Targeted blocking of EGFR and GLUT1 by compound H reveals a new strategy for treatment of triple-negative breast cancer and nasopharyngeal carcinoma.

BACKGROUND: Cytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR. METHODS: Compound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism. RESULTS: Compound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo. CONCLUSIONS: Synergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.

Actinomycosis presenting as a nasopharyngeal mass: A case report.

Actinomycetes are predominantly pathogenic bacteria that lack aerial hyphae and do not form spores. They are generally anaerobic or facultative anaerobic Gram-positive bacteria, belonging to the prokaryotic group. Actinomycetes are widely distributed in nature, similar to other bacteria, and are mostly saprophytic, with a few being parasitic. They are named as such due to their colony's radial form. The symptoms and signs of actinomycosis are atypical and rarely manifest in the nasopharynx. Consequently, it can be challenging to distinguish actinomycosis from nasopharyngeal carcinoma, making diagnosis difficult. Histopathology is usually relied upon for diagnosis, although culture may pose challenges. Fortunately, actinomycetes are highly sensitive to penicillin. Therefore, timely treatment with high doses of penicillin is crucial for successful recovery. In this case study, we present the details of a 53-year-old female patient with no history of mucosal damage or tooth decay but with a previous partial thyroidectomy. The patient experienced recurring neck pain accompanied by progressive limitation of neck movement. Nasopharyngoscopy revealed the presence of a smooth-surfaced mass. Subsequent biopsy, clinical imaging, microbiological analysis, and histological findings confirmed the diagnosis of actinomycosis.Following a comprehensive treatment plan involving a combination of penicillin and doxycycline for a duration of two months, the disease was successfully eradicated.

How aromatic dissolved organic matter differs in competitiveness against organic micropollutant adsorption.

Activated carbon is employed for the adsorption of organic micropollutants (OMPs) from water, typically present in concentrations ranging from ng L-1 to µg L-1. However, the efficacy of OMP removal is considerably deteriorated due to competitive adsorption from background dissolved organic matter (DOM), present at substantially higher concentrations in mg L-1. Interpreting the characteristics of competitive DOM is crucial in predicting OMP adsorption efficiencies across diverse natural waters. Molecular weight (MW), aromaticity, and polarity influence DOM competitiveness. Although the aromaticity-related metrics, such as UV254, of low MW DOM were proposed to correlate with DOM competitiveness, the method suffers from limitations in understanding the interplay of polarity and aromaticity in determining DOM competitiveness. Here, we elucidate the intricate influence of aromaticity and polarity in low MW DOM competition, spanning from a fraction level to a compound level, by employing direct sample injection liquid chromatography coupled with ultrahigh-resolution Fourier-transform ion cyclotron resonance mass spectrometry. Anion exchange resin pre-treatment eliminated 93% of UV254-active DOM, predominantly aromatic and polar DOM, and only minimally alleviated DOM competition. Molecular characterization revealed that nonpolar molecular formulas (constituting 26% PAC-adsorbable DOM) with medium aromaticity contributed more to the DOM competitiveness. Isomer-level analysis indicated that the competitiveness of highly aromatic LMW DOM compounds was strongly counterbalanced by increased polarity. Strong aromaticity-derived π-π interaction cannot facilitate the competitive adsorption of hydrophilic DOM compounds. Our results underscore the constraints of depending solely on aromaticity-based approaches as the exclusive interpretive measure for DOM competitiveness. In a broader context, this study demonstrates an effect-oriented DOM analysis, elucidating counterbalancing interactions of DOM molecular properties from fraction to compound level.

Ubiquitous occurrence of 1,4-dioxane in drinking water of China and its ecological and human health risk.

The occurrence and distribution of 1,4-dioxane was investigated in 280 source and finished drinking water samples from 31 Chinese cities, based on which its ecological and health risks were systematically evaluated. The findings demonstrated that 1,4-dioxane was detected in about 80.0 % samples with values ranging from n.d. to 7757 ng/L in source water and n.d. to 2918 ng/L in drinking water. 1,4-Dioxane showed limited removal efficiency using conventional coagulation-sedimentation-filtration processes (14 % ± 48 %), and a removal efficiency of 35 % ± 44 % using ozonation-biological activated carbon advanced treatment processes. Relatively higher concentrations, detection frequency and environmental risk were observed in Taihu Lake, Yellow River, Yangtze River, Zhujiang River, and Huaihe River mainly in the eastern and southern regions, where there are considerable industrial activities and comparatively high population densities. The widespread presence as by-products during manufacturing consumer products e.g., ethoxylated surfactants, suggested municipal wastewater discharges were the dominant source for the ubiquitous occurrence of 1,4-dioxane, while industrial activities, e.g. resin manufacturing, also contribute considerably to the elevated concentrations of 1,4-dioxane. The estimated risk quotients were in the range of <1.5 × 10-4 for ecological risk, <5.0 × 10-3 by oral exposure and < 5.0 × 10-2 by inhalation exposure for health risk, illustrating limited ecological harm to water environment or chronic toxicity to human health. For carcinogenic risk, 1,4-Dioxane presented a mean risk of 1.8 × 10-6 by oral exposure, which slightly surpassed the recommended acceptable levels of U.S. EPA (<10-6), and risk from inhalation exposure could be negligible. The pervasiveness in drinking water, low removal efficiencies during water treatment processes, and suspected health impacts, highlighted the necessity to set related water quality standards of 1,4-dioxane in order to improve water environment in China.

Identification of odor-causing compounds in six species of odor-producing microalgae separated from drinking water source with distinct fishy odor: Insight into microalgae growth and odor characteristics.

Fishy odor, as an offensive and unpleasant odor, could occur in drinking water source with poor nutrition, it is usually considered to be associated with odor-producing microalgae. However, the specific relations among fishy odor, fishy odorants and responsible microalgae were not elucidated comprehensively. In this paper, the odor-causing compounds generated from six microalgae with fishy odor characteristic, isolated in drinking water source Tongyu River, were identified simultaneously. The sensory evaluation result indicated that Tongyu River was principally related to fishy odor (odor intensity 6.5-7.6). Correspondingly, seven, nine, seven, six, seven and seven olfactory detection peaks (ODP) were screened by combining data of GC/O/MS and GC/GC/TOFMS in Cyclotella, Cryptomonas ovate, Melosira, Dinobryon sp., Synedra and Ochromonas sp., which were isolated in Tongyu River and cultured in laboratory. Totally twenty odor-causing compounds, including hexanal, 2-hexenal, 3-hexen-1-ol, heptanal, 1-octen-3-one, 2,4-heptadienal, 2-tetradecanone, 3,5-octadien-2-one, octanal, 1-octen-3-ol, 2-octenal, nonanal, 2,4-octadienal, 2-nonenal, decanal, 2,6-nonadienal, 2-decenal, undecanal, 2,4-decadienal and dodecanal, were screened and identified in all isolated microalgae. Additionally, fishy odor intensity for all identified microalgae increased obviously as microalgae cell number increased and microalgae cell ruptured in cultivation cycles through pearson and spearman correlation analysis. For the first time, twenty odor-causing compounds associating with fishy odor were recognized from six isolated microalgae, which would provide more scientific basis and theoretical support for preventing and treating fishy odor episode of drinking water source.

Visible-light-induced halocyclization of 2-alkynylthioanisoles with simple alkyl halides towards 3-halobenzo[b]thiophenes without an external photocatalyst.

A new strategy for the preparation of 3-halobenzo[b]thiophenes via a photo-driven halocyclization/demethylation of 2-alkynylthioanisoles with simple alkyl halides was developed. The reaction can proceed smoothly at room temperature under visible-light irradiation without any external photocatalyst, and the protocol has a range of advantages, including simplicity and mildness of the reaction conditions, good functional-group tolerance, and excellent yields of the products.

Characteristics and potential human health risks of microplastics identified in typical clams from South Yellow Sea Mudflat.

The ingestion of clams (Meretrix) with microplastics (MP) contamination could pose potential risk to human health. The characteristics and potential risks of MP identified in wild-clam and farm-clam from South Yellow Sea Mudflat were studied comprehensively in this paper. The results indicated that MP were identified in both wild-clam (3.4-21.3 items/individual, 2.11-10.65 items/g) and farm-clam (1.3-20.8 items/individual, 0.62-8.67 items/g) among 21 sampling sites along South Yellow Sea Mudflat. The MP abundance of clams from marine estuarine or coast ports were significantly higher than those from purely marine coast mudflat, implying that environmental habitats played an important role on MP characteristics. MP abundance were significantly and positively related to shell length, shell height, shell width and soft tissue wet weight by Pearson test, suggesting the bigger the shell, there existed more MP abundance. Among MP in wild-clams and farm-clams, fragment, fiber were most abundant MP shapes, most MP's sizes were lower than 0.25 mm, the predominant colors were black, red, blue and transparent, chlorinated polyethylene (CPE) was the major polymer. Additionally, estimated dietary intake (EDI) of MP for adults via consumption of wild-clam and farm-clam were 1123.33 ± 399.97 and 795.07 ± 326.72 items/kg/year, respectively, suggesting EDI values of wild-clams were higher than those of farm-clams, and MP intake via wild-clam consumption were more than that via farm-clam consumption. The polymer risk indexes (PRI) of MP in total tissue and digestive system for wild-clam were 1297.8 ± 92.15 (hazard level: IV ~ V), 1038 ± 69.55 (IV ~ V), respectively, while PRI of MP in total tissue and digestive system for farm-clam were 979.92 ± 75.45 (III ~ IV), 735 ± 47.78 (III ~ IV), respectively, implying that PRI and hazard level of MP from wild-clam were higher than those from farm-clam, and the potential risks would decrease greatly when digestive systems of clams are removed during ingestion.

Unraveling the source-water fishy odor occurrence during low-temperature periods: Odorants identification, typical algae species and odor-producing potential.

In this study, odor characteristics and phytoplankton composition were systematically investigated in two winter periods in a reservoir with fishy odor in north China. Ten potential fishy odor-producing algae were isolated and odorant-producing potentials were evaluated. Olfactometry profile and odorant composition of water samples were analyzed using GC-Olfactometry combined with GC × GC-TOFMS. The results showed that 2,4-heptadienal and hexanal were major fishy odor contributors. The abundance of Uroglena sp., Synura sp. and Peridinium sp. was negatively correlated with total dissolved organic carbon, ammonia nitrogen, and nitrate, illustrating nutrient level might be major drivers for the succession of fishy odor-producing algae. Dinobryon sp. and Uroglena sp. made the greatest contribution to fishy odor, followed by Peridinium sp., Synura sp., and Ochromonas sp. Fishy odor in 2016 winter and the early of 2017 winter was mainly caused by Dinobryon sp., while Uroglena sp. contributes mostly in March in 2017 winter. This study demonstrates the main odorants and algae causing fishy odor in reservoir, which will provide a scientific basis for the management of seasonal fishy odor problems in water source.

Solvent-like bis (2-chloro-1-methylethyl) ether occurrence in drinking water: Multidimensional risk assessment integrated health and aesthetic aspects.

Bis (2-chloro-1-methylethyl) ether (DCIP), one U.S. Environmental Protection Agency priority pollutant, could pose health and/or odor risk in water environment. In this study, odor characteristics, occurrence and source of DCIP in drinking waters of China were investigated based on sensory analysis and a nation-wide investigation covering 140 drinking water treatment plants. Then multi-risk integrated health and aesthetic aspects through oral and inhalation (showering) exposure by drinking water were first estimated. Sensory evaluation showed DCIP exhibited "solvent-like" odor with thresholds of 34.8 ng/L in air and 142.0 ng/L in water. DCIP was detected at comparable concentrations in raw and finished waters (<1280 ng/L) and was by-product from industrial production of epichlorohydrin/propylene oxide. Lifetime Average Daily Dose through oral exposure was 0-36.65 ng/day/kg, corresponding to odor activity values of 0-8.4 and hazard quotients of far < 1, indicating drinking tap water might cause odor issues rather than significant health hazard. The proportion of sensitive population to DCIP's odor was 6.1%. In contrast, residents rarely detect DCIP's odor by inhalation. The presence in drinking water as industrial by-product, poor removal using conventional water treatment and potential to be T&O issues, indicates urgent demand for pollutant source control to protect DCIP from entering source waters.

Identification and evaluation of fishy odorants produced by four algae separated from drinking water source during low temperature period: Insight into odor characteristics and odor contribution of fishy odor-producing algae.

Disgusting fishy odor could break out inside oligotrophic drinking waterbody in winter with low temperature. Nevertheless, fishy odor-producing algae and corresponding fishy odorants were not very clear, odor contribution of fishy odorant and odor-producing algae to overall odor profile were also not well understood. In this study, the fishy odorants, produced by four algae separated from Yanlong Lake, were identified simultaneously. Odor contribution of identified odorant, separated algae to overall fishy odor profile were both evaluated. The results indicated Yanlong Lake was mainly associated with fishy odor (flavor profile analysis (FPA) intensity: 6), eight, five, five and six fishy odorants were identified and determined in Cryptomonas ovate, Dinobryon sp., Synura uvella, Ochromonas sp., respectively, which were separated and cultured from water source. Totally sixteen odorants with concentration range of 90-880 ng/L, including hexanal, heptanal, 2,4-heptadienal, 1-octen-3-one, 1-octen-3-ol, octanal, 2-octenal, 2,4-octadienal, nonanal, 2-nonenal, 2,6-nonadienal, decanal, 2-decenal, 2,4-decadienal, undecanal, 2-tetradecanone, were verified in separated algae and associated with fishy odor. Although more odorants' odor activity value (OAV) were lower than one, approximately 89%, 91%, 87%, 90% of fishy odor intensities could be explained by reconstituting identified odorants for Cryptomonas ovate, Dinobryon sp., Synura uvella, Ochromonas sp., respectively, suggesting synergistic effect could exist among identified odorants. By calculating and evaluating total odorant production, total odorant OAV and cell odorant yield of separated algae, odor contribution rank to overall fishy odor should be Cryptomonas ovate (28.19%), Dinobryon sp. (27.05%), Synura uvella (24.27%), Ochromonas sp. (20.49%). This is the first study for identifying fishy odorants from four actually separated odor-producing algae simultaneously, this is also for the first time evaluating and explaining odor contribution of identified odorant, separated algae to overall odor profile comprehensively, this study will supply more understanding for controlling and managing fishy odor in drinking water treatment plant.

Shenlian extract decreases mitochondrial autophagy to regulate mitochondrial function in microvascular to alleviate coronary artery no-reflow.

Shenlian (SL) extract has been proven to be effective in the prevention and treatment of atherosclerosis and myocardial ischemia. However, the function and molecular mechanisms of SL on coronary artery no-reflow have not been fully elucidated. This study was designed to investigate the contribution of SL extract in repressing excessive mitochondrial autophagy to protect the mitochondrial function and prevent coronary artery no-reflow. The improvement of SL on coronary artery no-reflow was observed in vivo experiments and the molecular mechanisms were further explored through vitro experiments. First, a coronary artery no-reflow rat model was built by ligating the left anterior descending coronary artery for 2 hr of ischemia, followed by 24 hr of reperfusion. Thioflavin S (6%, 1 ml/kg) was injected into the inferior vena cava to mark the no-reflow area. Transmission electron microscopy was performed to observe the cellular structure, mitochondrial structure, and mitochondrial autophagy of the endothelial cells. Immunofluorescence was used to observe the microvascular barrier function and microvascular inflammation. Cardiac microvascular endothelial cells (CMECs) were isolated from rats. The CMECs were deprived of oxygen-glucose deprivation (OGD) for 2 hr and reoxygenated for 4 hr to mimic the Myocardial ischemia-reperfusion (MI/R) injury-induced coronary artery no-reflow in vitro. Mitochondrial membrane potential was assessed using JC-1 dye. Intracellular adenosine triphosphate (ATP) levels were determined using an ATP assay kit. The cell total reactive oxygen species (ROS) levels and cell apoptosis rate were analyzed by flow cytometry. Colocalization of mitochondria and lysosomes indirectly indicated mitophagy. The representative ultrastructural morphologies of the autophagosomes and autolysosomes were also observed under transmission electron microscopy. The mitochondrial autophagy-related proteins (LC3II/I, P62, PINK, and Parkin) were analyzed using Western blot analysis. In vivo, results showed that, compared with the model group, SL could reduce the no-reflow area from 37.04 ± 9.67% to 18.31 ± 4.01% (1.08 g·kg-1 SL), 13.79 ± 4.77% (2.16 g·kg-1 SL), and 12.67 ± 2.47% (4.32 g·kg-1 SL). The extract also significantly increased the left ventricular ejection fraction (EF) and left ventricular fractional shortening (FS) (p < 0.05 or p < 0.01). The fluorescence intensities of VE-cadherin, which is a junctional protein that preserves the microvascular barrier function, decreased to ~74.05% of the baseline levels in the no-reflow rats and increased to 89.87%(1.08 g·kg-1 SL), 82.23% (2.16 g·kg-1 SL), and 89.69% (4.32 g·kg-1 SL) of the baseline levels by SL treatment. SL administration repressed the neutrophil migration into the myocardium. The oxygen-glucose deprivation/reoxygenation (OGD/R) model was induced in vitro to mimic microvascular ischemia-reperfusion injury. The impaired mitochondrial function after OGD/R injury led to decreased ATP production, calcium overload, the excessive opening of the Mitochondrial Permeability Transition Pore, decreased mitochondrial membrane potential, and reduced ROS scavenging ability (p < 0.05 or p < 0.01). The normal autophagosomes (double-membrane vacuoles with autophagic content) in the sham group were rarely found. The large morphology and autophagosomes were frequently observed in the model group. By contrast, SL inhibited the excessive activation of mitochondrial autophagy. The mitochondrial autophagy regulated by the PINK/Parkin pathway was excessively activated. However, administration of SL prevented the activation of the PINK/Parkin pathway and inhibited excessive mitochondrial autophagy to regulate mitochondrial dysfunction. Results also demonstrated that mitochondrial dysfunction stimulated endothelial cell barrier dysfunction, but Evans blue transmission was significantly decreased and transmembrane resistance was increased significantly by SL treatment (p < 0.05 or p < 0.01). Carbonylcyanide-3-chlorophenylhydrazone (CCCP) could activate the PINK/Parkin pathway. CCCP reversed the regulation of SL on mitochondrial autophagy and mitochondrial function. SL could alleviate coronary artery no-reflow by protecting the microvasculature by regulating mitochondrial function. The underlying mechanism was related to decreased mitochondrial autophagy by the PINK/Parkin pathway.

Novel anthraquinone derivatives trigger endoplasmic reticulum stress response and induce apoptosis.

Background: Endoplasmic reticulum (ER) stress is a therapeutic target in cancer given its regulation of bioenergetics and cell death. Methodology & results: We synthesized 14 ER stress-triggered anthraquinone derivatives by introducing an amino group at the 3-position side chain of the lead compound obtained previously. Most of the anthraquinone derivatives exhibited good antitumor activity due to their ability to induce ER damage through cytoplasmic vacuoles. The mechanisms of ER stress caused by compound KA-4c were related to increasing the expression levels of the ATF6 and Bip proteins and upregulating CHOP and cleaved PARP. Conclusion: Compound KA-4c triggers ER stress response and induces apoptosis via the ATF6-CHOP signaling pathway.

Enhancement of thioethers removal by pre-oxidation-coagulation: Effects of background organic matter.

Swampy/septic odor caused by thioethers has become the main taste and odor (T&O) problem in drinking water of China. Improving its removal performance by commonly traditional water treatment process is significant. In our study, we have found that pre-oxidation could modify the background dissolved organic matter (DOM) properties and thus improve the coagulation performance of thioethers, increasing the coagulation removal rates by 1.5-3 times. Particularly, after pre-ozonation only protein-like substances remained, and thioethers removal was 1.5 times higher than that after pre-chlorination (only coagulation not including oxidation). Compared with humic acid (HA), the thioethers compounds removal efficiencies under bovine serum albumin (BSA) as background DOM was increased by 0.3-3 times. Through Freundlich model analysis, the binding strength of BSA (KF = 20.712, at 298 K) to dimethyl disulfide (DMDS) was enhanced by 60 % compared to HA (KF = 12.778, at 298 K). According to thermodynamic parameters, the binding effect between HA/BSA and thioethers compounds was mainly van der Waals forces and hydrogen bond. BSA with more amino structure and oxygen groups was more easily to adsorb DMDS through hydrogen bond and thus achieved better coagulation performance. Therefore, pre-ozonation combined with coagulation was suggested to be more suitable for thioethers compounds control.

Plasma and vitreous selenium concentrations in patients with type 2 diabetes and diabetic retinopathy.

BACKGROUND: This work aimed to determine and compare plasma and vitreous selenium (Se) concentrations in patients with type 2 diabetes and diabetic retinopathy (DR). METHODS: A total of 60 type-2-diabetes patients including 20 without DR, 20 with non-proliferative DR (NPDR), and 20 with proliferative diabetic retinopathy (PDR), were involved in this study. Blood plasma samples were collected from above 60 patients and 20 normal controls (without diabetes). Twenty control vitreous samples were obtained from the eyes presenting a macular hole and epimacular membrane. Vitreous samples were also collected from PDR patients receiving one-week intravitreal anti-VEGF therapy or not. Plasma and vitreous Se concentrations were determined by inductively coupled plasma mass spectrometry. RESULTS: Plasma Se concentrations in PDR patients (163.74 ±â€…32.68 µg/L) were significantly higher than those in normal control patients (121.59 ±â€…28.33 µg/L), NPDR patients (130.34 ±â€…29.11 µg/L), and the patients without DR (81.23 ±â€…20.59 µg/L) (all P < .001). Similarly, Se concentrations in vitreous samples of PDR patients (56.30 ±â€…12.03 µg/L) were consistently higher than those in control vitreous samples (26.26 ±â€…6.53 µg/L). In addition, vitreous Se concentrations in PDR patients decreased to 47.76 ±â€…9.72 µg/L after intravitreal injection of the anti-VEGF drug ranibizumab for one week, which was significantly lower than those before injection (P = .02). Plasma VEGF levels of diabetic patients were lower than those of the normal controls (P < .001). On the contrary, the vitreous VEGF level in the PDR group (913.61 ±â€…193.32 pg/mL) was significantly higher than that of the normal control group (101.23 ±â€…21.33 pg/mL) (P < .001). CONCLUSION: The elevation of Se concentrations may be an important risk factor in plasma and vitreous with diabetic retinopathy among type-2-diabetes patients. The elevated VEGF may be also closely related to the intraocular Se concentration in PDR patients.

LTBP2 Knockdown Promotes Ferroptosis in Gastric Cancer Cells through p62-Keap1-Nrf2 Pathway.

Gastric cancer (GC) is one of the most common gastrointestinal malignancies. Ferroptosis is a new type of peroxidation-driven and iron-dependent cell death. However, the biological functions and exact regulatory mechanisms of ferroptosis in GC remain elusive. Here, we performed RNAi and gene transfection, cell viability assay, lipid peroxidation assay, reactive oxygen species (ROS) assay, glutathione assay, qRT-PCR, Western blotting, and transmission electron microscopy (TEM) to study ferroptosis in gastric cancer. The results revealed that silencing latent transforming growth factor ß binding proteins (LTBP2) can significantly inhibit GC cell proliferation and decrease cellular GSH levels, reduce GPX4 activity, and increase ROS generation and malondialdehyde (MDA) levels, leading to ferroptosis in GC cells. In addition, we demonstrate that suppression of LTBP2 could regulate the p62-Keap1-Nrf2 pathway, thereby downregulating the GPX4 and xCT expression and upregulating the PTGS2 and 4HNE expression. Our findings described a new role of LTBP2 in regulating ferroptosis, which heralds the prospect of ferroptosis-mediated cancer therapy.

Frailty is an independent determinant of COVID-19 vaccine hesitancy in the elderly: a cross-sectional study.

COVID-19 vaccines have become an important hope for slowing down or stopping the pandemic. As the population ages, older adults will comprise a greater proportion of the vaccinated population. We aimed to assess influencing factors of COVID-19 vaccine hesitancy in older adults. For this aim, We conducted a cross-sectional study on a questionnaire survey of the elderly over 65 years living in the community of Haikou City from August 1st to September 30th, 2021. Univariate and multivariate Logistic regression analyses were performed to identify factors related to vaccine hesitancy. We analyzed completed questionnaires from 225 respondents (42.2% women, mean age 73.4±6.2 years). There were 99 people in the vaccine hesitation group and 126 people in the vaccine acceptance group, the incidence of vaccine hesitation in the elderly population is about44%（99/225）. The incidence of frailty in the vaccine hesitation group was much higher than that in the vaccine trust group (62.63 vs. 30.95%, P＜0.001). The risk factors of vaccine hesitancy in the elderly aged 70-75years and over 75 years were 2.987 times and 3.587 times higher than that in the population aged 65-70 years (OR=2.987,95%CI: 1.424-6.265, P＜0.001; OR=3.587,95% CI:1.804-7.131, P＜0.001). Frailty is also an independent risk factor of vaccine hesitancy in the elderly population (OR=2.624,95%CI: 1.447-4.757, P＜0.001). Then the vaccination rate of the COVID-19 vaccine is far from reaching the requirements of herd immunity, and more flexible and comprehensive efforts are needed to increase the vaccination willingness of the frail elderly.

Novel Insights into the Cardioprotective Effects of Calcitriol in Myocardial Infarction.

BACKGROUND: Increasing evidence indicates that vitamin D deficiency negatively affects the cardiovascular system. Here we studied the therapeutic effects of calcitriol in myocardial infarction (MI) and investigated its underlying mechanisms. METHODS: A MI model of Kun-ming mice induced by left anterior descending coronary artery ligation was utilized to study the potential therapeutic effects of calcitriol on MI. AC16 human cardiomyocyte-like cells treated with TNF-α were used for exploring the mechanisms that underlie the cardioprotective effects of calcitriol. RESULTS: We observed that calcitriol reversed adverse cardiovascular function and cardiac remodeling in post-MI mice. Mechanistically, calcitriol suppressed MI-induced cardiac inflammation, ameliorated cardiomyocyte death, and promoted cardiomyocyte proliferation. Specifically, calcitriol exerted these cellular effects by upregulating Vitamin D receptor (VDR). Increased VDR directly interacted with p65 and retained p65 in cytoplasm, thereby dampening NF-κB signaling and suppressing inflammation. Moreover, up-regulated VDR was translocated into nuclei where it directly bound to IL-10 gene promoters to activate IL-10 gene transcription, further inhibiting inflammation. CONCLUSION: We provide new insights into the cellular and molecular mechanisms underlying the cardioprotective effects of calcitriol, and we present comprehensive evidence to support the preventive and therapeutic effects of calcitriol on MI.

Co-occurrence of odor-causing dioxanes and dioxolanes with bis(2-chloro-1-methylethyl) ether in Huangpu River source water and fates in O3-BAC process.

In recent years, dioxanes and dioxolanes have been intermittently detected in water environment and have caused several offensive drinking water odor incidents worldwide. In this study, the co-occurrence of eight dioxanes, twelve dioxolanes and bis(2-chloro-1-methylethyl) ether was investigated in Huangpu River watershed to explore potential sources and contributions to septic/chemical odor. Totally 8 dioxanes and dioxolanes were detected in river, with 1,4-dioxane (212 -8310 ng/L) and 2,5,5-trimethyl-1,3-dioxane (n.d.-133 ng/L) as the dominated dioxanes, 2-methyl-1,3-dioxolane (49.5 -2278 ng/L), 2-ethy-4-methyl-1,3-dioxolane (n.d.-167 ng/L) and 1,3-dioxolane (n.d.-225 ng/L) as the major dioxolanes. Bis(2-chloro-1-methylethyl) ether was detected (n.d.-1094 ng/L) with significant correlation with dioxanes and dioxolanes, illustrating their similar polyester resin-related industrial origins. 2-Ethy-4-methyl-1,3-dioxolane, 2,5,5-trimethyl-1,3-dioxane and bis(2-chloro-1-methylethyl) ether with individual maximum odor activity value above 1, should contribute to septic/chemical odor in Huangpu River water. The increased concentrations of these chemicals in the downstream of some industrial areas illustrated the association with industrial discharge. Fates in a waterworks using the river water as source water were further explored. The adopting ozone-biological activated carbon treatment could permit a relatively high removal for bis(2-chloro-1-methylethyl) ether and 2,5,5-trimethyl-1,3-dioxane (> 80%), while limited removal for other chemicals. This study provides valuable information for the management of drinking source water and water environment.

Network pharmacology analysis and experimental validation to explore the mechanism of Shenlian extract on myocardial ischemia.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlian extract (SL), extracted from Salvia miltiorrhiza Bunge and Andrographis paniculata (Burm. f.) Nees, has been proved to be effective in the prevention and treatment of atherosclerosis. Recently, we have partially elucidated the mechanisms involved in the therapeutic effects of SL on myocardial ischemia (MI). However, the underlying mechanisms remain largely unclear. AIM OF THE STUDY: This study aims to explore the potential molecular mechanism of SL on MI on the basis of network pharmacology. MATERIALS AND METHODS: First, the main active ingredients of SL were screened in the Traditional Chinese Medicine Integrated Database, and the MI-associated targets were collected from the DisGeNET database. Then, we used compound-target and target-pathway networks to uncover the therapeutic mechanisms of SL. On the basis of network pharmacology analysis results, we assessed the effects of SL in MI rat model and oxygen glucose deprivation model of H9c2 cells and validated the possible molecular mechanisms of SL on myocardial injury in vivo and in vitro. RESULTS: The network pharmacology results showed that 37 potential targets were recognized, including TNF-α, Bcl-2, STAT3, PI3K and MMP2. These results revealed that the possible targets of SL were involved in the regulation of inflammation and apoptosis signaling pathway. Then, in vivo experiments indicated that SL significantly reduced the myocardial infarction size of MI rats. Serum CK-MB, cTnT, CK, LDH, and AST levels were significantly decreased by SL (P < 0.05 or P < 0.01). In vitro, SL significantly increased H9c2 cell viability. The levels of inflammation factors including TNF-α and MMP2 were significantly decreased by SL (P < 0.05 or P < 0.01). TUNEL and Annexin V/propidium iodide assays indicated that SL could significantly decrease the cell apoptotic rate in vivo and in vitro (P < 0.05 or P < 0.01). The remarkable upregulation of anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax protein level further confirmed this result. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the PI3K-AKT and JAK2-STAT3 pathways were significantly enriched in SL. Compared with the model group, SL treatment significantly activated the PI3K-AKT and JAK2-STAT3 pathways in vivo and in vitro according to Western blot analyses. CONCLUSION: SL could protect the myocardium from MI injury. The underlying mechanism may be related to the reduction of inflammation and apoptosis by activating the PI3K/AKT and JAK2/STAT3 pathways.

Data Analytics Determines Co-occurrence of Odorants in Raw Water and Evaluates Drinking Water Treatment Removal Strategies.

A complex dataset with 140 sampling events was generated using triple quadrupole gas chromatography-mass spectrometer to track the occurrence of 95 odorants in raw and finished water from 98 drinking water treatment plants in 31 cities across China. Data analysis identified more than 70 odorants with concentrations ranging from not detected to thousands of ng/L. In raw water, Pearson correlation analysis determined that thioethers, non-oxygen benzene-containing compounds, and pyrazines were classes of chemicals that co-occurred, and geosmin and p(m)-cresol, as well as cyclohexanone and benzaldehyde, also co-occurred, indicating similar natural or industrial sources. Based on classification and regression tree analysis, total dissolved organic carbon and geographical location were identified as major factors affecting the occurrence of thioethers. Indoles, phenols, and thioethers were well-removed through conventional and advanced treatment processes, while some aldehydes could be generated. For other odorants, higher removal was achieved by ozonation-biological activated carbon (39.3%) compared to the conventional treatment process (14.5%). To our knowledge, this is the first study to systematically identify the major odorants in raw water and determine suitable treatment strategies to control their occurrence by applying data analytics and statistical methods to the complex dataset. These provide informative reference for odor control and water quality management in drinking water industry.