Mitochondrial endogenous substance transport-inspired nanomaterials for mitochondria-targeted gene delivery.

Mitochondrial genome (mtDNA) independent of nuclear gene is a set of double-stranded circular DNA that encodes 13 proteins, 2 ribosomal RNAs and 22 mitochondrial transfer RNAs, all of which play vital roles in functions as well as behaviors of mitochondria. Mutations in mtDNA result in various mitochondrial disorders without available cures. However, the manipulation of mtDNA via the mitochondria-targeted gene delivery faces formidable barriers, particularly owing to the mitochondrial double membrane. Given the fact that there are various transport channels on the mitochondrial membrane used to transfer a variety of endogenous substances to maintain the normal functions of mitochondria, mitochondrial endogenous substance transport-inspired nanomaterials have been proposed for mitochondria-targeted gene delivery. In this review, we summarize mitochondria-targeted gene delivery systems based on different mitochondrial endogenous substance transport pathways. These are categorized into mitochondrial steroid hormones import pathways-inspired nanomaterials, protein import pathways-inspired nanomaterials and other mitochondria-targeted gene delivery nanomaterials. We also review the applications and challenges involved in current mitochondrial gene editing systems. This review delves into the approaches of mitochondria-targeted gene delivery, providing details on the design of mitochondria-targeted delivery systems and the limitations regarding the various technologies. Despite the progress in this field is currently slow, the ongoing exploration of mitochondrial endogenous substance transport and mitochondrial biological phenomena may act as a crucial breakthrough in the targeted delivery of gene into mitochondria and even the manipulation of mtDNA.

High-Temporal-Resolution In Situ Sensor for Oceanic CO2 Isotope Measurement Enabling Multidimensional Isotope Tracing Analysis (R13C, R18O, and R17O) via Laser Absorption Spectroscopy.

Combined in situ analysis of oceanic CO2 concentrations and diverse C and O isotope characteristics can offer a unique perspective with multiple isotopic tracing dimensions for identifying marine biogeochemical processes. Applying this strategy in marine environments is urgently required, yet it faces inherent challenges in terms of existing analytical methods and instruments, e.g., a lack of in situ sensors, limited detectable isotope variety, and low-temporal-resolution data. Here, we report an underwater in situ dissolved CO2 isotope sensor based on mid-infrared tunable diode laser absorption spectroscopy (MIR-TDLAS) and membrane extraction technology. Through the proposed targeted strategies, the sensor is capable of providing high-temporal-resolution in situ measurement of all monosubstituted isotopes of dissolved CO2 (16O13C16O, 18O12C16O, and 17O12C16O) at marine background concentrations. The sensor is demonstrated to provide comparable precision to that of isotope ratio mass spectrometry. At 400 ppmv, the precision for R13C, R18O, and R17O could achieve 0.084, 0.042, and 0.013‰, respectively, for a 1 s integration time. By enabling a high-frequency in situ analysis in fixed-point time-series field deployment, a 17O anomaly with strong regularity is observed, which is not obvious in 18O and 13C, and therefore, the superiority of the proposed multidimensional in situ isotope tracing strategy is demonstrated. The developed sensor has great potential to open up new prospects for advancing marine carbon research.

Research on the impact of internet use on fertilizer and pesticide inputs: Empirical evidence from China.

Fertilizers and pesticides are important agricultural production materials. Excessive use of fertilizers and pesticides can cause negative impacts such as decline in the quality of farm products and damage to the ecological environment. Increasing the efficiency of fertilizers and pesticides is an important step to accelerate the green transformation of agriculture. Using data from the 2015 China Household Finance Survey, this paper analyzes the impacts of Internet use on fertilizers and pesticides by farmers, and the mechanism behind the action with the help of the propensity score matching method and the instrumental variable method. The findings are: (1) Farmers who use the Internet have greater inputs of fertilizers and pesticides compared to farmers who do not use the Internet. (2) Farmers who do not use the Internet would have their inputs of fertilizers and pesticides increased by 21.9% and 47.7%, respectively, if they had used the Internet under the counterfactual hypothesis. (3) In the heterogeneity analysis, Internet use plays a positive and significant role in the inputs of fertilizer and pesticide in the eastern part of China, and Internet use has greater impact on pesticide inputs than on fertilizer in central and western regions. (4) Internet use has a positive and significant effect on fertilizer and pesticide inputs in both lower scale and higher scale operations, and a positive but not significant effect in moderate-scale operations.

The inhibitory effect of Gremlin-2 on adipogenesis suppresses breast cancer cell growth and metastasis.

BACKGROUND: Gremlin-1 (GREM1) and Gremlin-2 (GREM2) are bone morphogenetic protein antagonists that play important roles in organogenesis, tissue differentiation, and tissue homeostasis. Although GREM1 has been reported to be involved in promoting various cancers, little has been reported about effects of GREM2 on cancer. Recently, it has been reported that GREM2 can inhibit adipogenesis in adipose-derived stromal/stem cells. However, as an inhibitor of adipogenesis, the role of GREM2 in cancer progression is not well understood yet. METHODS: Pre-adipocyte 3T3-L1 cells overexpressing mock or Grem2 were established using a lentiviral transduction system and differentiated into adipocytes-mock and adipocytes-Grem2, respectively. To investigate the effect of adipocyte-Grem2 on breast cancer cells, we analyzed the proliferative and invasion abilities of spheroids using a 3D co-culture system of breast cancer cells and adipocytes or conditioned medium (CM) of adipocytes. An orthotopic breast cancer mouse model was used to examine the role of adipocytes-Grem2 in breast cancer progression. RESULTS: Grem2 overexpression suppressed adipogenesis of 3T3-L1 cells. Proliferative and invasion abilities of spheroids formed by co-culturing MTV/TM-011 breast cancer cells and adipocytes-Grem2 were significantly reduced compared to those of spheroids formed by co-culturing MTV/TM-011 cells and adipocytes-mock. Compared to adipocytes-mock, adipocytes-Grem2 showed decreased mRNA expression of several adipokines, notably IL-6. The concentration of IL-6 in the CM of these cells was also decreased. Proliferative and invasive abilities of breast cancer cells reduced by adipocytes-Grem2 were restored by IL-6 treatment. Expression levels of vimentin, slug, and twist1 in breast cancer cells were decreased by treatment with CM of adipocytes-Grem2 but increased by IL-6 treatment. In orthotopic breast cancer mouse model, mice injected with both MTV/TM-011 cells and adipocytes-Grem2 showed smaller primary tumors and lower lung metastasis than controls. However, IL-6 administration increased both the size of primary tumor and the number of metastatic lung lesions, which were reduced by adipocytes-Grem2. CONCLUSIONS: Our study suggests that GREM2 overexpression in adipocytes can inhibit adipogenesis, reduce the expression and secretion of several adipokines, including IL-6, and ultimately inhibit breast cancer progression.

Diesel exhaust particle exposure accelerates oxidative DNA damage and cytotoxicity in normal human bronchial epithelial cells through PD-L1.

Diesel exhaust particles (DEPs) are a major cause of cancer progression as well as a variety of acute and chronic diseases. It is well-known that programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that can induce immune escape in tumor cells. However, the function of PD-L1 in bronchial epithelial cells or how PD-L1 relates to cellular oxidation under DEPs-mediated oxidative stress is not well known. In this study, we investigated how PD-L1 affected DEPs-induced oxidative stress and cytotoxicity in human bronchial epithelial (HBE) cells, Beas-2B. DEPs not only induced intracellular reactive oxygen species (ROS) production, but also increased PD-L1 expression in HBE cells. Beas-2B cells overexpressing PD-L1 showed higher levels of ROS production, DNA damage, and apoptosis after DEPs treatment compared to control cells. In particular, the expression of an antioxidant enzyme heme-oxygenase-1 (HO-1) and nuclear translocation and transcriptional activity of Nrf2, a major regulator of HO-1, were lower in Beas-2B overexpressing PD-L1 cells than in control cells. DEPs-induced ROS generation, DNA damage and apoptosis in Beas-2B cells overexpressing PD-L1 were significantly restored by overexpressing HO-1. Collectively, our results suggest that DEPs can increase the expression of PD-L1 in HBE cells and that overexpressing PD-L1 might eventually promote DEPs-induced oxidative DNA damage and apoptosis.

Effectiveness of S-curve leakage testing method on flexible endoscope / 中华消化内镜杂志

To investigate the effects of the S-curve leakage testing method on the detection of flexible endoscope and occurrence of medium to high-level faults of flexible endoscope. A convenience sampling method was used to study the information of endoscopic leak detection at the digestive endoscopic centre of the First Affiliated Hospital of Air Force Medical University. From July 2016 to December 2017, 58 endoscopes which received conventional leakage testing were set as the control group (29 116 tests). From January 2018 to June 2019, 56 endoscopes which received S-curve leakage testing were set as the observation group (28 112 tests). The results showed that the detection proportion of angular abnormalities in the observation group was higher than that in the control group [65.6% (59/90) VS 40.4% (36/89), χ2=11.330, P<0.001]. However, the detection proportion of medium to high-grade faults such as damaged charge coupled device (CCD) components and broken insertion section in the observation group was lower than that in the control group [0.04% (10/28 112) VS 0.08% (23/29 116), χ2=4.680, P=0.030]. Moreover, the overall maintenance cost was lower in the observation group than that in the control group (313.7 thousand yuan VS 942.6 thousand yuan). It is indicated that the S-curve leakage testing method can detect low-level endoscopic faults early such as angular abnormalities, and reduce the occurrence of medium to high-level endoscopic faults, which contributes to cost reduction and efficiency increase.

Retrospective Study of Aging and Sex-Specific Risk Factors of COVID-19 with Hypertension in China.

Background: Coronavirus disease 2019 (COVID-19) has been a global threat that pushes healthcare to its limits. Hypertension is one of the most common risk factors for cardiovascular complications in COVID-19 and is strongly associated with disease severity and mortality. To date, clinical mechanisms by which hypertension leads to increased risk in COVID-19 are still unclear. Furthermore, additional factors might increase these risks, such as the consideration of age and sex, which are of interest when in search of personalized treatments for hypertensive COVID-19 patients. Methods: We conducted a retrospective cohort study of 543 COVID-19 patients in seven provinces of China to examine the epidemiological and clinical characteristics of COVID-19 in this population and to determine risk factors of hypertensive COVID-19 patients. We also used univariable and multivariable logistic regression methods to explore the risk factors associated with hypertensive COVID-19 patients in different age and sex subgroups. Results: Among the enrolled COVID-19 patients, the median age was 47 years (interquartile range (IQR) 34.0-57.0), and 99 patients (18.23%) were over 60 years old. With regard to comorbidities, 91 patients (16.75%) were diagnosed with hypertension, followed by diabetes, coronary disease, and cerebrovascular disease. Of the hypertensive COVID-19 patients, 51 (56.04%) were male. Multivariable analysis showed that old age, comorbid diabetes or coronary heart disease on admission, increased D-dimer, increased glucose, and decreased lymphocyte count were independent risk factors associated with hypertensive COVID-19 patients. Elevated total bilirubin (odds ratio [OR]: 1.014, 95% confidence interval [CI]: 0.23-1.05; p = 0.043) and triglycerides (OR: 1.173, 95% CI: 0.049-1.617; p = 0.007) were found to be associated with elderly hypertensive COVID-19 patients. In addition, we found that decreased lymphocytes, basophil, high-density lipoprotein, and increased fibrinogen and creatinine were related to a higher risk of disease severity in male patients. The most common abnormal clinical findings pertaining to female hypertensive COVID-19 patients were hemoglobin, total bile acid, total protein, and low-density lipoprotein. Conclusions: Factors associated with increased risk of hypertensive COVID-19 patients were identified. Results to the different age and sex subgroups in our study will allow for better possible personalized care and also provide new insights into specific risk stratification, disease management, and treatment strategies for COVID-19 patients with hypertension in the future.

Control Strategies of Plastic Biodegradation through Adjusting Additives Ratios Using In Silico Approaches Associated with Proportional Factorial Experimental Design.

Plastics, as a polymer material, have long been a source of environmental concern. This paper uses polystyrene plastics as the research object, and the relative contribution of each component of plastic additives to plastic degradation is screened using the molecular dynamics method. The factorial experimental design method is combined with molecular dynamics simulation to adjust the additive composition scheme, analyze the mechanism of interaction between the additive components, and select the plastic additive combination that is most readily absorbed and degraded by microorganisms. Seven different types of plastic additives, including plasticizers, antioxidants, light and heat stabilizers, flame retardants, lubricants, and fillers, are chosen as external stimuli affecting the biodegradability of plastics. Using molecular dynamics simulation technology, it is demonstrated that plastic additives can promote the biodegradability of plastics. The factorial experimental design analysis revealed that all plastic additives can promote plastic biodegradation and plasticizer is the most favorable factor affecting plastic degradation, that hydrophobicity interactions are the primary reason for enhancing plastic degradation, and that screening No. 116-45 (plasticizer A, light stabilizer C, flame retardant E) is the most advantageous combination of biodegradable plastic additives. The plastic biodegradation effect regulation scheme proposed in this study is based on optimizing the proportion of additive components. To continue research on aquatic biodegradable plastics, the optimal combination of plastic components that can be absorbed and degraded by microorganisms is recommended.

Celastrol suppresses the growth of vestibular schwannoma in mice by promoting the degradation of ß-catenin.

Vestibular schwannoma (VS), one of characteristic tumors of neurofibromatosis type 2 (NF2), is an intracranial tumor that arises from Schwann cells of the vestibular nerve. VS results in hearing loss, tinnitus, dizziness, and even death, but there are currently no FDA-approved drugs for treatment. In this study, we established a high-throughput screening to discover effective compounds that could inhibit the viability of VS cells. Among 1019 natural products from the Korea Chemical Bank screened, we found that celastrol, a pentacyclic triterpene derived from a Tripterygium Wilfordi plant, exerted potent inhibitory effect on the viability of VS cells with an IC50 value of 0.5 µM. Celastrol (0.5, 1 µM) dose-dependently inhibited the proliferation of primary VS cells derived from VS patients. Celastrol also inhibited the growth, and induced apoptosis of two other VS cell lines (HEI-193 and SC4). Aberrant activation of Wnt/ß-catenin signaling has been found in VS isolated from clinically defined NF2 patients. In HEI-193 and SC4 cells, we demonstrated that celastrol (0.1, 0.5 µM) dose-dependently inhibited TOPFlash reporter activity and protein expression of ß-catenin, but not mRNA level of ß-catenin. Furthermore, celastrol accelerated the degradation of ß-catenin by promoting the formation of the ß-catenin destruction complex. In nude mice bearing VS cell line SC4 allografts, administration of celastrol (1.25 mg · kg-1 · d-1, i.p. once every 3 days for 2 weeks) significantly suppressed the tumor growth without showing toxicity. Collectively, this study demonstrates that celastrol can inhibit Wnt/ß-catenin signaling by promoting the degradation of ß-catenin, consequently inhibiting the growth of VS.

PAEs Derivatives' Design for Insulation: Integrated In-Silico Methods, Functional Assessment and Environmentally Friendly Molecular Modification.

As a common substance in production and life, phthalic acid esters (PAEs), the main component of plastics, have brought more and more serious problems to the environment. This study normalized the insulation, toxicity, and bioconcentration data of 13 PAEs to eliminate the dimensional coefficients of each index, and then used the comprehensive index method to calculate the comprehensive effect value of PAEs with three properties. The comprehensive effect value was used as the data source to construct the 3D-QSAR model of PAE molecular comprehensive effect. The DAP was selected as the target molecule, the distribution of each force field in the three-dimensional equipotential map was analyzed, and 30 molecular modification schemes were created. The constructed single-effect models of insulation, toxicity, and bioconcentration of PAEs and the scoring function module of DS software were used to evaluate the stability and environmental friendliness of PAE derivative molecules. Four PAE derivatives were screened for increased comprehensive effects, enhanced insulation, and reduced toxicity and bioconcentration. By calculating the binding energy of the target molecule and the derivative molecule with the degrading enzyme under different applied electric fields, it was found that the binding energy of DAP-1-NO2-2-CH2C6H5 decreases more than DAP does when there is an applied electric field, indicating that the degradation ability of degrading enzymes on PAE derivative molecules is reduced, which indirectly proves that the insulation is enhanced. The innovation of this paper lies in the insulation, toxicity, and bioenrichment data of PAEs being processed by mathematical method for the first time, and PAEs with high insulation, low toxicity, and low bioconcentration were designed by building a comprehensive model.

Sauchinone inhibits the proliferation, migration and invasion of breast cancer cells by suppressing Akt-CREB-MMP13 signaling pathway.

Sauchinone, a lignan isolated from Saururus chinenesis, is known to exhibit anti-inflammatory and anti-oxidant effects. Recently, sauchinone has been reported to inhibit the growth of various cancer cells, but its effects on breast cancer cells remain poorly understood. In the present study, we investigated the effects of sauchinone on the growth of breast cancer cells along with the underlying molecular mechanisms. Our results show that sauchinone treatment markedly inhibited the proliferation, migration, and invasion of breast cancer cells. Sauchinone reduced the phosphorylation of Akt, ERK, and CREB increased by transforming growth factor-ß (TGF-ß). In particular, sauchinone treatment suppressed the expression of matrix metalloproteinase (MMP)-13 (MMP13) by regulating the Akt-CREB signaling pathway. Sauchinone was less effective in inhibiting cell migration in Mmp13-knockdown cells than in control cells, suggesting that MMP13 may be a novel target for sauchinone. Our study suggests that sauchinone inhibits the growth of breast cancer cells by attenuating the Akt-CREB-MMP13 pathway. In addition, the targeted inhibition of MMP13 by sauchinone represents a promising approach for the treatment of breast cancer.

Risk Factors in Patients with Diabetes Hospitalized for COVID-19: Findings from a Multicenter Retrospective Study.

METHODS: In this multicenter retrospective study, patients with COVID-19 in China were included and classified into two groups according to whether they were complicated with diabetes or not. Demographic symptoms and laboratory data were extracted from medical records. Univariable and multivariable logistic regression methods were used to explore the risk factors. RESULTS: 538 COVID-19 patients were finally included in this study, of whom 492 were nondiabetes and 46 were diabetes. The median age was 47 years (IQR 35.0-56.0). And the elderly patients with diabetes were more likely to have dry cough, and the alanine aminotransferase, lactate dehydrogenase, Ca, and mean hemoglobin recovery rate were higher than the other groups. Furthermore, we also found the liver and kidney function of male patients was worse than that of female patients, while female cases should be paid more attention to the occurrence of bleeding and electrolyte disorders. Moreover, advance age, blood glucose, gender, prothrombin time, and total cholesterol could be considered as risk factors for COVID-19 patients with diabetes through the multivariable logistic regression model in our study. CONCLUSION: The potential risk factors found in our study showed a major piece of the complex puzzle linking diabetes and COVID-19 infection. Meanwhile, focusing on gender and age factors in COVID-19 patients with or without diabetes, specific clinical characteristics, and risk factors should be paid more attention by clinicians to figure out a targeted intervention to improve clinical efficacy worldwide.

Clinical characteristics and treatment outcome of COVID-19 patients with stroke in China: A multicenter retrospective study.

OBJECTIVE: Previous studies mainly reported the clinical characteristics of novel coronavirus 2019 (COVID-19) infections, but the research on clinical characteristics and treatment outcomes of COVID-19 patients with stroke is still rare. METHODS: A multi-center retrospective study was conducted at 11 hospitals in 4 provinces of China, and COVID-19 patients with stroke were enrolled from February 24 to May 4, 2020. We analyzed epidemiological, demographic, and clinical characteristics of cases as well as the laboratory test results, treatment regimens and outcomes, and the clinical characteristics and therapeutic outcomes were compared between severe and nonsevere patients, and by age group, respectively. RESULTS: A total of 27 patients [mean age: 66.41 (SD 12.1) years] were enrolled. Among them, 9 (33.3%) were severe patients and 18 (66.7%) were nonsevere patients; 17 (63.0%) were female; 19 (70.4%) were aged 60 years and above. The most common symptoms were fever [19 (70.4%)], fatigue [12 (44.4%)] and cough [11 (40.7%)], respectively. Abnormal laboratory findings of COVID-19 patients with stroke included high levels of C-reactive protein [19 (73.1%)], D-dimer [14 (58.3%)], blood glucose [14 (53.8%)], fibrinogen [13 (50.0%)], and decreased lymphocytes [12 (44.4%)]. Comparing to nonsevere cases with stroke, severe patients with stroke were likely to be older, susceptible to receiving oxygen inhalation, and had more complications (p < 0.05). In addition, there were significant differences in lymphocytes, neutrophils, lactate dehydrogenase, C-reactive protein, creatine kinase between the severe cases and nonsevere cases (p < 0.05). The older patients had a decreased platelet count and elevated fibrinogen, compared with the younger (p < 0.05). All patients (100%) received antiviral treatment, 12 (44.4%) received antibiotics treatment, 26 (96.3%) received Traditional Chinese Medicine (Lung cleansing & detoxifying decoction), and oxygen inhalation was in 18 (66.7%). The median duration of hospitalization was 16 days. By May 4, 2020, a total of 26 (96.3%) patients were cured and discharged, and 1 (3.7%) patients died. CONCLUSION: COVID-19 patients with stroke had poor indicators of coagulation system, and severe and older patients might have a higher risk of complications and unfavorable coagulation system. However, the overall treatment outcome is favorable.

Clinical features and risk factors for severe inpatients with COVID-19: A retrospective study in China.

BACKGROUND: A worldwide outbreak of coronavirus disease (COVID-19), since 2019, has brought a disaster to people all over the world. Many researchers carried out clinical epidemiological studies on patients with COVID-19 previously, but risk factors for patients with different levels of severity are still unclear. METHODS: 562 patients with laboratory-confirmed COVID-19 from 12 hospitals in China were included in this retrospective study. Related clinical information, therapies, and imaging data were extracted from electronic medical records and compared between patients with severe and non-severe status. We explored the risk factors associated with different severity of COVID-19 patients by logistic regression methods. RESULTS: Based on the guideline we cited, 509 patients were classified as non-severe and 53 were severe. The age range of whom was 5-87 years, with a median age of 47 (IQR 35.0-57.0). And the elderly patients (older than 60 years old) in non-severe group were more likely to suffer from fever and asthma, accompanied by higher level of D-dimer, red blood cell distribution width and low-density lipoprotein. Furthermore, we found that the liver and kidney function of male patients was worse than that of female patients in both severe and non-severe groups with different age levels, while the severe females had faster ESR and lower inflammatory markers. Of major laboratory markers in non-severe cases, baseline albumin and the lymphocyte percentage were higher, while the white blood cell and the neutrophil count were lower. In addition, severe patients were more likely to be accompanied by an increase in cystatin C, mean hemoglobin level and a decrease in oxygen saturation. Besides that, advanced age and indicators such as count of white blood cell, glucose were proved to be the most common risk factors preventing COVID-19 patients from aggravating. CONCLUSION: The potential risk factors found in our study have shown great significance to prevent COVID-19 patients from aggravating and turning to critical cases during treatment. Meanwhile, focusing on gender and age factors in groups with different severity of COVID-19, and paying more attention to specific clinical symptoms and characteristics, could improve efficacy of personalized intervention to treat COVID-19 effectively.

Gremlin-1 Promotes Metastasis of Breast Cancer Cells by Activating STAT3-MMP13 Signaling Pathway.

Gremlin-1 (GREM1), one of the bone morphogenetic protein (BMP) antagonists, can directly bind to BMPs. GREM1 is involved in organogenesis, tissue differentiation, and organ fibrosis. Recently, numerous studies have reported the oncogenic role of GREM1 in cancer. However, the role of GREM1 in metastasis of breast cancer cells and its underlying mechanisms remain poorly understood. The role of GREM1 in breast cancer progression was assessed by measuring growth, migration, and invasion of breast cancer cells. An orthotopic breast cancer mouse model was used to investigate the role of GREM1 in lung metastasis of breast cancer cells. GREM1 knockdown suppressed the proliferation of breast cancer cells, while its overexpression increased their growth, migration, and invasion. Cells with Grem1-knockdown showed much lower tumor growth rates and lung metastasis than control cells. GREM1 enhanced the expression of matrix metalloproteinase 13 (MMP13). A positive correlation between GREM1 and MMP13 expression was observed in breast cancer patients. GREM1 activated signal transducer and activator of transcription 3 (STAT3) transcription factor involved in the expression of MMP13. Our study suggests that GREM1 can promote lung metastasis of breast cancer cells through the STAT3-MMP13 pathway. In addition, GREM1 might be a promising therapeutic target for breast cancer metastasis.

Gremlin-1 activates Akt/STAT3 signaling, which increases the glycolysis rate in breast cancer cells.

Gremlin-1 (GREM1), one of the antagonists of bone morphogenetic proteins (BMPs), has recently been reported to be overexpressed in a variety of cancers including breast cancer. GREM1 is involved in tumor promotion, but little is known about its role in the glycolysis of cancer cells. In this study, we investigated the role of GREM1 in glycolysis of breast cancer cells and its underlying molecular mechanisms. We first observed that glucose uptake and lactate production were increased in GREM1-overexpressing breast cancer cells. GREM1 increased the expression of hexokinase-2 (HK2), which catalyzes the phosphorylation of glucose, the first step in glycolysis. In addition, GREM1 activated STAT3 transcription factor through the ROS-Akt signaling pathway. The ROS-Akt-STAT3 axis activated by GREM1 was involved in promoting glucose uptake by increasing the expression of HK2 in breast cancer cells. Therefore, our study suggested a new mechanism by which GREM1 is involved in breast cancer promotion by increasing glycolysis in breast cancer cells.

Theoretical Design of Biodegradable Phthalic Acid Ester Derivatives in Marine and Freshwater Environments.

The biodegradability of phtalic acid esters in marine and freshwater environments was characterized by their binding free energy with corresponding degrading enzymes. According to comprehensive biodegradation effects weights, the binding free energy values were converted into dimensionless efficacy coefficient using ratio normalization method. Then, considering comprehensive dual biodegradation effects value and the structural parameters of PAEs in both marine and freshwater environments, a 3D-QSAR pharmacophore model was constructed, five PAE derivatives (DBP-COOH, DBP-CHO, DBP-OH, DINP-NH2, and DINP-NO2) were screened out based on their environmental friendliness, functionality and stability. The prediction of biodegradation effects on five PAE derivatives by biodegradation models in marine and freshwater environment increased by 15.90 %, 15.84 %, 27.21 %, 12.33 %, and 8.32 %, and 21.57 %, 15.21 %, 20.99 %, 15.10 %, and 9.74 %, respectively. By simulating the photodegradation path of the PAE derivative molecular, it was found that DBP-OH can generate .OH and provides free radicals for the photodegradation of microplastics in the environment.

A Modified 3D-QSAR Model Based on Ideal Point Method and Its Application in the Molecular Modification of Plasticizers with Flame Retardancy and Eco-Friendliness.

The addition of plasticizers makes plastics flammable, and thus, poses a potential risk to the environment. In previous researches, plasticizers with flame retardancy had been synthesized, but their eco-friendliness had not been tested or described. Thus, in this paper, eco-friendliness plasticizers with flame retardancy were designed based on phthalic acid esters (PAEs), which are known as common plasticizers and major plastic additives. For a comprehensive analysis, such as flammability, biotoxicity, and enrichment effects, 17 PAEs' comprehensive evaluation values were calculated based on the ideal point method. Further, a multi-effect three-dimensional quantitative structure-activity relationship (3D-QSAR) model of PAEs' flammability, biotoxicity and enrichment effects was constructed. Thus, 18 dimethyl phthalate (DMP) derivatives and 20 diallyl phthalate (DAP) derivatives were designed based on three-dimensional contour maps. Through evaluation of eco-friendliness and flammability, six eco-friendly PAE derivatives with flame retardancy were screened out. Based on contour maps analysis, it was confirmed that the introduction of large groups and hydrophobic groups was beneficial to the simultaneous improvement of PAEs' comprehensive effects, and multiple effects. In addition, the group properties were correlated significantly with improved degrees of the comprehensive effects of corresponding PAE derivatives, confirming the feasibility of the comprehensive evaluation method and modified scheme.

Enhanced Biodegradation of Phthalic Acid Esters' Derivatives by Plasticizer-Degrading Bacteria (Burkholderia cepacia, Archaeoglobus fulgidus, Pseudomonas aeruginosa) Using a Correction 3D-QSAR Model.

A phthalic acid ester's (PAEs) comprehensive biodegradability three-dimensional structure-activity relationship (3D-QSAR) model was established, to design environmentally friendly PAE derivatives, which could be simultaneously degraded by plasticizer-degrading bacteria, such as Burkholderia cepacia, Archaeoglobus fulgidus, and Pseudomonas aeruginosa. Only three derivatives of diethyl phthalate (DEP (DEP-27, DEP-28 and DEP-29)) were suited for their functionality and environmental friendliness, which had an improved stability in the environment and improved the characteristics (bio-toxicity, bioaccumulation, persistence, and long-range migration) of the persistent organic pollutants (POPs). The simulation inference of the microbial degradation path before and after DEP modification and the calculation of the reaction energy barrier exhibited the energy barrier for degradation being reduced after DEP modification and was consistent with the increased ratio of comprehensive biodegradability. This confirmed the effectiveness of the comparative molecular similarity index analysis (CoMSIA) model of the PAE's comprehensive biodegradability. In addition, a molecular dynamics simulation revealed that the binding of the DEP-29 derivative with the three plasticizer-degradation enzymes increased significantly. DEP-29 could be used as a methyl phthalate derivative that synergistically degrades with microplastics, providing directional selection and theoretical designing for plasticizer replacement.

DHA inhibits Gremlin-1-induced epithelial-to-mesenchymal transition via ERK suppression in human breast cancer cells.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid abundant in fish oils. It is known to have an inhibitory effect on various diseases such as inflammation, diabetes, and cancer. Epithelial-to-mesenchymal transition (EMT) is a process that epithelial cells gain migratory property to become mesenchymal cells involved in wound healing, organ fibrosis, and cancer progression. Gremlin-1 (GREM1) is a bone morphogenetic protein antagonist known to play a role in EMT. However, the role of GREM1 in the induction of EMT in human breast cancer cells and the effect of DHA on GREM1-induced EMT remain unclear. Establishment of GREM1 knockdown cell lines was performed using lentiviral shRNAs. Expression of EMT markers was determined by qRT-PCR and Western blotting. Effect of GREM1 and/or DHA on cell migration was investigated using wound healing assay. The level of GREM1 expression in human breast cancer tissues was determined by Oncomine database mining. GREM1 induced the expression of genes including N-cadherin, vimentin, and Slug. GREM1 promoted the migration of human breast cancer cells. GREM1 enhanced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and the ERK activation was involved in EMT. Interestingly, DHA reduced the expression of GREM1. DHA also inhibited the expression of mesenchymal cell-associated genes and cell migration induced by GREM1. Furthermore, DHA suppressed the expression of p-ERK induced by GREM1. These results indicate that GREM1-ERK axis plays a role in EMT in human breast cancer cells and DHA is a putative compound that can inhibit EMT by inhibiting GREM1 signal transduction.