Using omics approaches to dissect the therapeutic effects of Chinese herbal medicines on gastrointestinal cancers.

Chinese herbal medicines offer a rich source of anti-cancer drugs. Differences between the pharmacology of Chinese herbal medicines and modern synthetic chemicals hinder the development of drugs derived from herbal products. To address this challenge, novel omics approaches including transcriptomics, proteomics, genomics, metabolomics, and microbiomics have been applied to dissect the pharmacological benefits of Chinese herbal medicines in cancer treatments. Numerous Chinese herbal medicines have shown potential anti-tumor effects on different gastrointestinal (GI) cancers while eliminating the side effects associated with conventional cancer therapies. The present study aimed to provide an overview of recent research focusing on Chinese herbal medicines in GI cancer treatment, based on omics approaches. This review also illustrates the potential utility of omics approaches in herbal-derived drug discovery. Omics approaches can precisely and efficiently reveal the key molecular targets and intracellular interaction networks of Chinese herbal medicines in GI cancer treatment. This study summarizes the application of different omics-based approaches in investigating the effects and mechanisms of Chinese herbal medicines in GI cancers. Future research directions are also proposed for this area of study.

Effects of the Powder from Hoggery Desulfurization Tanks on the Salinity Resistance of Lettuce.

Lettuce is an important vegetable cultivated worldwide, even in regions with highly saline soils. A large amount of research discusses the application of sulfur on the increase of antioxidation in plants. The powder from hoggery desulfurization tanks contained high amounts of sulfur and small amounts of other nutrients for plants. This powder can be added to liquid fertilizer to create high-sulfur liquid fertilizer (HSLF). This study observed the cell morphologies of lettuce root apices under salt stress after the application of HSLF. Lettuce plants were cultivated in hydroponic solutions containing one of two NaCl (0 and 40 mM) and three HSLF (0.0, 1.5, and 3.0 g L-1) concentrations. Salinity reduced the K+/Na+ ratio in the plant leaves; however, this reduction was smaller in the HSLF-treated plants. Except for phosphate and potassium, nutrient absorption is inhibited under conditions of high salinity. Using scanning electron microscopy, we observed apices more integrated on cell roots after increasing HSLF supplement under non-salt-stressed conditions. In addition, the cells were repaired after increasing the supplement of HSLF under the condition of 40 mM NaCl. Although salt stress reduced plant growth, the reductions were minimized in the HSLF-treated plants. The application of HSLF potentially alleviated salt injury in lettuce root apices and was probably associated with the improvement of phosphorus and potassium absorption and increasing K+/Na+ ratios in lettuce plants.

An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues.

Existing first-line cancer therapies often fail to cope with the heterogeneity and complexity of cancers, so that new therapeutic approaches are urgently needed. Among novel alternative therapies, adoptive cell therapy (ACT) has emerged as a promising cancer treatment in recent years. The limited clinical applications of ACT, despite its advantages over standard-of-care therapies, can be attributed to (i) time-consuming and cost-intensive procedures to screen for potent anti-tumor immune cells and the corresponding targets, (ii) difficulties to translate in-vitro and animal-derived in-vivo efficacies to clinical efficacy in humans, and (iii) the lack of systemic methods for the safety assessment of ACT. Suitable experimental models and testing platforms have the potential to accelerate the development of ACT. Immunocompetent microphysiological systems (iMPS) are microfluidic platforms that enable complex interactions of advanced tissue models with different immune cell types, bridging the gap between in-vitro and in-vivo studies. Here, we present a proof-of-concept iMPS that supports a triple culture of three-dimensional (3D) colorectal tumor microtissues, 3D cardiac microtissues, and human-derived natural killer (NK) cells in the same microfluidic network. Different aspects of tumor-NK cell interactions were characterized using this iMPS including: (i) direct interaction and NK cell-mediated tumor killing, (ii) the development of an inflammatory milieu through enrichment of soluble pro-inflammatory chemokines and cytokines, and (iii) secondary effects on healthy cardiac microtissues. We found a specific NK cell-mediated tumor-killing activity and elevated levels of tumor- and NK cell-derived chemokines and cytokines, indicating crosstalk and development of an inflammatory milieu. While viability and morphological integrity of cardiac microtissues remained mostly unaffected, we were able to detect alterations in their beating behavior, which shows the potential of iMPS for both, efficacy and early safety testing of new candidate ACTs.

Influence of LncRNA NKILA on Bloodstream Infection of Hypervirulent Klebsiella pneumoniae and Its Ability to Induce Delayed Neutrophil Apoptosis.

OBJECTIVE: Pneumonia due to hypervirulent Klebsiella pneumoniae (hvKP) is a high-risk subtype of pneumonia with high mortality and disability rates. An in-depth understanding of hvKP's pathogenic process and mechanism of action is the focus of achieving early disease diagnosis and early symptomatic treatment. This study conducted a preliminary analysis on the influence of lncRNA NKILA (NKILA) on hvKP, aiming at providing a new approach to the diagnosis and treatment of hvKP and laying a reliable foundation for subsequent NKILA-related studies. METHODS: Selected from our hospital from October 2016 to February 2018, 67 patients who were examined for the pathogenic microorganisms of alveolar lavage fluid were selected as the research subjects. Among them, 29 were diagnosed as hvKP (research group), and the other 38 had no pathogenic bacteria (control group). Serum and bronchoalveolar lavage fluid (BALF) NKILA and inflammatory factors were detected, and the clinical significance of NKILA was analyzed. In addition, neutrophils from research group were extracted and NKILA expression was increased to observe the alterations in cell apoptosis, respiratory burst intensity, and NF-kappa B inhibitor alpha (NF-κB) p65 protein. RESULTS: Serum and BALF levels of NKILA and inflammatory factors were higher in research group than in control group, and NKILA decreased in both cohorts after treatment (P < 0.05). NKILA had an excellent predictive effect on the occurrence of hvKP (P < 0.001) and was positively correlated with inflammatory factors (P < 0.05). Prognostic follow-up revealed that NKILA also had a good predictive value for death in hvKP patients (P < 0.05), and increased posttreatment levels predicted an increased risk of death (P < 0.05). In vitro, increased NKILA hindered the delayed apoptosis rate, decreased respiratory burst intensity of hvKP neutrophils, and activated NF-κB p65 protein (P < 0.05). CONCLUSION: With an elevated expression profile in hvKP, NKILA can induce the delayed apoptosis of neutrophils, enhance the ability of releasing inflammatory mediators, and promote the progression of hvKP via activating NF-κB p65.

Evaluation of the Influence of Zhenwu Tang on the Pharmacokinetics of Digoxin in Rats Using HPLC-MS/MS.

Digoxin (DIG) is a positive inotropic drug with a narrow therapeutic window that is used in the clinic for heart failure. The active efflux transporter of DIG, P-glycoprotein (P-gp), mediates DIG absorption and excretion in rats and humans. Up to date, several studies have shown that the ginger and Poria extracts in Zhenwu Tang (ZWT) affect P-gp transport activity. This study aimed to explore the effects of ZWT on the tissue distribution and pharmacokinetics of DIG in rats. The deionized water or ZWT (18.75 g/kg) was orally administered to male Sprague-Dawley rats once a day for 14 days as a pretreatment. On day 15, 1 hour after receiving deionized water or ZWT, the rats were given the solution of DIG at 0.045 mg/kg dose, and the collection of blood samples was carried out from the fundus vein or excised tissues at various time points. HPLC-MS/MS was used for the determination of the DIG concentrations in the plasma and the tissues under investigation. The pharmacokinetic interactions between DIG and ZWT after oral coadministration in rats revealed significant reductions in DIG Cmax and AUC0-∞, as well as significant increases in T1/2 and MRT0-∞. When coadministered with ZWT, the DIG concentration in four of the investigated tissues statistically decreased at different time points except for the stomach. This study found that combining DIG with ZWT reduced not only DIG plasma exposure but also DIG accumulation in tissues (heart, liver, lungs, and kidneys). The findings of our study could help to improve the drug's validity and safety in clinical applications and provide a pharmacological basis for the combined use of DIG and ZWT.

Geriatric Elements and Oral Anticoagulant Prescribing in Older Atrial Fibrillation Patients: SAGE-AF.

OBJECTIVES: Oral anticoagulants are the cornerstone of stroke prevention in high-risk patients with atrial fibrillation (AF). Geriatric elements, such as cognitive impairment and frailty, commonly occur in these patients and are often cited as reasons for not prescribing oral anticoagulants. We sought to systematically assess geriatric impairments in patients with AF and determine whether they were associated with oral anticoagulant prescribing. DESIGN: Cross-sectional analysis of baseline data from the ongoing Systematic Assessment of Geriatric Elements in Atrial Fibrillation (SAGE-AF) prospective cohort study. SETTING: Multicenter study with site locations in Massachusetts and Georgia that recruited participants from cardiology, electrophysiology, and primary care clinics from 2016 to 2018. PARTICIPANTS: Participants with AF age 65 years or older, CHA2 DS2 -VASc (congestive heart failure; hypertension; aged ≥75 y [doubled]; diabetes mellitus; prior stroke, transient ischemic attack, or thromboembolism [doubled]; vascular disease; age 65-74; female sex) score of 2 or higher, and no oral anticoagulant contraindications (n = 1244). MEASUREMENTS: A six-component geriatric assessment included validated measures of frailty, cognitive function, social support, depressive symptoms, vision, and hearing. Oral anticoagulant use was abstracted from the medical record. RESULTS: A total of 1244 participants (mean age = 76 y; 49% female; 85% white) were enrolled; 42% were cognitively impaired, 14% frail, 53% pre-frail, 12% socially isolated, and 29% had depressive symptoms. Oral anticoagulants were prescribed to 86% of the cohort. Oral anticoagulant prescribing did not vary according to any of the geriatric elements (adjusted odds ratios [ORs] for oral anticoagulant prescribing and cognitive impairment: OR = .75; 95% confidence interval [CI] = .51-1.09; frail OR = .69; 95% CI = .35-1.36; social isolation OR = .90; 95% CI = .52-1.54; depression OR = .79; 95% CI = .49-1.27; visual impairment OR = .98; 95% CI = .65-1.48; and hearing impairment OR = 1.05; 95% CI = .71-1.54). CONCLUSION: Geriatric impairments, particularly cognitive impairment and frailty, were common in our cohort, but treatment with oral anticoagulants did not differ by impairment status. These geriatric impairments are commonly cited as reasons for not prescribing oral anticoagulants, suggesting that prescribers may either be unaware or deliberately ignoring the presence of these factors in clinical settings. J Am Geriatr Soc 68:147-154, 2019.

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation.

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

Enhancement of hypothalamic STAT3 acetylation by nuclear receptor Nur77 dictates leptin sensitivity.

Leptin, an anorexigenic hormone in the hypothalamus, suppresses food intake and increases energy expenditure. Failure to respond to leptin will lead to obesity. Here, we discovered that nuclear receptor Nur77 expression is lower in the hypothalamus of obese mice compared with normal mice. Injection of leptin results in significant reduction in body weight in wild-type mice but not in Nur77 knockout (KO) littermates or mice with specific Nur77 knockdown in the hypothalamus. Hypothalamic Nur77 not only participates in leptin central control of food intake but also expands leptin's reach to liver and adipose tissues to regulate lipid metabolism. Nur77 facilitates signal transducer and activator of transcription 3 (STAT3) acetylation by recruiting acetylase p300 and disassociating deacetylase histone deacetylase 1 (HDAC1) to enhance the transcriptional activity of STAT3 and consequently modulates the expression of downstream gene Pomc in the hypothalamus. Nur77 deficiency compromises response to leptin in mice fed a high-fat diet. Severe leptin resistance in Nur77 KO mice with increased appetite, lower energy expenditure, and hyperleptinemia contributes to aging-induced obesity. Our study opens a new avenue for regulating metabolism with Nur77 as the positive modulator in the leptin-driven antiobesity in the hypothalamus.

Generation of recombinant pandemic H1N1 influenza virus with the HA cleavable by bromelain and identification of the residues influencing HA bromelain cleavage.

The proteolytic enzyme bromelain has been traditionally used to cleave the hemagglutinin (HA) protein at the C-terminus of the HA2 region to release the HA proteins from influenza virions. The bromelain cleaved HA (BHA) has been routinely used as an antigen to generate antiserum that is essential for influenza vaccine product release. The HA of the 2009 pandemic H1N1 influenza A/California/7/2009 (CA09) virus could not be cleaved efficiently by bromelain. To ensure timely delivery of BHA for antiserum production, we generated a chimeric virus that contained the HA1 region from CA09 and the HA2 region from the seasonal H1N1 A/South Dakota/6/2007 (SD07) virus that is cleavable by bromelain. The BHA from this chimeric virus was antigenically identical to CA09 and induced high levels of HA-specific antibodies and protected ferrets from wild-type H1N1 CA09 virus challenge. To determine the molecular basis of inefficient cleavage of CA09 HA by bromelain, the amino acids that differed between the HA2 of CA09 and SD07 were introduced into recombinant CA09 virus to assess their effect on bromelain cleavage. The D373N or E374G substitution in the HA2 stalk region of CA09 HA enabled efficient cleavage of CA09 HA by bromelain. Sequence analysis of the pandemic H1N1-like viruses isolated from 2010 revealed emergence of the E374K change. We found that K374 enabled the HA to be cleaved by bromelain and confirmed that the 374 residue is critical for HA bromelain cleavage.

[Recent advances of Drynaria fortunei].

Drynaria fortunei (Kunze) is a common medicine in department of orthopaedics and traumaology, more researches about it recently, including basic theory, pharmaco and clinical study.

A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair.

DNA damage repair is crucial for the maintenance of genome integrity and cancer suppression. We found that loss of the mouse transcription factor YY1 resulted in polyploidy and chromatid aberrations, which are signatures of defects in homologous recombination. Further biochemical analyses identified a YY1 complex comprising components of the evolutionarily conserved INO80 chromatin-remodeling complex. Notably, RNA interference-mediated knockdown of YY1 and INO80 increased cellular sensitivity toward DNA-damaging agents. Functional assays revealed that both YY1 and INO80 are essential in homologous recombination-based DNA repair (HRR), which was further supported by the finding that YY1 preferentially bound a recombination-intermediate structure in vitro. Collectively, these observations reveal a link between YY1 and INO80 and roles for both in HRR, providing new insight into mechanisms that control the cellular response to genotoxic stress.