Human umbilical cord-derived mesenchymal stem cells attenuate hepatic stellate cells activation and liver fibrosis.

BACKGROUND: Liver cirrhosis, a prevalent chronic liver disease, is characterized by liver fibrosis as its central pathological process. Recent advancements highlight the clinical efficacy of umbilical cord mesenchymal stem cell (UC-MSC) therapy in the treatment of liver cirrhosis. METHODS AND RESULTS: We investigated the pharmacodynamic effects of UC-MSCs and MSC conditional medium (MSC-CM) in vivo, utilizing a carbon tetrachloride (CCl4)-induced fibrotic rat model. Concurrently, we assessed the in vitro impact of MSCs and MSC-CM on various cellular process of hepatic stellate cells (HSCs), including proliferation, apoptosis, activation, immunomodulatory capabilities, and inflammatory factor secretion. Our results indicate that both MSCs and MSC-CM significantly ameliorate the pathological extent of fibrosis in animal tissues, reducing the collagen content, serum biochemical indices and fibrosis biomarkers. In vitro, MSC-CM significantly inhibited the activation of the HSC line LX-2. Notably, MSC-CM modulated the expression of type I procollagen and TGFß-1 while increasing MMP1 expression. This modulation restored the MMP1/TIMP1 ratio imbalance and extracellular matrix deposition in TGFß-1 induced fibrosis. Both MSCs and MSC-CM not only induced apoptosis in HSCs but also suppressed proliferation and inflammatory cytokine release from activated HSCs. Furthermore, MSCs and MSC-CM exerted a suppressive effect on total lymphocyte activation. CONCLUSIONS: UC-MSCs and MSC-CM primarily modulate liver fibrosis severity by regulating HSC activation. This study provides both in vivo and in vitro pharmacodynamic evidence supporting the use of MSCs in liver fibrosis treatment.

Metabolome genome-wide association study provides biochemical and genetic insights into natural variation of primary metabolites in sesame.

Plants' primary metabolites are of great importance from the survival and nutritional perspectives. However, the genetic bases underlying the profiles of primary metabolites in oilseed crops remain largely unclear. As one of the main oilseed crops, sesame (Sesamum indicum L.) is a potential model plant for investigating oil metabolism in plants. Therefore, the objective of this study is to disclose the genetic variants associated with variation in the content of primary metabolites in sesame. We performed a comprehensive metabolomics analysis of primary metabolites in 412 diverse sesame accessions using gas chromatography-mass spectrometry and identified a total of 45 metabolites, including fatty acids, monoacylglycerols (MAGs), and amino acids. Genome-wide association study unveiled 433 significant single-nucleotide polymorphism loci associated with variation in primary metabolite contents in sesame. By integrating diverse genomic analyses, we identified 10 key candidate causative genes of variation in MAG, fatty acid, asparagine, and sucrose contents. Among them, SiDSEL was significantly associated with multiple traits. SiCAC3 and SiKASI were strongly associated with variation in oleic acid and linoleic acid contents. Overexpression of SiCAC3, SiKASI, SiLTPI.25, and SiLTPI.26 in transgenic Arabidopsis and Saccharomyces cerevisiae revealed that SiCAC3 is a potential target gene for improvement of unsaturated fatty acid levels in crops. Furthermore, we found that it may be possible to breed several quality traits in sesame simultaneously. Our results provide valuable genetic resources for improving sesame seed quality and our understanding of oilseed crops' primary metabolism.

Genome-Wide Analysis of nsLTP Gene Family and Identification of SiLTPs Contributing to High Oil Accumulation in Sesame (Sesamum indicum L.).

The biosynthesis and storage of lipids in oil crop seeds involve many gene families, such as nonspecific lipid-transfer proteins (nsLTPs). nsLTPs are cysteine-rich small basic proteins essential for plant development and survival. However, in sesame, information related to nsLTPs was limited. Thus, the objectives of this study were to identify the Sesamum indicum nsLTPs (SiLTPs) and reveal their potential role in oil accumulation in sesame seeds. Genome-wide analysis revealed 52 SiLTPs, nonrandomly distributed on 10 chromosomes in the sesame variety Zhongzhi 13. Following recent classification methods, the SiLTPs were divided into nine types, among which types I and XI were the dominants. We found that the SiLTPs could interact with several transcription factors, including APETALA2 (AP2), DNA binding with one finger (Dof), etc. Transcriptome analysis showed a tissue-specific expression of some SiLTP genes. By integrating the SiLTPs expression profiles and the weighted gene co-expression network analysis (WGCNA) results of two contrasting oil content sesame varieties, we identified SiLTPI.23 and SiLTPI.28 as the candidate genes for high oil content in sesame seeds. The presumed functions of the candidate gene were validated through overexpression of SiLTPI.23 in Arabidopsis thaliana. These findings expand our knowledge on nsLTPs in sesame and provide resources for functional studies and genetic improvement of oil content in sesame seeds.

Synthesis and structure-activity relationship of novel cinnamamide derivatives as antidepressant agents.

Cinnamamide 3a, a leading compound with antidepressant-like activity, and its derivatives were synthesized and their antidepressant activity and structure-activity relationship were investigated. Most of the compounds with trifluoromethyl group in methylenedioxyphenyl moiety (3f, 4b-c and 6a-b) exhibited significant antidepressant activity, measured in terms of percentage decrease in immobility duration by tail suspension test. In addition, the dose-dependent antidepressant effect of the most potent compound 3f was subsequently confirmed in tail suspension test and forced swim test. The test results showed that 3f was equal to or more effective than the standard drug fluoxetine at a concentration of 10mg/kg. Furthermore, compound 3f did not show any central nervous system stimulant properties in the open-field test and the preliminary results were promising enough to warrant further detailed antidepressant research around this scaffold.

New directions on membranes for removal and degradation of emerging pollutants in aqueous systems.

Emerging pollutants (EPs) refer to a group of non-regulated chemical or biological substances that have been recently introduced or detected in the environment. These pollutants tend to exhibit resistance to conventional treatment methods and can persist in the environment for prolonged periods, posing potential adverse effects on ecosystems and human health. As we enter a new era of managing these pollutants, membrane-based technologies hold significant promise in mitigating impact of EPs on the environment and safeguarding human health due to their high selectivity, efficiency, cost-effectiveness and capability for simultaneous separation and degradation. Moreover, these technologies continue to evolve rapidly with the development of new membrane materials and functionalities, advanced treatment strategies, and analyses for effectively treating EPs of more recent concerns. The objective of this review is to present the latest directions and advancements in membrane-based technologies for addressing EPs. By highlighting the progress in this field, we aim to share valuable perspectives with researchers and contribute to the development of future directions in sustainable treatments for EPs.

Meta-analysis on last ten years of clinical injection of bone marrow-derived and umbilical cord MSC to reverse cirrhosis or rescue patients with acute-on-chronic liver failure.

BACKGROUND: Recent studies have shown that mesenchymal stem cell (MSC) therapy has potential therapeutic effects for patients with end-stage liver diseases. However, a consensus on the efficacy and safety of MSCs has not been reached. METHODS: A systemic literature review was conducted by searching the Cochrane Library and PubMed databases for articles that evaluated the impact of MSC therapy on the outcomes among patients with end-stage liver disease. Various parameters, including pre- and post-treatment model of end-stage liver disease (MELD) score, serum albumin (ALB), total bilirubin (TB), coagulation function, aminotransferase, and survival rate, were evaluated. RESULTS: This meta-analysis included a final total of 13 studies and 854 patients. The results indicated improved liver parameters following MSC therapy at different time points, including in terms of MELD score, TB level, and ALB level, compared with conventional treatment. Furthermore, the MSC treatment increased the overall survival rate among patients with liver cirrhosis and acute-on-chronic liver failure (ACLF). The changes in transaminase level and coagulation function differed between the different therapies at various post-treatment time points, indicating that MSC therapy provided no significant benefits in this regard. The further subgroup analysis stratified by liver background revealed that patients with ACLF benefit more from MSC therapy at most time points with improved liver function, including in terms of MELD score, TB level, and ALB level. In addition, no serious side effects or adverse events were reported following MSC therapy. CONCLUSIONS: The meta-analysis results suggest that MSC therapy is safe and results in improved liver function and survival rates among patients with end-stage liver disease. The subgroup analysis stratified by liver background indicated that patients with ACLF benefit more from MSC therapy than patients with liver cirrhosis at most time points.

Integrating transcriptome and phytohormones analysis provided insights into plant height development in sesame.

Plant height is a key agronomic trait influencing crops yield. The height of sesame plants is important for yield performance, lodging resistance and plant architecture. Although plant height is significantly distinct among sesame varieties, the genetic basis of plant height remains largely unknown. In this study, in order to tackle genetic insights into the sesame plant height development, a comprehensive transcriptome analysis was conducted using the stem tips from two sesame varieties with distinct plant height, Zhongzhi13 and ZZM2748, at five time points by BGI MGIseq2000 sequencing platform. A total of 16,952 genes were differentially expressed between Zhongzhi13 and ZZM2748 at five time points. KEGG and MapMan enrichment analyses and quantitative analysis of phytohormones indicated that hormones biosynthesis and signaling pathways were associated with sesame plant height development. Plenty of candidate genes involved in biosynthesis and signaling of brassinosteroid (BR), cytokinin (CK) and gibberellin (GA) which were major differential hormones between two varieties were identified, suggesting their critical roles in plant height regulation. WGCNA revealed a module which was significantly positively associated with the plant height trait and founded SiSCL9 was the hub gene involved in plant height development in our network. Further overexpression in transgenic Arabidopsis validated the function of SiSCL9 in the increase of plant height by 26.86%. Collectively, these results increase our understanding of the regulatory network controlling the development of plant height and provide a valuable genetic resource for improvement of plant architecture in sesame.

Deciphering in vivo metabolic profile and pharmacological mechanisms of Jitongning Tablet for the treatment of Ankylosing spondylitis.

Jitongning tablet (JTNT) is a Traditional Chinese Medicine (TCM) prescription used for the treatment of Ankylosing spondylitis (AS). Currently, it is in phase II clinical trial (NCT03932019) for patients with active axial Spondyloarthritis (axSpA), showing great promise for the treatment of AS. However, the potential material basis and the underlying mechanisms for JTNT to treat AS remain elusive. Here, we performed UPLC-Q-TOF-MS to determine the in vivo metabolic profile of JTNT in rats and conducted in vivo studies including acetic acid-induced writhing, hot plate models, and collagen-induced arthritis (CIA) in rats to evaluate and validate the analgesic and anti-inflammatory effects of JTNT, two main symptoms for AS. Additionally, network pharmacology combined with molecular docking was performed to investigate the potential underlying mechanisms. As a result, a total of 116 xenobiotics were identified from the plasma, urine, and brain tissues of rats after oral administration of JTN extracts. Pharmacological evaluation revealed that fractions JTN-3 and JTN-4 exerted significant analgesic activities by reducing the number of writhes in an acetic acid-induced writhing mice model. JTN extract also exerted excellent therapeutic effects in the CIA model by ameliorating paw edema and decreasing systemic manifestation of inflammation and the level of circulating immune complex (CIC) and interferon γ (IFN-γ). Fractions of JTN extract, especially JTN-2 and JTN-4, on the other hand, ameliorated the secondary lesions caused by chicken type II collagen (CII) to a certain extent. Further, network pharmacology combined with molecular docking suggested crucial roles of inflammation and immune-related genes such as MAPK1, MAPK14, NOS3, and RELA in the treatment of AS by JTNT. In conclusion, our studies suggest that the isoquinoline and diterpenoid alkaloids from Corydalis Rhizoma and Aconiti Radix Cocta, along with coumarins from Angelicae Pubescentis Radix, may be the main bioactive components, and the AS treatment mechanism may mainly involve immune regulation of JTNT. These results help clarify the potential material basis and underlying mechanisms of JTNT for the treatment of AS, facilitating the broad application of this TCM in clinical practice.

Genome-wide association analysis and transcriptome reveal novel loci and a candidate regulatory gene of fatty acid biosynthesis in sesame (Sesamum indicum L.).

The regulatory mechanisms of fatty acid (FA) biosynthesis and triacylglycerols (TAGs) assembly remain largely misunderstood in sesame. Gas chromatography was used to analyze the natural variation in FA compositions and oil content (OC) in 400 sesame accessions grown in three different environments. The phenotypic data was associated with the newly released SNP data from whole-genome resequencing, and 43 significant loci for FA and OC were identified. Comparative transcriptomics analysis of high-OC and low-OC materials was performed, and 515 differentially expressed genes (DEGs) were identified across three seed developmental stages. By integrating the genome-wide association study (GWAS) and DEGs analysis, twenty candidate genes were identified, of which SiTPS1 (trehalose-6-phosphate synthase 1) has emerged as a key regulatory gene of FAs and TAGs metabolism in sesame. Overexpression of SiTPS1 in transgenic Arabidopsis influenced FA composition and significantly increased OC. Our study provides resources for the markers-based improvement of OC and quality in sesame and other crops.

The Dark Pigment in the Sesame (Sesamum indicum L.) Seed Coat: Isolation, Characterization, and Its Potential Precursors.

Sesame is a worldwide oilseed crop used in the food pharmacy. Its seed phenotypes determine the seed quality values. However, a thorough assessment of seed coat metabolites is lacking, and the dark pigment in the seed coat is not well-characterized. Herein, we report the isolation of melanin by the alkali method from the black and brown sesame seeds. Physicochemical methods, including scanning electron microscopy (SEM), solubility, precipitation, UV-Vis spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, and thermogravimetric-differential scanning calorimetry (TG-DSC), were used to characterize the sesame melanins. The results clearly showed that the isolated pigments were similar to melanin from other sources. Both melanins were heat-stable and exhibited numerous characteristic absorption peaks. Through a comprehensible LC-MS/MS-based metabolome profiles analysis of NaOH and methanol extracts of black and white sesame seeds, caffeic, protocatechuic, indole-carboxylic, homogentisic, ferulic, vanillic, and benzoic acids were identified as the potential precursors of the sesame melanin. Our findings widen our understanding of dark seeds pigmentation in sesame. Furthermore, they show that black sesame seeds are promising sources of edible melanin for food and biotechnological applications.

Antidepressant effects of 3-(3,4-methylenedioxy-5-trifluoromethyl phenyl)-2E-propenoic acid isobutyl amide involve TSPO-mediated mitophagy signalling pathway.

Piper laetispicum C. DC is one of the Chinese herbal medicines used for alleviating depressive disorders. G11-5 [3-(3, 4-methylenedioxy-5-trifluoromethyl phenyl)-2E-propenoic acid isobutyl amide] is synthesized based on the chemical structure of an active integrant of Piper laetispicum C. DC. The present study assessed the antidepressant effect of G11-5 and investigated the underlying mechanism with learned helplessness (LH) and social defeat stress (SDS) mice model of depression. In the LH model, mice were exposed to 60 inescapable electric shocks once a day for three consecutive days followed by 2-week drug administration and helpless behaviour assessment. In the SDS model, mice were subjected to repeated social defeat by an aggressive CD-1 mouse once a day for consecutive 10 days. Following oral administration for 2 weeks, the mice were subjected to a series of behavioural tests including social interaction test. G11-5 significantly decreased the number of escape failures induced by LH paradigm, meanwhile increased the social interaction ratio and shortened the immobility time in forced swimming test for the SDS-exposed mice, suggesting remarkable antidepressant effect. Moreover, G11-5 ameliorated the changes in mitophagy-related proteins induced by two stress exposures and restored retrograde axonal transport and neurotransmitter release. Our findings suggested that G11-5 exhibited an obvious antidepressant through TSPO-mediated mitophagy pathway.

Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism.

Pu-erh tea displays cholesterol-lowering properties, but the underlying mechanism has not been elucidated. Theabrownin is one of the most active and abundant pigments in Pu-erh tea. Here, we show that theabrownin alters the gut microbiota in mice and humans, predominantly suppressing microbes associated with bile-salt hydrolase (BSH) activity. Theabrownin increases the levels of ileal conjugated bile acids (BAs) which, in turn, inhibit the intestinal FXR-FGF15 signaling pathway, resulting in increased hepatic production and fecal excretion of BAs, reduced hepatic cholesterol, and decreased lipogenesis. The inhibition of intestinal FXR-FGF15 signaling is accompanied by increased gene expression of enzymes in the alternative BA synthetic pathway, production of hepatic chenodeoxycholic acid, activation of hepatic FXR, and hepatic lipolysis. Our results shed light into the mechanisms behind the cholesterol- and lipid-lowering effects of Pu-erh tea, and suggest that decreased intestinal BSH microbes and/or decreased FXR-FGF15 signaling may be potential anti-hypercholesterolemia and anti-hyperlipidemia therapies.

Protective effect of Pu-erh tea extracts against ethanol-induced gastric mucosal damage in rats.

Pu-erh tea has become a focus of research due to its reported biological activities, including anti-oxidation, anti-inflammation and anti-immunosenescence. The present study was performed to evaluate the potential gastroprotective function of Pu-erh tea extracts against ethanol-induced gastric mucosal damage in rats. Sprague Dawley rats were randomly divided into seven groups: A normal control, a model control, a cimetidine (0.08 g/kg) group, three Pu-erh tea extracts groups (low, moderate and high-dose; 0.50, 1.00 and 1.50 g/kg, respectively, and a green tea powder (1.00 g/kg) group. The normal and model groups were pre-treated with distilled water while the other groups were respectively administered cimetidine, Pu-erh tea extracts and green tea powder for 14 days. Then, absolute ethanol was orally administered to the rats of all groups excluding the normal controls. The effects of the pretreatments on gastric mucosal injury were evaluated by gross assessment of gastric lesions, examination of histopathology and determination of myeloperoxidase (MPO) activity and asymmetric arginine (ADMA) concentration in gastric mucosal homogenate. Pre-treatment with cimetidine or Pu-erh tea extracts markedly suppressed the formation of ethanol-induced gastric lesions. Furthermore, clear decreases in MPO activity and ADMA concentration in the gastric mucosal homogenate were observed following pretreatment with cimetidine or Pu-erh tea extracts. The anti-gastric ulcer activity of green tea was less than that of Pu-erh tea. Overall, these effects of Pu-erh tea extracts may be due to potential functions in protecting the gastric mucus layer and suppressing inflammation.

Preventive effect of Silibinin in combination with Pu-erh tea extract on non-alcoholic fatty liver disease in ob/ob mice.

There are presently no miracle drugs for non-alcoholic fatty liver disease (NAFLD). This study investigates the synergistic effect of Silibinin combined with Pu-erh tea extract (PTE) against NAFLD and explores the suggested mechanism of action. Ob/ob mice were fed a high fat diet along with the oral administration of Silibinin (86 mg per kg per day), PTE (250 mg per kg per day) or their combination for 6 weeks. Their lean littermates who were fed with standard chow diet were used as the control group. The blood biochemical index and histopathological evaluation were analyzed. The expression of genes involved in the lipogenesis pathway and cholesterol metabolism were evaluated. When compared with that of the NAFLD group, the body weight and blood lipid of the mice from the PTE group or combination group were significantly reduced. To some degree, fat metabolism and the inflammatory response were ameliorated by Silibinin and PTE used alone or in combination. It was notable that the combination group had a stronger efficacy in adjusting fat metabolism and inhibiting oxidative stress than that of Silibinin or PTE used alone. Silibinin and PTE inhibited fat synthesis by regulating the mRNA expression of CRTC2, SREBP-1c, and SCD-1. Moreover, the cholesterol homeostasis was improved in the treatment groups via regulating the mRNA expression of ABCA1 and ApoB100. The improvement of the combination group was superior to each drug used alone. In conclusion, Silibinin in combination with PTE can prevent NAFLD with greater potential than Silibinin or PTE used alone and may be a new therapeutic strategy.

Cerebral protection of salvianolic acid A by the inhibition of granulocyte adherence.

Ischemic stroke is one of the most common causes of death and disability that is induced by ischemia reperfusion (IR). Granulocyte adherence has been proven to be a principal cause of IR. Salvianolic acid A (Sal A) is one of the major active components of Danshen, a Chinese herbal medicine used for the treatment of cardiovascular and cerebrovascular diseases, such as ischemic stroke. Some experimental studies have shown the strong cerebral protection effect of Sal A. However, little information is available about the effect of Sal A on granulocyte adherence to brain micro-vascular endothelial cells (BMEC). Therefore, the aim of the present study was to investigate the effect of Sal A on the leukocyte adhesion rate and the intercellular cell adhesion molecule-1 (ICAM-1) expression in BMEC injured by hypoxia/reoxygenation (H/R), using a rheometer, qRT-PCR, and flow cytometry (FCM). The results of the adhesion rate gathered by the rheometer showed that Sal A could remarkably inhibit the adherence of granulocytes on BMEC in the case of H/R injury. Moreover, PCR and FCM results showed that Sal A could decrease the expression of ICAM-1 on BMEC on the gene and protein levels. In conclusion, the study demonstrated that the inhibition of granulocyte adherence is one of the targets of Sal A in the treatment of ischemic stroke. Meanwhile, Sal A inhibits of granulocyte adherence by decreasing the expression of ICAM-1 in BMEC.