[Effect and mechanism of Yueju Pills on breast cancer induced by DMBA in rats].

This paper aims to explore the inhibitory effect of Yueju Pills on breast cancer and decipher the underlying mechanism. A total of 92 SPF-grade SD female rats were involved in this study, and 14 of them were randomly selected into control group. The remaining 78 rats were administrated with 7,12-dimethylbenzanthracene(DMBA) by gavage to establish the breast cancer model. The modeled rats were randomized into model, tamoxifen(1.9 mg·kg~(-1)·d~(-1)), and low-and high-dose(17, 34 g·kg~(-1)·d~(-1)) Yueju Pills groups. The mental state, food intake, and activities of the rats were observed daily, and the body weight was measured on alternate days. After 12 weeks of administration, the rats were sacrificed and the tumor weight was measured. The serum estrogen and progeste-rone levels were determined by enzyme-linked immunosorbent assay. The histopathological changes of the breast and tumor were observed by hematoxylin-eosin staining. Western blot was employed to measure the protein levels of glucose transporter 1(GLUT1), lactate dehydrogenase A(LDHA), phosphofructokinase muscle(PFKM), pyruvate kinase isozyme type M2(PKM2), hexokinase 2(HK2), nuclear factor-kappaB(NF-κB), and phosphorylated NF-κB. The intestinal microbiome was examined by 16S rRNA high-throughput sequencing. The results showed that compared with the model group, high and low-dose Yueju Pills showed the tumor inhibition rate of 15.8% and 64.5%, respectively, and the low dose group had stronger inhibitory effect. Compared with the control group, the model group presented elevated the levels of estrogen and progesterone in serum. The administration of Yueju Pills lowered such ele-vation, and the low-dose group showed stronger lowering effect(P<0.05). Compared with the model group, Yueju Pills reduced the glands with increased breast tissue, the degree of breast duct expansion, the number and area of acinar cavity, the secretions, and the layers of mammary epithelial cells. Furthermore, Yueju Pills down-regulated the expression of GLUT1, LDHA, PFKM, PKM2, HK2, and NF-κB(P<0.05) and altered the diversity, composition, structure, and abundance of intestinal flora. The results showed that Yueju Pills could inhibit breast cancer by regulating the secretion of estrogen and progesterone, glycolysis, inflammatory cytokines, and intestinal flora.

The JMJD3 histone demethylase inhibitor GSK-J1 ameliorates lipopolysaccharide-induced inflammation in a mastitis model.

Jumonji domain-containing 3 (JMJD3/KDM6B) is a histone demethylase that plays an important role in regulating development, differentiation, immunity, and tumorigenesis. However, the mechanisms responsible for the epigenetic regulation of inflammation during mastitis remain incompletely understood. Here, we aimed to investigate the role of JMJD3 in the lipopolysaccharide (LPS)-induced mastitis model. GSK-J1, a small molecule inhibitor of JMJD3, was applied to treat LPS-induced mastitis in mice and in mouse mammary epithelial cells in vivo and in vitro. Breast tissues were then collected for histopathology and protein/gene expression examination, and mouse mammary epithelial cells were used to investigate the mechanism of regulation of the inflammatory response. We found that the JMJD3 gene and protein expression were upregulated in injured mammary glands during mastitis. Unexpectedly, we also found JMJD3 inhibition by GSK-J1 significantly alleviated the severity of inflammation in LPS-induced mastitis. These results are in agreement with the finding that GSK-J1 treatment led to the recruitment of histone 3 lysine 27 trimethylation (H3K27me3), an inhibitory chromatin mark, in vitro. Furthermore, mechanistic investigation suggested that GSK-J1 treatment directly interfered with the transcription of inflammatory-related genes by H3K27me3 modification of their promoters. Meanwhile, we also demonstrated that JMJD3 depletion or inhibition by GSK-J1 decreased the expression of toll-like receptor 4 and negated downstream NF-κB proinflammatory signaling and subsequently reduced LPS-stimulated upregulation of Tnfa, Il1b, and Il6. Together, we propose that targeting JMJD3 has therapeutic potential for the treatment of inflammatory diseases.

Rapid shifts in thermal reaction norms and tolerance of brooded coral larvae following parental heat acclimation.

Thermal priming of reef corals can enhance their heat tolerance; however, the legacy effects of heat stress during parental brooding on larval resilience remain understudied. This study investigated whether preconditioning adult coral Pocillopora damicornis to high temperatures (29°C and 32°C) could better prepare their larvae for heat stress. Results showed that heat-acclimated adults brooded larvae with reduced symbiont density and shifted thermal performance curves. Reciprocal transplant experiments demonstrated higher bleaching resistance and better photosynthetic and autotrophic performance in heat-exposed larvae from acclimated adults compared to unacclimated adults. RNA-seq revealed strong cellular stress responses in larvae from heat-acclimated adults that could have been effective in rescuing host cells from stress, as evidenced by the widespread upregulation of genes involved in cell cycle and mitosis. For symbionts, a molecular coordination between light harvesting, photoprotection and carbon fixation was detected in larvae from heat-acclimated adults, which may help optimize photosynthetic activity and yield under high temperature. Furthermore, heat acclimation led to opposing regulations of symbiont catabolic and anabolic pathways and favoured nutrient translocation to the host and thus a functional symbiosis. Notwithstanding, the improved heat tolerance was paralleled by reduced light-enhanced dark respiration, indicating metabolic depression for energy saving. Our findings suggest that adult heat acclimation can rapidly shift thermal tolerance of brooded coral larvae and provide integrated physiological and molecular evidence for this adaptive plasticity, which could increase climate resilience. However, the metabolic depression may be maladaptive for long-term organismal performance, highlighting the importance of curbing carbon emissions to better protect corals.

Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages.

Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.

Sediminihaliea albiluteola gen. nov., sp. nov., a new member of the family Halieaceae, isolated from marine sediment.

A Gram-stain-negative, rod-shaped and facultatively aerobic bacterial strain, designated F7430T, was isolated from coastal sediment collected at Jingzi Wharf in Weihai, PR China. Cells of strain F7430T were 0.3-0.4 µm wide, 2.0-2.6 µm long, non-flagellated, non-motile and formed pale-beige colonies. Growth was observed at 4-40 °C (optimum, 30 °C), pH 6.0-9.0 (optimum, pH 7.5-8.0) and at NaCl concentrations of 1.0-10.0 % (w/v; optimum, 1.0 %). The sole respiratory quinone of strain F7430T was ubiquinone 8 and the predominant cellular fatty acids were summed feature 8 (C18 : 1 ω7c / C18 : 1 ω6c; 60.7 %), summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c; 30.2 %) and C15 : 0 iso (13.9 %). The polar lipids of strain F7430T consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, one unidentified phospholipid and three unidentified lipids. Results of 16S rRNA gene sequences analyses indicated that this strain belonged to the family Halieaceae and had high sequence similarities to Parahaliea aestuarii JCM 51547T (95.3 %) and Halioglobus pacificus DSM 27932T (95.2 %) followed by 92.9-95.0 % sequence similarities to other type species within the aforementioned family. The rpoB gene sequences analyses indicated that the novel strain had the highest sequence similarities to Parahaliea aestuarii JCM 51547T (82.2 %) and Parahaliea mediterranea DSM 21924T (82.2 %) followed by 75.2-80.5 % sequence similarities to other type species within this family. Phylogenetic analyses showed that strain F7430T constituted a monophyletic branch clearly separated from the other genera of family Halieaceae. Whole-genome sequencing of strain F7430T revealed a 3.3 Mbp genome size with a DNA G+C content of 52.6 mol%. The genome encoded diverse metabolic pathways including the Entner-Doudoroff pathway, assimilatory sulphate reduction and biosynthesis of dTDP-l-rhamnose. Based on results from the current polyphasic study, strain F7430T is proposed to represent a novel species of a new genus within the family Halieaceae, for which the name Sediminihaliea albiluteola gen. nov., sp. nov. is proposed. The type strain of the type species is F7430T (=KCTC 72873T=MCCC 1H00420T).

Stappia albiluteola sp. nov., isolated from marine sediment.

A Gram-stain negative, rod-shaped, facultatively aerobic, pale-beige-coloured bacterial strain, designated F7233T, was isolated from coastal sediment sampled at Jingzi Bay, Weihai, PR China. Cells of strain F7233T were 0.3-0.4 µm wide, 1.2-1.4 µm wide long, non-spore-forming and motile with one flagellum. Optimum growth occurred at 30 °C, with 1.0 % (w/v) NaCl and at pH 6.5-7.0. Positive for nitrate reduction, hydrolysis of Tweens and oxidase activity. The sole respiratory quinone of strain F7233T was ubiquinone-10 and the predominant cellular fatty acid was summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and one unidentified aminophospholipid. The G+C content of the chromosomal DNA was 63.3 mol%. Phylogenetic analysis of the 16S rRNA gene sequence revealed that the newly isolate belonged to the genus Stappia, with 96.8 % sequence similarity to Stappia indica MCCC 1A01226T, 96.1 % similarity to Stappia stellulata JCM 20692T and 95.5% similarity to Stappia taiwanensis CC-SPIO-10-1T. On the basis of phylogenetic, phenotypic and chemotaxonomic data, it is considered that strain F7233T should represent a novel species within the genus Stappia, for which the name Stappia albiluteola sp. nov. is proposed. The type strain is F7233T (=MCCC 1H00419T=KCTC 72859T).

Selective targeting of cancer cells using a hydrogen peroxide-activated Hsp90 inhibitor.

Heat shock protein 90 (Hsp90) plays an important role in cancer cell proliferation, survival, and migration by regulating the maturation and stabilization of numerous oncoproteins. Despite significant efforts in developing Hsp90 inhibitors, none of these have been approved for clinical use, mostly due to toxicity, such as liver, cardiac, and retinal toxicity. To avoid undesirable toxicity, we herein report a hydrogen peroxide-activated Hsp90 inhibitor, Boro-BZide (3), which is capable of selectively targeting cancer cells over normal cells. Boro-BZide (3) can be activated by high levels of hydrogen peroxide, releasing its parent active Hsp90 inhibitor. The mechanism of action was determined by a series of experiments including fluorescence polarization assay, cell viability assay, western blotting, high-pressure liquid chromatography (HPLC), and fluorescence-activated cell sorting (FACS) analysis. These efforts ultimately led to the identification of a novel hydrogen peroxide-activated Hsp90 prodrug with improved therapeutic index, which was less prone to furnish unwanted adverse effects. This hydrogen peroxide-responsive prodrug strategy will be beneficial for overcoming the toxicity hurdles of Hsp90 inhibitors for clinical application.

High fidelity underwater wireless optical communication with a phase-conjugated frame structure.

In this paper, the influence factors of phase noise are first analyzed in detail and verified by experiments, and its principle is theoretically derived. Besides, we propose a novel, to the best of our knowledge, frame structure for m-quadrature amplitude modulation-orthogonal frequency division multiplexing (m-QAM-OFDM) in underwater wireless optical communication. The frame structure contains OFDM signals and their phase-conjugated signals. At the receiving end, by the simple superposition of phase-conjugated symbols, the noise suppression can be achieved. The feasibility is experimentally demonstrated by transmitting m-QAM-OFDM signal in different modulation formats and scenarios. The results show that bit error rate performance can be significantly improved, and there is also a significant increase in transmission capacity compared to the traditional phase-conjugated method. Moreover, the proposed frame structure can provide a robust and simple compromise between transmission capacity and distance.

Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells.

Chlorambucil is a nitrogen mustard-based DNA alkylating drug, which is widely used as a front-line treatment of chronic lymphocytic leukaemia (CLL). Despite its widespread application and success for the initial treatment of leukaemia, a majority of patients eventually develop acquired resistance to chlorambucil. In this regard, we have designed and synthesised a novel hybrid molecule, chloram-HDi that simultaneously impairs DNA and HDAC enzymes. Chloram-HDi efficiently inhibits the proliferation of HL-60 and U937 leukaemia cells with GI50 values of 1.24 µM and 1.75 µM, whereas chlorambucil exhibits GI50 values of 21.1 µM and 37.7 µM against HL-60 and U937 leukaemia cells, respectively. The mechanism behind its remarkably enhanced cytotoxicity is that chloram-HDi not only causes a significant DNA damage of leukaemia cells but also downregulates DNA repair protein, Rad52, resulting in the escalation of its DNA-damaging effect. Furthermore, chloram-HDi inhibits HDAC enzymes to induce the acetylation of α-tubulin and histone H3.

Evaluation of the Inhibitory Effects of (E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one (DiNap), a Natural Product Analog, on the Replication of Type 2 PRRSV In Vitro and In Vivo.

DiNap [(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one], an analog of a natural product (the chalcone flavokawain), was synthesized and characterized in this study. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most challenging threat to the swine industry worldwide. Currently, commercially available vaccines are ineffective for controlling porcine reproductive and respiratory syndrome (PRRS) in pigs. Therefore, a pharmacological intervention may represent an alternative control measure for PRRSV infection. Hence, the present study evaluated the effects of DiNap on the replication of VR2332 (a prototype strain of type 2 PRRSV). Initially, in vitro antiviral assays against VR2332 were performed in MARC-145 cells and porcine alveolar macrophages (PAMs). Following this, a pilot study was conducted in a pig model to demonstrate the effects of DiNap following VR2332 infection. DiNap inhibited VR2332 replication in both cell lines in a dose-dependent manner, and viral growth was completely suppressed at concentrations ≥0.06 mM, without significant cytotoxicity. Consistent with these findings, in the pig study, DiNap also reduced viral loads in the serum and lungs and enhanced the weight gain of pigs following VR2332 infection, as indicated by comparison of the DiNap-treated groups to the untreated control (NC) group. In addition, DiNap-treated pigs had fewer gross and microscopic lesions in their lungs than NC pigs. Notably, virus transmission was also delayed by approximately 1 week in uninfected contact pigs within the same group after treatment with DiNap. Taken together, these results suggest that DiNap has potential anti-PRRSV activity and could be useful as a prophylactic or post-exposure treatment drug to control PRRSV infection in pigs.

MiR-338-5p suppresses rheumatoid arthritis synovial fibroblast proliferation and invasion by targeting ADAMTS-9.

OBJECTIVES: We proposed to find out the role of miR-338-5p played in cell proliferation and invasion of rheumatoid arthritis synovial fibroblasts (RASFs) by regulating ADAMTS-9. METHODS: QRT-PCR was performed to quantify the miR-338-5p and ADAMTS-9 mRNA expression in RA sample tissues and normal synovial tissues. Western blot was performed to evaluate the ADAMTS-9 protein levels in transfected RASFs. Luciferase reporter assays were used to demonstrate whether miR338-5p directly targets ADAMTS-9. MTT, Transwell and wound healing assays were respectively used to evaluate the growth and mobility of RASFs. Flow cytometry was applied to detect cell cycle distributions and apoptosis rates in transfected RASFs. RESULTS: MiR-338-5p was significantly downregulated in rheumatoid arthritis (RA) tissues while ADAMTS-9 was obviously overexpressed (p<0.001). Luciferase reporter assays demonstrated that miR-338-5p directly targeted ADAMTS-9. Moreover, overexpression of miR-338-5p suppressed RASFs biological functions and induced G0/G1 arrest and apoptosis of RASFs (p<0.001), while all the effects could be efficiently attenuated by the upregulation of ADAMTS-9. CONCLUSIONS: By inhibiting ADAMTS-9, miR-338-5p suppressed the proliferation and metastasis of rheumatoid arthritis synovial fibroblasts. Thus, replenishing miR-338-5p may be a potential therapy for the clinic management of RA.

[Quality Optimization Method for Ambient CO(2) Inversion of High Resolution Fourier Transform Infrared Spectrum].

CO(2) retrievals with high quality facilitate resolving the sources and sinks of CO(2) are helpful in predicting the trend in climate change and understanding the global carbon cycle. Based on a nonlinear least squares spectral fitting algorithm, we investigate the optimization method for CO2 products derived from ground-based high resolution Fourier transform infrared spectra. The CO(2) vertical column densities (VCDs) are converted into column-averaged dry air mole fraction XCO(2) by using the fitted O(2) VCDs, and thus the system errors (e. g. pointing errors, ILS errors, zero-level offset) are corrected greatly. The virtual daily variation which is related to air mass factor is corrected with an empirical model. The spectra screening rule proposed in this paper can greatly improve the XCO2 quality. The CO(2) retrievals before and after the optimized method are compared using a typical CO(2) daily time series. After using the optimized method, the fitting error is reduced by 60%, and the two-hours-averaged precision is ~0.071% (equals to ~0.28 ppm), which is perfectly in line with the TCCON (the total carbon column observing network) threshold, i. e., less than 0.1%.

Determination of hexabromocyclododecane enantiomers in chicken whole blood by a modified quick, easy, cheap, effective, rugged, and safe method with liquid chromatography and tandem mass spectrometry.

A rapid and simple analytical method has been developed for the determination of hexabromocyclododecane enantiomers in chicken whole blood, based on a modified quick, easy, cheap, effective, rugged, and safe approach before liquid chromatography coupled with tandem mass spectrometry. The factors influencing performance of method were investigated by single factor experiment, and further optimized by the response surface methodology based on Box-Behnken design. The matrix effects were also evaluated by the isotopic dilution method. Under the optimal conditions, the proposed method showed good linearity within the range of 1-500 µg/L and good repeatability with relative standard deviation less than 9.5% (n = 5). The limits of detection (S/N = 3) were 0.03-0.19 µg/L. The developed method was successfully applied for the analysis of hexabromocyclododecane enantiomers in real chicken blood samples. The satisfactory recoveries ranging of 83.6-115.0% were obtained (at spiked levels of 5, 20, and 100 µg/L). The results demonstrated that the proposed method would be a practical value method for the determination of hexabromocyclododecane enantiomers in animal blood. It would be further developed with confidence to analyze other lipophilic organic pollutants in blood sample.

[Sensitivity Study of Aerosol Properties from Observation of Atmospheric Ring Effect].

Ring effect is defined as the phenomenon that the depth of solar Fraunhofer lines in scattered light is less than those observed in direct sunlight. The aerosol could change the light path and the scattering properties in the atmospheric, and influence Raman Scattering Possibility of the photons, and finally affect the filling-up effect. Aerosol parameters (aerosol optical depth, boundary layer height, single scattering albedo, asymmetric factor) could be obtained by observation of the Ring effect in different aerosol condition. The Ring effect is measured by ground-based MAX-DOAS instrument under clear days and the measurement results is compared with McAritim results. The comparison has a good agreement. Radiation transfer model McArtim is used to study the sensitivity of the Ring effect to the aerosol parameters. The study shows that in most conditions, aerosol optical depth (AOD) and boundary layer (bh) height has a great influence to RSP, and in 90 degree elevation angle, RSP has a decrease of 24.6% when AOD varies from 0.1 to 1, and a decrease of 4.4% when bh varies from 1km to 3 km. The study shows RSP is more sensitive to AOD and boundary layer height, which may provide a new method for aerosol profile.

Elucidating pharmacological mechanisms of natural medicines by biclustering analysis of the gene expression profile: a case study on curcumin and Si-Wu-Tang.

Natural medicines have attracted wide attention in recent years. It is of great significance to clarify the pharmacological mechanisms of natural medicines. In prior studies, we established a method for elucidating pharmacological mechanisms of natural products contained in connectivity map (cMap), in terms of module profiles of gene expression in chemical treatments. In this study, we explore whether this methodology is applicable to dissecting the pharmacological mechanisms of natural medicines beyond the agents contained in cMap. First, the gene expression profiles of curcumin (a typical isolated natural medicine) and Si-Wu-Tang (a classic traditional Chinese medicine formula) treatments were merged with those of cMap-derived 1309 agents, respectively. Then, a biclustering analysis was performed using FABIA method to identify gene modules. The biological functions of gene modules provide preliminary insights into pharmacological mechanisms of both natural medicines. The module profile can be characterized by a binary vector, which allowed us to compare the expression profiles of natural medicines with those of cMap-derived agents. Accordingly, we predicted a series of pharmacological effects for curcumin and Si-Wu-Tang by the indications of cMap-covered drugs. Most predictions were supported by experimental observations, suggesting the potential use of this method in natural medicine dissection.

[Analysis of lorentzian line shape function broadened by non-sinusoidal wavelength modulation].

In the present work, the Fourier analysis of Lorentzian line shape broadened by non-sinusoidal wavelength modulation was investigated, in which the third order and above harmonic items were ignored. The analytical expression of n-order Fourier coefficient was brought out, where a variable K named harmonic distortion to characterize the ratio of the second harmonic to the first harmonic was introduced. Numerical simulations based on the cases of K > 0.01 and K < 0.01 were carried out, and the result shows: non-sinusoidal modulation has little effect compared with the sinusoidal modulation when K value is less than 0.01, however, if K value is about 0.1 or higher, the center of the Fourier amplitude curve would deviate from the origin of coordinates. With the increase in the harmonic distortion, the deviation of the curve grows, and high order harmonics are more sensitive to the non-sinusoidal modulation compared with the low order harmonics. In addition, when harmonic distortion cannot be ignored, for example K > 0.01, the effect of different depths of modulation on the odd and even order harmonic amplitude curve is significant. And the numerical simulation shows there exists an optimum value of modulation depth which could minimize the impact of the harmonic distortion, and both large K value and small K value would cause a great error. The conclusion of this work could be applied in error analysis of wavelength modulation spectroscopy system And the results are helpful to deepening understanding of WMS and would be the important reference for some kind of frequency stabilization technology in laser instrument.

[Characteristics and Source Analysis of Volatile Organic Compounds in Typical Ozone Pollution Processes During Summer in Jinan, China].

Based on a typical ozone （O3） pollution process in Jinan City from June 16 to 26, 2021, the variation characteristics of O3 and its precursor volatile organic compounds （VOCs） during different pollution periods （clean period （CP）, pollution rise period （PRP）, heavy pollution period （HPP）, and pollution decline period （PDP）） in the urban area were analyzed. Both positive matrix factorization （PMF） and an observation-based model （OBM） were used to identify the main sources of VOCs, O3 production mechanisms, and sensitive species. The results showed that the average value of ρ（O3-8h） during the HPP period in the urban area was （246.67±11.24） µg·m-3, and ρ（O3-1h） had a peak value of 300 µg·m-3. The volume fractions of VOCs and NO2 concentration were affected by the decrease in planetary boundary layer and wind speed, which were 76.99%-145.36% and 127.78%-141.18% higher than those in the other three periods, respectively, and were the main reasons for the aggravation of O3 pollution. Alkanes, oxygenated volatile organic compounds （OVOCs）, and halogenated hydrocarbons accounted for 43.81%, 20.98%, and 17.43% of VOCs in urban areas, respectively. All of them showed significant growth during the HPP period, with acetone, propane, and ethane being the top three species by volume in each stage and isopentane showing the highest growth during the HPP period. Alkene, alkanes, and aromatic hydrocarbons accounted for 40.19%, 28.06%, and 21.92% of the ozone generation potential （OFP）. 1-butene, toluene, isopentane, and isoprene were the species with higher OFP. Isoprene had the highest OFP during the PRP phase, and 1-butene had the highest OFP during the HPP phase. The volume fraction of isopentane significantly increased OFP. The correlation coefficient between VOCs and CO preliminarily indicated that motor vehicle exhaust and oil and gas volatilization were the main sources of VOCs during the HPP period. Further use of PMF revealed that solvent use sources, combustion sources, motor vehicle exhaust+oil and gas volatilization sources, industrial emission sources, and plant sources were important sources of VOCs in urban areas. The contribution of motor vehicle exhaust+oil and gas volatilization sources in the HPP period to VOCs was 3.09-14.72 times higher than that in other periods. The contribution of solvent use sources to VOCs was approximately 2.50 times higher than that in the CP and PRP periods. The main sources of VOCs volume fraction increase were motor vehicle exhaust, oil and gas volatilization sources, and solvent use sources. Potential sources and concentration weight analysis found that VOCs were also affected by the transmission of VOCs to Binzhou and Dongying in the northeast direction. The OBM results indicated that the main pathway of O3 formation in urban areas was the reaction of peroxide hydroxyl radicals （HO2·ï¼‰ and methyl peroxide radicals （CH3O2·ï¼‰ with NO, and the net ozone generation rate during the HPP phase [P（O3）net] was 24×10-9 h-1. Based on the sensitivity experiment results, the alkene components of 1-butene, propylene, cis-2-butene, and ethylene were the dominant species for O3 production.

Dose-response relationship between physical activity and frailty: A systematic review and meta-analysis.

Objective: Frailty is a significant public health issue facing aging societies and can be reduced by physical activity (PA), but the dose-response relationship between PA and frailty is not clear. This systematic review and dose-response meta-analysis aimed to assess the effect of PA on frailty in adults by aggregating data from observational studies. Methods: PubMed, Embase, Web of Science, Cochrane Library, Scopus, SAGE Reference Online, SinoMed, CINAHL and CNKI were retrieved for articles published before May 2024. After quality evaluation, data on PA and the risk of frailty were extracted. Stata/MP 17.0 was used for dose-response meta-analysis. Results: A total of 15 articles were included, involving 34,754 participants, including 4250 subjects with frailty or pre-frailty. The consequence of the dose-response meta-analysis revealed that compared with those who were not active at all, a 22 % (95 % CI, 16 %-28 %) reduction in the risk of frailty in individuals with 11.25 MET h/week of cumulative activity and a 55 % (95 % CI, 44 %-63 %) reduction in the risk of frailty in those with 22.5 MET h/week of cumulative activity; for higher activity levels (36.75 MET h/week), the risk of frailty was reduced by 68 % (95 % CI, 58 %-76 %) and continued to be reduced as PA volum increased. Conclusions: There is a non-linear dose-response relationship between PA and frailty risk. Even small amounts of PA could reduce the risk of frailty. Meeting the minimum recommended PA target could reduce some risks, and doubling the recommended PA volumes could reduce most risks, which continue to increase as the volum of PA accumulates.

Design, synthesis, and biological evaluation of HDAC6 inhibitors targeting L1 loop and serine 531 residue.

Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones, leading to the silencing of genes. Targeting specific isoforms of HDACs has emerged as a promising approach for cancer therapy, as it can overcome drawbacks associated with pan-HDAC inhibitors. HDAC6 is a unique HDAC isoform that deacetylates non-histone proteins and is primarily located in the cytoplasm. It also has two catalytic domains and a zinc-finger ubiquitin binding domain (Zf-UBD) unlike other HDACs. HDAC6 plays a critical role in various cellular processes, including cell motility, protein degradation, cell proliferation, and transcription. Hence, the deregulation of HDAC6 is associated with various malignancies. In this study, we report the design and synthesis of a series of HDAC6 inhibitors. We evaluated the synthesized compounds by HDAC enzyme assay and identified that compound 8g exhibited an IC50 value of 21 nM and 40-fold selective activity towards HDAC6. We also assessed the effect of compound 8g on various cell lines and determined its ability to increase protein acetylation levels by Western blotting. Furthermore, the increased acetylation of α-tubulin resulted in microtubule polymerization and changes in cell morphology. Our molecular docking study supported these findings by demonstrating that compound 8g binds well to the catalytic pocket via L1 loop of HDAC6 enzyme. Altogether, compound 8g represents a preferential HDAC6 inhibitor that could serve as a lead for the development of more potent and specific inhibitors.

Ginsenoside compound K suppresses tumour growth in the 22Rv1 xenograft model and inhibits androgenic responses via the transcriptional mechanism in human prostate cancer cells.

Androgen receptor (AR) signalling is known to be dispensable for the biology of castration-resistant prostate cancer (CRPC), whereas the AR itself and the residual androgens after castration are crucial for the growth and progression of CRPC. Therefore, there is high demand for novel therapeutic candidates targeting AR itself or aberrant AR signalling to suppress the progression to or the growth of CPRC. Here, we report that ginsenoside compound K (GCK), the primary bioactive metabolite biotransformed from protopanaxadiol (PPD) ginsenoside, acts as a novel AR signalling inhibitor by transcriptionally suppressing AR expression and tumour growth in athymic nude mice. GCK inhibited cell growth in LNCaP, PC-3 and 22Rv1 prostate cancer cell lines and suppressed the expression levels of cell cycle regulators. GCK down-regulated epithelial-mesenchymal transition markers such as vimentin and matrix metalloproteinase 9 (MMP9), whereas E-cadherin was significantly increased in GCK-stimulated LNCaP and 22Rv1 cells. Moreover, GCK treatment markedly decreased both AR and AR-V7 protein levels in LNCaP and 22Rv1 cells, possibly by decreasing AR promoter activity. Experiments with AR promoter-deleted constructs revealed that the region between -412 and -227 is critical for GCK regulation. GCK treatment in athymic nude mice implanted with 22Rv1 CRPC cell lines significantly suppressed tumour growth and AR expression levels in tumour tissues. Collectively, our results suggest that GCK, as a novel AR inhibitor, could be a potential therapeutic agent against prostate cancer and an effective chemopreventive agent to delay the progression to CRPC.