Comparative chloroplast genomes of Argentina species: genome evolution and phylogenomic implications.

The genus Argentina Hill belongs to the tribe Potentilleae Sweet and contains approximately 75 species predominantly distributed in the Sino-Himalayan region and the Malesian archipelago. So far we have less knowledge on the phylogenetic relationships within Argentina owing to limited sampling of Argentina taxa or gene fragments in previous studies. Moreover, to date there is no phylogenetic study on Argentina from the perspective of comparative chloroplast (cp) genomics. Here we performed comparative genomic analyses on the cp genomes of 39 accessions representing 18 taxa of Argentina. The Argentina cp genomes presented the typical quadripartite structure, with the sizes ranging from 155 096 bp to 157 166 bp. The 39 Argentina cp genomes contained a set of 112 unique genes, comprising four ribosomal RNA (rRNA) genes, 30 transfer RNA (tRNA) genes, as well as 78 protein-coding genes (PCGs). The cp genome organization, gene content and order in Argentina were highly conserved, but some visible divergences were present in IR/SC boundary regions. Ten regions (trnH-GUG-psbA, trnG-GCC-trnfM-CAU, trnD-GUC-trnY-GUA, rpl32-trnL-UAG, atpH-atpI, rps16-trnQ-UUG, trnS-GCU-trnG-UCC, ndhF-rpl32, trnR-UCU-atpA, and accD-psaI) were identified as excellent candidate DNA markers for future studies on species identification, population genetics and phylogeny of Argentina. Our results indicated that Argentina is monophyletic. In the current sampling, the A. smithiana - A. anserina clade was sister to the remainder of Argentina. Our results corroborated the previous taxonomic treatments to transfer A. phanerophlebia and A. micropetala from the genus Sibbaldia L. to Argentina. Our results showed close relationships among A. stenophylla, A. microphylla, A. taliensis, and A. tatsienluensis, congruent with previous studies based on the morphology of these species. Twenty-six genes (rps3, rps15, rps16, rps19, rpl16, rpl20, rpl22, rpoA, rpoB, rpoC1, rpoC2, atpA, atpF, psbB, psbF, ndhA, ndhB, ndhC, ndhD, ndhF, rbcL, accD, ccsA, matK, ycf1, ycf2) were with sites under positive selection, and adaptive evolution of these genes might have played crucial roles in Argentina species adaptation to the harsh mountain environment. This study will facilitate future work on taxonomy, phylogenetics, and adaptive evolution of Argentina.

Origins of formaldehyde in a mountainous background atmosphere of southern China.

Formaldehyde (HCHO) is one of the key indicators of severe photochemical pollution and strong atmospheric oxidation capacity in southern China. However, current information on the origins of regional HCHO and the impacts of polluted air masses remains scarce and unclear. In this study, an intensive observation of HCHO was conducted at a mountainous background site in southern China during typical photochemical pollution episodes. The concentrations of HCHO reached up to 6.14 ppbv and averaged at 2.68 ± 1.11 ppbv. Source appointment using a photochemical age-based parameterization method revealed significant contributions of secondary formation (50 %) and biomass burning (42 %). Meanwhile, under the influence of the East Asian Winter Monsoon, polluted air masses from central and western China can significantly increase the regional HCHO levels. The simulation results adopting the Rapid Adaptive Optimization Model for Atmospheric Chemistry model further demonstrated that the intrusion of active anthropogenic pollutants (e.g., small-molecule alkenes) can accelerate the net production rate of HCHO, particularly through BVOC-oxidation pathways. This study suggests a potential enhanced mechanism of HCHO production resulting from anthropogenic-biogenic interactions. It highlights that polluted air masses carrying abundant HCHO from upwind areas may facilitate severe photochemical pollution in the Greater Bay Area.

Photochemical loss with consequential underestimation in active VOCs and corresponding secondary pollutions in a petrochemical refinery, China.

The photochemical loss of volatile organic compounds (VOCs) significantly alters the capturing source profiles in high-reactivity VOC species and results in an underestimation of secondary pollutants such as ozone (O3) and secondary organic aerosol (SOA). Utilising speciated VOC data from large petrochemical refineries, the research assesses the photochemical loss of various VOC species. Air samples from multiple sites revealed over 99 VOCs, with initial concentrations estimated via a photochemical age-based parameterisation method. The comparative analysis of initial and measured VOC values provided insights into the VOCs' photochemical degradation during transport. Findings highlight that the average photochemical loss of total VOCs (TVOCs) across different refinery process areas varied between 4.9 and 506.8 ppb, averaging 187.5 ± 128.7 ppb. Alkenes dominated the consumed VOCs at 83.1 %, followed by aromatic hydrocarbons (9.3 %), alkanes (6.1 %), and oxygenated VOCs (OVOCs) at 1.6 %. The average consumption-based ozone formation potential (OFP) and SOA formation potential (SOAP) were calculated at 1767.3 ± 1251.1 ppb and 2959.6 ± 2386.3 ppb, respectively. Alkenes, primarily isoprene, 1,3-butadiene, and acetylene, were the most significant contributors to OFP, ranging from 19.9 % to 95.5 %. Aromatic hydrocarbons, predominantly monocyclic aromatics like toluene, xylene, styrene, and n-dodecane, were the primary contributors to SOAP, accounting for 5.0 % to 81.3 %. This research underscores the significance of considering photochemical losses in VOCs for accurate secondary pollution assessment, particularly in high-reactivity VOC species. It also provides new detection methods and accurate data for the characterization, source analysis and chemical conversion of volatile organic compounds in the petroleum refining industry.

Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone.

The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 µM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

Sources of elevated organic acids in the mountainous background atmosphere of southern China.

Formic acid (FA) and acetic acid (AA) are pivotal organic acids in the troposphere, significantly influencing atmospheric chemistry. However, their abundance and sources in the mountainous background atmosphere remain underexplored. We undertook continuous measurements of FA and AA in Nanling mountains, southern China, during autumn 2020 using a high-resolution time-of-flight chemical ionization mass spectrometer (HR-ToF-CIMS). Both acids registered higher concentrations than in other global high-altitude or forested locations, averaging at 0.89 (max: 3.91) and 0.95 (max: 3.52) ppbv for FA and AA, respectively. High concentrations of FA and AA in this forested background area arose from secondary formation and biomass burning, collectively contributing 71 % to 89 %. During episodes, FA and AA concentrations surged 2-3 times, owing to the enhanced atmospheric oxidation capacity. The secondary FA production was predominantly due to isoprene oxidation among the VOC precursors studied. However, observed inconsistencies between calculated and actual FA concentrations suggest overlooked precursors or mechanisms warranting further investigation. Our findings can enhance the understanding of organic acid characteristics and the interplay of biogenic and anthropogenic sources in the background atmosphere.

Lusianthridin ameliorates high fat diet-induced metabolic dysfunction-associated fatty liver disease via activation of FXR signaling pathway.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease, but there are few specific medications for it. Lusianthridin, a major phenanthrene component that originates from Dendrobium Sonia, has various in vitro biological functions. In this study, we aimed to evaluate the therapeutic effects of lusianthridin on high-fat diet (HFD)-induced MAFLD as well as to examine the mechanism of its effects. We fed male mice high-fat-diet for 12 weeks to induce MAFLD and then continued to feed them, either with or without lusianthridin, for another six weeks. We found that lusianthridin decreased serum triacylglycerol, hepatic triacylglycerol, and serum low density lipoprotein cholesterol. It also reduced hepatic lipid accumulation based on the results of morphology analysis. Besides, it improved hepatic inflammation as well, including a decrease in serum alanine aminotransferase and a reduction in macrophage and neutrophil infiltration. Mechanistically, surface plasmon resonance, cell thermal shift assay and dual-luciferase report system results suggested that lusianthridin combined with farnesoid X receptor (FXR) ligand binding region and activated its transcriptional activity. Lusianthridin also decreased de no lipogenesis though inhibiting Srebp1c and downstream Scd-1, Lpin1 and Dgat2 expression in a FXR-dependent manner in oleic acid treated L02 cells. Correspondingly, lusianthridin inhibited Srebp1c and downstream lipogenesis in MAFLD liver tissues of mice at both of genetic and protein levels. Finally, the protective effects of lusianthridin on hepatic steaotosis were abolished in Fxr-/- mice. Taken together, our results suggested that lusianthridin attenuated high-fat-diet induced MAFLD via activation the FXR signaling pathway.

Mechanisms and structure-activity relationships of polysaccharides in the intervention of Alzheimer's disease: A review.

Alzheimer's disease (AD) is a complex neurodegenerative disease. Despite several decades of research, the development of effective treatments and responses for Alzheimer's disease remains elusive. The utilization of polysaccharides for Alzheimer's disease became more popular due to their beneficial characteristics, notably their multi-target activity and low toxicity. This review mainly focuses on the researches of recent 5 years in the regulation of AD by naturally derived polysaccharides, systematically lists the possible intervention pathways of polysaccharides from different mechanisms, and explores the structure-activity relationship between polysaccharide structural activities, so as to provide references for the intervention and treatment of AD by polysaccharides.

Plastid phylogenomics of the tribe potentilleae (Rosaceae).

The tribe Potentilleae comprises approximately 1700 species in 13 genera, making it one of the largest of the 16 tribes in Rosaceae. Our understanding of the composition and relationships among members of Potentilleae has advanced dramatically with the application of molecular markers in the last two decades. Yet there is still much work remaining toward a robust phylogenetic framework for the entire Potentilleae and a comprehensive genus-level dating framework for the tribe. The goals of the present study were to establish a phylogenetic framework for Potentilleae, infer the origin and diversification of the tribe using a temporal framework, and explore the taxonomic implications in light of the updated phylogenetic framework. We used the plastome sequences from 158 accessions representing 139 taxa covering all 13 recognized genera of the tribe to reconstruct the Potentilleae phylogeny. High phylogenetic resolution was recovered along the Potentilleae backbone. Two major clades were recovered within Potentilleae, corresponding to the two subtribes Fragariinae and Potentillinae. Within Fragariinae, two subclades were recovered. In one subclade, Sibbaldia sensu stricto is sister to a clade containing Sibbaldianthe, Comarum, Farinopsis, and Alchemilla sensu lato. In the other subclade, Fragaria is sister to a clade comprising Chamaerhodos, Chamaecallis, Drymocallis, Dasiphora, and Potaninia. Within Potentillinae, Argentina is sister to Potentilla sensu stricto. Within Potentilla sensu stricto, clade Himalaya is sister to Alba, and the Himalaya-Alba clade together is sister to a clade comprising Reptans, Potentilla ancistrifolia Bunge, Fragarioides, Ivesioid, and Argentea. Divergence time estimates indicated that tribe Potentilleae originated during the middle Eocene, and subtribes Fragariinae and Potentillinae diverged around the Eocene-Oligocene transition, and divergence times dated for Potentilleae genera ranged from the early Miocene to the late Pleistocene.

The complete chloroplast genome of Geum longifolium (Maxim.) Smedmark 2006 (Rosaceae: Colurieae) and its phylogenomic implications.

Geum longifolium (Maxim.) Smedmark 2006 belongs to the family Rosaceae, subfamily Rosoideae, tribe Colurieae. Geum longifolium is endemic to China and its whole herb is used in Chinese medicine. Here, the first complete chloroplast (cp) genome of G. longifolium was assembled and annotated based on genome skimming, and its phylogenetic position was investigated using phylogenomic evidence. The cp genome size of G. longifolium was 155,884 bp with the total GC content of 36.7%. Its cp genome presented a typical tetrad structure, composed of a large single copy (LSC) region (85,338 bp), a small single copy (SSC) region (18,358 bp), and a pair of inverted repeat (IR) regions (26,094 bp). The cp genome encoded 129 genes, including 84 protein-coding genes, 37 tRNA genes, and eight rRNA genes. Phylogenetic analysis indicated that G. longifolium was sister to G. elatum Wall. ex G.Don 1832 in current taxa sampling. This study can enrich the chloroplast genomic resource of Geum and lay the foundation for future phylogenetic studies on Geum.

Tibetan Plateau is vulnerable to aromatic-related photochemical pollution and health threats: A case study in Lhasa.

Anthropogenic aromatics play a key role in photochemical pollution and pose a serious threat to human health. Current knowledge on source characteristics of aromatics in the urban region of the Tibetan Plateau (TP), the "Third Pole" and ecologically sensitive area, remains limited. In this study, an intensive observation of 17 aromatic hydrocarbons was conducted in Lhasa, the cultural and economic center of TP, during the second Tibetan Plateau Scientific Expedition and Research in summer 2020. The results showed that the average concentration of aromatics in Lhasa (7.6 ± 7.4 ppbv) was unexpectedly higher than those in megacities such as Beijing, Shanghai, and Guangzhou. Tripled concentrations and corresponding ozone formation potential during pollution episodes were recorded. Further source apportionment using positive matrix factorization revealed that solvent usage (60.0 %) was the dominant source, which may be due to the extremely low atmospheric pressure. Vehicle exhaust (15.4 %), industrial emissions (12.8 %), fuel evaporation (6.2 %), and burning emissions (5.7 %) were also important sources. The concentration weighted trajectory analysis revealed that the observed high levels of aromatics were mainly driven by local anthropogenic emissions, rather than the regional transport by the Indian summer monsoon. Long-term exposure to aromatics in Lhasa was assessed to pose carcinogenic risks to the population, with the risks of benzene and ethylbenzene 5 times the criteria. Our results suggest that, given the magnified emissions of aromatics in this extreme environment (low atmospheric pressure and strong solar radiation), the implementation of targeted pollution controls is urgently needed to mitigate the aromatic-related photochemical pollution and health threats in TP.

Three-dimensional visualization and evaluation of hilar cholangiocarcinoma resectability and proposal of a new classification.

BACKGROUND: As digital medicine has exerted profound influences upon diagnosis and treatment of hepatobiliary diseases, our study aims to investigate the accuracy of three-dimensional visualization and evaluation (3DVE) system in assessing the resectability of hilar cholangiocarcinoma (hCCA), and explores its potential clinical value. MATERIALS AND METHODS: The discovery cohort, containing 111 patients from April 2013 to December 2019, was retrospectively included to determine resectability according to revised criteria for unresectability of hCCA. 3D visualization models were reconstructed to evaluate resectability parameters including biliary infiltration, vascular involvement, hepatic atrophy and metastasis. Evaluation accuracy were compared between contrast-enhanced CT and 3DVE. Logistic analysis was performed to identify independent risk factors of R0 resection. A new comprehensive 3DVE classification of hCCA based on factors influencing resectability was proposed to investigate its role in predicting R0 resection and prognosis. The main outcomes were also analyzed in cohort validation, including 34 patients from January 2020 to August 2022. RESULTS: 3DVE showed an accuracy rate of 91% (95%CI 83.6-95.4%) in preoperatively evaluating hCCA resectability, significantly higher than 81% (95%CI 72.8-87.7%) of that of CT (p = 0.03). By multivariable analysis, hepatic artery involvement in 3DVE was identified an independent risk factor for R1 or R2 resection (OR = 3.5, 95%CI 1.4,8.8, P < 0.01). New 3DVE hCCA classification was valuable in predicting patients' R0 resection rate (p < 0.001) and prognosis (p < 0.0001). The main outcomes were internally validated. CONCLUSIONS: 3DVE exhibited a better efficacy in evaluating hCCA resectability, compared with contrast-enhanced CT. Preoperative 3DVE demonstrated hepatic artery involvement was an independent risk factor for the absence of R0 margin. 3DVE classification of hCCA was valuable in clinical practice.

An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression.

Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.

Case report: Prenatal diagnosis of rare chromosome mosaicism: discordant results between chorionic villi and amniotic fluid samples.

Objective: We described a unique case of near-negative chromosome mosaicism in chorionic villi but complete monosomy X in amniotic fluid. Methods: Chorionic villus sampling and amniocentesis were performed separately in the first and second trimesters. Chromosomal microarray (CMA) and rapid aneuploidy detection (QF-PCR and FISH) were performed on placental villi and uncultured amniotic fluid. After pregnancy termination, the placenta, umbilical cord, and fetal muscle tissues were sampled for FISH detection. Results: The CMA revealed a lower signal from chromosome X in chorionic villi, with a copy number of 1.85, implying the presence of mosaic monosomy X. However, the QF-PCR and FISH results were nearly normal. In uncultured amniotic fluid, CMA and rapid aneuploidy detection indicated complete monosomy X. Across different sampling points on the aborted fetus, the FISH results varied from normal, to mosaic, and then complete monosomy X. Conclusion: This case presents a rare and complex situation where sampling from uncultured chorionic villi indicated low-level chromosome mosaicism, while sampling from amniotic fluid revealed complete monosomy X. Although some of these discordant outcomes may be due to methodological limitations, we conclude that prenatal consultation should be combined with fetal ultrasound phenotype and genetic testing for a comprehensive evaluation of fetal genetic abnormalities.

Association between C-reactive protein-albumin-lymphocyte (CALLY) index and overall survival in patients with colorectal cancer: From the investigation on nutrition status and clinical outcome of common cancers study.

Background: Colorectal cancer (CRC) is among the most common malignant cancers worldwide, and its development is influenced by inflammation, nutrition, and the immune status. Therefore, we combined C-reactive protein (CRP), albumin, and lymphocyte, which could reflect above status, to be the CRP-albumin-lymphocyte (CALLY) index, and evaluated its association with overall survival (OS) in patients with CRC. Methods: The clinicopathological and laboratory characteristics of 1260 patients with CRC were collected from the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) study. Cox regression analysis was performed to assess the association between the CALLY index and OS. A nomogram including sex, age, the CALLY index and TNM stage was constructed. The Concordance Index (C-index) was utilized to evaluate the prognostic value of the CALLY index and classical CRC prognostic factors, such as modified Glasgow prognostic score (mGPS), neutrocyte to lymphocyte ratio (NLR), systemic immune inflammation index (SII), and platelet to lymphocyte ratio (PLR), as well as to assess the prognostic value of the nomogram and TNM stage. Results: Multivariate Cox regression analyses demonstrated that the CALLY index was independently associated with OS in patients with CRC [Hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.87-0.95, P<0.001]. The CALLY index showed the highest prognostic value (C-index = 0.666, 95% CI = 0.638-0.694, P<0.001), followed by mGPS, NLR, SII, and PLR. The nomogram demonstrated higher prognostic value (C-index = 0.784, 95% CI = 0.762-0.807, P<0.001) than the TNM stage. Conclusion: The CALLY index was independently associated with OS in patients with CRC and showed higher prognostic value than classical CRC prognostic factors. The nomogram could provide more accurate prognostic prediction than TNM stage.

Systemic inflammation with sarcopenia predicts survival in patients with gastric cancer.

OBJECTIVE: The levels of platelet-related inflammation indicators and sarcopenia have been reported to affect the survival of patients with cancer. To evaluate the prognostic influence of platelet count (PLT), platelet lymphocyte ratio (PLR), and systemic immune inflammation index (SII), and SII combined with sarcopenia on the survival of patients with gastric cancer (GC). METHODS: A total of 1133 patients with GC (812 male and 321 female, average age: 59.43 years) were evaluated. Receiver-operating characteristic curves were used to determine the best cutoff values of PLT, PLR, and SII, and univariate and multivariate Cox risk regression models were used to evaluate whether SII is an independent predictor of overall survival (OS). The prognostic SS (SII-sarcopenia) was established based on SII and sarcopenia. Finally, a comprehensive analysis of the prognostic SS was performed. RESULTS: SII had the strongest prognostic effect. The SII and OS of patients with GC were in an inverted U-shape (adjusted HR = 1.07; 95% CI 0.97-1.19; adjusted P = 0.179). In patients with SII > 1800, SII was negatively correlated with OS (adjusted HR = 0.57; 95% CI 0.29-1.12; adjusted P = 0.102), however, there is no statistical difference. Interestingly, a high SS was associated with a poorer prognosis. The higher the SS score was, the worse the OS (P < 0.001). CONCLUSION: SII is an independent prognostic indicator of GC, and high SII is related to poor prognosis. A higher SS score had worse survival. Thus, the prognostic SS is a reliable predictor of OS in patients with GC.

Handgrip weakness, systemic inflammation indicators, and overall survival in lung cancer patients with well performance status: A large multicenter observational study.

BACKGROUND: Systemic inflammation and handgrip weakness have been used to predict mortality in many cancers. The purpose of current study was to evaluate the association of co-occurrence of inflammation indicators and handgrip weakness with overall survival (OS) of lung cancer (LC) patients with good performance status. METHODS: The cutoff points for handgrip strength (HGS) and the four inflammation indicators were calculated using Maxstat. The time-dependent receiver operating characteristic curve and C-index were used to select optimal inflammation indicator for predicting OS of LC patients. The Cox proportional hazard regression model was used to calculate the hazard ratio (HR) of mortality. Kaplan-Meier curves were constructed to evaluate the association of indicators and the OS of LC patients. RESULTS: Among the 1951 patients, the mean ± standard deviation (SD) age was 60.6 ± 9.9 years, and 1300 (66.6%) patients were male. In patients with good performance status (PS), handgrip weakness (HR, 1.49; 95% confidence interval [95% CI], 1.30-1.70, p < 0.001) and low advanced lung cancer inflammation index (ALI) (HR, 2.05; 95%CI, 1.79-2.34, p < 0.001), high systemic immune-inflammation index (SII) (HR, 1.91; 95%CI, 1.66-2.19, p < 0.001), high platelet: lymphocyte ratio (PLR) (HR, 1.60; 95%CI, 1.40-1.82, p < 0.001), or high neutrophil: lymphocyte ratio (NLR) (HR, 2.01; 95%CI, 1.76-2.30, p < 0.001) were associated with increased mortality risk of LC patients. ALI had better C-index (0.624) and time-AUC in the prediction of OS in LC patients with good PS than other three combinations. The co-occurrence of handgrip weakness and low ALI more than doubled the risk of death in LC with good PS (HR, 2.44; 95% CI, 2.06-2.89, p < 0.001). CONCLUSION: In LC patients who have good PS, patients with combined handgrip weakness and low ALI have the worst prognosis. THE TRIAL REGISTRATION NUMBER: ChiCTR1800020329.

Schisantherin A alleviates non-alcoholic fatty liver disease by restoring intestinal barrier function.

Background: Non-alcoholic fatty liver disease (NAFLD) is intricately linked to dysregulation of the gut-liver axis, and correlated with intestinal inflammation and barrier disruption. Objectives: To investigate the protective effects and possible molecular mechanism of Schisantherin A (Sin A) in a high-fat diet (HFD) induced NAFLD mouse model. Methods: HFD-fed NAFLD mice were treated with the vehicle and 80 mg/kg Sin A every day for 6 weeks. The gut permeability of the NAFLD mice was assessed by intestinal permeability assays in vivo and transepithelial electrical resistance (TEER) measurements in vitro were also used to evaluate the function of the gut barrier. TLR4 inhibitor was then used to investigate the impact of Sin A in the LPS- TLR4 signaling pathway. Alternatively, the composition of the microbiome was assessed using 16S rRNA amplification. Finally, the experiment of antibiotic treatment was performed to elucidate the roles of the gut microbiome mediating Sin A induced metabolic benefits in the NAFLD mice. Results: We found that Sin A potently ameliorated HFD-induced hepatic steatosis and inflammation, alleviated gut inflammation, and restored intestinal barrier function. We also observed that Sin A improved gut permeability and reduced the release of lipopolysaccharide (LPS) into circulation and further found that Sin A can suppress LPS-TLR4 signaling to protect against HFD-induced NAFLD. Sin A treatment altered the composition of the microbiome in NAFLD mice compared to vehicle controls. Conclusions: Sin A is an effective and safe hepatoprotective agent against HFD-induced NAFLD by partly ameliorating gut inflammation, restoring intestinal barrier function, and regulating intestinal microbiota composition.

Synthetic flavokawain analog (E)-1-(2'-hydroxy-4',6'-dimethoxyphenyl)-3-(3-methoxy-4-(3-morpholinopropoxy)phenyl)prop-2-en-1-one (FK-morph) effectively regresses endometriotic implants in rats.

Endometriosis is an estrogen-dependent inflammatory gynecological disorder that is pathologically defined as the growth of endometrial glands and stroma outside of the uterine cavity. It is estimated that more than 15% of women of reproductive age are affected by endometriosis. Immunological and inflammatory responses, anti-apoptotic effects and angiogenesis processes have been reported to be involved in endometriosis. Surgery and pharmacotherapy are applied in the treatment of this disease. Frustratingly, a high recurrence rate and/or side effects are observed during and after the treatments. In our previous study, we designed and synthesized serial analogs of naturally occurring flavokawain chalcones. Among these molecules, FK-morph exhibited excellent anti-inflammatory activity and showed therapeutic potential in vitro and in vivo. In the current study, we demonstrate the beneficial effects of FK-morph on a surgically induced endometriosis rat model. After treatment with FK-morph, the volumes and adhesion scores of implants in rats were effectively reduced and the levels of inflammatory cytokines and related chemokines in peritoneal fluid and blood were significantly downregulated. FK-morph also mediated cell apoptosis of endometriosis foci. In addition, the angiogenesis process was attenuated by decreasing the expression of VEGF. Meanwhile, the underlying mechanism was further explored. FK-morph effectively reduced the expression of Akt, p-Akt, PI3K, p-PI3K and NF-κB in endometriosis lesions. Overall, the results revealed the efficacy of FK-morph against endometriosis by reducing the levels of inflammatory factors, accelerating apoptosis and attenuating angiogenesis, which may be associated with blocking the activation of the PI3K/Akt and NF-κB signaling pathways.

Metabolomics reveals the mechanism of polyethylene microplastic toxicity to Daphnia magna.

Microplastic exposure leads to various toxic effects in Daphnia magna; however, the effects of microplastics on the metabolic processes in D. magna and the corresponding molecular toxicity mechanisms remain unclear. In the present study, the effects of acute exposure to polyethylene microplastics with different particle sizes (20 µm [MPs-20] and 30 µm [MPs-30]) on metabolites in D. magna and the mechanisms of toxicity were investigated by combining metabolomics and traditional toxicology techniques. Exposure to both MPs-20 and MPs-30 resulted in significant accumulation of microplastics in the gut of D. magna and significantly reduced D. magna survival and heart rate. Metabolomics analysis revealed that MPs-20 and MPs-30 induced significant changes in up to 88 and 91 differential metabolites, respectively, and collectively induced significant changes in 75 metabolites in D. magna. Among lipid metabolites, MPs-20 specifically downregulated phosphatidylcholine and upregulated phosphatidylethanolamine, which mainly affected phospholipid metabolism, whereas MPs-30 specifically downregulated amino acid metabolites l-glutamine, l-glutamate and malic acid, which mainly interfered with energy metabolism. The results of this study provide novel insights into the mechanism of effects of microplastics on metabolic processes in D. magna.