Protective Zika vaccines engineered to eliminate enhancement of dengue infection via immunodominance switch.

Antibody-dependent enhancement (ADE) is an important safety concern for vaccine development against dengue virus (DENV) and its antigenically related Zika virus (ZIKV) because vaccine may prime deleterious antibodies to enhance natural infections. Cross-reactive antibodies targeting the conserved fusion loop epitope (FLE) are known as the main sources of ADE. We design ZIKV immunogens engineered to change the FLE conformation but preserve neutralizing epitopes. Single vaccination conferred sterilizing immunity against ZIKV without ADE of DENV-serotype 1-4 infections and abrogated maternal-neonatal transmission in mice. Unlike the wild-type-based vaccine inducing predominately cross-reactive ADE-prone antibodies, B cell profiling revealed that the engineered vaccines switched immunodominance to dispersed patterns without DENV enhancement. The crystal structure of the engineered immunogen showed the dimeric conformation of the envelope protein with FLE disruption. We provide vaccine candidates that will prevent both ZIKV infection and infection-/vaccination-induced DENV ADE.

E-learning platforms in ideological and political education at universities: students' motivation and learning performance.

BACKGROUND: The study aimed to examine the impact of using the MOODLE e-learning platform in ideological and political education on Chinese students' motivation and academic performance. METHODS: The study involved 447 students from China-based universities (the experimental group - 232 students who studied using electronic educational platforms, and the control group - 215 students who used no digital technologies in their learning). The following methods were used: Measuring the need to achieve success among students; T. I. Ilyina's method for studying motivation to study at university; Method for studying student success motivation; Method for studying the motives of students' educational activities; Method for determining the main motives for choosing a profession (E. M. Pavlyutenkov); Motivation of learning activities: Levels and types (I. S. Dombrovskaya). Students' academic performance was assessed by testing in the studied disciplines at the beginning and end of the study. RESULTS: As a result, the significance of the motivational component in achieving the success of ideological and political education and the impact on students' motivation to use e-learning platforms is theoretically substantiated. CONCLUSIONS: It has been confirmed that using e-learning platforms in ideological and political education helps increase student motivation and academic performance.

5-Aminosalicylic acid ameliorates dextran sulfate sodium-induced colitis in mice by modulating gut microbiota and bile acid metabolism.

Colitis develops via the convergence of environmental, microbial, immunological, and genetic factors. The medicine 5-aminosalicylic acid (5-ASA) is widely used in clinical practice for colitis (especially ulcerative colitis) treatment. However, the significance of gut microbiota in the protective effect of 5-ASA on colitis has not been explored. Using a dextran sulfate sodium (DSS)-induced colitis mouse model, we found that 5-ASA ameliorated colitis symptoms in DSS-treated mice, accompanied by increased body weight gain and colon length, and a decrease in disease activity index (DAI) score and spleen index. Also, 5-ASA alleviated DSS-induced damage to colonic tissues, as indicated by suppressed inflammation and decreased tight junction, mucin, and water-sodium transport protein levels. Moreover, the 16S rDNA gene sequencing results illustrated that 5-ASA reshaped the disordered gut microbiota community structure in DSS-treated mice by promoting the abundance of Bifidobacterium, Lachnoclostridium, and Anaerotruncus, and reducing the content of Alloprevotella and Desulfovibrio. Furthermore, 5-ASA improved the abnormal metabolism of bile acids (BAs) by regulating the Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5) signaling pathways in DSS-treated mice. In contrast, 5-ASA did not prevent the occurrence of colitis in mice with gut microbiota depletion, confirming the essential role of gut microbiota in colitis treatment by 5-ASA. In conclusion, 5-ASA can ameliorate DSS-induced colitis in mice by modulating gut microbiota and bile acid metabolism. These findings documented the new therapeutic mechanisms of 5-ASA in clinical colitis treatment.

Angiopoietin-like protein 4 promotes hyperlipidemia-induced renal injury by down-regulating the expression of ACTN4.

OBJECTIVE: The molecular mechanism of in hyperlipidemia-induced renal injury has not been elucidated. Angiogenin-like protein 4 (ANGPTL4) is a key regulator of lipid metabolism. The role of ANGPTL4 hyperlipidemia-induced renal injury has not been reported. METHODS: Wild type C57 mice and gene angptl4 knockout mice were fed with 60% high fat diet or normal diet respectively. The serum lipid, urinary albumin and renal pathology were tested at the 9th, 13th, 17th and 21st week with high fat diet. RESULTS: Elevated blood lipids in the wild-type mice with high-fat diet were found at 9th week. At the 17th week, the level of urinary albumin in high-fat fed wild type mice were significantly higher than which with normal diet, correspondingly, segmental fusion of podocyte foot process in kidney could be observed in these hyperlipidemia mice. IHC showed that the expression of ANGPTL4 in glomeruli of high-fat fed wild type mice began significant elevated since the 9th week. When given high fat diet, compared to the wild type, the gene angptl4 knockout mice showed significantly alleviated the levels of hyperlipidemia, proteinuria and effacement of podocyte foot process. Finally, the expression of ACTN4 showed remarkably lower in glomeruli podocyte of wild type mice fed high fat diet than that of wild type mice with normal diet at each time-point (P < 0.01). Differently, the expression of ACTN4 in gene angptl4 knockout mice did not happen significantly weaken when given the same dose of high fat diet. CONCLUSION: ANGPTL4 could play a role in hyperlipidemic-induced renal injury via down-regulating the expression of ACTN4 in kidney podocyte.

Bile acid profiles in bile and feces of obese mice by a high-performance liquid chromatography-tandem mass spectrometry.

Bile acids (BAs) play a pivotal role in manipulating the development of metabolic diseases. However, due to the compositional complexity and functional variation of BAs, it remains unclear about the changes in BA pool for individuals with obesity or metabolic syndrome. We established a high-performance liquid chromatography-mass spectrometer detection system for the simultaneous analysis of both unconjugated and conjugated BAs in the bile and feces of mice. Ten BAs were completely separated, identified, and quantified with low limit of detection (0.5 ng/mL) and inter/intraday precision (relative standard deviation < 12%). By using this method, these BAs in bile and feces of mice were quantified. The result showed that taurochenodeoxycholic acid, taurine-conjugated α-muricholic acids, and taurine-conjugated ß-muricholic acids were the dominated BAs in bile, whereas deoxycholic acid and chenodeoxycholic acid predominated in feces. Further, most of the BA levels were significantly elevated in either bile or fecal samples of high-fat diet-fed mice as compared with those in normal chow diet-fed mice, indicating that excessive production of BAs was closely associated with the occurrence of lipid metabolism disorders. In summary, the present method is practicable for analysis of BAs in bile and fecal samples of patients with obesity.

Breast Cancer Challenges and Screening in China: Lessons From Current Registry Data and Population Screening Studies.

BACKGROUND: As one of its responses to the increasing global burden of breast cancer (BC), China has deployed a national registration and BC screening campaign. The present report describes these programs and the initial results of these national BC control strategies, highlighting the challenges to be considered. MATERIALS AND METHODS: The primary BC incidence and prevalence data were obtained from the Chinese National Central Cancer Registry. MapInfo software was used to map the geographic distribution and variation. The time trends were estimated by the annual percentage of change from 2003 to 2009. The description of the screening plans and preliminary results were provided by the Ministry of Health. RESULTS: Chinese cancer registries were primarily developed and activated in the East and Coastal regions of China, with only 12.5% of the registries located in West China. Geographic variation was noted, with the incidence of BC higher in North China than in South China and in urban areas compared with rural areas. Of great interest, these registries reported that the overall BC incidence has been increasing in China, with an earlier age of onset compared with Western countries and a peak incidence rate at age 50. In response to this increasing incidence and early age of onset, BC screening programs assessed 1.46 million women aged 35-59 years, using clinical breast examinations and ultrasound as primary screening tools between 2009 and 2011. The diagnostic rate for this screening program was only 48.0/10(5) with 440 cases of early stage BC. Early stage BC was detected in nearly 70% of screened patients. Subsequently, a second-generation screening program was conducted that included older women aged 35-64 years and an additional 6 million women were screened. CONCLUSION: The cancer registration system in China has been uneven, with a greater focus on East rather than West China. The data from these registries demonstrate regional variation, an increasing BC incidence, and an early age of onset. The 2009 to 2011 BC screening program targeting women aged 35-59 years had a low detection rate that resulted in a second-generation screening program that extended the cohort size and ages screened to 35-64 years. IMPLICATIONS FOR PRACTICE: Cancer registration has been active in China for decades; however, a national survey of registries has not been routinely reported. This study used MapInfo to describe the reported data and found asymmetric registration activities, geographic variations in breast cancer (BC) burdens, and an increasing incidence with a peak at age 50. The initial Chinese BC screening programs focused on a relatively young population of women aged 35-59 years and had a low detection rate, but 69.7% of patients had early stage BC. Older women were included in the second-generation screening programs, and an additional 6 million women were screened. Consideration of regional variations and age is necessary to optimize the efficiency and utility of BC screening in China, with the ultimate goal to reduce BC mortality.

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

BACKGROUND: The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. METHODS: 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. RESULTS: GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. CONCLUSIONS: These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

Ramipril protects the endothelium from high glucose-induced dysfunction through CaMKKß/AMPK and heme oxygenase-1 activation.

This study aims to investigate the effects of ramipril (RPL) on endothelial dysfunction associated with diabetes mellitus using cultured human aortic endothelial cells (HAECs) and a type 2 diabetic animal model. The effect of RPL on vasodilatory function in fat-fed, streptozotocin-treated rats was assessed. RPL treatment of 8 weeks alleviated insulin resistance and inhibited the decrease in endothelium-dependent vasodilation in diabetic rats. RPL treatment also reduced serum advanced glycation end products (AGE) concentration and rat aorta reactive oxygen species formation and increased aorta endothelium heme oxygenase-1 (HO-1) expression. Exposure of HAECs to high concentrations of glucose induced prolonged oxidative stress, apoptosis, and accumulation of AGEs. These effects were abolished by incubation of ramiprilat (RPT), the active metabolite of RPL. However, treatment of HAECs with STO-609, a CaMKKß (Ca(2+)/calmodulin-dependent protein kinase kinase-ß) inhibitor; compound C, an AMPK (AMP-activated protein kinase) inhibitor; and Zn(II)PPIX, a selective HO-1 inhibitor, blocked these beneficial effects of RPT. In addition, RPT increased nuclear factor erythroid 2-related factor-2 (Nrf-2) nuclear translocation and activation in a CaMKKß/AMPK pathway-dependent manner, leading to increased expression of the Nrf-2-regulated antioxidant enzyme, HO-1. The inhibition of CaMKKß or AMPK by pharmaceutical approach ablated RPT-induced HO-1 expression. Taken together, RPL ameliorates insulin resistance and endothelial dysfunction in diabetes via reducing oxidative stress. These effects are mediated by RPL activation of CaMKK-ß, which in turn activates the AMPK-Nrf-2-HO-1 pathway for enhanced endothelial function.

Electroacupuncture blocked motor dysfunction and gut barrier damage by modulating intestinal NLRP3 inflammasome in MPTP-induced Parkinson's disease mice.

Parkinson's disease (PD) is a neurodegenerative disorder commonly accompanied by gut dysfunction. EA has shown anti-inflammatory and neuroprotective effects. Here, we aim to explore whether EA can treat Parkinson's disease by restoring the intestinal barrier and modulating NLRP3 inflammasome. We applied 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish a PD mouse model and EA at the GV16, LR3, and ST36 for 12 consecutive days. The open-field test results indicated that EA alleviated depression and behavioral defects, upregulated the expressions of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), and blocked the accumulation of α-synuclein (α-syn) in the midbrain. Moreover, EA blocked the damage to intestinal tissues of PD mice, indicative of suppressed NLRP3 inflammasome activation and increased gut barrier integrity. Notably, the antibiotic-treated mouse experiment validated that the gut microbiota was critical in alleviating PD dyskinesia and intestinal inflammation by EA. In conclusion, this study suggested that EA exhibited a protective effect against MPTP-induced PD by alleviating behavioral defects, reversing the block of motor dysfunction, and improving the gut barrier by modulating intestinal NLRP3 inflammasome. Above all, this study could provide novel insights into the pathogenesis and therapy of PD.

Elevated level of peripheral CD8(+)CD28(-) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy.

PURPOSE: Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells' growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-ß1 were quantitated from MBC and healthy volunteers. EXPERIMENTAL DESIGN: This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured. RESULTS: Both CD8(+)CD28(-) and CD4(+)CD25(+) were elevated in MBC patients compared to the control cohort (P < 0.05). In contrast, CD3(+) and CD8(+)CD28(+)cells were significantly lower in MBC patients (P < 0.0001, P = 0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8(+)CD28(-) and CD4(+)CD25(+) cells showed increased levels of IL-6, and only patients with elevated CD8(+)CD28(-) had decreased interferon-γ. Univariate analysis indicated increased CD3(+)CD4(+) or CD8(+)CD28(+)correlated with prolonged progression-free survival (PFS), while elevated CD8(+)CD28(-)associated with shorten PFS. The percent of CD8(+)CD28(-) T lymphocytes is an independent predictor for PFS through multivariate analysis. CONCLUSIONS: This study suggests that progressive elevated levels of CD8(+)CD28(-) suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.

Structural characterization and anti-inflammatory activity of polysaccharides from Astragalus membranaceus.

In this study, two homogeneous polysaccharides (APS-A1 and APS-B1) were isolated from Astragalus membranaceus by DEAE-52 cellulose and Sephadex G-100 column chromatography. Their chemical structures were characterized by molecular weight distribution, monosaccharide composition, infrared spectrum, methylation analysis, and NMR. The results revealed that APS-A1 (2.62 × 106 Da) was a 1,4-α-D-Glcp backbone with a 1,4,6-α-D-Glcp branch every ten residues. APS-B1 (4.95 × 106 Da) was a heteropolysaccharide composed of glucose, galactose, and arabinose (75.24:17.27:19.35). Its backbone consisted of 1,4-α-D-Glcp, 1,4,6-α-D-Glcp, 1,5-α-L-Araf and the sidechains composed of 1,6-α-D-Galp and T-α/ß-Glcp. Bioactivity assays showed that APS-A1 and APS-B1 had potential anti-inflammatory activity. They could inhibit the production of inflammatory factors (TNF-α, IL-6, and MCP-1) in LPS-stimulated RAW264.7 macrophages via NF-κB and MAPK (ERK, JNK) pathways. These results suggested that the two polysaccharides could be potential anti-inflammatory supplements.

Immuno-stimulatory activity of Astragalus polysaccharides in cyclophosphamide-induced immunosuppressed mice by regulating gut microbiota.

Evidence has indicated the immune-stimulatory effect of Astragalus polysaccharides (APS), yet it remains unknown whether the potential mechanism is associated with gut microbiota. In this study, we aimed to investigate the role of gut microbiota in APS-initiated immune-enhancing activity in mice. BALB/c mice were injected with cyclophosphamide to establish a mouse immunosuppression model. We found that APS significantly ameliorated the immunosuppression in mice, indicative of the increased immune organ indices, the promoted proliferation of immune cells, and the up-regulated intestinal inflammation. Western blot analysis demonstrated that APS treatment significantly activated Toll-like receptor 4 (TLR4) and mitogen-activated protein kinase (MAPK) pathways in the intestine. By 16S rDNA sequencing, APS treatment reversed the gut microbiota dysbiosis in immunocompromised mice. At the genus level, APS increased the abundance of bacteria (like Lactobacillus, Bifidobacteria, Roseburia, and Desulfovibrio) and decreased the content of several bacteria (like Oscillibacter, Tyzzerella, and Lachnoclostridium). However, APS had no immune-enhancing effect on immunocompromised mice with gut microbiota depletion. In conclusion, APS can enhance immune responses in immunocompromised mice by modulating gut microbiota dysbiosis.

Poria cocos oligosaccharides ameliorate dextran sodium sulfate-induced colitis mice by regulating gut microbiota dysbiosis.

Poria cocos, a widely accepted function food in China, has multiple pharmacological activities. This study aimed to investigate the therapeutic effect and molecular mechanism of Poria cocos oligosaccharides (PCOs) against dextran sodium sulfate (DSS)-induced mouse colitis. In this study, BALB/c mice were treated with 3% (w/v) DSS for seven days to establish a colitis model. The results showed that oral administration of PCOs (200 mg per kg per day) significantly reversed the changes in the physiological indices in colitis mice, including body weight, disease activity index scores (DAI), spleen index, and colon length. From the qRT-PCR assay, it was observed that PCOs suppressed the mRNA expression of pro-inflammatory cytokines, such as Tnf-α, Il-1ß, and Il-6. In addition, PCOs protected the intestinal barrier from damage by promoting the expression of mucins and tight junction proteins at both mRNA and protein levels. Upon 16S rDNA sequencing, it was observed that PCO treatment partly reversed the changes in the gut microbiota of colitis mice by selectively regulating the abundance of specific bacteria. And Odoribacter, Muribaculum, Desulfovibrio, Oscillibacter, Escherichia-Shigella, and Turicibacter might be the critical bacteria in improving colitis via PCOs. Finally, using antibiotic mixtures to destroy the intestinal bacteria, we documented that PCO fermentation broth (PCO FB) instead of PCOs prevented the occurrence of colitis in gut microbiota-depleted mice. In conclusion, PCOs showed a protective effect on colitis by reversing gut microbiota dysbiosis. Our study sheds light on the potential application of PCOs as a prebiotic for treating colitis.

Suppressive effect of Tripterygium hypoglaucum (Levl.) Hutch extract on rheumatoid arthritis in mice by modulating inflammasome and bile acid metabolism.

Tripterygium hypoglaucum (Levl.) Hutch (THH) has long been used as a remedy for rheumatoid arthritis (RA) in China. However, it is unclear whether the anti-RA mechanism of THH is associated with inflammasome or gut-joint axis. In this study, we aimed to explore the critical role of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and bile acid (BA) in the anti-RA mechanism. Complete Freund's adjuvant (CFA)-injected mice were treated with THH extract (250 mg/kg/d) for 35 days, and joint swelling and disease scores were measured. After THH treatment, the joint swelling and RA disease score in CFA-treated mice significantly subsided. The increased ratios of lymphocytes, monocytes, and white blood cells were attenuated by THH treatment. Notably, THH treatment blocked the inflammation in both joints and colons by suppressing the NLRP3-mediated inflammasome, as indicated by NLRP3, interleukin 1beta (IL-1ß), and Caspase-1. Meanwhile, THH significantly remodeled the bile acid (BA) profiles in RA mice. Spearman's analysis shed light on the close link between BAs, NLRP3 inflammasome, and RA indicators. However, THH treatment failed to improve inflammasome activation, snoptivis, and joint swelling in RA mice with gut microbiota depletion. In summary, we revealed the pivotal role of BA-mediated gut-joint axis and inflammasome in THH's RA amelioration. In the future, more work should be done to explain the in-depth mechanism between altered BAs and inflammasome.

Preclinical evaluation of ISH0339, a tetravalent broadly neutralizing bispecific antibody against SARS-CoV-2 with long-term protection.

BACKGROUND: Ending the global COVID-19 pandemic requires efficacious therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nevertheless, the emerging Omicron sublineages largely escaped the neutralization of current authorized monoclonal antibody therapies. Here we report a tetravalent bispecific antibody ISH0339, as a potential candidate for long-term and broad protection against COVID-19. METHODS: We report here the making of ISH0339, a novel tetravalent bispecific antibody composed of a pair of non-competing neutralizing antibodies that binds specifically to two different neutralizing epitopes of SARS-CoV-2 receptor-binding domain (RBD) and contains an engineered Fc region for prolonged antibody half-life. We describe the preclinical characterization of ISH0339 and discuss its potential as a novel agent for both prophylactic and therapeutic purposes against SARS-CoV-2 infection. RESULTS: ISH0339 bound to SARS-CoV-2 RBD specifically with high affinity and potently blocked the binding of RBD to the host receptor hACE2. ISH0339 demonstrated greater binding, blocking and neutralizing efficiency than its parental monoclonal antibodies, and retained neutralizing ability to all tested SARS-CoV-2 variants of concern. Single dosing of ISH0339 showed potent neutralizing activity for treatment via intravenous injection and for prophylaxis via nasal spray. Preclinical studies following single dosing of ISH0339 showed favorable pharmacokinetics and well-tolerated toxicology profile. CONCLUSION: ISH0339 has demonstrated a favorable safety profile and potent anti-SARS-CoV-2 activities against all current variants of concern. Furthermore, prophylactic and therapeutic application of ISH0339 significantly reduced the viral titer in lungs. Investigational New Drug studies to evaluate the safety, tolerability and preliminary efficacy of ISH0339 for both prophylactic and therapeutic purposes against SARS-CoV-2 infection have been filed.

Non-genetic risk factors and predicting efficacy for docetaxel--drug-induced liver injury among metastatic breast cancer patients.

BACKGROUND AND AIM: Docetaxel has been chosen as one of the most popular anticancer drugs in the treatment of breast cancer for more than a decade. There is increasingly awareness for the occurrence of docetaxel and/or docetaxel-drug-induced liver injury (DILI), although the underlying mechanism of occurrence and its risk factors remain unclear. METHODS: We conducted a retrospective cohort study to identify non-genetic risk factors for docetaxel-DILI among 647 metastasis breast cancer patients treated with docetaxel-containing regimens. RESULTS: Sixty-seven (10.36%) patients were diagnosed as docetaxel-DILI. By logistic regression analysis, premenopausal status (odds ratio [OR][95% confidence interval {CI}] = 2.24 [1.30-3.87]), past hepatitis B virus (HBV) infections (OR [95% CI] = 4.23 [1.57-11.42]), liver metastasis (OR [95% CI] = 3.70 [2.16-6.34]). The predominant occurrence of DILI was seen in groups with docetaxel combination regimens. (OR [95% CI] = 2.66 [1.59-4.55]). The potential increasing occurrence of docetaxel-DILI was associated with multiple risk factors in an exposure-response manner (P < 0.001), and patients with more than three risk factors would be exposed to a 36.61-fold risk of DILI (95% CI = 10.18-131.62). Further analysis by the risk score and area under the receiver-operator characteristic curve (AUC) showed that those four factors contributed to an AUC of 0.7536 (95% CI = 0.70-0.81), with a predictive sensitivity of 74.63% and specificity of 65.17%. CONCLUSIONS: Docetaxel-DILI with a relatively higher incidence should be addressed among metastatic breast cancer patients. Four predominant risk factors, including premenopausal status, past HBV infection, liver metastasis, and docetaxel combination regimens, were potential predicators for DILI.

Vine Tea (Ampelopsis grossedentata) Extract Attenuates CCl4 -Induced Liver Injury by Restoring Gut Microbiota Dysbiosis in Mice.

SCOPE: Vine tea (Ampelopsis grossedentata), a traditional Chinese tea, has displayed various biological activities. The authors aim to investigate the effect of Vine Tea (Ampelopsis grossedentata) extract (VTE) on carbon tetrachlorid (CCl4 )induced acute liver injury (ALI) in mice and to explore the underlying role of gut microbiota during the treatment. METHODS AND RESULTS: C57BL/6J mice injected with CCl4 are treated with VTE for 6 weeks. By using H&E staining, immunofluorescence staining, quantitative real-time (qRT)-PCR, and western blot, it is shown that VTE treatment significantly ameliorates hepatocyte necrosis, alleviates the mRNA levels of toll-like receptor 4 (Tlr4), interleukin (Il)-6, inducible nitric oxide synthase (iNOS), acetyl-CoA carboxylase 1 (Acc1), and increases the mRNA levels of peroxisome proliferator-activated receptor gamma (Ppar-γ) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmg-coar) compared to the CCl4 group. Also, VTE abrogates the decreased mRNA expressions of zonula occludens-1 (Zo-1), Occludin, and Mucin1 in colon tissues. Using microbial 16S rDNA sequencing, VTE treatment significantly downregulates the abundances of some harmful intestinal bacteria like Helicobacter and Oscillibacter. In contrast, VTE upregulates the contents of several beneficial bacteria, such as Ruminococcaceae_UCG-014 and Eubacterium_fissicatena_group. Further, VTE fails to improve ALI in the mice with gut microbiota depletion using antibiotic treatment. CONCLUSIONS: The studies suggest that VTE exhibits a protective effect against CCl4 -induced ALI in mice by alleviating hepatic inflammation, suppressing intestinal epithelial barrier injury, and restoring gut microbiota dysbiosis.

Plasma metabolomic profiles reveal regulatory effect of chitosan oligosaccharides on loperamide-induced constipation in mice.

Chitosan oligosaccharides (COS) can improve the symptoms of constipation. In this study, we further explored the regulator effect of COS on aberrant plasma metabolomics in constipated mice. Using untargeted metabolomic analysis by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS), we identified several most significantly changed metabolic pathways in plasma of constipated mice induced by loperamide, including those correlated with the metabolisms of sphingolipid, glycerophospholipid, tryptophan, bile acids, unsaturated fatty acids, and amino acids. The changes in these metabolic pathways were reversed by COS treatment largely. Furthermore, the mRNA levels of some key target genes related to the above metabolic pathways in colon samples were detected by reverse transcription-polymerase chain reaction analysis. We showed that COS significantly suppressed the abnormal expression of these genes, including ceramide glucosyltransferase (CGT), sphingolipid 4-desaturase (DEGS2), alkaline ceramidase (ACER1), sphingosine kinase 2 (SPHK2), lysophosphatidylcholine acyltransferase (LPCAT1), and aromatic-L-amino-acid (DDC). These data provide insight into the mechanisms by which COS ameliorates loperamide-induced constipation in mice.

Structural characterization and preventive effect on non-alcoholic fatty liver disease of oligosaccharides from Bletilla striata.

In this study, Bletilla striata polysaccharides were degraded into oligosaccharides. The structural features were analyzed by HPLC, HPLC-MS, FT-IR, and NMR spectroscopy. The results indicated that Bletilla striata oligosaccharides (BOs) were composed of mannose and glucose with a molar ratio of 5.2 : 1, and the main backbones of BOs contained (1→4)-linked-α-D-Man, (1→2)-linked-α-D-Man, and (1→2)-linked-α-D-Glc. By using a high-fat diet (HFD)-induced mouse model, we demonstrated that BOs had an improving effect on non-alcoholic fatty liver disease (NAFLD). Using the metabolomics assay, we found that BOs significantly regulated the hepatic metabolism of fatty acids, arachidonic acid, and other related metabolites in HFD-fed mice, accompanied by the reduction of lipid accumulation and fibrosis in liver tissues. In summary, BOs displayed high potential for the treatment of NAFLD as a functional food.

Structural characterization of Poria cocos oligosaccharides and their effects on the hepatic metabolome in high-fat diet-fed mice.

In this study, novel Poria cocos oligosaccharides (PCO) were prepared by enzymatic degradation, and their polymerization degree was determined to be 2-6 by LC-MS analysis. By monosaccharide composition analysis, methylation assay, FT-IR, and NMR analysis, PCO were deduced to contain the sugar residues of (1 → 2)-ß-D-Glcp, (1 → 2)-α-D-Glcp, and (1 → 4)-α-D-Glcp. Using an HFD-fed mouse model with dyslipidemia, PCO could significantly suppress lipid metabolism disorders, characterized by the reduction of lipid accumulation and inflammatory responses in the blood and liver tissues. Based on the non-targeted metabolomic analysis and Spearman's correlation analysis, we presume that the preventive effect of PCO on dyslipidemia might contribute to the reversal of changed metabolic pathways, which were related to the metabolisms of glycerophospholipids, unsaturated fatty acids, amino acids, choline, bile acids, tryptophan, sphingolipids, and glutathione. Our research shed light on the potential application of PCO for the treatment of dyslipidemia.