Targeting histone deacetylases in head and neck squamous cell carcinoma: molecular mechanisms and therapeutic targets.

The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.

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Cholelithiasis is a common disease of the digestive system. The risk factors for cholelithiasis have been reported and summarized many times in the published literature, which primarily focused on cross-sectional studies. Due to the inherent limitations of the study design, the reported findings still need to be validated in additional longitudinal studies. Moreover, a number of new risk factors for cholelithiasis have been identified in recent years, such as bariatric surgery, hepatitis B virus infection, hepatitis C virus infection, kidney stones, colectomy, osteoporosis, etc. These new findings have not yet been included in published reviews. Herein, we reviewed the 101 cholelithiasis-associated risk factors identified through research based on longitudinal investigations, including cohort studies, randomized controlled trials, and nested case control studies. The risk factors associated with the pathogenesis of cholelithiasis were categorized as unmodifiable and modifiable factors. The unmodifiable factors consist of age, sex, race, and family history, while the modifiable factors include 37 biological environmental factors, 25 socioenvironmental factors, and 35 physiochemical environmental factors. This study provides thorough and comprehensive ideas for research concerning the pathogenesis of cholelithiasis, supplying the basis for identifying high-risk groups and formulating relevant prevention strategies.

A novel log odds of positive lymph nodes-based nomogram for predicting overall survival in patients with colorectal signet ring cell carcinoma: a SEER population-based study.

PURPOSE: Considering the poor prognosis and high lymph node (LN) involvement rate of colorectal signet ring cell carcinoma (SRCC), this study aimed to construct a prognostic nomogram to predict overall survival (OS) with satisfactory accuracy and utility, based on LN status indicators with superior predictability. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we obtained cases of colorectal SRCC patients and employed univariate and multivariate Cox analyses to determine independent prognostic factors. Kaplan-Meier curves were utilized to visualize survival differences among these factors. Receiver operating characteristic curves were generated to assess predictive performances of models incorporating various LN status indicators. A novel nomogram, containing optimal LN status indicators and other prognostic factors, was developed to predict OS, whose discriminatory ability and accuracy were evaluated using calibration curves and decision curve analysis. RESULTS: A total of 1663 SRCC patients were screened from SEER database. Older patients and those with grades III-IV, tumor sizes > 39 mm, T3/T4 stage, N1/N2 stage, M1 stage, and higher log odds of positive lymph nodes (LODDS) values exhibited poorer prognoses. Age, grade, tumor size, TNM stage, and LODDS were independent prognostic factors. The model containing N stage and LODDS outperformed the one relying solely on N stage as LN status indicator, resulting in a validated nomogram for accurately predicting OS in SRCC patients. CONCLUSION: The integration of LODDS, N stage, and other risk factors into a nomogram offered precise OS predictions, enhancing therapeutic decision-making and tailored follow-up management for colorectal SRCC patients.

A multifunctional cascade enzyme system for enhanced starvation/chemodynamic combination therapy against hypoxic tumors.

Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO3@MnO2-NH2@GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO3 nanoparticles wrapped in a MnO2 shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO2 decomposes H2O2 in cancer cells into O2, which enhances the efficiency of GOx-mediated starvation therapy. CaCO3 can be decomposed in the acidic cancer cell environment, causing Ca2+ overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the H2O2 and gluconic acid produced during glucose consumption by GOx are utilized by MnO2 with catalase-like activity to enhance O2 production and Mn2+ release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO3 decomposition, promoting the Ca2+ release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca2+ overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy.

Synchronization analyze of k-uniform hyper-networks.

Hyper-networks tend to perform better in representing multivariate relationships among nodes. Yet, due to the complexity of the hyper-network structure, research in synchronization dynamics is rarely involved. In this paper, a Kuramoto model more suitable for k-uniform hyper-networks is proposed. And the generalized Laplacian matrix expression of the k-uniform hyper-network is present. We use the eigenvalue ratio of the generalized Laplacian matrix to quantify synchronization. And we studied the effects of some important structure parameters on the synchronization of three types of k-uniform hyper-networks. And obtained different relationships between synchronization and these parameters. The results show the synchronization of the k-uniform hyper-networks is related to both structure and parameters. And as the size of the nodes increases, the synchronization ability gradually increases for ER random hyper-network, while that gradually decreases for NW small-world hyper-network and BA scale-free hyper-network. As the uniformity increases, the synchronization ability of all three types of uniform hyper-networks increases. In addition, when the structure and node size are fixed, the synchronization ability increases with the increase of the hyper-clustering coefficient in BA scale-free hyper-network and ER random hyper-network, while it decreases with the increase of the hyper-clustering coefficient in NW small-world hyper-network.

Enhancer of zeste homolog 2 facilitates phenotypic transition of vascular smooth muscle cells leading to aortic aneurysm/dissection.

Thoracic aortic aneurysms (TAAs) are a major cause of death owing to weaker blood vessel walls and higher rupture rates in affected individuals. Vascular smooth muscle cells (VSMCs) are the predominant cell type within the aortic wall and their dysregulation may contribute to TAA progression. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, is involved in several pathological processes; however, the biological functions and mechanisms underlying VSMC phenotype transition and vascular intimal hyperplasia remain unclear. The present study aimed to determine the involvement of EZH2 in mediating VSMC function in the development of TAAs. The expression of EZH2 was revealed to be elevated in patients with thoracic aortic dissection and TAA mouse model through western blotting and reverse transcription-quantitative PCR experiments. Subsequently, a mouse model was established using ß-aminopropionitrile. In vitro, EdU labeling, Transwell assay, wound healing assay and hematoxylin-eosin staining revealed that knocking down the Ezh2 gene could reduce the proliferation, invasion, migration, and calcification of mouse primary aortic smooth muscle cells. Flow cytometry analysis found that EZH2 deficiency increased cell apoptosis. Depletion of Ezh2 in mouse primary aortic VSMCs promoted the transformation of VSMCs from a synthetic to a contractile phenotype. Using RNA-sequencing analysis, it was demonstrated that Ezh2 regulated a group of genes, including integrin ß3 (Itgb3), which are critically involved in the extracellular matrix signaling pathway. qChIP found Ezh2 occupies the Itgb3 promoter, thereby suppressing the expression of Itgb3. Ezh2 promotes the invasion and calcification of VSMCs, and this promoting effect is partially reversed by co-knocking down Itgb3. In conclusion, the present study identified a previously unrecognized EZH2-ITGB3 regulatory axis and thus provides novel mechanistic insights into the pathophysiological function of EZH2. EZH2 may thus serve as a potential target for the management of TAAs.

Reclassified the phenotypes of cancer types and construct a nomogram for predicting bone metastasis risk: A pan-cancer analysis.

BACKGROUND: Numerous of models have been developed to predict the bone metastasis (BM) risk; however, due to the variety of cancer types, it is difficult for clinicians to use these models efficiently. We aimed to perform the pan-cancer analysis to create the cancer classification system for BM, and construct the nomogram for predicting the BM risk. METHODS: Cancer patients diagnosed between 2010 and 2018 in the Surveillance, Epidemiology, and End Results (SEER) database were included. Unsupervised hierarchical clustering analysis was performed to create the BM prevalence-based cancer classification system (BM-CCS). Multivariable logistic regression was applied to investigate the possible associated factors for BM and construct a nomogram for BM risk prediction. The patients diagnosed between 2017 and 2018 were selected for validating the performance of the BM-CCS and the nomogram, respectively. RESULTS: A total of 50 cancer types with 2,438,680 patients were included in the construction model. Unsupervised hierarchical clustering analysis classified the 50 cancer types into three main phenotypes, namely, categories A, B, and C. The pooled BM prevalence in category A (17.7%; 95% CI: 17.5%-17.8%) was significantly higher than that in category B (5.0%; 95% CI: 4.5%-5.6%), and category C (1.2%; 95% CI: 1.1%-1.4%) (p < 0.001). Advanced age, male gender, race, poorly differentiated grade, higher T, N stage, and brain, lung, liver metastasis were significantly associated with BM risk, but the results were not consistent across all cancers. Based on these factors and BM-CCS, we constructed a nomogram for predicting the BM risk. The nomogram showed good calibration and discrimination ability (AUC in validation cohort = 88%,95% CI: 87.4%-88.5%; AUC in construction cohort = 86.9%,95% CI: 86.8%-87.1%). The decision curve analysis also demonstrated the clinical usefulness. CONCLUSION: The classification system and prediction nomogram may guide the cancer management and individualized BM screening, thus allocating the medical resources to cancer patients. Moreover, it may also have important implications for studying the etiology of BM.

Histone deacetylase 9-mediated phenotypic transformation of vascular smooth muscle cells is a potential target for treating aortic aneurysm/dissection.

Aortic aneurysm/dissection (AAD) is a serious cardiovascular condition characterized by rapid onset and high mortality rates. Currently, no effective drug treatment options are known for AAD. AAD pathogenesis is associated with the phenotypic transformation and abnormal proliferation of vascular smooth muscle cells (VSMCs). However, endogenous factors that contribute to AAD progression remain unclear. We aimed to investigate the role of histone deacetylase 9 (HDAC9) in AAD pathogenesis. HDAC9 expression was considerably increased in human thoracic aortic dissection specimens. Using RNA-sequencing (RNA-seq) and chromatin immunoprecipitation, we demonstrated that HDAC9 transcriptionally inhibited the expression of superoxide dismutase 2 and insulin-like growth factor-binding protein-3, which are critically involved in various signaling pathways. Furthermore, HDAC9 triggered the transformation of VSMCs from a systolic to synthetic phenotype, increasing their proliferation and migration abilities and suppressing their apoptosis. Consistent with these results, in vivo experiments revealed that TMP195, a pharmacological inhibitor of HDAC9, suppressed the formation of the ß-aminopropionitrile-induced AAD phenotype in mice. Our findings indicate that HDAC9 may be a novel endogenous risk factor that promotes the onset of AAD by mediating the phenotypic transformation of VSMCs. Therefore, HDAC9 may serve as a potential therapeutic target for drug-based AAD treatment. Furthermore, TMP195 holds potential as a therapeutic agent for AAD treatment.

Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Gallstones are common and associated with substantial health and economic burden. We aimed to comprehensively evaluate the prevalence and incidence of gallstones in the 21st century. METHODS: We systematically searched PubMed and Embase to identify studies reporting the prevalence and/or incidence of gallstones between January 1, 2000, and November 18, 2023. Pooled prevalence and incidence were calculated using DerSimonian and Laird's random-effects model. We performed subgroup analyses and meta-regression based on age, sex, geographic location, population setting, and modality of detection to examine sources of heterogeneity. RESULTS: Based on 115 studies with 32,610,568 participants, the pooled prevalence of gallstones was 6.1% (95% CI, 5.6-6.5). Prevalence was higher in females vs males (7.6% vs 5.4%), in South America vs Asia (11.2% vs 5.1%), in upper-middle-income countries vs high-income countries (8.9% vs 4.0%), and with advancing age. On sensitivity analysis of population-based studies, the prevalence of gallstones was 5.5% (95% CI, 4.1-7.4; n = 44 studies), and when limiting subgroup analysis to imaging-based detection modalities, the prevalence was 6.7% (95% CI, 6.1-7.3; n = 101 studies). Prevalence has been stable over the past 20 years. Based on 12 studies, the incidence of gallstones was 0.47 per 100 person-years (95% CI, 0.37-0.51), without differences between males and females, and with increasing incidence in more recent studies. CONCLUSIONS: Globally, 6% of the population have gallstones, with higher rates in females and in South America. The incidence of gallstones may be increasing. Our findings call for prioritizing research on the prevention of gallstones.

Seasonal variation in structural and functional distribution of periphyton in a macrolide antibiotics-contaminated river.

Periphyton, a microbial assemblage of autotrophic and heterotrophic organisms, is vital to aquatic ecosystems. While exposure to macrolide antibiotics has been confirmed to reduce the biodiversity and damage the critical ecological functions in indoor microcosm bioassays, the distribution of periphyton along a macrolide antibiotic pollution gradient in a river has yet to be determined. Herein, we established the spatiotemporal distribution of five major macrolides, i.e., azithromycin (AZI), roxithromycin (ROX), erythromycin (ERY), clarithromycin (CLA), and anhydro erythromycin (ERY-H2O) in water and periphyton of Zao River (Xi'an, China), after which we evaluated the effects on the structures, photosynthetic activity, and carbon utilization capacity of periphyton in March, June, and September 2023. In contrast with the reference sites, the macrolides were identified in all sewage treatment plants (STPs) impacted sites with concentrations ranging from 0.05 to 2.18 µg/L in water and from not detected - 9.67 µg/g in periphyton. Regarding community structure, the occurrence of macrolides was negatively linked to FirmicutesExiguobacterium undae and Exiguobacterium sibiricum, CyanobacteriaOscillatoriales and Vischeria sp., and ChlorophytaMonostroma grevillei, Selenastrum sp. LU21 and Desmodesmus subspicatus. At the functional level, only the metabolism of phenolic acids was significantly decreased in river reach with high antibiotic levels in June, compared to the other five carbon sources that were not altered. The overall photosynthetic activity of periphytic photosystem II remained unchanged in both reference and STPs impacted groups throughout three seasons. Overall, the macrolides released from STPs were correlated with the altered periphytic structures in the river, whereas a similar trend was not detected for the community functions owing to the functional redundancy. A mesocosm experiments warrants further consideration to validate the field results.

The mediating role of pregnancy-induced hypertension on pre-pregnancy body mass index and adverse neonatal outcomes in women with assisted reproductive technology.

OBJECTIVE: To explore whether pregnancy-induced hypertension (PIH) mediates the association between pre-pregnancy body mass index (BMI) and adverse neonatal outcomes in women undergoing assisted reproductive technology (ART) for singleton pregnancies. METHODS: This cohort study collected 79437 maternal data from the National Vital Statistics System (NVSS) between 2020 and 2021. Univariable and multivariable logistic regression models were applied to estimate the association between pre-pregnancy BMI and PIH in women receiving ART as well as the associations between pre-pregnancy BMI and PIH and adverse neonatal outcomes. The mediation effect of PIH on the association between pre-pregnancy BMI and adverse neonatal outcomes was estimated according to the total effect, natural direct effect, natural indirect effect, and percentage of mediation. RESULTS: There were 25769 participants had adverse neonatal outcomes at the end of the follow-up. After adjusting for confounding factors, an increased risk of PIH in women receiving ART was identified in those with pre-pregnancy BMI ≥25 kg/m2 [odds ratio (OR)=1.92, 95% confidence interval (CI):1.84-2.01]. Pre-pregnancy BMI ≥25 kg/m2 was associated with an increased risk of adverse neonatal outcomes (OR = 1.26, 95%CI:1.22-1.30). Women with PIH had an increased risk of adverse neonatal outcomes (OR = 1.79, 95%CI:1.71-1.87). The percentage mediated by PIH in the association between pre-pregnancy BMI and adverse neonatal outcomes was 21.30%. CONCLUSION: PIH partially mediated the association between pre-pregnancy BMI and adverse neonatal outcomes in women receiving ART, which recommends that women control weight before receiving ART.

Non-heme Iron Single-Atom Nanozymes as Peroxidase Mimics for Tumor Catalytic Therapy.

Single-atom nanozymes (SAzymes) open new possibilities for the development of artificial enzymes that have catalytic activity comparable to that of natural peroxidase (POD). So far, most efforts have focused on the structural modulation of the Fe-N4 moiety to mimic the metalloprotein heme center. However, non-heme-iron POD with much higher activity, for example, HppE, has not been mimicked successfully due to its structural complexity. Herein, carbon dots (CDs)-supported SAzymes with twisted, nonplanar Fe-O3N2 active sites, highly similar to the non-heme iron center of HppE, was synthesized by exploiting disordered and subnanoscale domains in CDs. The Fe-CDs exhibit an excellent POD activity of 750 units/mg, surpassing the values of conventional SAzymes with planar Fe-N4. We further fabricated an activatable Fe-CDs-based therapeutic agent with near-infrared enhanced POD activity, a photothermal effect, and tumor-targeting ability. Our results represent a big step in the design of high-performance SAzymes and provide guidance for future applications for synergistic tumor therapy.

Extracellular vesicles long RNA profiling identifies abundant mRNA, circRNA and lncRNA in human bile as potential biomarkers for cancer diagnosis.

Extracellular vesicles (EVs) are bilayered membrane vesicles produced by living cells and secreted into the extracellular matrix. Bile is a special body fluid that is secreted by the liver cells, and extracellular vesicles long RNAs (exLRs) have not been explored in bile. In this study, exLR sequencing (exLR-seq) was performed on 19 bile samples from patients with malignant cancer or patients with biliary stones. A total of 8649 mRNAs, 13 823 circRNAs and 1105 lncRNAs were detected. The KEGG pathway analysis revealed that differentially expressed exLRs were enriched in mTOR and AMPK signaling pathway. We identified five mRNAs (EID2, LLPH, ATP6V0A2, RRP9 and MTRNR2L10), three lncRNAs (AC015922.2, AL135905.1 and LINC00921) and six circRNAs (circASH1L, circATP9A, circCLIP1, circRNF138, circTIMMDC1 and circANKRD12) were enriched in bile EV samples with cancer, and these exLRs may be potential markers used to distinguish malignant cancers from benign biliary diseases. Moreover, the tissue/cellular source components of EVs were analyzed using the EV-origin algorithm. The absolute abundance of CD4_naive and Th1 cell source in bile EVs from cancer patients were significantly increased. In summary, our study presented abundant exLRs in human bile EVs and provides some basis for the selection of tumor diagnostic markers.

Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1.

Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the mouth, characterised by rapid progression and poor prognosis. Hence, an urgent need exists for the development of predictive targets for early diagnosis, prognosis determination, and clinical therapy. Dysregulation of lymphoid enhancer-binding factor 1 (LEF1), an important transcription factor involved in the Wnt-ß-catenin pathway, contributes to the poor prognosis of OSCC. Herein, we aimed to explore the correlation between LEF1 and histone lysine demethylase 4 A (KDM4A). Results show that the KDM4A complex is recruited by LEF1 and specifically binds the LATS2 promoter region, thereby inhibiting its expression, and consequently promoting cell proliferation and impeding apoptosis in OSCC. We also established NOD/SCID mouse xenograft models using CAL-27 cells to conduct an in vivo analysis of the roles of LEF1 and KDM4A in tumour growth, and our findings show that cells stably suppressing LEF1 or KDM4A have markedly decreased tumour-initiating capacity. Overall, the results of this study demonstrate that LEF1 plays a pivotal role in OSCC development and has potential to serve as a target for early diagnosis and treatment of OSCC.

Not all Rectal Cancer Patients Could Benefit From the Surgery on the Primary Site.

AIM: Previous studies have provided evidence that primary site surgery can improve the prognosis of rectal cancer patients, even in those with advanced age and distant metastasis, though results have been inconsistent. The current study aims to determine if all rectal cancer patients are likely to benefit from surgery in terms of overall survival. METHODS: This study examined the impact of primary site surgery on the prognosis of rectal cancer patients diagnosed between 2010 and 2019 using multivariable Cox regression analysis. The study also stratified patients by age group, M stage, chemotherapy, radiotherapy, and number of distant metastatic organs. The propensity score matching method was used to balance observed covariates between patients who received and did not receive surgery. The Kaplan-Meier method was used to analyze the data, and the log-rank test was used to determine differences between patients who did and did not undergo surgery. RESULTS: The study included 76,941 rectal cancer patients, with a median survival of 81.0 months (95% CI: 79.2-82.8 months). Of these patients, 52,360 (68.1%) received primary site surgery, and they tended to be younger, have higher differentiated grade, earlier T, N, M stage, and lower rates of bone, brain, lung, and liver metastasis, chemotherapy, and radiotherapy than those without surgery. Multivariable Cox regression analysis revealed that surgery had a protective effect on the prognosis of rectal cancer patients, including those with advanced age, distant metastasis, and multiple organ metastasis, but not in patients with four organ metastases. The results were also confirmed using propensity score matching. CONCLUSION: Not all rectal cancer patients could benefit from the surgery on the primary site, especially the patients with more than four distant metastases. The results could help the clinicians to tailor targeted treatment regimens and provide a guideline for making surgical decisions.

DNA damage-inducible transcript 3 deficiency promotes bone resorption in murine periodontitis models.

BACKGROUND AND OBJECTIVE: Periodontitis is a multifactorial inflammatory disease that leads to the destruction of supporting structures of the teeth. DNA damage-inducible transcript 3 (DDIT3) plays crucial roles in cell survival and differentiation. DDIT3 regulates bone mass and osteoclastogenesis in femur. However, the role of DDIT3 in periodontitis has not been elucidated. This research aimed to explore the role and mechanisms of DDIT3 in periodontitis. METHODS: DDIT3 gene knockout (KO) mice were generated using a CRISPR/Cas9 system. Experimental periodontitis models were established to explore the role of DDIT3 in periodontitis. The expression of DDIT3 in periodontal tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The alveolar bone phenotypes were observed by micro-CT and stereomicroscopy. The inflammation levels and osteoclast activity were examined by histological staining, immunostaining, and qRT-PCR. Bone marrow-derived macrophages (BMMs) were isolated to confirm the effects of DDIT3 on osteoclast formation and function in vitro. RESULTS: The increased expression of DDIT3 in murine inflamed periodontal tissues was detected. DDIT3 knockout aggravated alveolar bone loss and enhanced expression levels of inflammatory cytokines in murine periodontitis models. Increased osteoclast formation and higher expression levels of osteoclast-specific markers were observed in the inflamed periodontal tissues of KO mice. In vitro, DDIT3 deficiency promoted the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts and the bone resorption activity of mature osteoclasts. CONCLUSIONS: Our results demonstrate that DDIT3 deletion aggravated alveolar bone loss in experimental periodontitis through enhanced inflammatory reactions and osteoclastogenesis. The anti-inflammation and the inhibition of bone loss by DDIT3 in murine periodontitis provides a potential novel therapeutic strategy for periodontitis.

Specific discrimination of zinc and manganese ions by label free dual emissive carbon dots by ratio-metric mode.

Due to the worldwide ecological and environmental issues induced by heavy metal pollution, including zinc and manganese, the ratio-metric discrimination of Zn2+ and Mn2+ based on CDs is urgently required. In this work, reduced CDs (re-CDs) with the intrinsic dual emissive peaks are obtained, and specific discrimination of Zn2+ and Mn2+ is realized by re-CDs with ratio-metric mode. With the addition of Zn2+, the fluorescent (FL) intensity at 650 nm increases obviously, while that at 680 nm progressively decreases. However, the presence of Mn2+ would induce the quenching of FL intensity at 680 nm while that at 650 nm remains constant. Then the Zn2+ and Mn2+ can be separately determined with the ratio of FL intensity at 650 nm to that at 680 mm (F650/F680). Under optimal conditions, the limit of detection (LOD) of Zn2+ is determined to be 9.09 nmol/L, and that for Mn2+ is estimated to be 0.93 nmol/L, which is much lower than previously reported work and standard level of Zn2+ and Mn2+ permitted in drinking water by WHO. Moreover, the specific recognition of Mn2+ and Zn2+ can be realized via the addition of different masking agents (ethylenediamine for Zn2+ and triethanolamine for Mn2+). Furthermore, our results reveal that the structural changes from -NH-CO to -NC-OH induced by Zn2+ contribute to the shift of FL peak from 680 to 650 nm while both static and dynamic quenching processes are involved in the detection of Mn2+. The ratio-metric probe was successfully applied to Zn2+ and Mn2+ determination in human serum samples and Sandy Lake water.

Targeting PPARs for therapy of atherosclerosis: A review.

Atherosclerosis, a chief pathogenic factor of cardiovascular disease, is associated with many factors including inflammation, dyslipidemia, and oxidative stress. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and are widely expressed with tissue- and cell-specificity. They control multiple genes that are involved in lipid metabolism, inflammatory response, and redox homeostasis. Given the diverse biological functions of PPARs, they have been extensively studied since their discovery in 1990s. Although controversies exist, accumulating evidence have demonstrated that PPAR activation attenuates atherosclerosis. Recent advances are valuable for understanding the mechanisms of action of PPAR activation. This article reviews the recent findings, mainly from the year of 2018 to present, including endogenous molecules in regulation of PPARs, roles of PPARs in atherosclerosis by focusing on lipid metabolism, inflammation, and oxidative stress, and synthesized PPAR modulators. This article provides information valuable for researchers in the field of basic cardiovascular research, for pharmacologists that are interested in developing novel PPAR agonists and antagonists with lower side effects as well as for clinicians.

CM3-SII polysaccharide obtained from Cordyceps militaris ameliorates hyperlipidemia in heterozygous LDLR-deficient hamsters by modulating gut microbiota and NPC1L1 and PPARα levels.

Accumulating evidence has demonstrated that polysaccharides derived from edible fungi have lipid-lowering effects in mice. However, the lipid metabolism mechanisms in mice and humans are different. We have previously elucidated the structural characteristics of the alkali-extracted polysaccharide CM3-SII obtained from Cordyceps militaris. This study aimed to investigate whether CM3-SII could ameliorate hyperlipidemia in a heterozygous low-density lipoprotein receptor (LDLR)-deficient hamster model of hyperlipidemia. Our data demonstrated that CM3-SII significantly decreased total plasma cholesterol, non-high-density lipoprotein cholesterol, and triglyceride levels in heterozygous LDLR-deficient hamsters. Unlike ezetimibe, CM3-SII could enhance the concentration of plasma apolipoprotein A1 and the expression of liver X receptor α/ATP-binding cassette transporter G8 mRNA pathway and suppress the expression of Niemann-Pick C1-like 1, which help to reduce cholesterol levels further. Moreover, the results of molecular docking analysis demonstrated that CM3-SII could directly bind to Niemann-Pick C1-like 1 with high affinity. The triglyceride-lowering mechanisms of CM3-SII were related to its downregulation of sterol regulatory element-binding protein 1c and upregulation of peroxisome proliferator-activated receptor α. Importantly, CM3-SII increased the abundance of Actinobacteria and Faecalibaculum and the ratio of Bacteroidetes/Firmicutes. Thus, CM3-SII attenuated hyperlipidemia by modulating the expression of multiple molecules involved in lipid metabolism and the gut microbiota.

Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model.

Ménière's disease, a multifactorial disorder of the inner ear, is characterized by severe vertigo episodes and hearing loss. Although the role of immune responses in Ménière's disease has been proposed, the precise mechanisms remain undefined. Here, we show that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in vestibular-resident macrophage-like cells from Ménière's disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1ß production which leads to the damage of inner ear hair cells and vestibular nerve. Mechanistically, serum/glucocorticoid-inducible kinase 1 binds to the PYD domain of NLRP3 and phosphorylates it at Serine 5, thereby interfering inflammasome assembly. Sgk-/- mice show aggravated audiovestibular symptoms and enhanced inflammasome activation in lipopolysaccharide-induced endolymphatic hydrops model, which is ameliorated by blocking NLRP3. Pharmacological inhibition of serum/glucocorticoid-inducible kinase 1 increases the disease severity in vivo. Our studies demonstrate that serum/glucocorticoid-inducible kinase 1 functions as a physiologic inhibitor of NLRP3 inflammasome activation and maintains inner ear immune homeostasis, reciprocally participating in models of Ménière's disease pathogenesis.