Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes.

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs-NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

Comparison of urethral parameters in females presenting cystoceles with and without stress urinary incontinence based on dynamic magnetic resonance imaging: are they different?

PURPOSE: To compare urethral parameters between cystocele patients with and without stress urinary incontinence (SUI) and explore factors influencing SUI in cystocele patients via dynamic MRI. METHODS: The two-dimensional parameters evaluated included the paravaginal defects, levator ani muscle defects, urethral length, urethral funnel shape, bladder neck funnel width, bladder neck funnel depth, urethral angle, posterior vesicourethral angle, and anterior bladder protrusion. The three-dimensional parameters included the proximal urethra rotation angle, the distal urethra rotation angle, bladder neck mobility, urethral midpoint mobility, and external urethral meatus mobility. The independent samples t test was used for continuous variables, and the chi-square test was used for categorical variables. Binary logistic regression was used to identify factors independently associated with SUI in cystocele patients. RESULTS: The baseline parameters were similar between the 2 groups. Cystocele patients with SUI had a significantly higher point Aa (1.63 ± 1.06 cm vs. 0.81 ± 1.51 cm, p = 0.008); more anterior bladder protrusion (33.3% vs. 11.4%, p = 0.017); greater bladder neck mobility (36.38 ± 11.46 mm vs. 28.81 ± 11.72 mm, p = 0.005); mid-urethral mobility (22.94 ± 6.50 mm vs. 19.23 ± 6.65 mm, p = 0.014); and external urethral meatus mobility (22.42 ± 8.16 mm vs. 18.03 ± 8.51 mm, p = 0.022) than did cystocele patients without SUI. The other urethral parameters were similar in the groups (p > 0.05). Binary logistic regression showed that bladder neck mobility was independently associated with SUI in females with cystoceles (odds ratio, 1.06; 95% CI 1.015-1.107; p = 0.009). CONCLUSION: Cystocele patients with SUI have a higher point Aa, more anterior bladder protrusion, and greater urethral mobility than those without SUI. Bladder neck mobility is independently associated with SUI in females with cystoceles. REGISTRATION NUMBER: NCT03146195.

OLFM2 promotes epithelial-mesenchymal transition, migration, and invasion in colorectal cancer through the TGF-ß/Smad signaling pathway.

BACKGROUND: Colorectal cancer (CRC) is an aggressive tumor of the gastrointestinal tract, which is a major public health concern worldwide. Despite numerous studies, the precise mechanism of metastasis behind its progression remains elusive. As a member of the containing olfactomedin domains protein family, olfactomedin 2 (OLFM2) may play a role in tumor metastasis. It is highly expressed in colorectal cancer, and its role in the metastasis of CRC is still unclear. As such, this study seeks to explore the function of OLFM2 on CRC metastasis and its potential mechanisms. METHODS: Real-time fluorescence quantitative PCR and western blotting were used to study the expression of OLFM2 in human CRC and adjacent normal tissues. Knockdown and overexpression OLFM2 cell lines were constructed using siRNA and overexpression plasmids to explore the role of OLFM2 in the migration and invasion of CRC through transwell, and wound healing experiments. Finally, the expression of epithelial-mesenchymal transition (EMT) -related proteins and TGF-ß/Smad signaling pathway-related proteins was investigated using western blotting. RESULTS: In this study, we observed an elevation of OLFM2 expression levels in CRC tissues. To investigate the function of OLFM2, we overexpressed and knocked down OLFM2. We discovered that OLFM2 knockdown inhibited migration and invasion of colon cancer cells. Furthermore, E-cadherin expression increased while N-cadherin and Vimentin expression were opposite. It is no surprise that overexpressing OLFM2 had the opposite effects. We also identified that OLFM2 knockdown resulted in reduced TGF-ßR1 and downstream molecules p-Smad2 and p-Smad3, which are related to the TGF-ß / Smad pathway. In contrast, overexpressing OLFM2 significantly boosted their expression levels. CONCLUSION: The protein OLFM2 has been identified as a crucial determinant in the progression of CRC. Its mechanism of action involves the facilitation of EMT through the TGF-ß/Smad signaling pathway. Given its pivotal role in CRC, OLFM2 has emerged as a promising diagnostic and therapeutic target for the disease. These results indicate the potential of OLFM2 as a valuable biomarker for CRC diagnosis and treatment and highlight the need for further research exploring its clinical significance.

JOSD2 mediates isoprenaline-induced heart failure by deubiquitinating CaMKIIδ in cardiomyocytes.

Prolonged stimulation of ß-adrenergic receptor (ß-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction (MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2 interacts with Calcium-calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2 overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2 in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential as a therapeutic target for combating the disease. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. All have been checked.

Genome-wide identification of MAPK family in papaya (Carica papaya) and their involvement in fruit postharvest ripening.

BACKGROUND: Papaya (Carica papaya) is an economically important fruit cultivated in the tropical and subtropical regions of China. However, the rapid softening rate after postharvest leads to a short shelf-life and considerable economic losses. Accordingly, understanding the mechanisms underlying fruit postharvest softening will be a reasonable way to maintain fruit quality and extend its shelf-life. RESULTS: Mitogen-activated protein kinases (MAPKs) are conserved and play essential roles in response to biotic and abiotic stresses. However, the MAPK family remain poorly studied in papaya. Here, a total of nine putative CpMAPK members were identified within papaya genome, and a comprehensive genome-wide characterization of the CpMAPKs was performed, including evolutionary relationships, conserved domains, gene structures, chromosomal locations, cis-regulatory elements and expression profiles in response to phytohormone and antioxidant organic compound treatments during fruit postharvest ripening. Our findings showed that nearly all CpMAPKs harbored the conserved P-loop, C-loop and activation loop domains. Phylogenetic analysis showed that CpMAPK members could be categorized into four groups (A-D), with the members within the same groups displaying high similarity in protein domains and intron-exon organizations. Moreover, a number of cis-acting elements related to hormone signaling, circadian rhythm, or low-temperature stresses were identified in the promoters of CpMAPKs. Notably, gene expression profiles demonstrated that CpMAPKs exhibited various responses to 2-chloroethylphosphonic acid (ethephon), 1-methylcyclopropene (1-MCP) and the combined ascorbic acid (AsA) and chitosan (CTS) treatments during papaya postharvest ripening. Among them, both CpMAPK9 and CpMAPK20 displayed significant induction in papaya flesh by ethephon treatment, and were pronounced inhibition after AsA and CTS treatments at 16 d compared to those of natural ripening control, suggesting that they potentially involve in fruit postharvest ripening through ethylene signaling pathway or modulating cell wall metabolism. CONCLUSION: This study will provide some valuable insights into future functional characterization of CpMAPKs, and hold great potential for further understanding the molecular mechanisms underlying papaya fruit postharvest ripening.

OTUD1 promotes isoprenaline- and myocardial infarction-induced heart failure by targeting PDE5A in cardiomyocytes.

Heart failure represents a major cause of death worldwide. Recent research has emphasized the potential role of protein ubiquitination/deubiquitination protein modification in cardiac pathology. Here, we investigate the role of the ovarian tumor deubiquitinase 1 (OTUD1) in isoprenaline (ISO)- and myocardial infarction (MI)-induced heart failure and its molecular mechanism. OTUD1 protein levels were raised markedly in murine cardiomyocytes after MI and ISO treatment. OTUD1 deficiency attenuated myocardial hypertrophy and cardiac dysfunction induced by ISO infusion or MI operation. In vitro, OTUD1 knockdown in neonatal rat ventricular myocytes (NRVMs) attenuated ISO-induced injuries, while OTUD1 overexpression aggravated the pathological changes. Mechanistically, LC-MS/MS and Co-IP studies showed that OTUD1 bound directly to the GAF1 and PDEase domains of PDE5A. OTUD1 was found to reverse K48 ubiquitin chain in PDE5A through cysteine at position 320 of OTUD1, preventing its proteasomal degradation. PDE5A could inactivates the cGMP-PKG-SERCA2a signaling axis which dysregulate the calcium handling in cardiomyocytes, and leading to the cardiomyocyte injuries. In conclusion, OTUD1 promotes heart failure by deubiquitinating and stabilizing PDE5A in cardiomyocytes. These findings have identified PDE5A as a new target of OTUD1 and emphasize the potential of OTUD1 as a target for treating heart failure.

SNX17 Mediates Dendritic Spine Maturation via p140Cap.

Sorting nexin17 (SNX17) is a member of the sorting nexin family, which plays a crucial role in endosomal trafficking. Previous research has shown that SNX17 is involved in the recycling or degradation of various proteins associated with neurodevelopmental and neurological diseases in cell models. However, the significance of SNX17 in neurological function in the mouse brain has not been thoroughly investigated. In this study, we generated Snx17 knockout mice and observed that the homozygous deletion of Snx17 (Snx17-/-) resulted in lethality. On the other hand, heterozygous mutant mice (Snx17+/-) exhibited anxiety-like behavior with a reduced preference for social novelty. Furthermore, Snx17 haploinsufficiency led to impaired synaptic transmission and reduced maturation of dendritic spines. Through GST pulldown and interactome analysis, we identified the SRC kinase inhibitor, p140Cap, as a potential downstream target of SNX17. We also demonstrated that the interaction between p140Cap and SNX17 is crucial for dendritic spine maturation. Together, this study provides the first in vivo evidence highlighting the important role of SNX17 in maintaining neuronal function, as well as regulating social novelty and anxiety-like behaviors.

Isoproterenol induces MD2 activation by ß-AR-cAMP-PKA-ROS signalling axis in cardiomyocytes and macrophages drives inflammatory heart failure.

Cardiac inflammation contributes to heart failure (HF) induced by isoproterenol (ISO) through activating ß-adrenergic receptors (ß-AR). Recent evidence shows that myeloid differentiation factor 2 (MD2), a key protein in endotoxin-induced inflammation, mediates inflammatory heart diseases. In this study, we investigated the role of MD2 in ISO-ß-AR-induced heart injuries and HF. Mice were infused with ISO (30 mg·kg-1·d-1) via osmotic mini-pumps for 2 weeks. We showed that MD2 in cardiomyocytes and cardiac macrophages was significantly increased and activated in the heart tissues of ISO-challenged mice. Either MD2 knockout or administration of MD2 inhibitor L6H21 (10 mg/kg every 2 days, i.g.) could prevent mouse hearts from ISO-induced inflammation, remodelling and dysfunction. Bone marrow transplantation study revealed that both cardiomyocyte MD2 and bone marrow-derived macrophage MD2 contributed to ISO-induced cardiac inflammation and injuries. In ISO-treated H9c2 cardiomyocyte-like cells, neonatal rat primary cardiomyocytes and primary mouse peritoneal macrophages, MD2 knockout or pre-treatment with L6H21 (10 µM) alleviated ISO-induced inflammatory responses, and the conditioned medium from ISO-challenged macrophages promoted the hypertrophy and fibrosis in cardiomyocytes and fibroblasts. We demonstrated that ISO induced MD2 activation in cardiomyocytes via ß1-AR-cAMP-PKA-ROS signalling axis, and induced inflammatory responses in macrophages via ß2-AR-cAMP-PKA-ROS axis. This study identifies MD2 as a key inflammatory mediator and a promising therapeutic target for ISO-induced heart failure.

Phosphorylation-dependent membraneless organelle fusion and fission illustrated by postsynaptic density assemblies.

Membraneless organelles formed by phase separation of proteins and nucleic acids play diverse cellular functions. Whether and, if yes, how membraneless organelles in ways analogous to membrane-based organelles also undergo regulated fusion and fission is unknown. Here, using a partially reconstituted mammalian postsynaptic density (PSD) condensate as a paradigm, we show that membraneless organelles can undergo phosphorylation-dependent fusion and fission. Without phosphorylation of the SAPAP guanylate kinase domain-binding repeats, the upper and lower layers of PSD protein mixtures form two immiscible sub-compartments in a phase-in-phase organization. Phosphorylation of SAPAP leads to fusion of the two sub-compartments into one condensate accompanied with an increased Stargazin density in the condensate. Dephosphorylation of SAPAP can reverse this event. Preventing SAPAP phosphorylation in vivo leads to increased separation of proteins from the lower and upper layers of PSD sub-compartments. Thus, analogous to membrane-based organelles, membraneless organelles can also undergo regulated fusion and fission.

Status and influential factors of spiritual well-being in cancer patients with drug clinical trials: a cross-sectional study.

PURPOSE: The purpose of this study was to investigate the spiritual well-being status of cancer patients in drug clinical trials and its influencing factors, and to provide theoretical support for the spiritual health intervention of clinical trial cancer patients. METHODS: This cross-section study was conducted among 244 cancer patients in clinical trials. The Memorial Symptom Assessment Scale Short Form (MSAS-SF), Connor-Davidson Resilience Scale 10 (CD-RISC 10), and Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-SP-12) were used to measure symptom burden, psychological resilience, and spiritual well-being. The Multiple Linear Regression Model was used to determine the influencing factors of patients' spiritual health. RESULTS: The overall spiritual health level of cancer patients with clinical trials was high (36.87 ± 11.0), and the spiritual health level was positively correlated with psychological resilience (r = 0.872, P < 0.001). Religious belief, nationality, treatment regimen, and resilience were independent risk factors for the spiritual health of cancer patients in clinical trials. Patients with religious beliefs (ß = 0.097, P = 0.012), ethnic minorities (ß = 0.087, P = 0.023), and high resilience scores (ß = 0.874, P < 0.001) had higher levels of spiritual health. Patients who received single antineoplastic therapy (ß = - 0.079, P = 0.028) had lower levels of spiritual health. CONCLUSION: Our study found that the spiritual health of cancer patients in clinical trials was at a high level, superior to cancer patients receiving conventional anti-tumor therapy. Religious belief, nationality, treatment regimen, and psychological resilience were the influential factors of spiritual health.

[Using Liver Function Indicators to Predict Massive Blood Transfusion in Orthotopic Liver Transplantation].

Objective: To explore the predictive effect of preoperative liver function indicators for intraoperative massive blood transfusion in orthotopic liver transplantation and to establish a prediction model. Methods: We retrospectively analyzed the relevant data of 607 patients who underwent orthotopic liver transplantation in the Department of Liver Surgery, West China Hospital, Sichuan University between January 1, 2015 and June 30, 2021. According to the intraoperative transfusion volume of leukocyte-reduced red blood cells in additive solution, the patients were divided into a massive blood transfusion (MBT) group and a non-massive blood transfusion (NMBT) group. Univariate and multivariate logistic regressions were performed to analyze the risk factors of intraoperative MBT in orthotopic liver transplantation, the calibration of the predictive model was assessed by Hosmer-Lemeshow test, and the discrimination power of the predictive model was measured by area under the curve ( AUC) of the receiver operating characteristic (ROC) curve. Results: According to the results of logistic regression, alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), and Child-Pugh score showed no correlation with the risk of MBT in orthotopic liver transplantation operation. Platelet count (PLT) (odds ratio [ OR]=0.90, 95% confidence interval [ CI]: 0.09-0.19, P=0.02), international normalized ratio (INR) ( OR=19.43, 95% CI: 7.64-19.44, P<0.01), prothrombin time (PT) ( OR=1.43, 95% CI: 1.25-1.63, P<0.01), and activated partial thromboplastin time (APTT) ( OR=0.92, 95% CI: 0.90-0.95, P<0.01) were identified as the risk factors of intraoperative MBT in orthotopic liver transplantation. The Hosmer-Lemeshow test showed that the predictive model had good calibration ( χ 2=9.06, P=0.48) and discrimination power ( AUC=0.80, 95% CI 0.766-0.834, P<0.01). Conclusion: A predictive model based on the preoperative PLT, INR, PT, and APTT of patients undergoing orthotopic liver transplantation was established and can be used to predict the risk of intraoperative MBT in liver transplantation patients.

Toll-like receptor-2 in cardiomyocytes and macrophages mediates isoproterenol-induced cardiac inflammation and remodeling.

Heart failure (HF) is the leading cause of morbidity and mortality worldwide. Activation of the innate immune system initiates an inflammatory response during cardiac remodeling induced by isoproterenol (ISO). Here, we investigated whether Toll-like receptor-2 (TLR2) mediates ISO-induced inflammation, hypertrophy, and fibrosis. TLR2 was found to be increased in the heart tissues of mouse with HF under ISO challenge. Further, cardiomyocytes and macrophages were identified as the main cellular sources of the increased TLR2 levels in the model under ISO stimulation. The effect of TLR2 deficiency on ISO-induced cardiac remodeling was determined using TLR2 knockout mice and bone marrow transplantation models. In vitro studies involving ISO-treated cultured cardiomyocytes and macrophages showed that TLR2 knockdown significantly decreased ISO-induced cell inflammation and remodeling via MAPKs/NF-κB signaling. Mechanistically, ISO significantly increased the TLR2-MyD88 interaction in the above cells in a TLR1-dependent manner. Finally, DAMPs, such as HSP70 and fibronectin 1 (FN1), were found to be released from the cells under ISO stimulation, which further activated TLR1/2-Myd88 signaling and subsequently activated pro-inflammatory cytokine expression and cardiac remodeling. In summary, our findings suggest that TLR2 may be a target for the alleviation of chronic adrenergic stimulation-associated HF. In addition, this paper points out the possibility of TLR2 as a new target for heart failure under ISO stimulation.

Red/processed meat consumption and non-cancer-related outcomes in humans: umbrella review.

The associations of red/processed meat consumption and cancer-related health outcomes have been well discussed. The umbrella review aimed to summarise the associations of red/processed meat consumption and various non-cancer-related outcomes in humans. We systematically searched the systematic reviews and meta-analyses of associations between red/processed meat intake and health outcomes from PubMed, Embase, Web of Science and the Cochrane Library databases. The umbrella review has been registered in PROSPERO (CRD 42021218568). A total of 40 meta-analyses were included. High consumption of red meat, particularly processed meat, was associated with a higher risk of all-cause mortality, CVD and metabolic outcomes. Dose-response analysis revealed that an additional 100 g/d red meat intake was positively associated with a 17 % increased risk of type 2 diabetes mellitus (T2DM), 15 % increased risk of CHD, 14 % of hypertension and 12 % of stroke. The highest dose-response/50 g increase in processed meat consumption at 95 % confident levels was 1·37, 95 % CI (1·22, 1·55) for T2DM, 1·27, 95 % CI (1·09, 1·49) for CHD, 1·17, 95 % CI (1·02, 1·34) for stroke, 1·15, 95 % CI (1·11, 1·19) for all-cause mortality and 1·08, 95 % CI (1·02, 1·14) for heart failure. In addition, red/processed meat intake was associated with several other health-related outcomes. Red and processed meat consumption seems to be more harmful than beneficial to human health in this umbrella review. It is necessary to take the impacts of red/processed meat consumption on non-cancer-related outcomes into consideration when developing new dietary guidelines, which will be of great public health importance. However, more additional randomised controlled trials are warranted to clarify the causality.

[Correlation Between 6 Characteristics of Perioperative Hypothermia and Allogeneic Red Blood Cell Transfusion in Abdominal Surgery Patients]. / è ¹éƒ¨æ‰‹æœ¯æ‚£è€ å›´æœ¯æœŸå ­ç§ä½Žä½“æ¸©ç‰¹å¾ä¸Žå¼‚ä½“çº¢ç»†èƒžè¾“æ³¨çš„å ³è”æ€§åˆ†æž.

Objective: To explore the correlation between six characteristics of perioperative hypothermia and allogeneic red blood cell (RBC) transfusions in patients who underwent abdominal surgeries. Methods: Patients who underwent abdominal surgeries at West China Hospital, Sichuan University between October 2019 and July 2021 were retrospectively enrolled. A wearable wireless temperature sensor was used to continuously monitor the core body temperature of patients throughout the perioperative period. The perioperative temperature nadir, maximum temperature loss, percentage of time with hypothermia, time-weighted average temperature, area under the curve (AUC) at 36 ℃, and AUC at 37 ℃ were calculated for the period from entering the operation room to 24 hours after the end of anesthesia. The restricted cubic spline (RCS) and multiple logistic regression models were used to explore the correlation between these temperature characteristics and perioperative allogeneic RBC transfusions. Results: A total of 3119 patients were included in the study, with an allogeneic RBC transfusion rate of 2.8%. The RCS model showed that allogeneic RBC transfusion was associated with the perioperative temperature nadir (Poverall=0.048) and AUC at 36 ℃ (Poverall=0.026) and no statistical significance was found in the nonlinear test. The association between allogeneic RBC transfusions and other temperature characteristics was not statistically significant. According to the RCS model results, cut-off points were taken to form groups based on the body temperature characteristics. Multivariate logistic regression showed that the perioperative temperature nadir<35.5 ℃ (odds ratio [OR]=2.47, 95% confidence interval [CI]: 1.21-5.03) and AUC at 36 ℃≥100 ℃·min (OR=2.24, 95% CI:1.09-4.58) were associated with increased demand for allogeneic RBC transfusion. Conclusion: Hypothermia is associated with an increased need for perioperative allogeneic RBC transfusions and has a cumulative effect over time. For patients at high risk of bleeding, attention should be paid to the prevention of perioperative hypothermia and reduction in the cumulative exposure to hypothermia, thereby reducing the need for blood transfusion.

Diacerein protects liver against APAP-induced injury via targeting JNK and inhibiting JNK-mediated oxidative stress and apoptosis.

BACKGROUND AND PURPOSE: An overdose of acetaminophen (APAP) causes acute liver damage and lead to liver failure. Therefore, it is of great clinical significance to find drugs for the treatment of APAP-induced liver injury. Diacerein is clinically used drug for the treatment of osteoarthritis. Here, we evaluate the pharmacological effects and potential mechanisms of diacerein in APAP-induced liver injury. METHODS AND RESULTS: C57BL/6 mice were treated with diacerein by gavage, followed by intraperitoneal injection of APAP (400 mg/kg) to induce acute liver injury in mice. RNA-sequencing analysis and in vitro kinase assay were performed to explore the underlying mechanisms of diacerein. The experimental results showed that pretreatment with diacerein could inhibit APAP-induced elevation of serum AST and ALT levels, hepatic histopathological damage, oxidative stress, hepatocyte death, and mitochondrial damage in mice. The RNA-sequencing analysis and in vitro kinase assay indicated that indicating that JNK (c-Jun N-terminal kinase) is involved in that liver-protective effects of Diacerein. Diacerein could directly and selectively inhibit JNK kinase phosphorylation in cell-free system. We further confirmed that diacerein inhibits APAP-activated JNK pathway to reduce injury response in mouse livers and cultured AML12 cells. Deficiency of JNK in AML12 cells abolished the anti-injury effects of diacerein. CONCLUSION: Our experimental results suggest that diacerein protects APAP-induced liver injury by the inhibition of JNK kinase phosphorylation, rendering diacerein may serve as a potential therapeutic drug for the prevention of acute liver injury.

Diacerein alleviates Ang II-induced cardiac inflammation and remodeling by inhibiting the MAPKs/c-Myc pathway.

BACKGROUND: Heart failure is a common event in the course of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertension-related cardiac inflammation and remodeling. A naturally occurring compound, diacerein, exhibits anti-inflammatory activities in various systems. HYPOTHESIS/PURPOSE: In this study, we have examined the potential effects of diacerein on Ang II-induced heart failure. METHODS: C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop hypertensive heart failure. Mice were treated with diacerein by gavage for final 2 weeks. RNA-sequencing analysis was performed to explore the potential mechanism of diacerein. RESULTS: We found that diacerein could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. To explore the potential mechanism of diacerein, RNA-sequencing analysis was performed, indicating that MAPKs/c-Myc pathway is involved in that cardioprotective effects of Diacerein. We further confirmed that diacerein inhibits Ang II-activated MAPKs/c-Myc pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Deficiency of MAPKs or c-Myc in cardiomyocytes abolished the anti-inflammatory effects of diacerein. CONCLUSION: Our results indicate that diacerein protects hearts in Ang II-induced mice through inhibiting MAPKs/c-Myc-mediated inflammatory responses, rendering diacerein a potential therapeutic candidate agent for hypertensive heart failure.

Dynamic reprogramming of H3K9me3 at hominoid-specific retrotransposons during human preimplantation development.

Reprogramming of H3K9me3-dependent heterochromatin is required for early development. How H3K9me3 is involved in early human development remains, however, largely unclear. Here, we resolve the temporal landscape of H3K9me3 during human preimplantation development and its regulation for diverse hominoid-specific retrotransposons. At the 8-cell stage, H3K9me3 reprogramming at hominoid-specific retrotransposons termed SINE-VNTR-Alu (SVA) facilitates interaction between certain promoters and SVA-derived enhancers, promoting the zygotic genome activation. In trophectoderm, de novo H3K9me3 domains prevent pluripotent transcription factors from binding to hominoid-specific retrotransposons-derived regulatory elements for inner cell mass (ICM)-specific genes. H3K9me3 re-establishment at SVA elements in the ICM is associated with higher transcription of DNA repair genes, when compared with naive human pluripotent stem cells. Our data demonstrate that species-specific reorganization of H3K9me3-dependent heterochromatin at hominoid-specific retrotransposons plays important roles during early human development, shedding light on how the epigenetic regulation for early development has evolved in mammals.

Corynoline protects ang II-induced hypertensive heart failure by increasing PPARα and Inhibiting NF-κB pathway.

Heart failure is a fairly common outcome of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertensive heart failure via inducing cardiac inflammation. Drugs that disrupt Ang II-induced cardiac inflammation may have clinical utility in the treatment of hypertensive heart failure. A naturally occurring compound, corynoline, exhibit anti-inflammatory activities in other systems. C57BL/6 mice were injected with Ang II via a micro-osmotic pump for four weeks to develop hypertensive heart failure. The mice were treated with corynoline by gavage for two weeks. RNA-sequencing analysis was performed to explore the potential mechanism of corynoline. We found that corynoline could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. RNA-sequencing analysis indicates that the PPARα pathway is involved Ang II-induced cardiac fibrosis and cardiac remodeling. Corynoline reversed Ang II-induced PPARα inhibition both in vitro and in vivo. We further found that corynoline increases the interaction between PPARα and P65 to inhibit the NF-κB pro-inflammatory pathway in H9c2 cells. Our studies show that corynoline relieves Ang II-induced hypertensive heart failure by increasing the interaction between PPARα and P65 to inhibit the NF-κB pathway.

Recapitulating early human development with 8C-like cells.

In human embryos, major zygotic genome activation (ZGA) initiates at the eight-cell (8C) stage. Abnormal ZGA leads to developmental defects and even contributes to the failure of human blastocyst formation or implantation. An in vitro cell model mimicking human 8C blastomeres would be invaluable to understanding the mechanisms regulating key biological events during early human development. Using the non-canonical promoter of LEUTX that putatively regulates human ZGA, we developed an 8C::mCherry reporter, which specifically marks the 8C state, to isolate rare 8C-like cells (8CLCs) from human preimplantation epiblast-like stem cells. The 8CLCs express a panel of human ZGA genes and have a unique transcriptome resembling that of the human 8C embryo. Using the 8C::mCherry reporter, we further optimize the chemical-based culture condition to increase and maintain the 8CLC population. Functionally, 8CLCs can self-organize to form blastocyst-like structures. The discovery and maintenance of 8CLCs provide an opportunity to recapitulate early human development.

Effects of EN combined with PN enriched with n-3 polyunsaturated fatty acids on immune related indicators and early rehabilitation of patients with gastric cancer: A randomized controlled trial.

BACKGROUND & AIMS: Patients who undergo gastrectomy often have a high risk of postoperative complications. This study aimed to investigate the effects of n-3 polyunsaturated fatty acids (PUFAs) on immune function, the inflammatory response, nutritional status, and rehabilitation of patients with gastric cancer. METHODS: A total of 120 patients with gastric cancer who underwent elective radical gastrectomy in the Department of Gastrointestinal Surgery, West China Hospital, Sichuan University from September 2019 to December 2020 were randomly divided into the n-3 PUFAs group (n = 60) and control group (n = 60). Patients in N-3 PUFAs group were treated with enteral nutrition (EN) combined with parenteral nutrition (PN) enriched with n-3 PUFAs from postoperative Day 1 to Day 5, whereas patients in the control group were administered EN combined with PN without n-3 PUFAs. Immune parameters (lymphocyte count [LYM], CD3+, CD4+, CD8+, CD4+/CD8+), inflammatory indicators (white blood cell [WBC], C-reactive protein [CRP], interleukin 6 [IL-6], tumor necrosis factor α [TNF-α]), nutrition parameters (hemoglobin [Hb], total protein [TP], albumin [Alb], prealbumin [PAB], transferrin [TRF]), the incidence of postoperative complications and rehabilitation parameters were compared between the two groups. RESULTS: The immune parameters (LYM, CD3+, CD4+, CD4+/CD8+) and nutritional parameters (TP, Alb, PAB) of the n-3 PUFAs group were significantly increased compared with the control group, and inflammatory indicators (CRP, IL-6, TNF-α) were lower compared with the control group. The rate of postoperative complications in the n-3 PUFAs group (7%) was significantly lower than that in the control group (20%), and the time to first aerofluxus and defecation were earlier in the n-3 PUFAs group. No differences in postoperative length of stay, unplanned 30-day readmission or reoperation after surgery were noted. CONCLUSION: The study shows that n-3 PUFAs contribute to the recovery of immune function, inflammatory response, and early rehabilitations of patients with gastric cancer undergoing gastrectomy. N-3 PUFAs were safe and effective in promoting the rehabilitation of patients with gastrectomy in our study. More high-quality and large sample studies are needed. Registration number of Clinical Trial: ChiCTR1900028381.