Psoralea corylifolia L. and its active component isobavachalcone demonstrate antibacterial activity against Mycobacterium abscessus.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia L. (Fabaceae) is a traditional medicinal herb used to treat various diseases, including kidney disease, asthma, psoriasis and vitiligo. AIM OF THE STUDY: To explore the antibacterial activity of Psoralea corylifolia L. and its bioactive components against Mycobacterium abscessus (M. abscessus). MATERIALS AND METHODS: Ultra high performance liquid chromatography was utilized to analyze the bioactive fractions and compounds present in 30%, 60%, and 90% ethanol extracts of Psoralea corylifolia L.. The antibacterial effects of Psoralea corylifolia L. and potential active ingredients were determined by minimum inhibitory concentration (MIC). The bactericidal activity of the active ingredient isobavachalcone was evaluated and then scanning electron microscopy was used to explore the bactericidal mechanism of isobavachalcone. RESULTS: The 90% ethanol extracts of Psoralea corylifolia L. showed significant antibacterial activity against M. abscessus, with an MIC of 156 µg/mL. Isobavachalcone was identified as the bioactive ingredient, and testing of 118 clinical isolates of M. abscessus indicated their MICs ranged from 2 to 16 µg/mL, with an average MIC of 8 µg/mL. Furthermore, the minimum bactericidal concentration/MIC ratio and the time-kill test indicated rapid bactericidal activity of isobavachalcone against M. abscessus. Finally, we found that the bactericidal mechanism of isobavachalcone involved damage to the bacterial cell membrane, causing wrinkled and sunken cell surface and a noticeable reduction in bacterial length. CONCLUSION: Psoralea corylifolia L. ethanol extracts as well as its active component isobavachalcone show promising antimicrobial activity against M. abscessus.

Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.

Observational studies of diet-related vitamins and lymphoma risk results were inconsistent. Our study aimed to estimate the causality between dietary vitamin intake and lymphoma through a Mendelian randomisation (MR) study. We enrolled dietary-related retinol, vitamin C, vitamin E, vitamin B6 and vitamin B12 as exposures of interest, with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) as the outcome. The causal effects were estimated using inverse variance weighting (IVW), MR-Egger regression analysis and weighted median, supplemented by sensitivity analyses. The results revealed that genetically predicted dietary vitamin B12 intake was associated with a reduced HL risk (OR = 0.22, 95% CI 0.05-0.91, p = 0.036). The Q test did not reveal heterogeneity, the MR-Egger test showed no significant intercepts, and the leave-one-out (LOO) analysis did not discover any SNP that affect the results. No causal relationship about dietary vitamin intake on the NHL risk was observed.

Non-hippo kinases: indispensable roles in YAP/TAZ signaling and implications in cancer therapy.

The transcriptional co-activators Yes-associated protein (YAP) and PDZ-binding domain (TAZ) are the known downstream effectors of the Hippo kinase cascade. YAP/TAZ have been shown to play important roles in cellular growth and differentiation, tissue development and carcinogenesis. Recent studies have found that, in addition to the Hippo kinase cascade, multiple non-Hippo kinases also regulate the YAP/TAZ cellular signaling and produce important effects on cellular functions, particularly on tumorigenesis and progression. In this article, we will review the multifaceted regulation of the YAP/TAZ signaling by the non-Hippo kinases and discuss the potential application of the non-Hippo kinase-regulated YAP/TAZ signaling for cancer therapy.

Effect of curcumin on regulatory B cells in chronic colitis mice involving TLR/MyD88 signaling pathway.

Curcumin (Cur) is a natural active phenolic compound extracted from the root of Curcuma Longa L. It has anti-inflammatory, anti-tumor and other pharmacological activities, and is commonly used to treat ulcerative colitis (UC). However, it is not clear whether curcumin regulates the function and differentiation of Breg cells to treat UC. In this study, mice with chronic colitis were induced by dextran sulfate sodium (DSS), and treated with curcumin for 12 days. Curcumin effectively improved the body weight, colonic weight, colonic length, decreased colonic weight index and pathological injury score under colonoscopy in mice with chronic colitis, and significantly inhibited the production of IL-1ß, IL-6, IL-33, CCL-2, IFN-γ, TNF-α, and promoted the secretion of IL-4, IL-10, IL-13 and IgA. Importantly, curcumin markedly upregulated CD3- CD19+ CD1d+ , CD3- CD19+ CD25+ , CD3- CD19+ Foxp3+ Breg cells level and significantly down-regulated CD3- CD19+ PD-L1+ , CD3- CD19+ tim-1+ , CD3- CD19+ CD27+ Breg cells level. In addition, our results also showed that curcumin observably inhibited TLR2, TLR4, TLR5, MyD88, IRAK4, p-IRAK4, NF-κB P65, IRAK1, TRAF6, TAB1, TAB2, TAK1, MKK3, MKK6, p38MAPK, p-p38MAPK and CREB expression in TLR/MyD88 signaling pathway. These results suggest that curcumin can regulate the differentiation and function of Breg cell to alleviate DSS-induced colitis, which may be realized by inhibiting TLR/MyD88 pathway.

Curcumin Alleviated Dextran Sulfate Sodium-Induced Colitis by Regulating M1/M2 Macrophage Polarization and TLRs Signaling Pathway.

Curcumin has shown good efficacy in mice with experimental colitis and in patients with ulcerative colitis, but the mechanism of action through the regulation of M1/M2 macrophage polarization has not been elaborated. The ulcerative colitis was modeled by dextran sulfate sodium; colitis mice were orally administrated with curcumin (10 mg/kg/day) or 5-ASA (300 mg/kg/day) for 14 consecutive days. After curcumin treatment, the body weight, colon weight and length, colonic weight index, and histopathological damage in colitis mice were effectively improved. The concentrations of proinflammatory cytokines IL-1ß, IL-6, and CCL-2 in the colonic tissues of colitis mice decreased significantly, while anti-inflammatory cytokines IL-33 and IL-10 increased significantly. Importantly, macrophage activation was suppressed and M1/M2 macrophage polarization was regulated in colitis mice, and the percentage of CD11b+F4/80+ and CD11b+F4/80+TIM-1+ and CD11b+F4/80+iNOS+ decreased significantly and CD11b+F4/80+CD206+ and CD11b+F4/80+CD163+ increased significantly. Additionally, curcumin significantly downregulated CD11b+F4/80+TLR4+ macrophages and the protein levels of TLR2, TLR4, MyD88, NF-κBp65, p38MAPK, and AP-1 in colitis mice. Our study suggested that curcumin exerted therapeutic effects in colitis mice by regulating the balance of M1/M2 macrophage polarization and TLRs signaling pathway.

Ginsenoside from ginseng: a promising treatment for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an autoimmune disease mediated by immune disorder and termed as one of the most refractory diseases by the Word Health Organization. Its morbidity has increased steadily over the past half century worldwide. Environmental, genetic, infectious, and immune factors are integral to the pathogenesis of IBD. Commonly known as the king of herbs, ginseng has been consumed in many countries for the past 2000 years. Its active ingredient ginsenosides, as the most prominent saponins of ginseng, have a wide range of pharmacological effects. Recent studies have confirmed that the active components of Panax ginseng have anti-inflammatory and immunomodulatory effects on IBD, including regulating the balance of immune cells, inhibiting the expression of cytokines, as well as activating Toll-like receptor 4, Nuclear factor-kappa B (NF-κB), nucleotide-binding oligomerization domain-like receptor (NLRP), mitogen-activated protein kinase signaling, and so on. Accumulated evidence indicates that ginsenosides may serve as a potential novel therapeutic drug or health product additive in IBD prevention and treatment in the future.

Genome-scale CRISPR activation screening identifies a role of LRP8 in Sorafenib resistance in Hepatocellular carcinoma.

Sorafenib may provide survival benefits for patients with advanced hepatocellular carcinoma. However, tumor cells can display primary or secondary resistance to Sorafenib. To identify genes capable of conveying Sorafenib resistance, we performed a genome-wide CRISPR transcriptional activation library (SAM) in human Huh7 cells. We identified that a group of sgRNAs were significantly enriched in Sorafenib resistant Huh7 cells, which indicated that these sgRNAs up-regulated their target genes and induced resistance. We finally identified LRP8 as a key gene that can drive HCC cell to acquire sorafenib resistance. All three sgRNAs targeting LRP8 were identified in Sorafenib resistant Huh7 cells with high copy. We also showed that sorafenib-acquired resistant Huh7 cells have much higher LRP8 expression level than parental Huh7 cells. We proved that overexpression of LRP8 in HCC cell lines activated ß-catenin and significantly promoted its resistance to Sorafenib. We further showed that overexpression of LRP8 reduced the apoptosis level of HCC cell lines. To summary, genome-scale CRISPR activation screening identifies a role of LRP8 in Sorafenib resistance in Hepatocellular carcinoma.

System-Pharmacology Dissection of Traditional Chinese herbs SINI Decoction for Treatment of Cardiovascular Diseases.

Abstract: Cardiovascular diseases (CVDs) are leading causes of death in the world, owing to noticeable incidence and mortality. Traditional Chinese Medicine (TCM) SINI Decoction (SND) is used to prevent and treat CVDs, which has attracted extensive attention for its moderate and little side effects. However, the involved molecular mechanisms are exceedingly complicated and remain unclear. Systems pharmacology, as a novel approach that integrates systems biology and pharmacology plays a significant role in investigating the molecular mechanism of TCM. In systems pharmacology approach, we use to systematically uncover the mechanisms of action in Chinese medicinal formula SND as an effective treatment for CVDs, which mainly includes:1) molecular database building; 2) ADME evaluation; 3) target-fishing 4) network construction and analysis. The results show that 78 underlying valid ingredients and their corresponding 71 direct targets of SND were obtained. And SND take part in cardiomyocyte protection, blood pressure regulation, and lipid regulation module in treatment of CVDs by cooperative way. Systems pharmacology as an emerging field that investigates the molecular mechanisms of TCM through pharmacokinetic evaluation target prediction, and pathway analysis, which will facilitate the development of traditional Chinese herbs in modern medicine.

Fucosylated chondroitin sulfate from Isostichopus badionotus alleviates metabolic syndromes and gut microbiota dysbiosis induced by high-fat and high-fructose diet.

Fucosylated chondroitin sulfate from Isostichopus badionotus (fCS-Ib) is a kind of sulfated polysaccharides with well-repeated structure. In our former publications, fCS-Ib has been reported to be a functional food ingredient with hypoglycemic and antilipemic activities. However, there is no systematic study to investigate the effects of fCS-Ib on metabolic syndromes. In the present study, C57BL/6 mice fed on a high-fat and high sucrose diet (HFSD) for 6 weeks was used to cause metabolic syndromes. The final results showed that fCS-Ib alleviated obesity, hyperlipidemia, hyperglycemia, inflammation, liver steatosis, and adipocyte hypertrophy caused by HFSD. Meanwhile, fCS-Ib showed powerful effects on moderating gut microbiota dysbiosis in the HFSD-fed mice. Supplement of fCS-Ib could reduce ratio of Firmicutes to Bacteroidetes by decreasing abundance of Lachnospiraceae and Allobaculum while increasing abundance of Porphyromonadaceae, Barnesiella, and Bacteroides. Our results showed that fCS-Ib could be further developed as a potential pharmaceutical agent to prevent metabolic syndromes and gut microbiota dysbiosis.

Clarifying of the potential mechanism of Sinisan formula for treatment of chronic hepatitis by systems pharmacology method.

Chronic hepatitis is a general designation class of diseases, which results in different degrees of liver necrosis and inflammatory reaction, followed by liver fibrosis, may eventually develop into cirrhosis. However, the molecular pathogenesis of chronic hepatitis is too complex to elucidate. Herbal medicines, featured with multiple targets and compounds, have long displayed therapeutic effect in treating chronic hepatitis, though their molecular mechanisms of contribution remain indistinct. This research utilized the network pharmacology to confirm the molecular pathogenesis of chronic hepatitis through providing a comprehensive analysis of active chemicals, drug targets and pathways' interaction of Sinisan formula for treating chronic hepatitis. The outcomes showed that 80 active ingredients of Sinisan formula interacting with 91 therapeutic proteins were authenticated. Sinisan formula potentially participates in immune modulation, anti-inflammatory and antiviral activities, even has regulating effects on lipid metabolism. These mechanisms directly or indirectly are involved in curing chronic hepatitis by an interaction way. The network pharmacology based analysis demonstrated that Sinisan has multi-scale curative activity in regulating chronic hepatitis related biological processes, which provides a new potential way for modern medicine in the treatment of chronic diseases.

Characterization of the Lycium barbarum fruit transcriptome and development of EST-SSR markers.

Lycium barbarum, commonly known as goji, is important in Chinese herbal medicine and its fruit is a very important agricultural and biological product. However, the molecular mechanism of formation of its fruit and associated medicinal and nutritional components is unexplored. Moreover, this species lacks SSR markers due to lack of genomic and transcriptomic information. In this study, a total of 139,333 unigenes with average length of 1049 bp and N50 of 1579 bp are obtained by trinity assembly from Illumina sequencing reads. A total of 92,498 (66.38%) unigenes showed similarities in at least one database including Nr (46.15%), Nt (56.56%), KO (15.56%), Swiss-prot (33.34%), Pfam (33.43%), GO (33.62%) and KOG/COG (17.55%). Genes in flavonoid and taurine biosynthesis pathways were found and validated by RT-qPCR. A total of 50,093 EST-SSRs were identified from 38,922 unigenes, and 22,537 EST-SSR primer pairs were designed. Four hundred pairs of SSR markers were randomly selected to validate assembly quality, of which 352 (88%) were successful in PCR amplification of genomic DNA from 11 Lycium accessions and 210 produced polymorphisms. The polymorphic loci showed that the genetic similarity of the 11 Lycium accessions ranged from 0.50 to 0.99 and the accessions could be divided into 4 groups. These results will facilitate investigations of the molecular mechanism of formation of L. barbarum fruit and associated medicinal and nutritional components, and will be of value to novel gene discovery and functional genomic studies. The EST-SSR markers will be useful for genetic diversity evaluation, genetic mapping and marker-assisted breeding.

Scallop phenylalanine hydroxylase implicates in immune response and can be induced by human TNF-α.

Phenylalanine hydroxylase (PAH) is an important metabolic enzyme of aromatic amino acids, which is responsible for the irreversible oxidation of phenylalanine to tyrosine. In the present study, the full-length cDNA encoding PAH from Chlamys farreri (designated CfPAH) was cloned by using rapid amplification of cDNA ends (RACE) approaches and expression sequence tag (EST) analysis. The open reading frame of CfPAH encoded a polypeptide of 460 amino acids, and its sequence shared 64.4-74.2% similarity with those of PAHs from other animals. There were an N-terminal regulatory ACT domain and a C-terminal catalytic Biopterin_H domain in the deduced CfPAH protein. The mRNA transcripts of CfPAH could be detected in all the tested tissues, including adductor muscle, mantle, gill, gonad, haemocytes and hepatopancreas. And its expression level in haemocytes was increased significantly during 3-48 h after bacteria Vibrio anguillarum challenge with the highest level (9.1-fold, P < 0.05) at 24 h. Furthermore, the mRNA expression of CfPAH in haemocytes also increased significantly to 2.6-fold (P < 0.05) at 4 h and 3.3-fold (P < 0.05) at 6 h after the stimulation of 50.0 ng mL(-1) human TNF-α. The cDNA fragment encoding the mature peptide of CfPAH was recombined and expressed in the prokaryotic expression system, and 1 mg recombinant CfPAH protein (rCfPAH) could catalyze the conversion of 192.23 ± 32.35 nmol phenylalanine to tyrosine within 1 min (nmol min(-1) mg(-1) protein) in vitro. These results indicated collectively that CfPAH, as a homologue of phenylalanine hydroxylase in scallop C. farreri, could be induced by cytokine and involved in the immunomodulation of scallops by supplying the starting material tyrosine for the synthesis of melanin and catecholamines.