evidence for the ability of vitamin K2 to improve type 2 diabetes mellitus symptoms by regulating gut microbial composition. Herein, we aimed to demonstrate the key role of the ...gut microbiota in the improvement of impaired glycemic homeostasis and insulin sensitivity by vitamin K2 intervention.
We first performed a 6-month RCT on 60 T2DM participants with or without MK-7 (a natural form of vitamin K2) intervention. In addition, we conducted a transplantation of the MK-7-regulated microbiota in diet-induced obesity mice for 4 weeks. 16S rRNA sequencing, fecal metabolomics, and transcriptomics in both study phases were used to clarify the potential mechanism.
After MK-7 intervention, we observed notable 13.4%, 28.3%, and 7.4% reductions in fasting serum glucose (P = 0.048), insulin (P = 0.005), and HbA1c levels (P = 0.019) in type 2 diabetes participants and significant glucose tolerance improvement in diet-induced obesity mice (P = 0.005). Moreover, increased concentrations of secondary bile acids (lithocholic and taurodeoxycholic acid) and short-chain fatty acids (acetic acid, butyric acid, and valeric acid) were found in human and mouse feces accompanied by an increased abundance of the genera that are responsible for the biosynthesis of these metabolites. Finally, we found that 4 weeks of fecal microbiota transplantation significantly improved glucose tolerance in diet-induced obesity mice by activating colon bile acid receptors, improving host immune-inflammatory responses, and increasing circulating GLP-1 concentrations.
Our gut-derived findings provide evidence for a regulatory role of vitamin K2 on glycemic homeostasis, which may further facilitate the clinical implementation of vitamin K2 intervention for diabetes management.
The study was registered at https://www.chictr.org.cn (ChiCTR1800019663).
To clarify the effects of dietary inflammatory and pro-oxidative potential, we investigated the impact of the Dietary Inflammation Index (DII) and the Dietary Oxidative Balance Score (DOBS) on ...all-cause and disease-specific mortality. For DII and DOBS, 17,550 and 24,527 participants were included. Twenty-six and seventeen dietary factors were selected for scoring. Cox proportional hazards regression models were used. DII and DOBS were significantly associated with all-cause, CVD, and cancer mortality in this nationally representative sample of American adults. Compared with the lowest DII, the multivariable-adjusted hazard ratios (95% CI) of all-cause, CVD, and cancer mortality for the highest were 1.49 (1.23-1.80), 1.58 (1.08-2.33), and 1.56 (1.07-2.25). The highest quartile of DOBS was associated with the risk of all-cause death (HR 0.71, 95% CI 0.59-0.86). Pro-inflammatory and pro-oxidative diets were associated with increased risk for all-cause (HR 1.59, 95% CI 1.28-1.97), and CVD (HR 2.29, 95% CI 1.33-3.94) death compared to anti-inflammatory and antioxidant diets. Similar results were observed among the stratification analyses. Inflammation-reducing and oxidative-balancing diets are linked to lower all-cause and CVD mortality. Diets impact health by regulating inflammation and oxidative stress.
In the American population, the relationship between the triglyceride-glucose (TyG) index and TYG combined with indicators of obesity and cardiovascular disease (CVD) and its mortality has been less ...well studied.
This cross-sectional study included 11,937 adults from the National Health and Nutrition Examination Survey (NHANES) 2003-2018. Cox proportional hazards model, binary logistic regression analyses, restricted cubic spline (RCS), and receiver operating characteristic (ROC) were used to analyze the relationship between TyG and its combined obesity-related indicators and CVD and its mortality. Mediation analysis explored the mediating role of glycated hemoglobin and insulin in the above relationships.
In this study, except for no significant association between TyG and CVD mortality, TyG, TyG-WC, TyG-WHtR, and TyG-BMI were significantly and positively associated with CVD and CVD mortality. TyG-WHtR is the strongest predictor of CVD mortality (HR 1.66, 95% CI 1.21-2.29). The TyG index correlated better with the risk of coronary heart disease (OR 2.52, 95% CI 1.66-3.83). TyG-WC correlated best with total CVD (OR 2.37, 95% CI 1.77-3.17), congestive heart failure (OR 2.14, 95% CI 1.31-3.51), and angina pectoris (OR 2.38, 95% CI 1.43-3.97). TyG-WHtR correlated best with myocardial infarction (OR 2.24, 95% CI 1.45-3.44). RCS analyses showed that most of the above relationships were linear (P-overall < 0.0001, P-nonlinear > 0.05). Otherwise, ROC curves showed that TyG-WHtR and TyG-WC had more robust diagnostic efficacy than TyG. In mediation analyses, glycated hemoglobin mediated in all the above relationships and insulin-mediated in partial relationships.
TyG-WC and TyG-WtHR enhance CVD mortality prediction, diagnostic efficacy of CVD and its mortality, and correlation with some CVD over and above the current hottest TyG. TyG-WC and TyG-WtHR are expected to become more effective metrics for identifying populations at early risk of cardiovascular disease and improve risk stratification.
Metabolic reprogramming is a hallmark of human cancer. Cancer cells exhibit enhanced glycolysis, which allows glycolytic intermediates to be diverted into several other biosynthetic pathways, such as ...serine synthesis. Here, we explored the anti-cancer effects of the pyruvate kinase (PK) M2 inhibitor PKM2-IN-1 alone or in combination with the phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503 in human NSCLC A549 cells
and
. PKM2-IN-1 inhibited proliferation and induced cell cycle arrest and apoptosis, with increased glycolytic intermediate 3-phosphoglycerate (3-PG) level and PHGDH expression. The combination of PKM2-IN-1 and NCT-503 further suppressed cancer cell proliferation and induced G2/M phase arrest, accompanied by the reduction of ATP, activation of AMPK and inhibition of its downstream mTOR and p70S6K, upregulation of p53 and p21, as well as downregulation of cyclin B1 and cdc2. In addition, combined treatment triggered ROS-dependent apoptosis by affecting the intrinsic Bcl-2/caspase-3/PARP pathway. Moreover, the combination suppressed glucose transporter type 1 (GLUT1) expression.
, co-administration of PKM2-IN-1 and NCT-503 significantly inhibited A549 tumor growth. Taken together, PKM2-IN-1 in combination with NCT-503 exhibited remarkable anti-cancer effects through induction of G2/M cell cycle arrest and apoptosis, in which the metabolic stress induced ATP reduction and ROS augmented DNA damage might be involved. These results suggest that the combination of PKM2-IN-1 and NCT-503 might be a potential strategy for the therapy of lung cancer.
Abstract
Background
Secondary brain damage caused by the innate immune response and subsequent proinflammatory factor production is a major factor contributing to the high mortality of intracerebral ...haemorrhage (ICH). Nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signalling has been reported to participate in the innate immune response and inflammatory response. Therefore, we investigated the role of NOD1/RIP2 signalling in mice with collagenase-induced ICH and in cultured primary microglia challenged with hemin.
Methods
Adult male C57BL/6 mice were subjected to collagenase for induction of ICH model in vivo. Cultured primary microglia and BV2 microglial cells (microglial cell line) challenged with hemin aimed to simulate the ICH model in vitro. We first defined the expression of NOD1 and RIP2 in vivo and in vitro using an ICH model by western blotting. The effect of NOD1/RIP2 signalling on ICH-induced brain injury volume, neurological deficits, brain oedema, and microglial activation were assessed following intraventricular injection of either ML130 (a NOD1 inhibitor) or GSK583 (a RIP2 inhibitor). In addition, levels of JNK/P38 MAPK, IκBα, and inflammatory factors, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) expression, were analysed in ICH-challenged brain and hemin-exposed cultured primary microglia by western blotting. Finally, we investigated whether the inflammatory factors could undergo crosstalk with NOD1 and RIP2.
Results
The levels of NOD1 and its adaptor RIP2 were significantly elevated in the brains of mice in response to ICH and in cultured primary microglia, BV2 cells challenged with hemin. Administration of either a NOD1 or RIP2 inhibitor in mice with ICH prevented microglial activation and neuroinflammation, followed by alleviation of ICH-induced brain damage. Interestingly, the inflammatory factors interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), which were enhanced by NOD1/RIP2 signalling, were found to contribute to the NOD1 and RIP2 upregulation in our study.
Conclusion
NOD1/RIP2 signalling played an important role in the regulation of the inflammatory response during ICH. In addition, a vicious feedback cycle was observed between NOD1/RIP2 and IL-1β/TNF-α, which could to some extent result in sustained brain damage during ICH. Hence, our study highlights NOD1/RIP2 signalling as a potential therapeutic target to protect the brain against secondary brain damage during ICH.
To explore the relationship between sleep patterns and cardiovascular disease (CVD) incidence and mortality risk in a population with type 2 diabetes through a UK Biobank sample.
A total of 6860 ...patients with type 2 diabetes were included in this study. Five sleep factors (including Chronotype, sleep duration, insomnia, daytime sleepiness, and snoring) were collected as a questionnaire. The calculation generates a sleep score of 0-5, and then three sleep patterns were defined based on the sleep scores: poor sleep pattern (0-2), Intermediate sleep pattern (3-4), and healthy sleep pattern (5). HRs and 95% confidence intervals were calculated by multivariate COX proportional risk model adjustment. Restricted cubic splines were used to validate linear associations between sleep scores CVD events.
Our results found a reduced risk of CVD events in individuals with healthy sleep patterns compared to participants with poor sleep patterns. CVD Mortality (HR, 0.690; 95% CI 0.519-0.916), ASCVD (Atherosclerosis CVD) (HR, 0.784; 95% CI 0.671-0.915), CAD (Coronary Artery Disease) (HR, 0.737; 95% CI 0.618-0.879), PAD (Peripheral Arterial Disease) (HR, 0.612; 95% CI 0.418-0.896), Heart Failure (HR, 0.653; 95% CI 0.488-0.875). Restricted cubic spline responded to a negative linear correlation between sleep scores and CVD Mortality, ASCVD, CAD, PAD, and Heart Failure.
Healthy sleep patterns are significantly associated with a reduced risk of CVD Mortality, ASCVD, CAD, PAD, and Heart Failure in the diabetes population.
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