circELP2 reverse-splicing biogenesis and function as a pro-fibrogenic factor by targeting mitochondrial quality control pathway.

Idiopathic pulmonary fibrosis (IPF) is considered as a chronic, fibrosing interstitial pneumonia with unknown mechanism. The present work aimed to explore the function, biogenesis and regulatory mechanism of circELP2 in pulmonary fibrosis and evaluate the value of blocking circELP2-medicated signal pathway for IPF treatment. The results showed that heterogeneous nuclear ribonucleoprotein L initiated reverse splicing of circELP2 resulting in the increase of circELP2 generation. The biogenetic circELP2 activated the abnormal proliferation and migration of fibroblast and extracellular matrix deposition to promote pulmonary fibrogenesis. Mechanistic studies demonstrated that cytoplasmic circELP2 sponged miR-630 to increase transcriptional co-activators Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ). Then, YAP1/TAZ bound to the promoter regions of their target genes, such as mTOR, Raptor and mLST8, which in turn activated or inhibited the genes expression in mitochondrial quality control pathway. Finally, the overexpressed circELP2 and miR-630 mimic were packaged into adenovirus vector for spraying into the mice lung to evaluate therapeutic effect of blocking circELP2-miR-630-YAP1/TAZ-mitochondrial quality control pathway in vivo. In conclusion, blocking circELP2-medicated pathway can alleviate pulmonary fibrosis, and circELP2 may be a potential target to treat lung fibrosis.

SIRT1 regulates mitochondrial fission to alleviate high altitude hypoxia inducedcardiac dysfunction in rats via the PGC-1α-DRP1/FIS1/MFF pathway.

High-altitude exposure has been linked to cardiac dysfunction. Silent information regulator factor 2-related enzyme 1 (sirtuin 1, SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, plays a crucial role in regulating numerous cardiovascular diseases. However, the relationship between SIRT1 and cardiac dysfunction induced by hypobaric hypoxia (HH) remains unexplored. This study aims to assess the impact of SIRT1 on HH-induced cardiac dysfunction and delve into the underlying mechanisms, both in vivo and in vitro. In this study, we have demonstrated that exposure to HH results in cardiomyocyte injury, along with the downregulation of SIRT1 and mitochondrial dysfunction. Upregulating SIRT1 significantly inhibits mitochondrial fission, improves mitochondrial function, reduces cardiomyocyte injury, and consequently enhances cardiac function in HH-exposed rats. Additionally, HH exposure triggers aberrant expression of mitochondrial fission-regulated proteins, with a decrease in PPARγ coactivator 1 alpha (PGC-1α) and mitochondrial fission factor (MFF) and an increase in mitochondrial fission 1 (FIS1) and dynamin-related protein 1 (DRP1), all of which are mitigated by SIRT1 upregulation. Furthermore, inhibiting PGC-1α diminishes the positive effects of SIRT1 regulation on the expression of DRP1, MFF, and FIS1, as well as mitochondrial fission. These findings demonstrate that SIRT1 alleviates HHinduced cardiac dysfunction by preventing mitochondrial fission through the PGC-1α-DRP1/FIS1/MFF pathway.

Naringenin protects against septic cardiomyopathy in mice by targeting HIF-1α.

Myocardial dysfunction is a prevalent complication of sepsis (septic cardiomyopathy) with a high mortality rate and limited therapeutic options. Naringenin, a natural flavonoid compound with anti-inflammatory and antioxidant properties, holds promise as a potential treatment for sepsis-induced myocardial dysfunction. This study investigated the pharmacological effects of naringenin on septic cardiomyopathy. In vivo and in vitro experiments demonstrated that naringenin improved cardiomyocyte damage. Network pharmacology and database analysis revealed that HIF-1α is a key target protein of naringenin. Elevated expression of HIF-1α was observed in damaged cardiomyocytes, and the HIF-1α inhibitor effectively protected against LPS-induced cardiomyocyte damage. Molecular docking studies confirmed the direct binding between naringenin and HIF-1α protein. Importantly, our findings demonstrated that naringenin did not provide additional attenuation of cardiomyocyte injury on the biases of HIF-1α inhibitor treatment. In conclusion, this study proves that naringenin protects against septic cardiomyopathy through HIF-1α signaling. Naringenin is a promising therapeutic candidate for treating septic cardiomyopathy.

hucMSCs Treatment Ameliorated Pulmonary Fibrosis via Downregulating the circFOXP1-HuR-EZH2/STAT1/FOXK1 Autophagic Axis.

This study was performed to determine the effect of human umbilical cord mesenchymal stem cells (hucMSCs) treatment on pulmonary fibrosis and investigate the circFOXP1-mediated autophagic mechanism of hucMSCs treatment. Pulmonary fibrosis models were established by spraying bleomycin in mice and TGF-ß1 treatment of MRC-5 cells. Results showed that hucMSCs were retained in lung and hucMSCs treatment alleviated pulmonary fibrosis. Morphological staining indicated that hucMSCs-treated mice had thinner alveolar walls, effectively improved alveolar structure, significantly reduced alveolar inflammation, and decreased collagen deposition than control mice. Fibrotic proteins, including vimentin, α-SMA, collagens I and III, and the differentiation-related protein S100 calcium-binding protein A4 was reduced considerably in the hucMSCs-treated group. The mechanistic study revealed that the inhibition of hucMSCs treatment on pulmonary fibrogenesis depended on downregulating circFOXP1, in which hucMSCs treatment promoted circFOXP1-mediated autophagy process via blocking the nuclear human antigen R (HuR) translocation and promoting the HuR degradation, leading to a marked decrease in autophagy negative regulators EZH2, STAT1, and FOXK1. In conclusion, hucMSCs treatment significantly improved pulmonary fibrosis by downregulating the circFOXP1-HuR-EZH2/STAT1/FOXK1 autophagic axis. hucMSCs can act as an effective treatment for pulmonary fibrosis.

Intermittent high altitude hypoxia induced liver and kidney injury leading to hyperuricemia.

About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but little is known about the possible mechanisms. This study aims to assess the effects of high altitude on hyperuricemia and explore the corresponding mechanisms at the histological, inflammatory and molecular levels. This study finds that intermittent hypobaric hypoxia (IHH) exposure results in an increase of serum uric acid level and a decrease of uric acid clearance rate. Compared with the control group, the IHH group shows significant increases in hemoglobin concentration (HGB) and red blood cell counts (RBC), indicating that high altitude hyperuricemia is associated with polycythemia. This study also shows that IHH exposure induces oxidative stress, which causes the injury of liver and renal structures and functions. Additionally, altered expressions of organic anion transporter 1 (OAT1) and organic cation transporter 1 (OCT1) of kidney have been detected in the IHH exposed rats. The adenosine deaminase (ADA) expression levels and the xanthione oxidase (XOD) and ADA activity of liver of the IHH exposure group have significantly increased compared with those of the control group. Furthermore, the spleen coefficients, IL-2, IL-1ß and IL-8, have seen significant increases among the IHH exposure group. TLR/MyD88/NF-κB pathway is activated in the process of IHH induced inflammatory response in joints. Importantly, these results jointly show that IHH exposure causes hyperuricemia. IHH induced oxidative stress along with liver and kidney injury, unusual expression of the uric acid synthesis/excretion regulator and inflammatory response, thus suggesting a potential mechanism underlying IHH-induced hyperuricemia.

Zinc finger protein ZBTB17 controls cellular senescence via interacting with nuclear receptor RXRA and its downstream calcium signaling.

Cellular senescence is broadly known as a stable cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP). In the past decades, calcium signaling has emerged as a key mediator of cellular senescence. However, the transcriptional regulation of calcium signaling during cellular senescence remains partially understood. We have previously identified the nuclear receptor RXRA as a key senescence repressor through inhibiting the endoplasmic reticulum (ER) calcium release channel inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) mediated intracellular calcium signaling. Nevertheless, as a transcriptional recruiter, the mechanism by which RXRA inhibits ITPR2 during cellular senescence remains unclear. Here we identified the zinc finger protein ZBTB17 can interact with RXRA. Interestingly, knockdown of ZBTB17 induces a cascade of RXRA-dependent intracellular calcium signaling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, DNA damages, and ultimately cellular senescence. Moreover, the signaling and senescence phenotype induced by knocking down of ZBTB17 can also be abolished after silencing ITPR2. Altogether, our work provides a new mechanism controlling intracellular calcium signaling and cellular senescence and unveils novel insight toward the role of zinc finger proteins.

First report of a p.Cys484Tyr Notch3 mutation in a CADASIL patient with acute bilateral multiple subcortical infarcts-case report and brief review.

BACKGROUND: CADASIL(Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)is an inherited small vessel disease caused by mutations in NOTCH3 gene. Although NOTCH3 has numerous hotspots of gene mutations, mutations in exons 9 are rare. The p.C484T gene mutation type associated with it has not been reported in any relevant cases yet. Furthermore, CADASIL patients rarely present with acute bilateral multiple subcortical infarcts. CASE PRESENTATION: We report the case of a Chinese female patient with CADASIL who experienced "an acute bilateral subcortical infarction" because of"hemodynamic changes and hypercoagulability". In genetic testing, we discovered a new Cys484Tyr mutation in exon 9, which has also been found in the patient's two daughters. CONCLUSIONS: It is important to note that this discovery not only expands the mutation spectrum of Notch3 mutations in CADASIL patients, but also examines the mechanism behind acute bilateral subcortical infarction in CADASIL patients via case reviews and literature reviews, in order to provide some clinical recommendations for early intervention, diagnosis, and treatment in similar cases in the future.

Structural visualization of the p53/RNA polymerase II assembly.

The master tumor suppressor p53 activates transcription in response to various cellular stresses in part by facilitating recruitment of the transcription machinery to DNA. Recent studies have documented a direct yet poorly characterized interaction between p53 and RNA polymerase II (Pol II). Therefore, we dissected the human p53/Pol II interaction via single-particle cryo-electron microscopy, structural docking, and biochemical analyses. This study reveals that p53 binds Pol II via the Rpb1 and Rpb2 subunits, bridging the DNA-binding cleft of Pol II proximal to the upstream DNA entry site. In addition, the key DNA-binding surface of p53, frequently disrupted in various cancers, remains exposed within the assembly. Furthermore, the p53/Pol II cocomplex displays a closed conformation as defined by the position of the Pol II clamp domain. Notably, the interaction of p53 and Pol II leads to increased Pol II elongation activity. These findings indicate that p53 may structurally regulate DNA-binding functions of Pol II via the clamp domain, thereby providing insights into p53-regulated Pol II transcription.

Association between oxidative stress, mitochondrial function of peripheral blood mononuclear cells and gastrointestinal cancers.

BACKGROUND: The incidence and mortality rate of gastrointestinal cancers are high worldwide. Increasing studies have illustrated that the occurrence, progression, metastasis and prognosis of cancers are intimately linked to the immune system. Mitochondria, as the main source of cellular energy, play an important role in maintaining the physiological function of immune cells. However, the relationship between mitochondrial function of immune cells and tumorigenesis has not yet been systematically investigated. METHODS: A total of 150 cases, including 60 healthy donors and 90 primary gastrointestinal cancer patients without anti-tumor treatments (30 with gastric cancer, 30 with liver cancer and 30 with colorectal cancer) were involved in our study. The oxidant/antioxidant and cytokine levels in plasma, the ROS level, mitochondrial function and apoptosis ratio of peripheral blood mononuclear cells (PBMCs) were evaluated. RESULTS: The imbalance between oxidant and antioxidant in plasma was discovered in the primary gastrointestinal cancer patients. The levels of cell reactive oxygen species (ROS) and mitochondrial ROS in PBMCs of primary gastrointestinal cancers were significantly increased compared with that in healthy donors. Meanwhile, the ATP content, the mtDNA copy number and the mitochondrial membrane potential (MMP) in PBMCs of patients with primary gastrointestinal cancers were lower than those in control group. The decreased MMP also occurred in immune cells of gastrointestinal cancers, including T cell, B cell, NK cell and monocyte. Furthermore, the PBMCs apoptosis ratio of primary gastrointestinal cancer patients was significantly higher than that of control group. Importantly, an increase of IL-2 and IL-6 and a decrease of IgG in plasma were found in the patients with primary gastrointestinal cancers. These changes of mitochondrial function in immune cells were consistent among primary gastrointestinal cancers without anti-tumor treatments, such as liver cancer, gastric cancer and colorectal cancer. CONCLUSION: Our study demonstrated that the imbalance of oxidation/antioxidation in primary gastrointestinal cancer patients without anti-tumor treatments results in excessive ROS. The oxidative stress was associated to the mitochondrial dysfunction, the apoptosis of immune cells and eventually the abnormal immune function in primary gastrointestinal cancers. The application of immune cell mitochondrial dysfunction into clinical evaluation is anticipated.

Beauvericin exerts an anti-tumor effect on hepatocellular carcinoma by inducing PI3K/AKT-mediated apoptosis.

Beauvericin is a world-spread mycotoxin isolated from the traditional Chinese medicine, Bombyx batryticatus (BB), which has been widely used to treat various neoplastic diseases. This study investigated the anti-hepatocellular carcinoma (HCC) activity of beauvericin and its potential mechanism. In this study, H22-bearing mice were intraperitoneally injected with 3, 5, 7 mg/kg of beauvericin once per-week over a three-week period. TUNEL staining determined the extent of tumor apoptosis induced by beauvericin. ELISA kits detected the level of IL-2, Perforin, and TNF-α, IFN-γ level in the serum. H22 hepatoma cells were exposed to beauvericin (5, 10, and 20 µmol/L) to investigate the underlying pathway. CCK-8 assay was used to observe the influence of beauvericin on the growth of H22 cells. Flow cytometry was used to detect the cell apoptosis and ROS level. Western blotting was performed to detect apoptotic and PI3K/AKT pathway protein production. The results showed that beauvericin could remarkably inhibit the growth of HCC in mice, combined with elevated TNF-α and IL-2. In vitro, beauvericin significantly promoted the generation of ROS, up-regulated Bax/Bcl-2 ratio and cleaved caspase-9, cleaved caspase-3 levels, down-regulated p-PI3K/PI3K ratio, p-AKT/AKT ratio, promoted the apoptosis of H22 cells, and inhibited the growth of H22 cells. Remarkably, treatment with PI3K/AKT activator (740Y-P and SC79) could prevent beauvericin-induced H22 cell apoptosis. These findings collectively indicate that beauvericin inhibits HCC growth by inducing apoptosis via the PI3K/AKT pathway.

Temporal Trends and Early Outcomes of Transcatheter versus Surgical Mitral Valve Repair in Atrial Fibrillation Patients.

Objectives: To study trends of utilization, in-hospital outcomes, and short outcomes in patients undergoing transcatheter mitral valve repair (TMVR) vs. surgical mitral valve repair (SMVR) in atrial fibrillation (AF). Background: TMVR is a treatment option in inoperable or high-risk patients with mitral regurgitation (MR). AF is a common comorbidity of MR. Data comparing between TMVR and SMVR in MR patients with AF is lacking. Methods: The National Readmission Database from 2016 to 2019 was utilized to identify hospitalizations undergoing TMVR or SMVR with AF. Outcomes of interest included mortality, postoperative complications, length of stay, and 30-day readmission rate. Results: A total of 9,195 patients underwent TMVR and 16,972 patients underwent SMVR with AF; the number of AF undergoing TMVR was increasing from 1,342 in 2016 to 4,215 in 2019 and SMVR. The incidence of in-hospital mortality decreased from 2.6% in 2016 to 1.8% in 2019. We identified length of stay>5 days, dyslipidemia, cerebrovascular disease, heart failure with reduced ejection fraction, and urgent/emergent admissions as independent risk factors for in-hospital mortality. After matching, we included 4,680 patients in each group; the in-hospital death, transfusion, acute kidney injury, sepsis, stroke, and mechanical ventilation were lower in TMVR compared with SMVR. TMVR was associated with a similar rate of all-cause readmission at 30 days compared with SMVR. Conclusion: Patients with AF receiving TMVR have been increasing along with progressive improvement in in-hospital death and length of stay. Compared to SMVR, AF patients receiving TMVR had a lower rate of in-hospital death and postoperative complications.

Unveiling orientation dependence of anisotropic plasticity in polycrystalline copper by nanoindentation.

The mechanical properties of crystalline materials are influenced by their deformation behavior, which is associated with their microstructural characteristics. Specifically, crystallographic orientation greatly affects the microscale plastic deformation of individual grains. In this study, experiments and finite element simulations of Berkovich nanoindentations are conducted to investigate the impact of crystallographic orientation in polycrystalline copper. A crystal plasticity constitutive model is developed for copper materials, which accurately captures their indentation mechanical response. The results showed that the indentation behavior of polycrystalline copper exhibits a high degree of anisotropy due to significant variation in slip systems for different crystallographic orientations. This results in different mechanical responses of individual grains and distinct material pileup morphologies on the indented surface. Additionally, the study revealed that crystallographic orientation plays a critical role in determining the indentation size effect. These findings have important implications for the design of materials where plasticity is a crucial factor.

hnRNPL-activated circANKRD42 back-splicing and circANKRD42-mediated crosstalk of mechanical stiffness and biochemical signal in lung fibrosis.

Increasing circular RNAs (circRNAs) are involved in the progression of idiopathic pulmonary fibrosis (IPF). However, circRNA biogenesis and circRNA-mediated crosstalk between mechanical stiffness and biochemical signals in IPF remain obscure. In this study, a novel circRNA-ankyrin repeat domain 42 (ANKRD42) from peripheral blood of patients with IPF, which participated in pulmonary fibrosis through the close communication of mechanical stiffness and biochemical signals, was identified. Mechanistic studies revealed that the heterogeneous nuclear ribonucleoprotein L (hnRNP L) activated the circANKRD42 reverse splicing biogenesis. The biogenetic circANKRD42 sponged miR-324-5p to promote the AJUBA expression, which blocked the binding between phosphorylated yes-associated protein 1 (YAP1) and large tumor suppressor kinase 1/2 (LATS1/2), leading to increased YAP1 entering the nucleus. circANKRD42 also sponged miR-136-5p to promote the YAP1 translation. Accumulating YAP1 in nucleus bound to TEAD, which initiated the transcription of genes related to mechanical stiffness. Finally, the therapeutic effect of circANKRD42 was evaluated in mice and the association between circANKRD42 and clinicopathological features was analyzed in IPF patients. Our findings supported that circANKRD42 is a promising biomarker and a potential therapeutic target related to cytoskeleton tension for IPF treatment.

Copper exposure induces ovarian granulosa cell apoptosis by activating the caspase-dependent apoptosis signaling pathway and corresponding changes in microRNA patterns.

Environmental copper (Cu) contamination is a complex worldwide public health problem. However, information on the effects of Cu pollution on human reproduction is limited. Although our previous studies have indicated that Cu exposure disrupts ovarian folliculogenesis, the underlying mechanism needs to be further explored. In this study, human luteinized ovarian granulosa cells and a rat animal model were used to investigate whether Cu exposure affects ovarian follicle development by inducing apoptosis and to elucidate the possible mechanisms. The results showed that Cu exposure from weaning to sexual maturity significantly decreased the proportion of preantral follicles but increased the proportion of atretic follicles (P < 0.05). In addition, 6 mg/kg Cu increased the proportion of antral follicles, while 12 and 25 mg/kg Cu decreased it (P < 0.05). We also found that 6 mg/kg Cu exposure inhibited apoptosis of ovarian granulosa cells, while 12 and 25 mg/kg Cu promoted apoptosis (P < 0.05). Experiments on primary human luteinized ovarian granulosa cells suggested that higher levels of Cu exposure induced a significant increase in the mRNA levels of Bcl2 Bax , Fas, Caspase8, and Caspase3 (P < 0.05), and the protein levels of BAX, BCL2, CASPASE3, CASPASE8, CLE-CASPASE3, CLE-CASPASE8 and BAX/BCL2 were also increased (P < 0.05). miRNA chip analyses identified a total of 95 upregulated and 10 downregulated miRNAs in human luteinized granulosa cells exposed to Cu. Hsa-miR-19b-3p, hsa-miR-19a-3p, miR-548ar-3p, hsa-miR-652-5p, and hsa-miR-29b-5p were decreased after Cu exposure (P < 0.05). Additionally, the level of hsa-miR-144-5p was increased (P < 0.05). Together, our results reveal that Cu exposure induces abnormal ovarian folliculogenesis by inducing ovarian granulosa cell apoptosis, which is triggered by the caspase-dependent apoptosis signaling pathway, and that miRNAs may be involved in this process.

High dietary copper intake induces perturbations in the gut microbiota and affects host ovarian follicle development.

Increasing evidence has shown that gut microbes play an important role in the reproductive endocrine system and the development of polycystic ovary syndrome (PCOS). However, whether environmental factors are involved in these gut microbiota alterations has seldom been studied. In this study, we aimed to explore the crucial role of an imbalanced gut microbiota on abnormal ovarian follicle development induced by Cu. A 1:1 matched case-control study with 181 PCOS patients and 181 controls was conducted using a propensity score matching protocol. Information regarding dietary Cu intake was obtained from a face-to-face dietary intake interview. Alterations in the gut microbiota were detected by high-throughput 16 S rDNA sequencing. The results showed that dietary Cu intake was positively correlated with the risk of PCOS, and the risk threshold was approximately 1.992 mg/d. Compared with those with dietary Cu intakes lower than 1.992 mg/d, those who had a higher dietary Cu intake had a 1.813-fold increased risk of PCOS (OR=1.813, 95% CI: 1.150-2.857). PCOS patients had a lower relative abundance of Bacteroides than controls (P = 0.003), and Bacteroides played a partial mediating role between dietary Cu exposure and PCOS (Pindirect effect=0.026, 95% CI: 0.002-0.072). In addition, an animal model of Cu exposure through the diet showed that Cu can induce gut microbiota disorder; increase serum levels of LPS, MDA, and IL-6; and alter host ovarian steroidogenesis to affect ovarian follicle development. Staphylococcus played a partial mediating role between Cu exposure and CYP17A1 (Pg_Staphylococcus=0.083, 95% CI: 0.001-0.228). Overall, this study shows that long-term exposure to high dietary Cu levels can affect the composition of the gut microbiota, cause inflammation and oxidative stress, and then interfere with hormone signaling, ultimately affecting ovarian follicle development.

Benzene induces spleen injury through the B cell receptor signaling pathway.

Benzene is a toxic environmental pollutant that disrupts the immune system in humans. Benzene exposure reduces the abundance of immune cells in multiple immune organs; however, the biological mechanisms underlying benzene-induced immunotoxicity has not been elucidated. In this study, benzene was used to develop mouse model for immune dysfunction. A significant decrease in IgG, IL-2 and IL-6 levels, an increase in oxidative stress and spleen injury were observed after benzene exposure in a dose-dependent manner. Quantitative proteomics revealed that benzene-induced immune dysfunction was associated with deregulation of the B cell receptor (BCR) signaling pathway. Benzene exposure suppressed the expression of CD22, BCL10 and NF-κb p65. Also, a significant decrease in proliferation and an increase in apoptosis of splenic lymphocytes were found after benzene exposure. Moreover, we found that benzene exposure increased mitochondrial reactive oxygen species (mito-ROS) and decreased adenosine triphosphate (ATP). Overall, we revealed the damaging effects of benzene on spleen-related immune function and the underlying biological mechanism, involving the disruption of BCR signaling pathway, NF-κB deactivation, and mitochondrial dysfunction.

Comparative analysis of the contribution of municipal waste management policies to GHG reductions in China.

Waste generation and disposal have been a global issue for decades. The total global greenhouse gas (GHG) emissions in 2019 were 49,758 MtCO2e with waste disposal accounting for 3.2%. With rapid urbanization trends, municipal solid waste (MSW) has become a global challenge which needs to be addressed. A large fraction of MSW such as food wastes, e-waste among others still ends up with unregulated dumps or openly burned in low-income countries. As a response, China initiated the 'zero-waste' pilot program which has been running since 2019. To investigate the potential contribution of MSW management to GHG reductions, this study selected four 'zero-waste' cities in China, namely Shenzhen, Panjin, Xining and Tongling, as case studies to assess the impacts of different MSW management policies on GHG reductions from 2015 to 2019. Results demonstrated that Shenzhen city achieved progress in reducing GHGs, which decreased by more than 40% between 2015 and 2019. This study provides policy recommendations and waste management approaches and practices to optimize MSW management and reduction of GHGs.

The regulatory roles of DDIT4 in TDCIPP-induced autophagy and apoptosis in PC12 cells.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate-based flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy. However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4 (DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot (WB) and Flow cytometry (FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II (LC3II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the mTOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.

Bromodomains regulate dynamic targeting of the PBAF chromatin-remodeling complex to chromatin hubs.

Chromatin remodelers actively target arrays of acetylated nucleosomes at select enhancers and promoters to facilitate or shut down the repeated recruitment of RNA polymerase II during transcriptional bursting. It is poorly understood how chromatin remodelers such as PBAF dynamically target different chromatin states inside a live cell. Our live-cell single-molecule fluorescence microscopy study reveals chromatin hubs throughout the nucleus where PBAF rapidly cycles on and off the genome. Deletion of PBAF's bromodomains impairs targeting and stable engagement of chromatin in hubs. Dual color imaging reveals that PBAF targets both euchromatic and heterochromatic hubs with distinct genome-binding kinetic profiles that mimic chromatin stability. Removal of PBAF's bromodomains stabilizes H3.3 binding within chromatin, indicating that bromodomains may play a direct role in remodeling of the nucleosome. Our data suggests that PBAF's dynamic bromodomain-mediated engagement of a nucleosome may reflect the chromatin-remodeling potential of differentially bound chromatin states.

Low expression of PCK2 in breast tumors contributes to better prognosis by inducing senescence of cancer cells.

Cell cycle arrest, one of the main characteristics of cellular senescence, has been described as a crucial barrier that needs to be bypassed for cancer progression. Typically, cellular senescence can be induced by multiple stresses including telomere shortening, oncogenic activation as well as therapy treatment, and contributes to the inhibition of epithelial-mesenchymal transition (EMT), tumor suppression or progression depending on the senescence-associated secretory phenotype (SASP) components. However, the mechanisms underlying cancer cell senescence remain partially understood. Here, according to METABRIC database, we identified that patients with senescent-like breast tumors show better short-term survival, lower tendency of neoplasm histological grades, lower tumor stages, and negative status of estrogen receptor (ER) and progesterone receptor (PR) compared with non-senescent ones. Interestingly, Kyoto encyclopedia of genes and genomes (KEGG) analysis identified insulin signaling was significantly repressed in senescent breast tumors. Further verification in cultured breast cancer cells indicated that phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly inhibited after therapy treatment. In addition, knockdown of PCK2 induced a senescent phenotype of breast cancer cells. Moreover, comparing with the non-senescent group, the senescent breast cancers displayed lower EMT capacity both in patients and breast cancer cell lines after knocking down PCK2. In conclusion, we described for the first time that low expression level of PCK2 may contribute to better prognosis via triggering senescent phenotype and thereby inhibiting EMT capacity in breast cancers.