GDNF improves the cognitive ability of PD mice by promoting glycosylation and membrane distribution of DAT.

The core of clinic treatment of Parkinson's disease (PD) is to enhance dopamine (DA) signaling within the brain. The regulation of dopamine transporter (DAT) is integral to this process. This study aims to explore the regulatory mechanism of glial cell line-derived neurotrophic factor (GDNF) on DAT, thereby gaining a profound understanding its potential value in treating PD. In this study, we investigated the effects of GDNF on both cellular and mouse models of PD, including the glycosylation and membrane transport of DAT detected by immunofluorescence and immunoblotting, DA signal measured by neurotransmitter fiber imaging technology, Golgi morphology observed by electron microscopic, as well as cognitive ability assessed by behavior tests. This study revealed that in animal trials, MPTP-induced Parkinson's Disease (PD) mice exhibited a marked decline in cognitive function. Utilizing ELISA and neurotransmitter fiber imaging techniques, we observed a decrease in dopamine levels and a significant reduction in the intensity of dopamine signal release in the Prefrontal Cortex (PFC) of PD mice induced by MPTP. Intriguingly, these alterations were reversed by Glial Cell Line-Derived Neurotrophic Factor (GDNF). In cellular experiments, following MPP + intervention, there was a decrease in Gly-DAT modification in both the cell membrane and cytoplasm, coupled with an increase in Nongly-DAT expression and aggregation of DAT within the cytoplasm. Conversely, GDNF augmented DAT glycosylation and facilitated its membrane transport in damaged dopaminergic neurons, concurrently reversing the effects of GRASP65 depletion and Golgi fragmentation, thereby reducing the accumulation of DAT in the Golgi apparatus. Furthermore, overexpression of GRASP65 enhanced DAT transport in PD cells and mice, while suppression of GRASP65 attenuated the efficacy of GDNF on DAT. Additionally, GDNF potentiated the reutilization of neurotransmitters by the PFC presynaptic membrane, boosting the effective release of dopamine following a single electrical stimulation, ultimately ameliorating the cognitive impairments in PD mice.Therefore, we propose that GDNF enhances the glycosylation and membrane trafficking of DAT by facilitating the re-aggregation of the Golgi apparatus, thereby amplifying the utilization of DA signals. This ultimately leads to the improvement of cognitive abilities in PD mouse models. Our study illuminates, from a novel angle, the beneficial role of GDNF in augmenting DA utilization and cognitive function in PD, providing fresh insights into its therapeutic potential.

Diterpenoids target SARS-CoV-2 RdRp from the roots of Euphorbia fischeriana Steud.

Introduction: Currently, the development of new antiviral drugs against COVID-19 remains of significant importance. In traditional Chinese medicine, the herb Euphorbia fischeriana Steud is often used for antiviral treatment, yet its therapeutic effect against the COVID-19 has been scarcely studied. Therefore, this study focuses on the roots of E. fischeriana Steud, exploring its chemical composition, antiviral activity against COVID-19, and the underlying basis of its antiviral activity. Methods: Isolation and purification of phytochemicals from E. fischeriana Steud. The elucidation of their configurations was achieved through a comprehensive suite of 1D and 2D NMR spectroscopic analyses as well as X-ray diffraction. Performed cytopathic effect assays of SARS-CoV-2 using Vero E6 cells. Used molecular docking to screen for small molecule ligands with binding to SARS-CoV-2 RdRp. Microscale thermophoresis (MST) was used to determine the dissociation constant Kd. Results: Ultimately, nine new ent-atisane-type diterpenoid compounds were isolated from E. fischeriana Steud, named Eupfisenoids A-I (compounds 1-9). The compound of 1 was established as a C-19-degraded ent-atisane-type diterpenoid. During the evaluation of these compounds for their antiviral activity against COVID-19, compound 1 exhibited significant antiviral activity. Furthermore, with the aid of computer virtual screening and microscale thermophoresis (MST) technology, it was found that this compound could directly bind to the RNA-dependent RNA polymerase (RdRp, NSP12) of the COVID-19, a key enzyme in virus replication. This suggests that the compound inhibits virus replication by targeting RdRp. Discussion: Through this research, not only has our understanding of the antiviral components and material basis of E. fischeriana Steud been enriched, but also the potential of atisane-type diterpenoid compounds as antiviral agents against COVID-19 has been discovered. The findings mentioned above will provide valuable insights for the development of drugs against COVID-19.

Yinxie I Formula attenuates imiquimod-induced psoriasis-like skin inflammation via IL-23/IL-17 axis.

Psoriasis is considered a chronic inflammatory skin disorder characterized by keratinocytes hyperproliferation. The IL-23/IL-17 immune pathway has been substantiated in numerous studies to be closely associated with psoriasis progression. Yinxie I Formula is a traditional Chinese medicine made from 9 herbal medicines, which has excellent clinical efficacy in psoriasis. However, to date, the mechanism of action of Yinxie I Formula against psoriasis remains unknown. In this perspective, we discuss the efficacy of Yinxie I Formula in mice with imiquimod (IMQ) induced psoriasis. Yinxie I Formula significantly reduced the area of skin lesions and the inflammatory response in mice with psoriasis. Furthermore, Yinxie I Formula alleviated the expression levels of inflammation-related genes IL-6, IL-17 A, IL-22, IL-23, TNF-α and IL-23, IL-18, IL-6 and IL-1ß-related proteins and alleviated the abnormal surge of dendritic cells, macrophages and T cells in the skin and spleen. Meanwhile we found that Yinxie I Formula reduced the release of NO, TNF-α, IL-1ß and IL-23 in lipopolysaccharide-induced mouse macrophage RAW264.7 cell line. The results suggest that the therapeutic mechanism of Yinxie I Formula may also be correlated with the STAT signaling pathway. We further analyzed the active ingredient of Yinxie I Formula, Buddleoside, which may be the main substance that exerts the therapeutic effect. In conclusion, we have investigated that Yinxie I Formula attenuates the IMQ-induced inflammatory response in psoriasis by inhibiting the IL-23/IL-17 axis, which lays the foundation for the antipsoriasis mechanism and provides a theoretical basis for the clinical promotion of Yinxie I Formula.

Acoustic modulation signal recognition based on endpoint detection.

The modulation recognition technology for acoustic signals holds significant research importance in signal demodulation and communication signal reconnaissance, serving as a crucial component and key aspect. This paper investigates the modulation recognition technology for acoustic signals (< 20 kHz) from the perspectives of signal preprocessing and feature extraction. Firstly, it selects seven modulation signals 2ASK, 4ASK, 2FSK, 4FSK, 2PSK, 4PSK, and OFDM as recognition targets and systematically compares the effectiveness of four different endpoint detection algorithms in modulation signal recognition. To further enhance the performance of the short-time energy entropy ratio algorithm, this study introduces three different noise reduction algorithms for optimization. Finally, to accurately identify and distinguish between 2 and 4FSK signals, this study optimizes the related algorithms of the cyclic spectrum by using the kurtosis coefficient value Kur of the cyclic spectrum parameter matrix when the cyclic frequency α = 0 to differentiate between these two signals. The results show that at SNR of 4 dB, the proposed modulation recognition algorithm can effectively distinguish between these two signals, achieving a recognition accuracy of over 99%.

Photoinduced Decarboxylative Thioacylation of N-Hydroxyphthalimide Esters with Tetraalkylthiuram Disulfides.

Dithiocarbamate is a key structural sequence in pharmaceuticals and agrochemicals, and its synthesis is crucial in organic chemistry. Although significant progress has been made in related synthesis research, developing a practical and universal synthesis method remains fascinating. Herein, we report a new visible-light-induced decarboxylation coupling reaction between N-hydroxyphthalimide esters and tetraalkylthiuram disulfides, which uses Ir(ppy)3 as a photocatalyst to promote the generation of corresponding decarboxylation thioacylation product-dithiocarbamates in high yields. This redox-neutral protocol uses inexpensive and readily available starting material under mild reaction conditions, exhibiting broad substrate scope and wide functional group compatibility. This method can be further used for post modification of complex natural products and bioactive drugs.

Unmasking Spatial Heterogeneity in Phytotoxicology Mechanisms Induced by Carbamazepine by Mass Spectrometry Imaging and Multiomics Analyses.

Previous studies have highlighted the toxicity of pharmaceuticals and personal care products (PPCPs) in plants, yet understanding their spatial distribution within plant tissues and specific toxic effects remains limited. This study investigates the spatial-specific toxic effects of carbamazepine (CBZ), a prevalent PPCP, in plants. Utilizing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), CBZ and its transformation products were observed predominantly at the leaf edges, with 2.3-fold higher concentrations than inner regions, which was confirmed by LC-MS. Transcriptomic and metabolic analyses revealed significant differences in gene expression and metabolite levels between the inner and outer leaf regions, emphasizing the spatial location's role in CBZ response. Notably, photosynthesis-related genes were markedly downregulated, and photosynthetic efficiency was reduced at leaf edges. Additionally, elevated oxidative stress at leaf edges was indicated by higher antioxidant enzyme activity, cell membrane impairment, and increased free fatty acids. Given the increased oxidative stress at the leaf margins, the study suggests using in situ Raman spectroscopy for early detection of CBZ-induced damage by monitoring reactive oxygen species levels. These findings provide crucial insights into the spatial toxicological mechanisms of CBZ in plants, forming a basis for future spatial toxicology research of PPCPs.

Elucidating the reproductive toxicity mechanisms in female zebrafish: A transcriptomic study of lifetime tris(2-chloroethyl) phosphate exposure.

Tris(2-chloroethyl) phosphate (TCEP), emerging as a predominant substitute for brominated flame retardants (BFRs), is now increasingly recognized as a prevalent contaminant in aquatic ecosystems. The extent of its reproductive toxicity in aquatic species, particularly in zebrafish (Danio rerio), remains insufficiently characterized. This study subjected zebrafish embryos to various concentrations of TCEP (0, 0.8, 4, 20, and 100 µg/L) over a period of 120 days, extending through sexual maturation, to assess its impact on female reproductive health. Notable reductions in body weight (0.59- and 0.76-fold) and length (0.71- and 0.77-fold) were observed at concentrations of 20 and 100 µg/L, with a concomitant decrease by 0.21- to 0.61-fold in the gonadal somatic index across all treatment groups. The reproductive output, as evidenced by egg production and hatchability, was adversely affected. Histopathological analysis suggested that TCEP exposure impedes ovarian development. Endocrine alterations were also evident, with testosterone and 11-ketotestosterone levels significantly diminished by 0.38- and 0.08-fold at the highest concentration tested, while 17ß-estradiol was elevated by 0.09- to 0.14-fold in all exposed groups. Transcriptomic profiling illuminated numerous differentially expressed genes (DEGs) integral to reproductive processes, including hormone regulation, neuroactive ligand-receptor interactions, oocyte meiosis, and progesterone-mediated maturation pathways. Collectively, these findings indicate that lifelong exposure to TCEP disrupts ovarian development and maturation in female zebrafish, alters gene expression within the hypothalamic-pituitary-gonadal axis, and perturbs sex hormone synthesis, culminating in pronounced reproductive toxicity.

A cross-sectional survey study on the correlation analysis of nutritional status and intestinal flora in patients with esophageal cancer.

Objective: This study aims to examine the nutritional status of individuals diagnosed with esophageal cancer and compare the nutritional indicators and intestinal flora between malnourished and non-malnourished patients. The findings aim to contribute to the early prevention of malnutrition and the development of interventions targeting the intestinal flora to treat esophageal cancer. Methods: An 80-patient sample of hospitalized individuals with esophageal cancer was selected from the radiotherapy department of our hospital between July 2021 and July 2022 to evaluate NRS2002 scores and PG-SGA scores. This cross-sectional analysis aimed to examine the disparities in dietary nutrient intake, blood indicators, body composition, and fecal intestinal flora between malnourished and non-malnourished patients with esophageal cancer. Additionally, we randomly selected 40 cases to predict and analyze the relationship between intestinal flora and malnutrition. Results: The incidence of nutritional risk and malnutrition in patients with esophageal cancer was 62.5% and 60%, respectively. The low intake of carbohydrates and dietary fiber in the malnutrition group was statistically significant compared to those in the non-malnutrition group (P < 0.05). The albumin (ALB) level was lower in the malnutrition group than in the non-malnutrition group, while the C-reactive protein (CRP) level was higher; these differences were also statistically significant (P < 0.05). The basal metabolic rate, phase angle, body cell mass, muscle mass, skeletal muscle index, and fat-free mass index in the malnutrition group all decreased compared to the non-malnutrition group. The extracellular water/total body water was higher than that in the non-malnutrition group, which was also statistically significant (P < 0.05). As shown by 16S rDNA sequencing of fecal intestinal flora, there was no significant difference in α and ß diversity between the malnutrition and non-malnutrition groups; at the genus level, significant differences were observed for Selimonas, Clostridioides, Dielma, Lactobacillus, and [Eubacterium]_siraeum_group. However, Dielma, Sellimonas, and Clostridioides were significantly lower in the malnutrition group than in the non-malnutrition group, while Anaerococcus, Atopobium, Eubacterium_siraeum_group, and Lactobacillus were significantly higher in the malnutrition group. Correlation analysis between different genera and clinical indicators showed that Lactobacillus was positively correlated with ALB, dietary energy, intracellular water/total body water (ICW/TBW), phase angle (PA), muscle mass (MM), skeletal muscle mass (SMM), body cell mass (BCM), basal metabolic rate (BMR), appendicular skeletal muscle mass (ASMM), total body water (TBW), fat-free mass index (FFMI), skeletal muscle index (SMI), fat-free mass (FFM), Weight, body mass index (BMI) (r > 0, P < 0.05), but negatively correlated with PG-SGA score, NRS2002 score, and extracellular water/total body water (ECW/TBW) (r < 0, P < 0.05). Based on PG-SGA, there was only a low accuracy for identifying nutrient deficiency (most areas under curve (AUC) values fell within 0.5 to 0.7, or even lower), with Lachnoclostridium's AUC being 0.688 (CI = 0.518-0.858) and Lactobacillus_salivarius_g_Lactobacillus's AUC being 0.257 (CI = 0.098-0.416). A KEGG functional analysis based on 16S data indicated potential differences affecting glucose metabolism pathways and the synthesis or division of DNA, influencing the onset, development, and prognosis of esophageal cancer patients. Conclusion: Esophageal cancer patients are more likely to be malnourished. The nutritional status of these patients is closely linked to the intake of carbohydrates and fiber, albumin levels, inflammation levels, and lean body mass. Furthermore, the patient's intestinal flora composition plays a significant role in their nutritional well-being. Consequently, modulating the intestinal flora holds promise as a potential therapeutic approach for addressing malnutrition in esophageal cancer patients. Clinical trial registration: ChiCTR2100048141.

Identifying therapeutic targets for breast cancer: insights from systematic Mendelian randomization analysis.

Background: Breast cancer (BC) exhibits a high incidence rate, imposing a substantial burden on healthcare systems. Novel drug targets are urgently needed for BC. Mendelian randomization (MR) has gained widespread application for identifying fresh therapeutic targets. Our endeavor was to pinpoint circulatory proteins causally linked to BC risk and proffer potential treatment targets for BC. Methods: Through amalgamating protein quantitative trait loci from 2,004 circulating proteins and comprehensive genome-wide association study data from the Breast Cancer Association Consortium, we conducted MR analyses. Employing Steiger filtering, bidirectional MR, Bayesian colocalization, phenotype scanning, and replication analyses, we further solidified MR study outcomes. Additionally, protein-protein interaction (PPI) network was harnessed to unveil latent associations between proteins and prevailing breast cancer medications. The phenome-wide MR (Phe-MR) was employed to assess potential side effects and indications for the druggable proteins of BC. Finally, we further affirmed the drugability of potential drug targets through mRNA expression analysis and molecular docking. Results: Through comprehensive analysis, we identified five potential drug targets, comprising four (TLR1, A4GALT, SNUPN, and CTSF) for BC and one (TLR1) for BC_estrogen receptor positive. None of these five potential drug targets displayed reverse causation. Bayesian colocalization suggested that these five latent drug targets shared variability with breast cancer. All drug targets were replicated within the deCODE cohort. TLR1 exhibited PPI with current breast cancer therapeutic targets. Furthermore, Phe-MR unveiled certain adverse effects solely for TLR1 and SNUPN. Conclusion: Our study uncovers five prospective drug targets for BC and its subtypes, warranting further clinical exploration.

Evaluation of hemostatic, anti-inflammatory, wound healing, skin irritation and allergy, and antimicrobial properties of active fraction from the ethanol extract of Chromolaena odorata (L.) R.M. King & H. Rob.

ETHNOPHARMACOLOGICAL RELEVANCE: Chromolaenaodorata (L.) R.M. King & H. Rob, a perennial herb, has been traditionally utilized as a herbal remedy for treating leech bites, soft tissue wounds, burn wounds, skin infections, and dento-alveolitis in tropical and subtropical regions. AIM OF THE STUDY: The present study was to analyze the active fraction of C. odorata ethanol extract and investigate its hemostatic, anti-inflammatory, wound healing, and antimicrobial properties. Additionally, the safety of the active fraction as an external preparation was assessed through skin irritation and allergy tests. MATERIALS AND METHODS: The leaves and stems of C. odorata were initially extracted with ethanol, followed by purification through AB-8 macroporous adsorption resin column chromatography to yield different fractions. These fractions were then screened for hemostatic activity in mice and rabbits to identify the active fraction. Subsequently, the hemostatic effect of the active fraction was assessed through the bleeding time of the rabbit ear artery in vivo and the coagulant time of rabbit blood in vitro. The anti-inflammatory activity of the active fraction was tested on mice ear edema induced by xylene and rat paw edema induced by carrageenin. Furthermore, the active fraction's promotion effect on wound healing was evaluated using a rat skin injury model, and skin safety tests were conducted on rabbits and guinea pigs. Lastly, antimicrobial activities against two Gram-positive bacteria (G+, Staphylococcus aureus and S. epidermidis) and three Gram-negative bacteria (G-, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa) were determined using the plate dilution method. RESULTS: The ethanol extract of C. odorata leaves and stems was fractionated into 30%, 60%, and 90% ethanol eluate fractions. These fractions demonstrated hemostatic activity, with the 30% ethanol eluate fraction (30% EEF) showing the strongest effect, significantly reducing bleeding time (P < 0.05). A concentration of 1.0 g/mL of the 30% EEF accelerated cutaneous wound healing in rats on the 3rd, 6th, and 9th day post-operation, with the healing effect increasing over time. No irritation or allergy reactions were observed in rabbits and guinea pigs exposed to the 30% EEF. Additionally, the 30% EEF exhibited mild inhibitory effect on mice ear and rat paw edema, as well as antimicrobial activity against tested bacteria, with varying minimal inhibitory concentration (MIC) values. CONCLUSIONS: The 30% EEF demonstrated a clear hemostatic effect on rabbit bleeding time, a slight inhibitory effect on mice ear edema and rat paw edema, significant wound healing activity in rats, and no observed irritation or allergic reactions. Antibacterial activity was observed against certain clinically isolated bacteria, particularly the G- bacteria. This study lays the groundwork for the potential development and application of C. odorata in wound treatment.

[Analysis of differential metabolites of spikes of Prunella vulgaris at different stages based on UPLC-MS/MS].

Prunella vulgaris, aptly named for its withering at the summer solstice, displays significant variation in quality arising from differing harvest time. However, research on the chemical composition changes of its spikes at various stages is limited, and the specific metabolites remain unclear. In order to elucidate the metabolites and metabolic pathways of the spikes of P. vulgaris, the current study deployed ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) and targeted metabolomics to characterize the compound variability in the spikes of P. vulgaris across different periods. Multivariate statistical techniques such as principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) were used to identify the differences in metabolites, and relevant metabolic pathways were analyzed. A total of 602 metabolites were identified by metabolomics, of which organic acids and their derivatives were the most abundant, followed by flavonoids. Multiple differential metabolites, including p-hydroxybenzoic acids and gallic acids were identified based on variable importance in projection(VIP)>1 and P<0.05. The results of enrichment analysis suggested that isoflavonoids biosynthesis, aminobenzoate degradation, benzoate degradation, anthocyanins biosynthesis, metabolic pathways, microbial metabolism in different environments, secondary plant metabolite biosynthesis, tryptophan metabolism, and phenylpropanoid synthesis were the main metabolic pathways. These results intend to elucidate the dynamic changes of differential metabolites of P. vulgaris and provide a theoretical basis for further study of the harvesting mechanism of spikes of P. vulgaris.

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD.

Transcriptome data reveal beneficial effects of Rickettsia (Rickettsiales: Rickettsiaceae) on Bemisia tabaci(Hemiptera: Aleyrodidae) through nutritional factors and defense mechanisms.

Whitefly Bemisia tabaci (Hemiptera: Aleyrodidae) is a destructive insect pest of many crops. Rickettsia infection in different cryptic species of B. tabaci has been observed worldwide. Understanding the interactions between these 2 organisms is critical to developing Rickettsia-based strategies to control B. tabaci and thereby reduce the transmission of related vector-borne viruses. In this study, we investigated the effects of Rickettsia infection on the biological characteristics of the Middle East Asia Minor 1 (MEAM1) strain of B. tabaci through biological analysis of infected and uninfected individuals. The results of this study suggest that Rickettsia may confer fitness benefits. These benefits include increased fertility, improved survival rates, accelerated development, and resulted in female bias. We also investigated the transcriptomics impact of Rickettsia infection on B. tabaci by performing a comparative RNA-seq analysis of nymphs and adult females, both with and without the infection. Our analysis revealed 218 significant differentially expressed genes (DEGs) in infected nymphs compared to uninfected ones and 748 significant DEGs in infected female adults compared to their uninfected whiteflies. Pathway analysis further revealed that Rickettsia can affect many important metabolic pathways in whiteflies. The results suggest that Rickettsia plays an essential role in energy metabolism, and nutrient synthesis in the B. tabaci MEAM1, and depends on metabolites obtained from the host to ensure its survival. Overall, our findings suggest that Rickettsia has beneficial effects on B. tabaci and offered insights into the potential molecular mechanisms governing the interactions between Rickettsia and B. tabaci MEAM1.

Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.

Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.

Behavioral and biochemical responses of the marine polychaete Perinereis aibuhitensis to 2-ethylhexyl-4-methoxycinnamate (EHMC) exposure.

2-ethylhexyl-4-methoxycinnamate (EHMC) is a commonly used UV filter, and is receiving increasing concerns due to its ubiquitous occurrence in a variety of environmental media and potential adverse effects. This study was aimed to assess the ecotoxicological potentials of EHMC on the marine polychaete Perinereis aibuhitensis. To this end, ragworms were exposed to 2, 20, 200 µg/L EHMC for 14 days and multiple toxicological endpoints were investigated. The results showed that EHMC significantly reduced burrowing rate, but did not affect AChE activity. Exposure to EHMC significantly elevated the activities of SOD and CAT and decreased the levels of lipid peroxidation. Besides, the induction of AKP activity indicated a stimulated immune response in the ragworms when exposed to high concentration of EHMC. Furthermore, the upregulated expression of caspase-8 suggested that EHMC might induce apoptosis in ragworms via the death receptor-mediated extrinsic pathway. Our findings highlight the potential environmental risks of EHMC to marine ecosystems.

The use of combined hormonal contraceptive for in-vitro fertilization cycle priming is not associated with decreased pregnancy rate in frozen embryo transfer cycles: a cohort study.

BACKGROUND: The objectives of this study are to evaluate the cycle outcomes from IVF treatment preceded by oral contraceptive pills (OCP) priming compared to estradiol pretreatment and to determine if there is a role for OCP priming for those undergoing frozen embryo transfers. METHODS: The study took place at a university-affiliated fertility center in Canada. The study included in-vitro fertilization (IVF) antagonist cycles from Jan 2016 to Jun 2019. Those with protocol deviation or treatment cancellation were excluded. RESULTS: There were 2237 cycles by 1958 patients; 27% of cycles utilized OCP priming. The average age in the OCP group was 34 years old compared to 36.5 in the estradiol group (P<0.01). AMH was reported in 43% of patients and was 3.7ng/mL in the OCP group versus 2.2 ng/mL in the estradiol group (P<0.01). The number of oocytes (15.2 vs. 12.5) and number of blastocysts (4.6 vs. 3.3) were higher in the OCP group (P all <0.01). After adjusting for age and AMH with linear regression for the 978 cycles with recorded AMH (24% with OCP prime), a significantly higher number of oocytes (13.8 vs. 11.9, P=0.002) was still noted in the OCP group. There were 866 euploid embryo transfer cycles (28% with OCP prime). There were no significant differences in implantation (77% vs. 76%) or ongoing pregnancy rates (56% vs. 54%) between those who had a frozen embryo transfer after OCP primed compared to estradiol primed stimulation cycles (P all >0.6). CONCLUSIONS: There were no differences in pregnancy outcomes from euploid frozen blastocyst transfers after OCP primed antagonist cycles compared to estradiol pretreatment. In fact, the use of OCP pretreatment was associated with increased oocyte yield, keeping in mind demographic differences with the OCP pretreatment group being younger with higher anti-Müllerian hormone and a higher prevalence of PCOS. Thus, OCP priming should still be considered in specific populations, such as those with oligo-ovulation or adequate ovarian reserve.

Reduction in NGAL at 48 h predicts the progression to CKD in patients with septic associated AKI: a single-center clinical study.

BACKGROUND: In this study, our objective was to investigate the predictive value of serum and urine fluctuations of neutrophil gelatinase-associated lipid transporters (NGAL) in relation to the progression of chronic kidney disease (CKD) among patients with septic associated AKI (SA-AKI). METHODS: A total of 425 SA-AKI patients were enrolled in this study and divided into the recovery group (n = 320) and the AKI-to-CKD group (n = 105) based on 3-month follow-up data. The serum and urine NGAL levels on the day of AKI diagnosis (T0) and 48 h after anti-AKI treatment (T1) were recorded and calculated. RESULTS: The levels of NGAL in serum and urine were found to be higher in the AKI-to-CKD group compared to the recovery group at T1 point (P < 0.05). The reductions of NGAL at 48 h in serum and urine were lower in the AKI-to-CKD group than those observed in the recovery group (P < 0.05). In comparison to T0, a significant decrease was noted for both serum and urine NGAL levels on T1 among patients who recovered from AKI (P < 0.05), whereas no such trend was observed among those with AKI-to-CKD transition (P > 0.05). After adjusting age, sex, and BMI through partial correlation analysis, the reduction of serum NGAL was found to be most strongly associated with the transition from AKI to CKD. ROC analysis showed an AUC of 0.832 for serum NGAL reduction, with a cut-off value of - 111.24 ng/ml and sensitivity and rates of 76.2% and 81.2%, respectively. Logistic regression analysis indicated that a reduction of serum NGAL ≥ - 111.24 ng/ml was the early warning indicator for the progression of CKD in SA-AKI patients. CONCLUSION: The reduction of serum NGAL following 48 h of anti-AKI therapy represents a distinct hazard factor for the advancement of CKD in patients with SA-AKI, independent of other variables.

Uptake and toxicity of micro-/nanoplastics derived from naturally weathered disposable face masks in developing zebrafish: Impact of COVID-19 pandemic on aquatic life.

The unprecedented proliferation of disposable face masks during the COVID-19 pandemic, coupled with their improper disposal, threatens to exacerbate the already concerning issue of plastic pollution. This study evaluates the role of environmentally weathered masks as potential sources of microplastics (MPs) and nanoplastics (NPs) and assesses their adverse impact on the early life stages of zebrafish. Experimental findings revealed that a single disposable mask could release approximately 1.79 × 109 particles, with nearly 70% measuring less than 1 µm, following 60 days of sunlight exposure and subsequent sand-induced physical abrasion. Remarkably, the MPs/NPs (MNPs) emanating from face masks have the potential to permeate the outer layer (chorion) of zebrafish embryos. Furthermore, due to their minute size, these particles can be consumed by the larvae's digestive system and subsequently circulated to other tissues, including the brain. Exposure to mask-derived MNPs at concentrations of 1 and 10 µg/L led to significant cases of developmental toxicity, incited oxidative stress, and prompted cell apoptosis. A subsequent metabolomics analysis indicated that the accumulation of these plastic particles perturbed metabolic functions in zebrafish larvae, primarily disrupting amino acid and lipid metabolism. The outcomes of this research underscore the accelerating possibility of environmental aging processes and physical abrasion in the release of MNPs from disposable face masks. Most importantly, these results shed light on the possible ecotoxicological risk posed by improperly disposed of face masks.

Comparing safety and efficacy: MemoLefort versus watchman for left atrial appendage closure.

BACKGROUND: The MemoLefort is a new plug occluder for left atrial appendage closure (LAAC) in patients with atrial fibrillation (AF). This study compares the safety and efficacy of MemoLefort and the well-established Watchman occluder for LAAC. METHODS: Between January 2021 and September 2022, a cohort of 189 consecutive patients who underwent LAAC with MemoLefort or Watchman at The Second Affiliated Hospital of Wenzhou Medical University were included. Patients with MemoLefort or Watchman devices were compared in terms of the primary safety endpoints encompassing major periprocedural complications and major bleeding events at follow-up, the primary efficacy endpoint of all-cause stroke, systemic embolism and cardiovascular/unexplained death, and the combined hazard endpoint, a composite of all the above-mentioned hazards. RESULTS: Of the MemoLefort group (n = 83) and Watchman group (n = 106), the mean age, CHA2DS2-VASc score, and HAS-BLED score were 67.6 ± 9.2 vs. 69.0 ± 10.6 years, 3.9 ± 1.9 vs. 3.8 ± 1.9, and 1.6 ± 1.0 vs. 1.7 ± 1.2, respectively. After a median follow-up duration of 198 (99-329) vs. 334 (171-497) days, the primary endpoints of efficacy [2/49, 4.1% (MemoLefort) vs. 2/97, 2.1% (Watchman); hazard ratio (HR), 1.50; 95% confidence interval (CI), 0.20-11.08; P = 0.68] and safety (1/49, 2.0% vs. 5/97, 5.2%; HR, 0.26; 95% CI, 0.05-1.31; P = 0.19), as well as the combined hazard endpoint (3/49, 61% vs. 6/97, 6.2%; HR, 0.70; 95% CI, 0.18-2.58; P = 0.59) were similar between groups. CONCLUSIONS: In the short term, LAAC with MemoLefort provided similar efficacy, safety, and net clinical benefit in comparison to Watchman devices.

Latest research progress in airway stenosis after lung transplantation / 器官移植

With the optimization of surgical technologies and postoperative management regimens, the number of lung transplantation has been significantly increased, which has become an important treatment for patients with end-stage lung disease. However, due to the impact of comprehensive factors, such as bronchial ischemia and immunosuppression, the incidence of airway stenosis after lung transplantation is relatively high, which severely affects postoperative survival and quality of life of lung transplant recipients. In recent years, with the improvement of perioperative management, organ preservation and surgical technologies, the incidence of airway stenosis after lung transplantation has been declined, but it remains at a high level. Early diagnosis and timely intervention play a significant role in enhancing clinical prognosis of patients with airway stenosis. In this article, the general conditions, diagnosis, treatment and prevention of airway stenosis after lung transplantation were reviewed, aiming to provide reference for comprehensive management of airway stenosis after lung transplantation and improving clinical prognosis of lung transplant recipients.