PubMed

medRxiv. 2023 Nov 27:2023.11.27.23298990. doi: 10.1101/2023.11.27.23298990. Preprint.ABSTRACTAlzheimer's disease (AD) is influenced by a variety of modifiable risk factors, including a person's dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD's metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean-ketogenic diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.PMID:38076824 | PMC:PMC10705656 | DOI:10.1101/2023.11.27.23298990

Physiol Mol Biol Plants. 2023 Oct;29(10):1395-1407. doi: 10.1007/s12298-023-01367-9. Epub 2023 Oct 8.ABSTRACTClimate change has altered cold weather patterns, resulting in irregular cold weather conditions, and changing the global plant distribution pattern affecting plant development processes resulting in severe yield losses. Although molecular mechanisms and interconnections are quite well studied, a cumulative understanding of plant responses to cold stress (CS) is still lacking. Through meta-analysis, integration of data at the multi-omics level and its correlation with known physiological changes to map and understand the global changes in response to CS was made. Meta-analysis was conducted using the metafor R package program based on physiological parameters like relative electrolytic leakage, malondialdehyde, soluble sugar, proline and antioxidant enzymes activity. Proline and soluble sugars showed the highest (> 1.5 mean fold) change over control thus qualifying as global markers for studying CS. Surprisingly most up-regulated (> 15-fold) DEGs corresponded with the dehydrin family and glyoxalase superfamily proteins. Functional annotations of DEGs corresponded with photosynthesis and glycolysis pathway. Proteins responsible for cell signalling and increased soluble sugars were common in all the datasets studied thus correlating with the transcriptome and proteomic data. Proline and soluble sugars were positively regulated in all the metabolomics datasets. This study supported the earlier known players like proline and soluble sugars. Surprisingly, a new player glyoxalase seems to be contributing in CS.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-023-01367-9.PMID:38076772 | PMC:PMC10709295 | DOI:10.1007/s12298-023-01367-9

Front Cell Infect Microbiol. 2023 Nov 21;13:1292864. doi: 10.3389/fcimb.2023.1292864. eCollection 2023.ABSTRACTMycobacterium tuberculosis (Mtb) is an intracellular bacterium that causes a highly contagious and potentially lethal tuberculosis (TB) in humans. It can maintain a dormant TB infection within the host. DosR (dormancy survival regulator) (Rv3133c) has been recognized as one of the key transcriptional proteins regulating bacterial dormancy and participating in various metabolic processes. In this study, we extensively investigate the still not well-comprehended role and mechanism of DosR in Mycobacterium bovis (M. bovis) Bacillus Calmette-Guérin (BCG) through a combined omics analysis. Our study finds that deleting DosR significantly affects the transcriptional levels of 104 genes and 179 proteins. Targeted metabolomics data for amino acids indicate that DosR knockout significantly upregulates L-Aspartic acid and serine synthesis, while downregulating seven other amino acids, including L-histidine and lysine. This suggests that DosR regulates amino acid synthesis and metabolism. Taken together, these findings provide molecular and metabolic bases for DosR effects, suggesting that DosR may be a novel regulatory target.PMID:38076461 | PMC:PMC10703047 | DOI:10.3389/fcimb.2023.1292864

Front Cell Infect Microbiol. 2023 Nov 24;13:1286977. doi: 10.3389/fcimb.2023.1286977. eCollection 2023.ABSTRACTINTRODUCTION: Clonorchiasis remains a serious global public health problem, causing various hepatobiliary diseases. However, there is still a lack of overall understanding regarding the molecular events triggered by Clonorchis sinensis (C. sinensis) in the liver.METHODS: BALB/c mouse models infected with C. sinensis for 5, 10, 15, and 20 weeks were constructed. Liver pathology staining and observation were conducted to evaluate histopathology. The levels of biochemical enzymes, blood routine indices, and cytokines in the blood were determined. Furthermore, alterations in the transcriptome, proteome, and metabolome of mouse livers infected for 5 weeks were analyzed using multi-omics techniques.RESULTS: The results of this study indicated that adult C. sinensis can cause hepatosplenomegaly and liver damage, with the most severe symptoms observed at 5 weeks post-infection. However, as the infection persisted, the Th2 immune response increased and symptoms were relieved. Multi-omics analysis of liver infected for 5 weeks identified 191, 402 and 232 differentially expressed genes (DEGs), proteins (DEPs) and metabolites (DEMs), respectively. Both DEGs and DEPs were significantly enriched in liver fibrosis-related pathways such as ECM-receptor interaction and cell adhesion molecules. Key molecules associated with liver fibrosis and inflammation (Cd34, Epcam, S100a6, Fhl2, Itgax, and Retnlg) were up-regulated at both the gene and protein levels. The top three metabolic pathways, namely purine metabolism, arachidonic acid metabolism, and ABC transporters, were associated with liver cirrhosis, fibrosis, and cholestasis, respectively. Furthermore, metabolites that can promote liver inflammation and fibrosis, such as LysoPC(P-16:0/0:0), 20-COOH-leukotriene E4, and 14,15-DiHETrE, were significantly up-regulated.CONCLUSION: Our study revealed that the most severe symptoms in mice infected with C. sinensis occurred at 5 weeks post-infection. Moreover, multi-omics analysis uncovered predominant molecular events related to fibrosis changes in the liver. This study not only enhances our understanding of clonorchiasis progression but also provides valuable insights into the molecular-level interaction mechanism between C. sinensis and its host liver.PMID:38076459 | PMC:PMC10710275 | DOI:10.3389/fcimb.2023.1286977

Front Bioeng Biotechnol. 2023 Nov 22;11:1298501. doi: 10.3389/fbioe.2023.1298501. eCollection 2023.ABSTRACTPanax ginseng C.A. Meyer is a shade plant, and its leaves are an important medicinal part of P. ginseng. Light intensity plays a crucial role in physiological activities and metabolite accumulation in P. ginseng. Currently, little is known about the molecular mechanisms underlying physiological changes and quality under different light intensities in P. ginseng leaves. Therefore, we investigated the changes in photosynthetic physiology, secondary metabolism, transcriptomics, and metabolomics of P. ginseng leaves under different light intensities [T20 (20 µmol m-2·s-1), T50 (50 µmol m-2·s-1), T100 (100 μmol m-2·s-1)]]. Higher light intensity positively influenced the yield, photosynthesis, and accumulation of polysaccharides, soluble sugars, terpenoids, and ginsenosides in P. ginseng leaves. The T100 treatment notably promoted the accumulation of ginsenosides in the leaves, resulting in a 68.32% and 45.55% increase in total ginsenosides compared to the T20 and T50 treatments, respectively. Ginsenosides Rg1, Re, Rb1, Rc, Rg2, Rb2, Rb3, and Rd were 1.28-, 1.47-, 2.32-, 1.64-, 1.28-, 2.59-, 1.66-, and 2.28-times higher than in the T20 treatment. Furthermore, 285 differentially accumulated metabolites (DAMs) and 4218 differentially expressed genes (DEGs) in the metabolome and transcriptome of P. ginseng leaves, respectively, were identified. 13 triterpenoid saponins were significantly upregulated, and three were downregulated. The expression of genes encoding photosystem II reaction center proteins was upregulated under the T100 treatment, thereby increasing photosynthetic activity. The T100 treatment enhanced the expression of genes involved in photosynthetic carbon and energy metabolism in P. ginseng. The expression of antenna protein synthesis genes was upregulated under the T20, which increased the ability to capture light in P. ginseng leaves. T100 upregulated the expression of HMGR, SS, CYP716A53v2, UGT74AE, PgUGT1, and UGTPg45, thereby promoting terpene and ginsenoside synthesis. In summary, 100 µmol m-2·s-1 was conducive to quality formation of P. ginseng leaves. This study elucidates molecular mechanisms underlying the photosynthetic physiology and ginsenoside synthesis in P. ginseng under varying light intensities and provides a theoretical basis for the P. ginseng cultivation and its industrial production of secondary metabolites.PMID:38076416 | PMC:PMC10703391 | DOI:10.3389/fbioe.2023.1298501

ACS Omega. 2023 Nov 21;8(48):46284-46291. doi: 10.1021/acsomega.3c07792. eCollection 2023 Dec 5.ABSTRACTHericium erinaceus is an edible mushroom with diverse pharmaceutical applications. Although this mushroom is an attractive source of natural products for cancer treatment, little is known about the bioactive compounds from this mushroom, which may possess antibreast cancer activity. Here, we report the isolation and structure elucidation of new compounds, 5'-hydroxyhericenes A-D (1-4) as an inseparable mixture, together with known compounds (5-16) from the fruiting body of H. erinaceus. Based on NMR spectroscopic data and MS fragmentation analysis, the structure of a previously reported natural product, 3-[2,3-dihydroxy-4-(hydroxymethyl)tetrahydrofuran-1-yl]-pyridine-4,5-diol (5), should be revised to adenosine (6). Compounds 1-4 inhibit xanthine oxidase activity, while compounds 6, 9, and 10 scavenge reactive oxygen species generated by xanthine oxidase. Moreover, hericerin (13) exhibits strong growth inhibitory activity against T47D breast cancer cells and, to a lesser extent, against MDA-MB-231 breast cancer and MRC-5 normal embryonic cells. Exposure of T47D and MDA-MB-231 cells slightly increased PARP cleavage, suggesting that the growth inhibitory effect of hericerin may be mediated through nonapoptotic pathways. Our results suggest that the bioactive compounds of mushroom H. erinaceus hold promise as antibreast cancer agents.PMID:38075774 | PMC:PMC10701869 | DOI:10.1021/acsomega.3c07792

Front Genet. 2023 Nov 22;14:1264237. doi: 10.3389/fgene.2023.1264237. eCollection 2023.ABSTRACTBackground: A rare X-linked hereditary condition known as ATP6AP2-congenital disorder of glycosylation (ATP6AP2-CDG) is caused by pathogenic variants in ATP6AP2, resulting in autophagic misregulation with reduced siganling of mammalian target of rapamycin (mTOR) that clinically presents with aberrant protein glycosylation, hepatosteatosis, immunodeficiency, cutis laxa, and psychomotor dysfunction. To date, only two missense mutations have been reported in three patients from two unrelated families. Methods: In order to extend the profiles of phenotype and genotype associated with ATP6AP2-CDG, we assessed the clinical history, whole exome sequencing (WES), and liver histology as well as immunohistochemistry in a Chinese patient, and performed quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and untargeted metabolomics in genetic exogenously constructed cells. Results: The 11-month-old Chinese boy presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. A novel mutation, c.185G>A (p.Gly62Glu), was identified in exon 3 of ATP6AP2. The expression of ATP6AP2 was observed to remain unchanged in the liver sample of the patient as well as in HEK293T cells harboring the p.Gly62Glu. This missense mutation was found to dysregulate autophagy and mTOR signaling. Moreover, metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. Conclusion: This study may enable a more detailed exploration of its precise pathogenesis and potential therapeutic interventions.PMID:38075676 | PMC:PMC10702736 | DOI:10.3389/fgene.2023.1264237

Nat Cardiovasc Res. 2023 Sep;2:835-852. doi: 10.1038/s44161-023-00325-8. Epub 2023 Aug 31.ABSTRACTDuring megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a lipid-centric multiomics approach to create a quantitative map of the MK lipidome during maturation and proplatelet formation. Data reveal that MK differentiation is driven by an increased fatty acyl import and de novo lipid synthesis, resulting in an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis blocked membrane remodeling and directly reduced MK polyploidization and proplatelet formation resulting in thrombocytopenia. The anionic lipid shift during megakaryopoiesis was paralleled by lipid-dependent relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which seems to be essential for sufficient platelet biogenesis. Overall, this study provides a framework to understand how the MK lipidome is altered during maturation and the impact of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.PMID:38075556 | PMC:PMC7615361 | DOI:10.1038/s44161-023-00325-8

Biomed Res Int. 2023 Nov 29;2023:9759620. doi: 10.1155/2023/9759620. eCollection 2023.ABSTRACT[This retracts the article DOI: 10.1155/2021/6649085.].PMID:38075362 | PMC:PMC10699975 | DOI:10.1155/2023/9759620

Front Endocrinol (Lausanne). 2023 Nov 20;14:1257457. doi: 10.3389/fendo.2023.1257457. eCollection 2023.ABSTRACTBACKGROUND: Abnormal gut microbiota and blood trimethylamine-N-oxide (TMAO) metabolome have been reported in patients with type 2 diabetes mellitus (T2DM) and advanced diabetic nephropathy. This study aimed to investigate the gut microbiota profiles and a group of targeted urine metabolic characteristics in T2DM patients with or without microalbuminuria, to determine the correlation between the gut microbiota composition, trimethylamine (TMA) metabolism, and the clinical features during progression of diabetic kidney disease (DKD).METHODS: This study included 26 T2DM patients with microalbuminuria (Micro), 26 T2DM patients with normoalbuminuria (Normo), and 15 healthy controls (HC). Urine and Fecal samples were detected using ultra performance liquid chromatography tandem mass spectrometry and 16S ribosomal DNA gene sequencing, respectively.RESULTS: The TMAO/TMA ratio decreased gradually during the HC-Normo-Micro transition. The levels of TMA, choline and betaine were significantly different between the HC group and the T2DM patients belonging to both Normo and Micro groups. At the operational taxonomic unit (OTU) level, the gut microflora diversity was significantly reduced in the Micro groups compared to the HC groups and the Normo groups. Taxonomic analyses revealed significant consumption in the relative abundances of eight bacterial genera and significant enrichment of two bacterial genera during the HC-Normo-Micro transition. Furthermore, the relative abundances of six bacterial genera, namely, Ruminococcus_1, [Eubacterium]_ruminantium_group, Roseburia, Faecalibacterium, Fusicatenibacter and Coprococcus_3 exhibited significant differences, and were associated with elevated urinary albumin creatinine ratio (UACR), TMAO/TMA, TMA and its precursors in the Micro group compared with the other groups.CONCLUSION: The imbalance of gut microbiota has occurred in patients with early-stage DKD, and the consumption of short-chain fatty acid-producing bacteria were associated with the accumulation of TMA and UACR.PMID:38075058 | PMC:PMC10698370 | DOI:10.3389/fendo.2023.1257457

World J Hepatol. 2023 Nov 27;15(11):1237-1249. doi: 10.4254/wjh.v15.i11.1237.ABSTRACTBACKGROUND: Chronic Hepatitis C (CHC) affects 71 million people globally and leads to liver issues such as fibrosis, cirrhosis, cancer, and death. A better understanding and prognosis of liver involvement are vital to reduce morbidity and mortality. The accurate identification of the fibrosis stage is crucial for making treatment decisions and predicting outcomes. Tests used to grade fibrosis include histological analysis and imaging but have limitations. Blood markers such as molecular biomarkers can offer valuable insights into fibrosis.AIM: To identify potential biomarkers that might stratify these lesions and add information about the molecular mechanisms involved in the disease.METHODS: Plasma samples were collected from 46 patients with hepatitis C and classified into fibrosis grades F1 (n = 13), F2 (n = 12), F3 (n = 6), and F4 (n = 15). To ensure that the identified biomarkers were exclusive to liver lesions (CHC fibrosis), healthy volunteer participants (n = 50) were also included. An untargeted metabolomic technique was used to analyze the plasma metabolites using mass spectrometry and database verification. Statistical analyses were performed to identify differential biomarkers among groups.RESULTS: Six differential metabolites were identified in each grade of fibrosis. This six-metabolite profile was able to establish a clustering tendency in patients with the same grade of fibrosis; thus, they showed greater efficiency in discriminating grades.CONCLUSION: This study suggests that some of the observed biomarkers, once validated, have the potential to be applied as prognostic biomarkers. Furthermore, it suggests that liquid biopsy analyses of plasma metabolites are a good source of molecular biomarkers capable of stratifying patients with CHC according to fibrosis grade.PMID:38075010 | PMC:PMC10698350 | DOI:10.4254/wjh.v15.i11.1237

World J Hepatol. 2023 Nov 27;15(11):1170-1173. doi: 10.4254/wjh.v15.i11.1170.ABSTRACTIn the management of the growing population of hepatitis C virus-infected patients, a significant clinical challenge exists in determining the most effective methods for assessing liver impairment. The prognosis and treatment of chronic hepatitis C depend, in part, on the evaluation of histological activity, specifically cell necrosis and inflammation, and the extent of liver fibrosis. These parameters are traditionally obtained through a liver biopsy. However, liver biopsy presents both invasiveness and potential sampling errors, primarily due to inadequate biopsy size. To circumvent these issues, several non-invasive markers have been proposed as alternatives for diagnosing liver damage. Different imaging techniques and blood parameters as single markers or combined with clinical information are included. This Editorial discusses the identification of a set of six distinctive lipid metabolites in every fibrosis grade that appear to show a pronounced propensity to create clusters among patients who share the same fibrosis grade, thereby demonstrating enhanced efficacy in distinguishing between the different grades.PMID:38075008 | PMC:PMC10698344 | DOI:10.4254/wjh.v15.i11.1170

World J Gastroenterol. 2023 Nov 21;29(43):5848-5864. doi: 10.3748/wjg.v29.i43.5848.ABSTRACTBACKGROUND: Atractylodes japonica Koidz. ex Kitam. (A. japonica, Chinese name: Guan-Cangzhu, Japanese name: Byaku-jutsu), a perennial herb, which is mainly distributed in northeast area of China, it's often used to treat digestive system diseases such as gastric ulcer (GU). However, the mechanism of its potential protective effects against GU remains unclear.AIM: To investigate the protective effects of A. japonica on acetic acid-induced GU rats.METHODS: The chemical constituents of A. japonica were determined by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analysis. The rat model of GU was simulated by acetic acid method. The pathological changes of gastric tissues were evaluated by hematoxylin-eosin stain, the levels of epidermal growth factor (EGF), EGF receptor (EGFR), nuclear factor kappa-B (NF-κB), interleukin-1β (IL-1β), IL-10, Na+-K+-ATPase (NKA) in serum and gastric tissues were determined by enzyme-linked immunosorbent assay, and the mRNA expressions of EGFR, NF-κBp65, IkappaBalpha (IκBα) and Zonula Occludens-1 (ZO-1) in gastric tissues were determined by real-time reverse transcription polymerase chain reaction, and the efficacy was observed. Then, plasma metabolomic analysis was performed by UPLC-MS/MS to screen the specific potential biomarkers, metabolic pathways and to explore the possible mechanisms.RESULTS: 48 chemical constituents were identified. Many of them have strong pharmacological activity, the results also revealed that A. japonica significantly improved the pathological damage of gastric tissues, increased the expression levels of IL-10, IκBα related to anti-inflammatory factors, decreased the expression levels of IL-1β, NF-κB, NF-κBp65, related to proinflammatory factors, restored the levels of factors about EGF, EGFR, ZO-1 associated with ulcer healing and the levels of factors about NKA associated with energy metabolism. Metabolomic analysis identified 10 potential differential metabolites and enriched 7 related metabolic pathways.CONCLUSION: These findings contribute to the understanding of the potential mechanism of A. japonica to improve acetic acid-induced GU, and will be of great importance for the development and clinical application of natural drugs related to A. japonica.PMID:38074916 | PMC:PMC10701307 | DOI:10.3748/wjg.v29.i43.5848

Front Oncol. 2023 Nov 23;13:1194462. doi: 10.3389/fonc.2023.1194462. eCollection 2023.ABSTRACTMetabolomics analysis revealed the metabolic heterogeneity of cervical cancer (CC) cell lines C33A and CaSki, and their molecular mechanisms were explored. Using the modified Bligh-Dyer method, the endogenous metabolites of C33A and CaSki cells were divided into polar and nonpolar fractions. The metabolites were analysed by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Then, the differential metabolites were screened by combining multivariate statistical analysis and volcano maps, and functional enrichment and pathway analysis of the differential metabolites were performed. Finally, association analysis was carried out in combination with transcriptomics, and the important differential metabolisms were experimentally verified by real-time PCR (RT-qPCR) and oil red staining. The results showed that between the C33A and CaSki cell lines, there were significant differences in amino acids, nucleotides and lipids, such as in threonine, arachidonic acid and hypoxanthine, in the metabolic pathways. These compounds could be used as markers of differences in cellular metabolism. The heterogeneity of lipid metabolism accounted for 87.8%, among which C33A cells exhibited higher contents of fatty acid polar derivatives, while CaSki cells showed higher contents of free fatty acids and glycerides. Based on correlation analysis of the above metabolic differences in HPV pathways as well as lipid metabolism-related genes, p53 and the genes involved in lipid metabolism pathways, such as Peroxisome Proliferator Activated Receptor Gamma(PPARG) and stearoyl-CoA desaturase (SCD), are relevant to the metabolic heterogeneity of the cells. The differential expression of some genes was validated by RT-qPCR. CaSki cells showed significantly higher glyceride levels than that of C33A cells, as verified by oil red O staining and glyceride assays. The above results showed that the metabolomic differences between C33A and CaSki cells were relatively obvious, especially in lipid metabolism, which might be related to the decreased expression of PPARG and p53 caused by HPV E6. Further studies on the molecular mechanism of lipid metabolism heterogeneity in cervical cancer cell lines with or without HPV could provide a new reference for the development of CC and individualized treatments of tumour patients.PMID:38074668 | PMC:PMC10701895 | DOI:10.3389/fonc.2023.1194462

Front Pharmacol. 2023 Nov 23;14:1253013. doi: 10.3389/fphar.2023.1253013. eCollection 2023.ABSTRACTBackground: Penthorum chinense Pursh (PCP) is widely utilized in China to treat a variety of liver diseases. It has been shown that flavonoids inhibit inflammation and have the potential to attenuate tissue damage and fibrosis. However, the mechanisms underlying how total flavonoids isolated from PCP (TFPCP) exert their anti-fibrotic effects remain unclear. Methods: The chemical composition of TFPCP was determined using UHPLC-Q-Orbitrap HRMS. Subsequently, rats were randomly assigned to a control group (Control), a carbon tetrachloride (CCl4)-induced hepatic fibrosis model group (Model), a positive control group [0.2 mg/(kg∙day)] of Colchicine), and three TFPCP treatment groups [50, 100, and 150 mg/(kg∙day)]. All substances were administered by gavage and treatments lasted for 9 weeks. Simultaneously, rats were intraperitoneally injected with 10%-20% CCl4 for 9 weeks to induce liver fibrosis. At the end of the experiment, the liver ultrasound, liver histomorphological, biochemical indicators, and inflammatory cytokine levels were tested respectively. The underlying mechanisms were assessed using Western blot, immunohistochemistry, immunofluorescence, RT-qPCR, and metabolomics. Results: Fourteen flavonoids were identified in TFPCP. Compared with control animals, CCl4-treated rats demonstrated obvious liver injury and fibrosis, manifested as increases in gray values, distal diameter of portal vein (DDPV) and a decrease in blood flow velocity (VPV) in the ultrasound analysis; increased biochemical index values (serum levels of ALT, AST, TBIL, and ALP); marked increases in the contents of fibrotic markers (PC III, COL4, LN, HA) and inflammatory factors (serum TNF-α, IL-6, and IL-1β); and significant pathological changes. However, compared with the Model group, the ultrasound parameters were significantly improved and the serum levels of inflammatory cytokines were reduced in the TFPCP group. In contrast, the expression of TGF-β1, TLR4, and MyD88, as well as the p-P65/P65 and p-IκBα/IκBα ratios, were considerably reduced following TFPCP treatment. In addition, we identified 32 metabolites exhibiting differential abundance in the Model group. Interestingly, TFPCP treatment resulted in the restoration of the levels of 20 of these metabolites. Conclusion: Our findings indicated that TFPCP can ameliorate hepatic fibrosis by improving liver function and morphology via the inactivation of the TLR4/MyD88-mediated NF-κB pathway and the regulation of liver metabolism.PMID:38074148 | PMC:PMC10701287 | DOI:10.3389/fphar.2023.1253013

Front Pharmacol. 2023 Nov 23;14:1287711. doi: 10.3389/fphar.2023.1287711. eCollection 2023.ABSTRACTIntroduction: Hypertension is a well-known risk factor for aneurysms, as high blood pressure can worsen the development and rupture of aneurysms. Ginsenoside, derived from ginseng and widely used in traditional herbal medicine, is believed to have antihypertensive properties. Recent research has also shown a connection between gut microbiota and various diseases, including hypertension. However, the relationship between ginsenosides, gut microbiota, blood pressure, and intracranial aneurysms needs further exploration. Methods: In this study, a rat model was used to investigate the effects of ginsenosides on both blood pressure and intracranial arteries. Comparative analysis was conducted, and 16S rRNA sequencing was employed to identify marker genera within the gut microbiota. Metabolites were also analyzed to uncover potential mediators of blood pressure regulation. Results and Discussion: The results of this study revealed that ginsenosides, particularly ginsenoside Rb1, demonstrated positive effects in reducing both blood pressure and the development of intracranial aneurysms in rats. Furthermore, the analysis of gut microbiota showed that certain genera, including Clostridium, Roseburia, Ruminococcus, and Treponema, were significantly influenced by ginsenoside treatment. Several metabolites, such as behenic acid, N-Acetylserotonin, Prostaglandin F2a, and Vitamin D2, were also detected, all of which play a role in regulating blood pressure. These findings provide valuable insights into the potential benefits of ginsenosides in hypertension and atheroma development. Furthermore, they suggest a possible link between ginsenosides, gut microbiota, and blood pressure regulation. Further research is needed to fully understand the mechanisms underlying these effects and to determine the clinical implications for treating hypertension and reducing the risk of aneurysm development.PMID:38074114 | PMC:PMC10701264 | DOI:10.3389/fphar.2023.1287711

J Intensive Care Med. 2023 Dec 10:8850666231216361. doi: 10.1177/08850666231216361. Online ahead of print.ABSTRACTBACKGROUND: There is limited understanding of alteration of gut microbiota and metabolome in children with sepsis/septic shock.METHODS: In this prospective observational study carried out in a pediatric intensive care unit of a tertiary care center from 2020 to 2022, patients aged <17 years with sepsis/septic shock and healthy children (HC) were enrolled. We characterized the gut bacterial compositions by metagenome sequencing and metabolomes by untargeted gas chromatography-mass spectrometry. The primary outcome was to compare the gut microbiota and metabolome of children with sepsis/septic shock with that of HC. The Firmicutes/Bacteroidetes (F/B) ratio was compared between children with sepsis/septic shock and HC. Key secondary outcomes were to evaluate association of factors associated with a low F/B ratio in children with sepsis/septic shock.RESULTS: A total of 40 children (63% boys) (15 children with sepsis and septic shock and 10 healthy children) with a median (IQR) age of 5.5 (1.5, 10) years were enrolled. In the fecal microbiota, the α-diversity index including Shannon and Simpson indices of the sepsis/septic shock groups was significantly lower than that of the HC. The samples lacked beneficial Bifidobacterium spp. and were dominated by Bacteroides, Enterobacteriaceae, and Enterococcaceae. There was reduction in short-chain fatty acids (SCFAs) in patients with sepsis/septic shock as compared to healthy children. A lower F/B ratio (≤1.57) of the gut microbiota discriminated well between children with sepsis/septic shock and HC. Factors associated with lower F/B ratio were male gender, clinical GI dysfunction, elevated inflammatory markers, and higher organ failure scores.CONCLUSION: There were significant alterations in the gut microbiota and metabolome in children with sepsis/septic shock as compared to healthy children. Larger study is needed to confirm these exploratory findings and develop potential therapeutic targets that will improve outcomes in children with sepsis/septic shock.PMID:38073164 | DOI:10.1177/08850666231216361

Cell Struct Funct. 2023 Dec 9. doi: 10.1247/csf.23066. Online ahead of print.ABSTRACTGaucher disease (GD) is a recessively inherited lysosomal storage disorder characterized by a deficiency of lysosomal glucocerebrosidase (GBA1). This deficiency results in the accumulation of its substrate, glucosylceramide (GlcCer), within lysosomes. Here, we investigated lysosomal abnormalities in fibroblasts derived from patients with GD. It is noteworthy that the cellular distribution of lysosomes and lysosomal proteolytic activity remained largely unaffected in GD fibroblasts. However, we found that lysosomal membranes of GD fibroblasts were susceptible to damage when exposed to a lysosomotropic agent. Moreover, the susceptibility of lysosomal membranes to a lysosomotropic agent could be partly restored by exogenous expression of wild-type GBA1. Here, we report that the lysosomal membrane integrity is altered in GD fibroblasts, but lysosomal distribution and proteolytic activity is not significantly altered.Key words: glucosylceramide, lysosome, Gaucher disease, lysosomotropic agent.PMID:38072450 | DOI:10.1247/csf.23066

J Thromb Haemost. 2023 Dec 8:S1538-7836(23)00863-2. doi: 10.1016/j.jtha.2023.11.025. Online ahead of print.ABSTRACTBACKGROUND: Platelet product (PLT) transfusion is a life-saving therapy for actively bleeding patients. There is an urgent need to maintain PLT function and extend shelf-life to improve outcomes in these patients. Cold storage of PLT (CS-PLT) maintains hemostatic potential better than room temperature-stored PLT (RT-PLT). However, whether function in long-term CS-PLT is maintained under physiological flow regimes and/or determined by cold-induced metabolic changes is unknown.OBJECTIVES: To (i) compare the function of RT-PLT and CS-PLT under physiological flow conditions, (ii) determine if CS-PLT maintain function after 3 weeks of storage, and (iii) identify metabolic pathways associated with the CS-PLT lesion.METHODS: We performed phenotypic and functional assessments of RT- and CS-PLT (22°C and 4°C storage, respectively; N=10 unique donors) were performed at storage day 0, 5, and/or 21 via metabolomics, flow cytometry, aggregation, thrombin generation, viscoelastic testing, and a microfluidic assay to measure primary hemostatic function.RESULTS: D21 4°C PLT formed an occlusive thrombus under arterial shear at a similar rate to D5 22°C PLT. D21 4°C PLT had enhanced thrombin generation capacity compared to D0 PLT and maintained functionality comparable to D5 RT-PLT across all assays performed. Key metrics from microfluidic assessment, flow cytometry, thrombin generation, and aggregation were associated with 4°C storage, and metabolites involved in taurine and purine metabolism significantly correlated with these metrics. Taurine supplementation of PLT during storage improved hemostatic function under flow.CONCLUSIONS: CS-PLT stored for 3 weeks maintain hemostatic activity, and storage-induced phenotype and function is associated with taurine and purine metabolism.PMID:38072374 | DOI:10.1016/j.jtha.2023.11.025

Chemosphere. 2023 Dec 8:140918. doi: 10.1016/j.chemosphere.2023.140918. Online ahead of print.ABSTRACTHexavalent chromium [Cr(VI)], known as "Top Hazardous Substances", poses a significant threat to the respiratory system. Nevertheless, the potential mechanisms of toxicity and the lung's repair ability after injury remain incompletely understood. In this study, Cr(VI) aerosol whole-body dynamic exposure system simulating real exposure scenarios of chromate workers was constructed to evaluate the lung injury and repair effects. Subsequently, miRNA sequencing, mRNA sequencing and metabolomics analyses on lung tissue were performed to explore the underlying mechanisms. Our results revealed that Cr(VI) exposure led to an increase in lactic dehydrogenase activity and a time-dependent decline in lung function. Notably, after 13 w of Cr(VI) exposure, alveolar hemorrhage, thickening of alveolar walls, emphysema-like changes, mitochondrial damage of alveolar epithelial cells and macrophage polarization changes were observed. Remarkably, a two-week repair intervention effectively ameliorated lung function decline and pulmonary injury. Furthermore, significant disruptions in the expressions of miRNAs and mRNAs involved in oxidative phosphorylation, glycerophospholipid metabolism and inflammatory signaling pathways were found. The two-week repair period resulted in the reversal of expression of oxidative phosphorylation related genes, and inhibited the inflammatory signaling pathways. This study concluded that the inhibition of the mitochondrial oxidative phosphorylation pathway and the subsequent enhancement of inflammatory response might be key mechanisms underlying Cr(VI) pulmonary toxicity, and timely cessation of exposure could effectively alleviate the pulmonary injury. These findings shed light on the potential mechanisms of Cr(VI) toxicity and provide crucial insights into the health protection for occupational populations exposed to Cr(VI).PMID:38072199 | DOI:10.1016/j.chemosphere.2023.140918