SIRT6 prevents inflamed response by way of regulating NRF2 within vascular endothelial tissue

Sox2 (SRY-box 2) is a transcription factor with critical roles in maintaining embryonic and adult stem cell functions and in tumorigenesis. However, how Sox2 exerts its transcriptional function remains unclear. Here we used an in vitro protein-protein interaction assay to discover transcriptional regulators for embryonic stem cell core transcription factors (Oct4, Sox2, Klf4 and c-Myc) and identified members of the steroid receptor coactivators (SRCs) as Sox2-specific interacting proteins. The SRC family coactivators have broad roles in transcriptional regulation, but it is unknown whether they also serve as Sox2 coactivators. We demonstrated that these proteins facilitate Sox2 transcriptional activity and acts synergistically with p300. Furthermore, we uncovered an acetylation-enhanced interaction between Sox2 and SRC-2/3, but not SRC-1, demonstrating it is Sox2 acetylation that promotes the interaction. We identified putative Sox2 acetylation sites required for acetylation-enhanced interaction between Sox2 and SRC-3, and demonstrated that acetylation on these sites contributes to Sox2 transcriptional activity and recruitment of SRC-3. We showed that activation domains 1 (AD1) and 2 (AD2) of SRC-3 both display a preferential binding to acetylated Sox2. Finally, functional analyses in mouse embryonic stem (ES) cells demonstrated that knockdown of SRC-2/3 but not SRC-1 in mouse ES cells significantly down-regulates the transcriptional activities of various Sox2 target genes and impairs ES cell stemness. Taken together, we identify specific SRC family proteins as novel Sox2 coactivators and uncover the role of Sox2 acetylation in promoting coactivator recruitment and Sox2 transcriptional function.Placental malaria infection is mediated by the binding of the malarial VAR2CSA protein to the placental glycosaminoglycan, chondroitin sulfate. Recombinant sub-fragments of VAR2CSA (rVAR2) have also been shown to bind specifically and with high affinity to cancer cells and tissues, suggesting the presence of a shared type of oncofetal chondroitin sulfate (ofCS) in the placenta and in tumors. However, the exact structure of ofCS and what determines the selective tropism of VAR2CSA remains poorly understood. In this study, ofCS was purified by affinity chromatography using rVAR2 and subjected to detailed structural analysis. We found high levels of N-acetylgalactosamine 4-O-sulfation (∼80-85%) in placenta- and tumor-derived ofCS. This level of 4-O-sulfation was also found in other tissues that do not support parasite sequestration, suggesting that VAR2CSA tropism is not exclusively determined by placenta- and tumor-specific sulfation. Here, we show that both placenta and tumors contain significantly more chondroitin sulfate moieties of higher molecular weight than other tissues. In line with this, CHPF and CHPF2, which encode proteins required for chondroitin polymerization, are significantly upregulated in most cancer types. this website CRISPR/Cas9 targeting of CHPF and CHPF2 in tumor cells reduced the average molecular weight of cell-surface chondroitin sulfate and resulted in a marked reduction of rVAR2 binding. Finally, utilizing a cell-based glycocalyx model, we showed that rVAR2 binding correlates with the length of the chondroitin sulfate chains in the cellular glycocalyx. These data demonstrate that the total amount and cellular accessibility of chondroitin sulfate chains impact rVAR2 binding and thus malaria infection.ER-to-Golgi transport is the first step in the constitutive secretory pathway, which, unlike regulated secretion, is believed to proceed non-stop independent of Ca2+ flux. However, here we demonstrate that penta-EF hand (PEF) proteins ALG-2 and peflin constitute a hetero-bifunctional COPII regulator that responds to Ca2+ signaling by adopting one of several distinct activity states. Functionally, these states can adjust the rate of ER export of COPII-sorted cargos up or down by ∼50%. We found that at steady-state Ca2+, ALG-2/peflin hetero-complexes bind to ER exit sites (ERES) through the ALG-2 subunit to confer a low, buffered secretion rate, while peflin-lacking ALG-2 complexes markedly stimulate secretion. Upon Ca2+ signaling, ALG-2 complexes lacking peflin can either increase or decrease the secretion rate depending on signaling intensity and duration-phenomena that could contribute to cellular growth and intercellular communication following secretory increases, or protection from excitotoxicity and infection following decreases. In epithelial normal rat kidney (NRK) cells, the Ca2+-mobilizing agonist ATP causes ALG-2 to depress ER export, while in neuroendocrine PC12 cells, Ca2+ mobilization by ATP results in ALG-2-dependent enhancement of secretion. Furthermore, distinct Ca2+ signaling patterns in NRK cells produce opposing ALG-2-dependent effects on secretion. Mechanistically, ALG-2-dependent depression of secretion involves decreased levels of the COPII outer shell and increased peflin targeting to ERES, while ALG-2-dependent enhancement of secretion involves increased COPII outer shell and decreased peflin at ERES. These data provide insights into how PEF protein dynamics affect secretion of important physiological cargoes such as collagen I and significantly impact ER stress.Empathy for pain has a strong adaptive function. It plays a protective role in survival and exerts a vital impact on successful social interaction. Sleep loss, however, is commonplace in current society, and people are increasingly plagued by it. Previous studies have investigated whether sleep loss affects empathy for pain, yet the results were undecided. We aimed to determine whether this effect is existed and further explore the temporal and frequency dynamics of neural activities involved in this effect by recording the electroencephalogram (EEG) signals. We recruited 25 healthy adults (11 females) who were required to perform a pain judgement and unpleasantness rating about the presented nociceptive and neutral pictures after nocturnal sleep (NS) and sleep deprivation (SD), and their neuronal activities were recorded by event-related potentials (ERPs). Results showed a significantly decreased amplitude in the early components (N2, N340) of vicarious pain processing after SD. In further time-frequency (TF) analysis, a reduced energy occurred in theta2 (5-7 Hz) band under SD condition. Moreover, the decreased theta2 was positively correlated with the subjective ratings of both other's pain and self-unpleasantness only under SD condition. Our results indicated that SD impairs affective sharing of empathy for pain.
Functional cure, defined by hepatitis B surface antigen (HBsAg) loss, is rare during nucleos(t)ide analogue (NA) therapy and guidelines on finite NA therapy have not been well established. We aim to analyze off-therapy outcomes following NA cessation in a large, international, multi-center, multi-ethnic cohort of chronic hepatitis B (CHB) patients.
This cohort study included virally suppressed CHB patients who were hepatitis B e antigen (HBeAg) negative and stopped NA therapy. Primary outcome was HBsAg loss after NA cessation, and secondary outcomes included virological, biochemical, and clinical relapse, ALT flare, retreatment, and liver-related events after NA cessation.
Among 1,552 CHB patients, cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up. HBsAg loss was higher among Caucasians (vs. Asians SHR 6.8; 95% CI 2.7-16.8; P < .001), and among patients with HBsAg levels <100 IU/mL at end of therapy (vs. ≥100 IU/mL SHR 22.5; 95% CI 13.1-38.7; P < .001). At 48 months of follow-up, Caucasians with HBsAg levels <1000 IU/mL and Asians with HBsAg levels <100 IU/mL at end of therapy had a high predicted probability of HBsAg loss (>30%). Incidence rate of hepatic decompensation and hepatocellular carcinoma (HCC) was 0.48 per 1000 person-years and 0.29 per 1000 person-years, respectively. Death occurred in 7/19 decompensated patients and 2/14 patients with HCC.
The best candidates for NA withdrawal are virally suppressed, HBeAg negative, non-cirrhotic CHB patients with low HBsAg levels, particularly Caucasians with <1000 IU/mL and Asians with <100 IU/mL. However, strict surveillance is recommended to prevent deterioration.
The best candidates for NA withdrawal are virally suppressed, HBeAg negative, non-cirrhotic CHB patients with low HBsAg levels, particularly Caucasians with less then 1000 IU/mL and Asians with less then 100 IU/mL. However, strict surveillance is recommended to prevent deterioration.In this paper we address the situation where a well-established, but invasive, expensive or time-consuming diagnostic test may be replaced by multiple repetitions of a different diagnostic test which is known to be imperfect but less invasive or expensive. With an imperfect diagnostic test repeated several times on the same patient, we first introduce the sensitivity and specificity of that test for any given number of test repetitions. We also derive the corresponding asymptotic limits for sensitivity and specificity as the number n of test repetitions increases. Given those limits, we then derive sharp upper bounds for the differences between the sensitivity and specificity, obtained for a given number n of test repetitions, and the corresponding asymptotic limit. Specifically, we provide exact rates for the convergence of the empirical sensitivities and specificities. Our analysis is motivated, among other things, by the current discussion on rapid SARS-CoV-2 testing where the real-time polymerase chain reaction (RT-PCR) test may be replaced with a sequence of rapid lateral-flow antigen tests.
3-n-Butylphthalide (NBP) is widely used for the treatment of cerebral ischaemic stroke but can causeliver injury in clinical practice. This study aims to elucidate the underlying mechanisms and propose potential preventive strategies.
NBP and its four major metabolites, 3-hydroxy-NBP (3-OH-NBP), 10-hydroxy-NBP, 10-keto-NBP and NBP-11-oic acid, were synthesized and evaluated in primary human or rat hepatocytes (PHHs, PRHs). NBP-related substances or amino acid adducts were identified and semi-quantitated by ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). The target proteins and binding sites were identified by shotgun proteomics based on peptide mass fingerprinting coupled with tandem mass spectrometry and verified by molecular docking.
The toxicity of NBP and its four major metabolites were compared in both PHHs and PRHs, and 3-OH-NBP was found to be the most toxic metabolite. 3-OH-NBP induced remarkable cell death and oxidative stresses in hepatocnt use of CYP3A4 inducers.Cancer is a heterogeneous disease with high morbidity and mortality rate involving changes in redox balance and deregulation of redox signalling. For decades, studies have involved developing an effective cancer treatment to combat treatment resistance. As natural products such as thymoquinone have numerous health benefits, studies are also focusing on using them as a viable method for cancer treatment, as they have minimal toxic effects compared with standard cancer treatments. Thymoquinone studies have shown numerous mechanisms of action, such as regulation of reactive species interfering with DNA structure, modulating various potential targets and their signalling pathways as well as immunomodulatory effects in vitro and in vivo. Thymoquinone's anti-cancer effect is mainly due to the induction of apoptotic mechanisms, such as activation of caspases, downregulation of precancerous genes, inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), anti-tumour cell proliferation, ROS regulation, hypoxia and anti-metastasis.