Ebola Virus Epidemiology, Transmission, and Evolution during Seven Months in Sierra Leone.

The 2013-2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission.

Scavenger receptor B2, a type III membrane pattern recognition receptor, senses LPS and activates the IMD pathway in crustaceans.

The immune deficiency (IMD) pathway is critical for elevating host immunity in both insects and crustaceans. The IMD pathway activation in insects is mediated by peptidoglycan recognition proteins, which do not exist in crustaceans, suggesting a previously unidentified mechanism involved in crustacean IMD pathway activation. In this study, we identified a Marsupenaeus japonicus B class type III scavenger receptor, SRB2, as a receptor for activation of the IMD pathway. SRB2 is up-regulated upon bacterial challenge, while its depletion exacerbates bacterial proliferation and shrimp mortality via abolishing the expression of antimicrobial peptides. The extracellular domain of SRB2 recognizes bacterial lipopolysaccharide (LPS), while its C-terminal intracellular region containing a cryptic RHIM-like motif interacts with IMD, and activates the pathway by promoting nuclear translocation of RELISH. Overexpressing shrimp SRB2 in Drosophila melanogaster S2 cells potentiates LPS-induced IMD pathway activation and diptericin expression. These results unveil a previously unrecognized SRB2-IMD axis responsible for antimicrobial peptide induction and restriction of bacterial infection in crustaceans and provide evidence of biological diversity of IMD signaling in animals. A better understanding of the innate immunity of crustaceans will permit the optimization of prevention and treatment strategies against the arising shrimp diseases.

SLC25A3 negatively regulates NLRP3 inflammasome activation by restricting the function of NLRP3.

The NACHT, leucine-rich repeat, and pyrin domains-containing protein 3 (collectively known as NLRP3) inflammasome activation plays a critical role in innate immune and pathogenic microorganism infections. However, excessive activation of NLRP3 inflammasome will lead to cellular inflammation and tissue damage, and naturally it must be precisely controlled in the host. Here, we discovered that solute carrier family 25 member 3 (SLC25A3), a mitochondrial phosphate carrier protein, plays an important role in negatively regulating NLRP3 inflammasome activation. We found that SLC25A3 could interact with NLRP3, overexpression of SLC25A3 and knockdown of SLC25A3 could regulate NLRP3 inflammasome activation, and the interaction of NLRP3 and SLC25A3 is significantly boosted in the mitochondria when the NLRP3 inflammasome is activated. Our detailed investigation demonstrated that the interaction between NLRP3 and SLC25A3 disrupted the interaction of NLRP3-NEK7, promoted ubiquitination of NLRP3, and negatively regulated NLRP3 inflammasome activation. Thus, these findings uncovered a new regulatory mechanism of NLRP3 inflammasome activation, which provides a new perspective for the therapy of NLRP3 inflammasome-associated inflammatory diseases.

GSK3ß: A ray of hope for the treatment of diabetic kidney disease.

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by its complex pathogenesis, high risk of chronic renal failure, and lack of effective diagnosis and treatment methods. GSK3ß (glycogen synthase kinase 3ß), a highly conserved threonine/serine kinase, was found to activate glycogen synthase. As a key molecule of the glucose metabolism pathway, GSK3ß participates in a variety of cellular activities and plays a pivotal role in multiple diseases. However, these effects are not only mediated by affecting glucose metabolism. This review elaborates on the role of GSK3ß in DKD and its damage mechanism in different intrinsic renal cells. GSK3ß is also a biomarker indicating the progression of DKD. Finally, the protective effects of GSK3ß inhibitors on DKD are also discussed.

The CREB1/WNK1 axis promotes the tumorigenesis of ovarian cancer via regulating HIF-1.

The aim of this study was to explore the functions and molecular mechanisms of the WNK lysine deficient protein kinase 1 (WNK1) in the development of ovarian cancer. Firstly, loss- and gain-of-function assays were carried out and subsequently cell proliferation, apoptosis, invasion and migration were detected. Furthermore, WNK1 action on glucose uptake, lactate production and adenosine triphosphate (ATP) level were assessed. The roles of WNK1 on cisplatin resistance were explored using CCK-8, colony formation, and flow cytometry in vitro. Immunohistochemistry, Western blot and qRT-PCR were conducted to determine the protein and mRNA expression. Additionally, tumor growth in vivo was also monitored. We found that the overexpression of WNK1 predicted a bad prognosis of ovarian cancer patients. WNK1 enhanced the malignant behavior and facilitated glycolysis of ovarian cancer cells. Moreover, WNK1 increased cisplatin resistance in ovarian cancer cells. Mechanistically, we found that WNK1 expression was promoted by CREB1 at the transcriptional level. And CREB1 could facilitate ovarian cancer cells malignant behavior through target upregulating WNK1. Besides, we also showed that WNK1 facilitated the malignant behavior by accelerating HIF-1 expression. In xenograft tumor tissues, the downregulation of WNK1 significantly reduced HIF-1α expression. These data demonstrated that the CREB1/WNK1 axis could promote the tumorigenesis of ovarian cancer via accelerating HIF-1 expression, suggesting that the CREB1/WNK1 axis could be a potential target during the therapy of ovarian cancer.

Total Synthesis of (±)-Rubriflordilactone A.

A new and efficient synthesis of rubriflordilactone A has been realized. The key transformations include the following: (1) an intramolecular Prins cyclization to establish the seven-membered ring containing two contiguous stereocenters; (2) a Mukaiyama hydration/oxa-Michael cascade to construct the B-ring; and (3) an unprecedented stereocontrol intermolecular o-QM type [4 + 2]-cycloaddition to rapidly assemble core structure of rubriflordilactone A.

Rhodium(I)-Catalyzed Annulation of Bicyclo[1.1.0]butyl-Substituted Dihydroquinolines and Dihydropyridines.

Bicyclo[1.1.0]butane-containing compounds feature a unique chemical reactivity, trigger "strain-release" reaction cascades, and provide novel scaffolds with considerable utility in the drug discovery field. We report the synthesis of new bicyclo[1.1.0]butane-linked heterocycles by a nucleophilic addition of bicyclo[1.1.0]butyl anions to 8-isocyanatoquinoline, or, alternatively, iminium cations derived from quinolines and pyridines. The resulting bicyclo[1.1.0]butanes are converted with high regioselectivity to unprecedented bridged heterocycles in a rhodium(I)-catalyzed annulative rearrangement. The addition/rearrangement process tolerates a surprisingly large range of functional groups. Subsequent chemo- and stereoselective synthetic transformations of urea, alkene, cyclopropane, and aniline moieties of the 1-methylene-5-azacyclopropa[cd]indene scaffolds provide several additional new heterocyclic building blocks. X-ray structure-validated quantum mechanical DFT calculations of the reaction pathway indicate the intermediacy of rhodium carbenoid and metallocyclobutane species.

White spot syndrome virus directly activates mTORC1 signaling to facilitate its replication via polymeric immunoglobulin receptor-mediated infection in shrimp.

Previous studies have shown that the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has antiviral functions or is beneficial for viral replication, however, the detail mechanisms by which mTORC1 enhances viral infection remain unclear. Here, we found that proliferation of white spot syndrome virus (WSSV) was decreased after knockdown of mTor (mechanistic target of rapamycin) or injection inhibitor of mTORC1, rapamycin, in Marsupenaeus japonicus, which suggests that mTORC1 is utilized by WSSV for its replication in shrimp. Mechanistically, WSSV infects shrimp by binding to its receptor, polymeric immunoglobulin receptor (pIgR), and induces the interaction of its intracellular domain with Calmodulin. Calmodulin then promotes the activation of protein kinase B (AKT) by interaction with the pleckstrin homology (PH) domain of AKT. Activated AKT phosphorylates mTOR and results in the activation of the mTORC1 signaling pathway to promote its downstream effectors, ribosomal protein S6 kinase (S6Ks), for viral protein translation. Moreover, mTORC1 also phosphorylates eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which will result in the separation of 4EBP1 from eukaryotic translation initiation factor 4E (eIF4E) for the translation of viral proteins in shrimp. Our data revealed a novel pathway for WSSV proliferation in shrimp and indicated that mTORC1 may represent a potential clinical target for WSSV control in shrimp aquaculture.

The targeting of DAPK1 with miR-190a-3p promotes autophagy in trophoblast cells.

Pre-eclampsia (PE) is a dangerous pathological status that occurs during pregnancy and is a leading reason for both maternal and fetal death. Autophagy is necessary for cellular survival in the face of environmental stress as well as cellular homeostasis and energy management. Aberrant microRNA (miRNA) expression is crucial in the pathophysiology of PE. Although studies have shown that miRNA (miR)-190a-3p function is tissue-specific, the precise involvement of miR-190a-3p in PE has yet to be determined. We discovered that miR-190a-3p was significantly lower and death-associated protein kinase 1 (DAPK1) was significantly higher in PE placental tissues compared to normal tissues, which is consistent with the results in cells. The luciferase analyses demonstrated the target-regulatory relationship between miR-190a-3p and DAPK1. The inhibitory effect of miR-190a-3p on autophagy was reversed by co-transfection of si-DAPK1 and miR-190a-3p inhibitors. Thus, our data indicate that the hypoxia-dependent miR-190a-3p/DAPK1 regulatory pathway is implicated in the development and progression of PE by promoting autophagy in trophoblast cells.

Enhancing Nix-dependent mitophagy relieves AKI by restricting TREM-1-mediated hyperactivation of inflammasome in platelets.

Platelets are highly involved in inflammation and organ injury under pathological conditions. The mitophagy in platelets may restrict hyperactivation of the inflammasome and relieve acute kidney injury (AKI). Cecal ligation puncture (CLP)/LPS-induced AKI Triggering receptor expressed on myeloid cells (TREM-1)-knockout mice models were established. Additionally, septic patients with AKI were also included. TREM-1 expression in platelets and inflammasome activation were examined. Platelet transfer assays were performed to investigate the contribution of platelet TREM-1 to renal injury. Mitophagy was evaluated in the context of inflammation. BNIP3L/Nix knockout mice were used to examine the relationship between platelet mitophagy and inflammatory activation. The results showed that the level of TREM-1 was increased and the platelet inflammasome was hyperactivated in CLP mice and septic patients, and TREM-1 activated platelet inflammasomes. TREM-1 deletion significantly abrogated hyperactivation of the platelet inflammasome and dramatically reduced AKI, whereas ablation of the mitophagy receptor BNIP3L/Nix induced the accumulation of damaged mitochondria and hyperactivation of platelet inflammasomes in CLP mice. BNIP3L/Nix controlled platelet inflammasome activation, and an amplification loop of platelet inflammasome activation and dysfunctional mitochondria controlled sepsis-related AKI. Therefore, targeting TREM-1 and NLRP3/BNIP3L in platelets may represent a novel therapeutic strategy for treating septic AKI.

The amino acid sensor MetRS is required for methionine-induced milk protein synthesis in a domestic pigeon model.

This study was conducted to investigate whether methionyl-tRNA synthetase (MetRS) is a mediator of Met-induced crop milk protein synthesis via the janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signalling pathway in breeding pigeons. In Experiment 1, a total of 216 pairs of breeding pigeons were divided into 3 groups (control, Met-deficient, and Met-rescue groups). In Experiments 2 and 3, forty pairs of breeding pigeons from each experiment were allocated into 4 groups. The 2nd experiment included a control group and 3 MetRS inhibitor (REP8839) groups. The 3rd experiment included a Met-deficient group, Met-sufficient group, REP8839 + Met-deficient group, and REP8839 + Met-sufficient group. Experiment 1 showed that Met supplementation increased crop development, crop milk protein synthesis, the protein expression of MetRS and JAK2/STAT5 signalling pathway, and improved squab growth. Experiment 2 showed that crop development, crop milk protein synthesis, and the protein expression of MetRS and the JAK2/STAT5 signalling pathway were decreased, and squab growth was inhibited by the injection of 1.0 mg/kg BW REP8839, which was the selected dose for the 3rd experiment. These results showed that Met supplementation increased crop development, crop milk protein synthesis, and the expression of MetRS and JAK2/STAT5 signalling pathway and rescued squab growth after the injection of REP8839. Moreover, the Co-IP results showed that there was an interaction between MetRS and JAK2. Taken together, these findings indicate that MetRS mediates Met-induced crop milk protein synthesis via the JAK2/STAT5 signalling pathway, resulting in improved squab growth in breeding pigeons.

Prognostic Utility of Left Atrial Strain From MRI Feature Tracking in Ischemic and Nonischemic Dilated Cardiomyopathy: A Multicenter Study.

BACKGROUND. MRI-based prognostic evaluation in patients with dilated cardiomyopathy (DCM) has historically used markers of late gadolinium enhancement (LGE) and feature tracking (FT)-derived left ventricular global longitudinal strain (LVGLS). Early data indicate that FT-derived left atrial strain (LAS) parameters, including reservoir, conduit, and booster, may also have prognostic roles in such patients. OBJECTIVE. The purpose of our study was to evaluate the prognostic utility of LAS parameters, derived from MRI FT, in patients with ischemic or nonischemic DCM, including in comparison with the traditional parameters of LGE and LVGLS. METHODS. This retrospective study included 811 patients with ischemic or nonischemic DCM (median age, 60 years; 640 men, 171 women) who underwent cardiac MRI at any of five centers. FT-derived LAS parameters and LVGLS were measured using two- and four-chamber cine images. LGE percentage was quantified. Patients were assessed for a composite outcome of all-cause mortality or heart failure hospitalization. Multivariable Cox regression analyses including demographic characteristics, cardiovascular risk factors, medications used, and a wide range of cardiac MRI parameters were performed. Kaplan-Meier analyses with log-rank tests were also performed. RESULTS. A total of 419 patients experienced the composite outcome. Patients who did, versus those who did not, experience the composite outcome had larger LVGLS (-6.7% vs -8.3%, respectively; p < .001) as well as a smaller LAS reservoir (13.3% vs 19.3%, p < .001), LAS conduit (4.7% vs 8.0%, p < .001), and LAS booster (8.1% vs 10.3%, p < .001) but no significant difference in LGE (10.1% vs 11.3%, p = .51). In multivariable Cox regression analyses, significant independent predictors of the composite outcome included LAS reservoir (HR = 0.96, p < .001) and LAS conduit (HR = 0.91, p < .001). LAS booster and LGE were not significant independent predictors in the models. LVGLS was a significant independent predictor only in a model that initially included LAS booster but not the other LAS parameters. In Kaplan-Meier analysis, all three LAS parameters were significantly associated with the composite outcome (p < .001). CONCLUSION. In this multicenter study, LAS reservoir and LAS conduit were significant independent prognostic markers in patients with ischemic or nonischemic DCM, showing greater prognostic utility than the currently applied markers of LVGLS and LGE. CLINICAL IMPACT. FT-derived LAS analysis provides incremental prognostic information in patients with DCM.

UiO-66/PIM-1 Mixed-Matrix Membrane for Hexane Isomer Separation.

The separation of high-octane dibranched alkanes from naphtha is critical in the refining of gasoline. To date, research on the membrane-based separation of alkane isomers has been limited, with a particular paucity of investigations into mixed-matrix membranes. Herein, the continuous and dense UiO-66/PIM-1 mixed-matrix membrane, which was prepared through precise control of the interfacial structure, was first applied to the differentiation of C6 alkane isomers. Due to the synergistic combination of UiO-66 with differential adsorption capabilities for alkanes and PIM-1 that possesses a cross-linkable structure, the resulting UiO-66/PIM-1-(20) membrane demonstrated remarkable separation performance and high stability. Pervaporation measurements showed that the mass fraction of 2,2-dimethylbutane in the feed side was increased from 50.0 to 75.8 wt % while an excellent flux of 1700 g m-2 h-1 was maintained over a continuous 40 h period. The UiO-66/PIM-1-(20) membrane, characterized by its facile replication and processing, shows potential for large-scale fabrication. This study offers a new approach to the membrane separation of alkane isomers.

The egg ribonuclease SjCP1412 accelerates liver fibrosis caused by Schistosoma japonicum infection involving damage-associated molecular patterns (DAMPs).

Schistosomiasis, a parasite infectious disease caused by Schistosoma japonicum, often leads to egg granuloma and fibrosis due to the inflammatory reaction triggered by egg antigens released in the host liver. This study focuses on the role of the egg antigens CP1412 protein of S. japonicum (SjCP1412) with RNase activity in promoting liver fibrosis. In this study, the recombinant egg ribonuclease SjCP1412, which had RNase activity, was successfully prepared. By analysing the serum of the population, it has been proven that the anti-SjCP1412 IgG in the serum of patients with advanced schistosomiasis was moderately correlated with liver fibrosis, and SjCP1412 may be an important antigen associated with liver fibrosis in schistosomiasis. In vitro, the rSjCP1412 protein induced the human liver cancer cell line Hep G2 and liver sinusoidal endothelial cells apoptosis and necrosis and the release of proinflammatory damage-associated molecular patterns (DAMPs). In mice infected with schistosomes, rSjCP1412 immunization or antibody neutralization of SjCP1412 activity significantly reduced cell apoptosis and necroptosis in liver tissue, thereby reducing inflammation and liver fibrosis. In summary, the SjCP1412 protein plays a crucial role in promoting liver fibrosis during schistosomiasis through mediating the liver cells apoptosis and necroptosis to release DAMPs inducing an inflammatory reaction. Blocking SjCP1412 activity could inhibit its proapoptotic and necrotic effects and alleviate hepatic fibrosis. These findings suggest that SjCP1412 may be served as a promising drug target for managing liver fibrosis in schistosomiasis japonica.

Structure-Guided Discovery of Diverse Cytotoxic Dimeric Xanthones/Chromanones from Penicillium chrysogenum C-7-2-1 and Their Interconversion Properties.

Xanthone-chromanone homo- or heterodimers are regarded as a novel class of topoisomerase (Topo) inhibitors; however, limited information about these compounds is currently available. Here, 14 new (1-14) and 6 known tetrahydroxanthone chromanone homo- and heterodimers (15-20) are reported as isolated from Penicillium chrysogenum C-7-2-1. Their structures and absolute configurations were unambiguously demonstrated by a combination of spectroscopic data, single-crystal X-ray diffraction, modified Mosher's method, and electronic circular dichroism analyses. Plausible biosynthetic pathways are proposed. For the first time, it was discovered that tetrahydroxanthones can convert to chromanones in water, whereas chromone dimerization does not show this property. Among them, compounds 5, 7, 8, and 16 exhibited significant cytotoxicity against H23 cell line with IC50 values of 6.9, 6.4, 3.9, and 2.6 µM, respectively.

Acetylcholine promotes chronic stress-induced lung adenocarcinoma progression via α5-nAChR/FHIT pathway.

Chronic stress significantly elevates the expression levels of various neurotransmitters in the tumour microenvironment, thereby promoting the cell growth and metastasis of lung adenocarcinoma (LUAD). However, the role of chronic stress in the progression of LUAD remains unclear. In this study, we found that chronic restraint stress increases the levels of the neurotransmitter acetylcholine (ACh), and the α5-nicotinic acetylcholine receptor (α5-nAChR) and decreased fragile histidine triad (FHIT) expression in vivo. Crucially, the increased ACh levels promoted LUAD cell migration and invasion via modulation of the α5-nAChR/DNA methyltransferase 1 (DNMT1)/FHIT axis. In a chronic unpredictable stress (CUMS) mouse model, chronic stress promotes tumour development, accompanied by changes in α5-nAChR, DNMT1, FHIT, and vimentin. Together, these findings reveal a novel chronic stress-mediated LUAD signalling pathway: chronic stress enforces lung adenocarcinoma cell invasion and migration via the ACh/α5-nAChR/FHIT axis, which could be a potential therapeutic target for chronic stress-related LUAD.

Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Clinical characteristics and effects of inhaled corticosteroid in patients with post-COVID-19 chronic cough during the Omicron variant outbreak.

BACKGROUND: Chronic cough is a common symptom in patients post the coronavirus disease 2019 (COVID-19). In this study, we aimed to investigate the efficacy of inhaled corticosteroids (ICS) and the clinical characteristics of patients with post-COVID-19 chronic cough during the Omicron era. METHODS: An ambispective, longitudinal cohort study was conducted that included patients with post-COVID-19 who attended the respiratory clinic at our hospital between January 1, 2023, and March 31, 2023 with a complaint of persistent cough lasting more than 8 weeks. At 30 and 60 days after the first clinic visit for post-COVID-19 chronic cough, enrolled patients were prospectively followed up. We compared the changes in symptoms and pulmonary function between patients receiving ICS treatment (ICS group) and those not receiving ICS treatment (NICS group) at the two visits. RESULTS: A total of 104 patients with post-COVID-19 chronic cough were enrolled in this study (ICS group, n = 51; NICS group, n = 53). The most common symptoms accompanying post-COVID-19 chronic cough were sputum (58.7%, 61/104) and dyspnea (48.1%, 50/104). Seventy-one (82.6%, 71/86) patients had airway hyperresponsiveness, and 49 patients (47.1%, 49/104) were newly diagnosed with asthma. Most patients (95.2%, 99/104) exhibited improvement at 60 days after the first visit. The pulmonary function parameters of the patients in the ICS group were significantly improved compared to the baseline values (P < 0.05), and the improvement in the FEV1/FVC was significantly greater than that in the NICS group (P = 0.003) after 60 days. CONCLUSIONS: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may contribute to the pathogenesis of asthma, which could be the underlying cause of persistent cough post-COVID-19 infection. Post-COVID-19 chronic cough during the Omicron era was often accompanied by sputum, dyspnea, and airway hyperresponsiveness. ICS treatment did not have a significant impact on symptom management of post-COVID-19 chronic cough; however, it can improve impaired lung function in in these individuals.

Metabolome evidence of CKDu risks after chronic exposure to simulated Sri Lanka drinking water in zebrafish.

It is still a serious public health issue that chronic kidney disease of uncertain etiology (CKDu) in Sri Lanka poses challenges in identification, prevention, and treatment. What environmental factors in drinking water cause kidney damage remains unclear. This study aimed to investigate the risks of various environmental factors that may induce CKDu, including water hardness, fluoride (HF), heavy metals (HM), microcystin-LR (MC-LR), and their combined exposure (HFMM). The research focused on comprehensive metabolome analysis, and correlation with transcriptomic and gut microbiota changes. Results revealed that chronic exposure led to kidney damage and pancreatic toxicity in adult zebrafish. Metabolomics profiling showed significant alterations in biochemical processes, with enriched metabolic pathways of oxidative phosphorylation, folate biosynthesis, arachidonic acid metabolism, FoxO signaling pathway, lysosome, pyruvate metabolism, and purine metabolism. The network analysis revealed significant changes in metabolites associated with renal function and diseases, including 20-Hydroxy-LTE4, PS(18:0/22:2(13Z,16Z)), Neuromedin N, 20-Oxo-Leukotriene E4, and phenol sulfate, which are involved in the fatty acyls and glycerophospholipids class. These metabolites were closely associated with the disrupted gut bacteria of g_ZOR0006, g_Pseudomonas, g_Tsukamurella, g_Cetobacterium, g_Flavobacterium, which belonged to dominant phyla of Firmicutes and Proteobacteria, etc., and differentially expressed genes (DEGs) such as egln3, ca2, jun, slc2a1b, and gls2b in zebrafish. Exploratory omics analyses revealed the shared significantly changed pathways in transcriptome and metabolome like calcium signaling and necroptosis, suggesting potential biomarkers for assessing kidney disease.

Synthesis, characterization and in vitro antiproliferative effects of isosteviol derivatives.

Nineteen isosteviol derivatives were designed and synthesized by C-16, C-19 and D-ring modifications of isosteviol. These compounds were screened for their cytotoxic activities against Hela and A549 cells in vitro. Among them, the inhibitory effect of compounds 3b and 16 on Hela cells was comparable to that of the positive control gefitinib, and the compounds 3b (IC50=7.84 ± 0.84 µM) and 7a (IC50=6.89 ± 0.33 µM) exhibited significant cytotoxicity superior to gefitinib (IC50=11.02 ± 3.27 µM) against A549 cells.