Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism.

BACKGROUND: Toxoplasmosis affects a quarter of the world's population. Toxoplasma gondii (T.gondii) is an intracellular parasitic protozoa. Macrophages are necessary for proliferation and spread of T.gondii by regulating immunity and metabolism. Family with sequence similarity 96A (Fam96a; formally named Ciao2a) is an evolutionarily conserved protein that is highly expressed in macrophages, but whether it play a role in control of T. gondii infection is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we utilized myeloid cell-specific knockout mice to test its role in anti-T. gondii immunity. The results showed that myeloid cell-specific deletion of Fam96a led to exacerbate both acute and chronic toxoplasmosis after exposure to T. gondii. This was related to a defectively reprogrammed polarization in Fam96a-deficient macrophages inhibited the induction of immune effector molecules, including iNOS, by suppressing interferon/STAT1 signaling. Fam96a regulated macrophage polarization process was in part dependent on its ability to fine-tuning intracellular iron (Fe) homeostasis in response to inflammatory stimuli. In addition, Fam96a regulated the mitochondrial oxidative phosphorylation or related events that involved in control of T. gondii. CONCLUSIONS/SIGNIFICANCE: All these findings suggest that Fam96a ablation in macrophages disrupts iron homeostasis and inhibits immune effector molecules, which may aggravate both acute and chronic toxoplasmosis. It highlights that Fam96a may autonomously act as a critical gatekeeper of T. gondii control in macrophages.

Plant polyphenol surfactant construction with strong surface activity and chelation properties as efficient decontamination of UO22+ on cotton fabric.

Chemically synthesized surfactants have promising applications in the treatment of uranium, however, their hazardous environmental effects, non-biodegradability, and numerous drawbacks prevent them from being widely used in practice. Herein, we successfully synthesized a green chelating and foaming integrated surfactant (BTBS) by Mannich reaction and acylation of bayberry tannin for the effective removal of UO22+ from aqueous environments or solid surfaces. The as-prepared surfactant was systematically characterized by FT-IR, showing that the hydrophobic groups were successfully grafted onto tannin. The modified material showed better foaming and emulsifying properties, which proved this method could improve the amphiphilicity of tannin. Moreover, for the first time, a foam fractionation method in conjunction with a tannin-based surfactant was applied for UO22+ removal from water. This surfactant was used as a co-surfactant and could readily remove 90 % of UO22+ (20 mg L-1) from water. The removal of UO22+ could be completed in a short time (30 min), and the maximum adsorption capacity was determined as 175.9 mg g-1. This surfactant can also be used for efficient decontamination of uranium-contaminated cotton cloth with a high removal rate of 94.55 %. In addition, the mechanism studies show that the adsorption of BTBS for UO22+ can be mainly attributed to a chelating mechanism between UO22+ and the adjacent phenolic hydroxyls. The novel biomass-derived BTBS with advantages such as high capture capacity, environmental friendliness, and cost-effectiveness suggests that it plays an important role in the remediation of radionuclide pollution.

Remimazolam versus propofol for deep sedation/anaesthesia in upper gastrointestinal endoscopy in elderly patients: A multicenter, randomized controlled trial.

BACKGROUND AND OBJECTIVE: Propofol is the most commonly used sedative in gastrointestinal endoscopic procedures, but is associated with cardiorespiratory suppression, particularly in elderly patients. Remimazolam is a new short-acting GABA(A) receptor agonist with minimal impact on cardiorespiratory suppression, and may be a viable alternative in elderly patients undergoing endoscopic procedures. METHODS: This multicenter, randomized controlled trial was conducted between September 2020 and September 2021. Elderly patients (65-85 years of age) scheduled to undergo upper gastrointestinal endoscopy were randomized in 1:1 ratio to receive remimazolam tosilate (300 mg/h) or propofol (3 g/h) in addition to 50-µg fentanyl, until the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) reached ≤1. MOAA/S was maintained at 0 or 1 throughout the procedure using 2.5 mg remimazolam or 0.5 mg/kg propofol boluses in the two groups, respectively. The primary outcome was the rate of hypotension (defined as systolic blood pressure at ≤90 mmHg or > 30% decline vs. the baseline). Bradycardia was defined as heart rate ≤50 per minute; respiratory depression was defined as respiratory rate <8 per minute and/or SpO2 < 90%. RESULTS: A total of 400 patients (161 men and 239 women; 70.4 ± 4.6 years of age) were enrolled (200 patients per group). Average body mass index was 22.2 ± 2.4 kg/m2 . The rate of hypotension was 36.5% in the remimazolam group and 69.6% in the propofol group (p < 0.001). The remimazolam group also had a lower rate of bradycardia (1.5% vs. 8.5%, p < 0.001), respiratory depression (4.5% vs. 10.0%, p < 0.05) and pain at the injection site (0% vs. 12.0%, p < 0.001). CONCLUSION: Remimazolam was associated with a lower rate of hypotension in elderly patients undergoing upper gastrointestinal endoscopy under deep sedation/anaesthesia than propofol.

The HVEM-BTLA Immune Checkpoint Restrains Murine Chronic Cholestatic Liver Injury by Regulating the Gut Microbiota.

The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.

Interface assembly of specific recognition gripper wrapping on activated collagen fiber for synergistic capture effect of iodine.

Efficient capture of radioactive iodine (129I, 131I) is of great significance in spent fuel treatment. In this paper, a new adsorbent named Catechin@ACF was successfully prepared through interface assembly of specific recognition gripper with plant polyphenols (catechin) on activated collagen fiber (ACF), and the catechin membrane with specific grip on iodine was successfully constructed on the surface of ACF. The results showed that the adsorbent assembled catechin membrane was rich in aromatic rings, hydroxyl groups and imine adsorption sites, and possessed specific recognition and capture characteristics of iodine. Moreover, the as-prepared Catechin@ACF showed excellent capture capacity for iodine vapor and iodine in organic solution with the maximum capture capacity of 2122.68 mg/g and 258.29 mg/g, respectively. In iodine-cyclohexane solution, the adsorption process was in according with the Pseudo first order kinetic and Langmuir isothermal model. In addition, the specific recognition and capture mechanism analysis indicated that the aromatic rings, phenolic hydroxyl groups and imine groups in the catechin membrane were the specific and effective grippers for iodine, and finally iodine formed a stable conjugated system with the adsorbent in the form of I- and I3-. Therefore, the as-prepared specific iodine capturer Catechin@ACF was expected to play a vital role in the capture of radioactive iodine in spent fuel off-gas because of its specific recognition, high capture capacity, large-scale preparation, and environment-friendly.

Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity.

A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota. An important next step is to elucidate a human-relevant "map'' of microbiota-host interactions that regulate the metabolic health of the host. An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity. Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions, including cancer, neurodegeneration, and aging. The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood. Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage. Changes in the composition and function of the gut microbiota, i.e., dysbiosis, are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction. Many effects of the microbiota on the host are mediated by microbiota-derived metabolites. In this review, we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases. The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.

Evaluation of the Effectiveness of Comprehensive Smoke-Free Legislation in Indoor Public Places in Shanghai, China.

This study evaluated compliance with the comprehensive smoke-free law in public indoor places introduced in Shanghai in March 2017. Observations and PM2.5 monitoring over 30 min intervals in 8 types of the venue were conducted three times: within a month before implementation and 3- and 12-months post implementation. Observations of evidence of smoking decreased from 66.2% before legislation to 52.8% three months after (p = 0.002) and 49.7% one year after (p < 0.001). The density of lit cigarettes also reduced significantly after implementation (p < 0.001). When adjusting for outdoor, indoor PM2.5 levels were significantly lower after the legislation, but only by a small amount (three months later: -0.27, p = 0.08; one year later: -0.12; p = 0.03). Evidence of compliance was weakest in farmer's markets and bars, and smoking in male toilets did not change significantly. The reduction in smoking was affected by the management performance of their obligations. The comprehensive smoke-free law led to modest reductions in smoking and PM2.5 levels as a result, but from levels suggesting quite high levels of pre-compliance. However, compliance was limited in some areas, suggesting more effort is required on management to gain better compliance in some places like farmer's markets, bars, and toilets.

Real-world data on EGFR/ALK gene status and first-line targeted therapy rate in newly diagnosed advanced non-small cell lung cancer patients in Northern China: A prospective observational study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) can significantly prolong overall survival for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-mutation or anaplastic lymphoma kinase (ALK)-rearrangement. However, the real-world evaluation status of ALK/EGFR in China remains unclear. METHODS: We conducted a prospective study including 1134 patients with cytologically or histologically confirmed advanced NSCLC (stage IIIb-IV) at 12 Chinese hospitals. RESULTS: The most common evaluation methods were amplification-refractory mutation system for EGFR status and immunohistochemistry targeting D5F3 for ALK status. Among patients with non-squamous, the EGFR mutation rate was 44.1% and the ALK rearrangement rate was 10.0%. Among patients with squamous cell carcinoma, the EGFR mutation rate was 8.3% and the ALK rearrangement rate was 3.7%. Among all patients, gender (HR = 1.7, 95%CI = 1.2-2.4, P = 0.006), smoking history (HR = 1.8, 95%CI = 1.3-2.7, P = 0.001), histology (HR = 5.0, 95%CI = 2.4-10.1, P < 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1-2.2, P = 0.017) were independent predictors of EGFR mutation, while age (HR = 2.6, 95%CI = 1.7-4.1, P < 0.001) was an independent predictor of ALK rearrangement. The median time from tumor diagnosis to EGFR or ALK status confirmation was 7 and 5 days, respectively. Targeted therapy rate was 73.8% in EGFR-positive patients and 51.4% in ALK-positive patients. There was a negative correlation between the first-line targeted therapy rate and the EGFR mutation detection period (r = -0.152, P = 0.02), while no significant correlation among patients with ALK rearrangement (r = -0.179, P = 0.076). CONCLUSION: Squamous NSCLC patients should also be routinely tested to determine their EGFR/ALK statuses. The first-line targeted therapy rate remains low in Chinese patients with NSCLC.

LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

The physiologic signals that regulate beige adipogenesis remain incompletely understood, especially those that limit browning and prevent overexpenditure of energy. In this study, the TNF family member cytokine lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells (LIGHT), also known as TNF super family protein 14 (TNFSF14), can inhibit adipose precursor differentiation into beige adipocytes. In acute cold stress, LIGHT deficiency in mice accelerated browning in the subcutaneous white adipose tissue (scWAT). Further experiments showed that LIGHT interacting with lymphotoxin-ß receptor (LTßR) on adipose precursors blocked beige fat biogenesis. LTßR signals attenuated the JNK pathway, which contributed to their antibeiging effect. Blocking JNK activation using a small molecular inhibitor prevented cold-induced scWAT beiging. Furthermore, LIGHT/LTßR signals acted as an attenuator of white adipogenesis. LIGHT deficiency in mice promoted obesity during high-fat diet feeding. These findings identify the LIGHT axis as a regulator of adipose tissue homeostasis and suggest that LIGHT signaling functions as a mechanism to divert energy in favor of immune activation.-Kou, Y., Liu, Q., Liu, W., Sun, H., Liang, M., Kong, F., Zhang, B., Wei, Y., Liu, Z., Wang, Y. LIGHT/TNFSF14 signaling attenuates beige fat biogenesis.

Sphallerocarpus gracilis polysaccharide protects pancreatic ß-cells via regulation of the bax/bcl-2, caspase-3, pdx-1 and insulin signalling pathways.

In this study, the structural characterization of Sphallerocarpus gracilis polysaccharide (SGP) and its hypoglycaemic activities are reported for the first time. SGP, which has a weight average molar mass (Mw) of 7.413×105, was isolated from Sphallerocarpus gracilis and purified by ion-exchange chromatography. The polysaccharide is composed of rhamnose, arabinose, mannose, glucose and galactose, with the molar ratio of 4.12: 8.99: 5.45: 65.94: 15.50. The mechanism underlying the hypoglycaemic effect of SGP was evaluated. Experimental results showed that SGP protected pancreatic ß-cells from alloxan damage by several possible mechanisms, including: (1) repairing free radical damage; (2) reducing the apoptosis of pancreatic ß-cells by inhibiting the activities of caspase-3 and bax, and enhancing the activity of bcl-2; (3) stimulating insulin secretion and upregulating the pancreatic and duodenal homeobox 1 gene and the insulin gene and the pancreatic in pancreatic ß-cells. The results obtained in this study suggest that SGP may be a promising therapeutic agent in the treatment of diabetes mellitus.

Core-shell nanocarriers with ZnO quantum dots-conjugated Au nanoparticle for tumor-targeted drug delivery.

Core-shell structured multifunctional nanocarriers (NCs) of ZnO quantum dots-conjugated gold nanoparticles (Au NPs) as core and amphiphilic hyperbranched block copolymer as shell were synthesized for targeted anticancer drug delivery. The amphiphilic hyperbranched block copolymer contained poly(l-lactide) (PLA) inner arm and folate (FA)-conjugated a sulfated polysaccharide from Gynostemma pentaphyllum Makino (GPPS-FA) outer arm. The structure and properties of core-shell structured multifunctional nanocarriers were characterized and determined by UV-visible spectra, FT-IR spectra, X-ray diffraction (XRD), fluorescence spectroscopy and TEM analyses. The release results indicated that camptothecin (CPT) release from NCs at pH 7.4 was much greater than that at pH 5.3. The cytotoxicity studies showed that both the blank NCs and the CPT-loaded NCs provided high anticancer activity against Hela cells. Furthermore, nanocarriers gained specificity to target model cancer cells in this study due to the enhanced cell uptake mediated by FA moiety. The results indicated that the NCs not only had great potential as tumor-targeted drug delivery nanocarrier, but also had an assistant role in the treatment of cancer.

[Proteomics analysis of the synergy effect of Radix Hedysari polysaccharides combined with chemotherapy on S180 tumor cells].

OBJECTIVE: To analyze the differentially expressed proteins of the synergy effect of Radix Hedysari polysaccharides (HPS)combined with chemotherapy (Cy) on S180 tumor cells. METHODS: The total proteins extracted from the HPS combined with Cy treated S180 cells in tumor-bearing mice were separated by two dimentional gel electrophoresis (2-DE)and compared with those from Cy treated S180 cells using PDQuest 8.0 software. Mass spectrometry was applied to identify the differentially expressed proteins. Western blot was used to determine the differential expression of one protein. RESULTS: Twenty-four differentially-expressed proteins in HPS group were discovered. The five differential expressed proteins among twenty-four proteins were later identified by mass spectrometry and Mascot software as heat-shock protein hsp84 (HSP90beta), apolipoprotein A, albumin, heat shock protein beta-1 (HSP27)and unnamed protein product, including one up regulated and four down regulated expressed proteins respectively. Results from Western blot manifested the same trend as from proteomics analysis. CONCLUSION: Proteomics technique can be used to discover target proteins associated with the synergy effect of HPS combined with Cy on S180 tumor cells, involving some important proteins related to energy metabolism, oxidative stress and apoptosis induction signal transduction.

Synthesis and biological evaluation of a series of podophyllotoxins derivatives as a class of potent antitubulin agents.

A series of eight novel podophyllotoxin derivatives were designed, synthesized and evaluated for biological activities. The antiproliferative activities were tested against a panel of human cancer cell lines (K562, SGC, Hela and HepG) and the inhibition of tubulin polymerization was also evaluated. Compound 8e displayed significant antiproliferative activities for all four cell lines and strong levels of tubulin polymerization inhibition effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that compound 3e that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities. The synthesis and biological studies provided an interesting new class of antitubulin agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs.

Proteomic analysis of the effect of triterpenes from Patrinia heterophylla on leukemia K562 cells.

For centuries, Patrinia heterophylla had been used in China to treat many diseases including tumor. Triterpenes has been identified as the major active constituents in Patrinia heterophylla. To elucidate the antitumor mechanism of triterpenes from Patrinia heterophylla1 (TPH), a proteomic analysis is carried out with TPH treatment in K562 cells. The total proteins extracted from TPH treated K562 cells are analyzed by two dimensional gel electrophoresis (2-DE) and compared with those untreated K562 cells. Mass spectrometry is applied to identify the differentially expressed proteins. Twenty-three differentially expressed significant proteins are discovered. Eight proteins are later identified by mass spectrometry (MALDI-TOF-MS) and Mascot software. Among them, four proteins are up-regulated (Aldolase A, Glyceraldehyde-3-phosphate dehydrogenase, Flavin reductase and Hemoglobin subunit) and four proteins were down-regulated (Heat-shock protein 90 〈Alpha〉 (HSP90-〈Alpha〉), Eukaryotic translation initiation factor 5A, Moesin, tublin) by TPH treatment in K562 cells. The identified proteins are associated with energy metabolism, oxidative stress, apoptosis, signal transduction, differential induction, and protein biosynthesis. These findings might provide valuable insights into the antitumor mechanism of TPH in K562 cells.

Sulfated modification, characterization and antitumor activities of Radix hedysari polysaccharide.

Sulfated modification of a polysaccharide obtained from Radix hedysari (RHP) was studied. Four sulfated derivatives (RHPS) with variable degrees of substitution (DS) were obtained by the chlorosulfonic acid method with ionic liquids (ILs) as solvent and 4-dimethylaminopyridine (DMAP) as catalyst. The structures of RHPS were characterized by FT-IR spectra and ¹³C NMR spectra, and the results indicated that the sulfated groups were modified mainly at the C-6 position and C-2 position. Four kinds of RHPS showed different DS ranging from 0.63 to 1.45, and different weight-average molecular mass (Mw) ranging from 60.8 to 71.1 kDa with a little degradation. Compared with RHP, all of RHPS exhibited obvious antitumor activity on A549 cells and BGC-823 cells in vitro. However, they had no obvious influence on HEK293 cells, which indicated that they had low toxicity to normal cells. Flow cytometric studies indicated that the treatment of RHPS against A549 cells and BGC-823 cells could mediate the cell-cycle arrest in the G1 phase.

[The effects of human 21.5 kDa MBP gene on HepG-2 proliferation and apoptosis].

OBJECTIVE: To test the effects of the 21.5 kDa human brain myelin basic protein (MBP) on the proliferation and apoptosis of HepG-2. METHODS: pSVCEP-MBP-CAT plasmid containing the full-length 21.5 kDa MBP cDNA was transfected into human hepatoma carcinoma cells (HepG-2). The pSVCEP-CAT vector transfected HepG-2 cells served as negative control. RT-PCR and Western blot were performed to confirm the effectiveness of the transfection. MTT measures were used to determine the proliferative curve of cells. H2O2 was then added to induce cell apoptosis. DNA ladder, immunohistochemistry assay, comet electrophoresis and TUNEL (Terminal Deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling) were used to detect the apoptosis and relevant protein expressions. RESULTS: The 21.5 KDa MBP cDNA was transfected into HepG-2 cells successfully. MTT measures of pSVCEP-MBP-CAT transfected group showed increased proliferation and anti-apoptosis. The control group displayed with more typical DNA ladders and much higher level of Caspase-3 than the MBP group. Comet and TUNEL assays revealed that the control group cells had significant DNA damages and serious apoptosis, whereas the MBP group showed slight changes. CONCLUSION: The 21.5 kDa MBP promotes the proliferation of HepG-2 and blocks apoptosis.