Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.

Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell-specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage-specific differentiation of mouse T-helper 17 (Th17) cells from naive CD4+ T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2, in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17-related inflammatory diseases, such as ulcerative colitis.

Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia.

OBJECTIVES: Systemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia. METHODS: This multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan-Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality. RESULTS: Based on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389-1.969). CONCLUSION: This study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.

Molecular characteristics and biofilm formation capacity of nontypeable Haemophilus influenza strains isolated from lower respiratory tract in children.

With the widespread introduction of the Hib conjugate vaccine, Nontypeable Haemophilus influenzae (NTHi) has emerged as the predominant strain globally. NTHi presents a significant challenge as a causative agent of chronic clinical infections due to its high rates of drug resistance and biofilm formation. While current research on NTHi biofilms in children has primarily focused on upper respiratory diseases, investigations into lower respiratory sources remain limited. In this study, we collected 54 clinical strains of lower respiratory tract origin from children. Molecular information and drug resistance features were obtained through whole gene sequencing and the disk diffusion method, respectively. Additionally, an in vitro biofilm model was established. All clinical strains were identified as NTHi and demonstrated the ability to form biofilms in vitro. Based on scanning electron microscopy and crystal violet staining, the strains were categorized into weak and strong biofilm-forming groups. We explored the correlation between biofilm formation ability and drug resistance patterns, as well as clinical characteristics. Stronger biofilm formation was associated with a longer cough duration and a higher proportion of abnormal lung imaging findings. Frequent intake of ß-lactam antibiotics might be associated with strong biofilm formation. While a complementary relationship between biofilm-forming capacity and drug resistance may exist, further comprehensive studies are warranted. This study confirms the in vitro biofilm formation of clinical NTHi strains and establishes correlations with clinical characteristics, offering valuable insights for combating NTHi infections.

MITF regulates the subcellular location of HIF1α through SUMOylation to promote the invasion and metastasis of daughter cells derived from polyploid giant cancer cells.

High concentrations of cobalt chloride (CoCl2) can induce the formation of polyploid giant cancer cells (PGCCs) in various tumors, which can produce daughter cells with strong proliferative, migratory and invasive abilities via asymmetric division. To study the role of hypoxia­inducible factor (HIF) 1α in the formation of PGCCs, colon cancer cell lines Hct116 and LoVo were used as experimental subjects. Western blotting, nuclear and cytoplasmic protein extraction and immunocytochemical experiments were used to compare the changes in the expression and subcellular localization of HIF1α, microphthalmia­associated transcription factor (MITF), protein inhibitor of activated STAT protein 4 (PIAS4) and von Hippel­Lindau disease tumor suppressor (VHL) after treatment with CoCl2. The SUMOylation of HIFα was verified by co­immunoprecipitation assay. After inhibiting HIF1α SUMOylation, the changes in proliferation, migration and invasion abilities of Hct116 and LoVo were compared by plate colony formation, wound healing and Transwell migration and invasion. In addition, lysine sites that led to SUMOylation of HIF1α were identified through site mutation experiments. The results showed that CoCl2 can induce the formation of PGCCs with the expression level of HIF1α higher in treated cells than in control cells. HIF1α was primarily located in the cytoplasm of control cell. Following CoCl2 treatment, the subcellular localization of HIF1α was primarily in the nuclei of PGCCs with daughter cells (PDCs). After treatment with SUMOylation inhibitors, the nuclear HIF1α expression in PDCs decreased. Furthermore, their proliferation, migration and invasion abilities also decreased. After inhibiting the expression of MITF, the expression of HIF1α decreased. MITF can regulate HIF1α SUMOylation. Expression and subcellular localization of VHL and HIF1α did not change following PIAS4 knockdown. SUMOylation of HIF1α occurs at the amino acid sites K391 and K477 in PDCs. After mutation of the two sites, nuclear expression of HIF1α in PDCs was reduced, along with a significant reduction in the proliferation, migration and invasion abilities. In conclusion, the post­translation modification regulated the subcellular location of HIF1α and the nuclear expression of HIF1α promoted the proliferation, migration and invasion abilities of PDCs. MITF could regulate the transcription and protein levels of HIF1α and participate in the regulation of HIF1α SUMOylation.

The winged helix domain of MORF binds CpG islands and the TAZ2 domain of p300.

Acetylation of histones by lysine acetyltransferases (KATs) provides a fundamental mechanism by which chromatin structure and transcriptional programs are regulated. Here, we describe a dual binding activity of the first winged helix domain of human MORF KAT (MORFWH1) that recognizes the TAZ2 domain of p300 KAT (p300TAZ2) and CpG rich DNA sequences. Structural and biochemical studies identified distinct DNA and p300TAZ2 binding sites, allowing MORFWH1 to independently engage either ligand. Genomic data show that MORF/MOZWH1 colocalizes with H3K18ac, a product of enzymatic activity of p300, on CpG rich promoters of target genes. Our findings suggest a functional cooperation of MORF and p300 KATs in transcriptional regulation.

Effect of continuous renal replacement therapy on the clinical efficacy and pharmacokinetics of polymyxin B in the treatment of severe pulmonary infection.

Objective: This study aimed to evaluate the pharmacokinetics of polymyxin B in patients with ventilator-associated pneumonia caused by multi-drug resistant bacteria, and to analyze the effect of continuous renal replacement therapy (CRRT) on pharmacokinetics of polymyxin B. Methods: Thirty-five patients with ventilator-associated pneumonia caused by multi-drug resistant bacteria admitted to our hospital from June 2021 to January 2022 were selected as the subjects. The patients were divided into the standard group (n = 20) and the non-standard group (n = 15) based on the factors affecting the compliance of polymyxin B plasma concentration. The patients received with polymyxin B and the plasma concentration was monitored. According to the monitoring results, they were divided into the standard group and the non-standard group, to analyze the influencing factors of polymyxin B on the blood concentration. Besides, the patients were then divided into the control group (n = 28) and the observation group (n = 7) according to whether the patients received CRRT treatment. Patients in the control group treated with polymyxin B alone, while patients in the observation group received with polymyxin B and CRRT. The general data of patients in the two groups were compared. The levels of plasma concentration of polymyxin B measured before the next administration (Cmin), peak plasma concentration of polymyxin B measured immediately after end of infusion (Cmax) and intermediate plasma concentration measured 6 h after administration (midpoint of the dosing interval) (C1/2t) were detected and compared between the two groups. Correlation between pharmacokinetics and efficacy was analyzed by Spearman correlation. The incidence of complications and the 28-day mortality rate of the two groups were recorded. Results: The age, body mass index (BMI) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores in the non-standard group were higher than these in the standard group (p < 0.05). BMI and APACHE II scores were independent risk factors affecting the pharmacokinetics of polymyxin B in patients with severe pulmonary infection (p < 0.05). There were no significant differences in age, BMI, APACHEII score, alanine aminotransferase level, aspartate aminotransferase level, albumin level, gender and diabetes ratio between the control group and the observation group (p > 0.05). The levels of Cmin, Cmax, and C1/2t in the observation group were lower than these in the control group (p < 0.001). The response rate was 50.00% in the control group and 36.36% in the observation group (p > 0.05). The levels of Cmin, Cmax, and C1/2t in the observation group were no significant correlation with the clinical efficacy (p > 0.05), while these in the control group were positive correlation with the clinical efficacy (r = 0.485, p < 0.05). There was no significant difference in the incidence of skin pigmentation, nephrotoxicity and 28-day mortality between the two groups (p > 0.05). Conclusion: In patients with ventilator-associated pneumonia not receiving multidrug-resistant bacteria, the rate of achieving blood drug concentration with the usual recommended dose of polymyxin B was satisfactory. However, the proportion of patients with a 6-h plasma concentration exceeding the maximum plasma concentration was high. BMI and APACHE II scores were important factors affecting the pharmacokinetics of polymyxin B. In patients undergoing CRRT, the plasma concentration of polymyxin B was significantly reduced, suggesting that in patients with severe disease, plasma concentration monitoring played an important role in drug efficacy and patient safety. In patients treated with CRRT, the dose of polymyxin B may need to be increased.

Dissecting the genome sequence of a clinical isolated Cunninghamella bertholletiae Z2 strain with rich cytochrome P450 enzymes (Article).

Mucormycosis is receiving much more attention because of its high morbidity and extremely high mortality rate in immunosuppressed populations. In this study, we isolated a Cunnignhamella bertholletiae Z2 strain from a skin lesion of a 14 year, 9 months old girl with acute lymphoblastic leukemia who die of infection from the Z2 strain. Genome sequencing was performed after isolation and amplification of the Z2 strain to reveal potential virulence factors and pathogenic mechanisms. The results showed that the genome size of the Z2 strain is 30.9 Mb with 9213 genes. Mucoral specific virulence factor genes found are ARF, CalN, and CoTH, while no gliotoxin biosynthesis gene cluster was found, which is a known virulence factor in Aspergillus fumigatus adapted to the environment. The Z2 strain was found to have 69 cytochrome P450 enzymes, which are potential drug resistant targets. Sensitivity testing of Z2 showed it was only inhibited by amphotericin B and posaconazole. Detailed genomic information of the C. bertholletiae Z2 strain may provide useful data for treatment.

Distinct Histone H3 Lysine 27 Modifications Dictate Different Outcomes of Gene Transcription.

Site-specific histone modifications have long been recognized to play an important role in directing gene transcription in chromatin in biology of health and disease. However, concrete illustration of how different histone modifications in a site-specific manner dictate gene transcription outcomes, as postulated in the influential "Histone code hypothesis", introduced by Allis and colleagues in 2000, has been lacking. In this review, we summarize our latest understanding of the dynamic regulation of gene transcriptional activation, silence, and repression in chromatin that is directed distinctively by histone H3 lysine 27 acetylation, methylation, and crotonylation, respectively. This represents a special example of a long-anticipated verification of the "Histone code hypothesis."

Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.

Observational studies of diet-related vitamins and lymphoma risk results were inconsistent. Our study aimed to estimate the causality between dietary vitamin intake and lymphoma through a Mendelian randomisation (MR) study. We enrolled dietary-related retinol, vitamin C, vitamin E, vitamin B6 and vitamin B12 as exposures of interest, with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) as the outcome. The causal effects were estimated using inverse variance weighting (IVW), MR-Egger regression analysis and weighted median, supplemented by sensitivity analyses. The results revealed that genetically predicted dietary vitamin B12 intake was associated with a reduced HL risk (OR = 0.22, 95% CI 0.05-0.91, p = 0.036). The Q test did not reveal heterogeneity, the MR-Egger test showed no significant intercepts, and the leave-one-out (LOO) analysis did not discover any SNP that affect the results. No causal relationship about dietary vitamin intake on the NHL risk was observed.

Design and implementation of an automatic nursing assessment system based on CDSS technology.

BACKGROUND: Various quantitative and quality assessment tools are currently used in nursing to evaluate a patient's physiological, psychological, and socioeconomic status. The results play important roles in evaluating the efficiency of healthcare, improving the treatment plans, and lowing relevant clinical risks. However, the manual process of the assessment imposes a substantial burden and can lead to errors in digitalization. To fill these gaps, we proposed an automatic nursing assessment system based on clinical decision support system (CDSS). The framework underlying the CDSS included experts, evaluation criteria, and voting roles for selecting electronic assessment sheets over paper ones. METHODS: We developed the framework based on an expert voting flow to choose electronic assessment sheets. The CDSS was constructed based on a nursing process workflow model. A multilayer architecture with independent modules was used. The performance of the proposed system was evaluated by comparing the adverse events' incidence and the average time for regular daily assessment before and after the implementation. RESULTS: After implementation of the system, the adverse nursing events' incidence decreased significantly from 0.43 % to 0.37 % in the first year and further to 0.27 % in the second year (p-value: 0.04). Meanwhile, the median time for regular daily assessments further decreased from 63 s to 51 s. CONCLUSIONS: The automatic assessment system helps to reduce nurses' workload and the incidence of adverse nursing events.

Prolonged vs intermittent intravenous infusion of ß-lactam antibiotics for patients with sepsis: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis.

BACKGROUND: The prolonged ß-lactam antibiotics infusion has been an attractive strategy in severe infections, because it provides a more stable free drug concentration and a longer duration of free drug concentration above the minimum inhibitory concentration (MIC). We conducted this systematic review of randomized clinical trials (RCTs) with meta-analysis and trial sequential analysis (TSA) to compare the effects of prolonged vs intermittent intravenous infusion of ß-lactam antibiotics for patients with sepsis. METHODS: This study was prospectively registered on PROSPERO database (CRD42023447692). We searched EMBASE, PubMed, and Cochrane Library to identify eligible studies (up to July 6, 2023). Any study meeting the inclusion and exclusion criteria would be included. The primary outcome was all-cause mortality within 30 days. Two authors independently screened studies and extracted data. When the I2 values < 50%, we used fixed-effect mode. Otherwise, the random effects model was used. TSA was also performed to search for the possibility of false-positive (type I error) or false-negative (type II error) results. RESULTS: A total of 4355 studies were identified in our search, and nine studies with 1762 patients were finally included. The pooled results showed that, compared with intermittent intravenous infusion, prolonged intravenous infusion of beta-lactam antibiotics resulted in a significant reduction in all-cause mortality within 30 days in patients with sepsis (RR 0.82; 95%CI 0.70-0.96; P = 0.01; TSA-adjusted CI 0.62-1.07). However, the certainty of the evidence was rated as low, and the TSA results suggested that more studies were needed to further confirm our conclusion. In addition, it is associated with lower hospital mortality, ICU mortality, and higher clinical cure. No significant reduction in 90-day mortality or the emergence of resistance bacteria was detected between the two groups. CONCLUSIONS: Prolonged intravenous infusion of beta-lactam antibiotics in patients with sepsis was associated with short-term survival benefits and higher clinical cure. However, the TSA results suggested that more studies are needed to reach a definitive conclusion. In terms of long-term survival benefits, we could not show an improvement.

Cytokeratin 7 Expression and Mismatch Repair Status for Survival Prediction in Patients With Low Rectal Cancer After Neoadjuvant Therapy.

BACKGROUND: More than half of the patients with locally advanced low rectal cancer exhibit no or minor response to nCRT. It is important to investigate the predictive and prognostic values of potential biomarkers in patients with locally advanced low rectal cancer receiving nCRT. MATERIALS AND METHODS: This retrospective study included 162 patients with locally advanced low rectal cancer who underwent nCRT, followed by total mesorectal excision (TME) between 2016 and 2019. Cytokeratin 7 (CK7) expression and mismatch repair (MMR) status were determined by immunohistochemistry (IHC). Categorical variables were compared using the chi-square test. Overall survival (OS) and disease-free survival (DFS) curves were estimated using the Kaplan-Meier and Cox methods. RESULTS: There were predominance significant differences in distance from anus margin (P < .0001) and circumferential extent of the tumor (P < .0001).CK7 positive expression was detected in 21 of the 162 patients (13%). The univariate and multivariate analysis revealed that patients whose tumors had CK7 positive expression had significantly shorter OS (HR = 3.878, P = .038; HR = 1.677, P = .035) and DFS (HR = 3.055, P = .027;HR = 3.569, P = .038) than those with CK7 negative expression. While patients with CK7 positive expression had a higher proportion of worse TRG compared with CK7 negative patients (P = .001). Patients with deficient mismatch repair (dMMR) just occupied a small proportion (8.6%), but there was still a close connection between the MMR status and recurrence after TME (P = .045). MMR status was an independent risk factor affecting the OS (HR = .307, P < .0001; HR = .123, P < .0001) and DFS (HR = .288, P < .0001; HR = .286, P < .0001) by univariate and multivariate analysis. But no significant difference in the proportion of TRG was observed between patients with dMMR and pMMR (P = .920). CONCLUSIONS: The result confirms negative prognostic role of CK7-positive and dMMR statuses, which have potential predictive value for neoadjuvant chemoradiotherapy response. This provides opportunity to modify individualized treatment strategies for patients with different CK7 expression levels and dMMR statuses.

Patterns of pediatric and adolescent female genital inflammation in China: an eight-year retrospective study of 49,175 patients in China.

Background: Genital inflammation is one of the most frequent clinical complaints among girls, which was easily overlooked by the general public. This study aimed to investigate the patterns and epidemiological characteristics of pediatric and adolescent female genital inflammation in China. Methods: A retrospective observational study (2011 to 2018) was conducted among all female patients under the age of 0-18 years at the Department of Pediatric and Adolescent Gynecology of The Children's Hospital, Zhejiang University School of Medicine. Data were collected from the electronic medical records. The abnormal vaginal discharge of patient was collected for microbiological investigation by bacterial and fungal culture. Descriptive analysis was conducted to evaluate the genital inflammation pattern and epidemiological characteristics, including age, season, and type of infected pathogens. Results: A total of 49,175 patients met the eligibility criteria of genital inflammation and 16,320 patients later came to the hospital for follow-up over the study period. The number of first-visit increased gradually from 3,769 in 2011 to 10,155 in 2018. The peak age of the first visit was 0-6 years old. Non-specific vulvovaginitis, lichen sclerosis, and labial adhesion were the top three genital inflammation. Among the top five potential common pathogens of vaginal infection, the prevalence of Haemophilus influenzae cases was the highest (31.42%, 203/646), followed by Streptococcus pyogenes (27.74%, 176/646), Candida albicans (14.09%, 91/646), Escherichia coli (8.51%, 55/646), and Staphylococcus aureus (6.35%, 41/636). The specific disease categories and pathogens of genital inflammation vary by age groups and season. Conclusion: Our study summarizes the pattern of pediatric and adolescent female genital inflammation over an 8-year period in China, emphasizing the need for more public awareness, healthcare services and research in this field.

Risk factors for nosocomial rectal colonisation with carbapenem-resistant Gram-negative bacilli in children with haematological malignancies: a case-control study.

BACKGROUND: Rectal colonisation with carbapenem-resistant Gram-negative bacilli (CR-GNB) may cause CR-GNB infection in children with haematological malignancies (HMs) haematological. To date, information on its epidemiology is limited. This study aimed to assess the the risk factors for rectal colonisation with CR-GNB in children with HMs. METHODS: A case-control study in a tertiary children's hospital in Hangzhou City, was conducted between July 2019, and September 2021. Based on the hospitalisation date, children in the CR-GNB colonisation group and control groups were matched at a ratio of 1:2. Conditional logistic regression models were used to compute the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of the risk factors for CR-GNB rectal colonisation in children with HMs. RESULTS: A total of 85 non-duplicated CR-GNB isolates were collected from rectal swab samples of 69 children with HMs. The 30-day mortality rates were 5.8% in the CR-GNB colonisation group and 0% in the control group (P = 0.020).colonisation In the conditional logistic regression model, the aORs were 6.84 (95% CI 1.86-25.20) for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), 4.16 (95% CI 1.17-14.84) for prior concomitant infections within the last 1 month, 2.33 (95% CI 1.16-4.69) for prior carbapenems usage within the last 1 month and 7.46 (95% CI 1.81-30.67) for prior hematopoietic stem-cell transplantation (HSCT). CONCLUSION: AML/ALL, prior concomitant infections within the last 1 month, prior carbapenems usage within the last 1 month, and prior HSCT are associated with an increased risk of rectal colonisation with CR-GNB in children with HMs.

Prevalence and Risk Factors of Hyperuricemia in the Urban Health Checkup Population in Xinjiang, China: A Cross-Sectional Study.

Purpose: In this study, the aim was to investigate the prevalence and risk factors of hyperuricemia (HUA) in the urban health checkup population in Urumqi, Xinjiang, and thus provide clues for the prevention of HUA. Methods: People who attended medical examinations from May 2021 to June 2022 at a hospital in Urumqi, Xinjiang, were selected for evaluation based on their general information, physical examination results, and laboratory test results. The chi-square test was used to determine whether there was a difference in the prevalence of HUA among participants with different characteristics. Using logistic regression analyses, risk factors for HUA were identified. Results: There were 8722 participants diagnosed with HUA, with an overall prevalence of 26.96%. The prevalence in men was 37.72%, significantly higher than in women (13.29%). Participants were characterized by a multiethnic composition, with Han (28.61%), Hui (27.88%) and Manchu (38.46%) being the three ethnicities with the highest prevalence. According to logistic regression analyses, HUA was associated with age, ethnicity, residence, marital status, body mass index (BMI), diastolic blood pressure (DBP), fasting blood glucose (FPG), triglyceride glucose (TyG) index, abdominal obesity, and dyslipidemia differently in males and females. Conclusion: The prevalence of HUA was high in the urban health checkup population in Urumqi, Xinjiang, particularly among men and youth. The early intervention for HUA should be enhanced to reduce the risk of cardiovascular disease and other related conditions.

Recent advances in shikonin for the treatment of immune-related diseases: Anti-inflammatory and immunomodulatory mechanisms.

Shikonin, the primary active compound found in the rhizome of the traditional Chinese medicinal herb known as "ZiCao", exhibits a diverse range of pharmacological effects. This drug has a wide range of uses, including as an anti-inflammatory, antioxidant, and anti-cancer agent. It is also effective in promoting wound healing and treating autoimmune diseases such as multiple sclerosis, diabetes, asthma, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, and rheumatoid arthritis. Although shikonin has a wide range of applications, its mechanisms are still not fully understood. This review article provides a comprehensive overview of the recent advancements in the use of shikonin for the treatment of immune-related diseases. The article also delves into the anti-inflammatory and immunoregulatory mechanisms of shikonin and offers insights into the inflammation and immunopathogenesis of related diseases. Overall, this article serves as a valuable resource for researchers and clinicians working in this field. These findings not only provide significant new information on the effects and mechanisms of shikonin but also establish a foundation for the development of clinical applications in treating autoimmune diseases.

Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.

Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.

Bioactive compound C498-0670 alleviates LPS-induced sepsis via JAK/STAT and NFκB signaling pathways.

The JAK/STAT and NFκB signaling pathways are two major inflammatory signaling pathways that are usually activated simultaneously in the body's inflammatory response to bacterial or viral infections. Hyperactivation of these two prominent signaling pathways is associated with various immune-related diseases and mortality, pointing to an urgent need for drug development targeting JAK/STAT and/or NFκB signaling. In this study, we screened 18,840 compounds using our well-established dual STAT-NFκB driven luciferase reporter based high-throughput screening system and identified a bioactive compound C498-0670, which inhibits both JAK/STAT and NFκB signaling. C498-0670 inhibits the activation of STATs and p-IKKα/ß in both the immortalized cell lines and primary peritoneal macrophages, while suppressing the expression of LPS-induced inflammatory mediators in vitro. In addition, the overall anti-inflammatory effects of C498-0670 were investigated using transcriptome sequencing and bioinformatics approaches. C498-0670 was predicted to alleviate sepsis/septic shock by disease/function analysis using IPA software, which was further verified in the LPS-induced mouse sepsis model in vivo. C498 reduced LPS-induced liver and kidney damage, myeloid cell infiltration, and pro-inflammatory cytokine and chemokine production in vivo. Furthermore, the SPR-HPLC-MS-based target fishing approach was used to identify the putative drug targets, and the high affinities of JAK2 (JAK/STAT signaling), NFKBIA (NFκB signaling), and IL-1ß, NLRP1b (inflammasome signaling) for C498-0670 were verified by molecular docking approach. These results suggest that C498-0670 can be used as a dual-target inhibitor of JAK/STAT and NFκB signaling pathways for the treatment of various inflammatory diseases, especially septic shock.

Bromodomain inhibitors and therapeutic applications.

The bromodomain acts to recognize acetylated lysine in histones and transcription proteins and plays a fundamental role in chromatin-based cellular processes including gene transcription and chromatin remodeling. Many bromodomain proteins, particularly the bromodomain and extra terminal domain (BET) protein BRD4 have been implicated in cancers and inflammatory disorders and recognized as attractive drug targets. Although clinical studies of many BET bromodomain inhibitors have made substantial progress toward harnessing the therapeutic potential of targeting the bromodomain proteins, the development of this new class of epigenetic drugs is met with challenges, especially on-target dose-limiting toxicity. In this review, we highlight the current development of new-generation small molecule inhibitors for the BET and non-BET bromodomain proteins and discuss the research strategies used to target different bromodomain proteins for a wide array of human diseases including cancers and inflammatory disorders.

Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS-dependent apoptosis and ferroptosis.

The application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has shifted lung cancer treatment from empirical chemotherapy to targeted molecular therapy. However, acquired drug resistance is inevitable in almost all non-small cell lung cancer (NSCLC) patients treated with gefitinib. Combined treatment with dihydroartemisinin (DHA) and gefitinib produced a better inhibitory effect on lung adenocarcinoma than gefitinib treatment alone; however, the specific mechanism remains unclear. In this study, we aimed to assess the underlying mechanism of this combination treatment. We prepared gefitinib-resistant A549 cells and investigated whether apoptosis and ferroptosis were involved in the sensitizing effect of DHA. Treatment with 5 µM gefitinib resulted in rupturing and floatation of A549 cells in the medium, while A549-GR cells were found to be insusceptible to gefitinib. However, treatment with DHA substantially inhibited the proliferation of A549-GR cells in a dose-dependent manner accompanied by increased apoptosis and ferroptosis. The accumulated reactive oxygen species (ROS) was crucial for the inhibitory effect of DHA on A549-GR cells. Moreover, cellular autophagy was significantly upregulated post-DHA treatment. The combined treatment of DHA and gefitinib resulted in inhibition of proliferation of A549, H1975, and HCC827 cells, and ROS accumulation and a remarkable induction of apoptosis was observed in A549-GR cells. DHA significantly induced apoptosis and ferroptosis in a dose-dependent manner and exhibited high cellular toxicity on A549-GR cells when combined with gefitinib.