Efficacy of intermittent versus daily vitamin D supplementation on improving circulating 25(OH)D concentration: a Bayesian network meta-analysis of randomized controlled trials.

Background: Vitamin D deficiency is a widespread issue globally, resulting in increased use of vitamin D supplements. However, it is unclear whether intermittent (weekly or monthly) vitamin D supplementation is as effective as daily supplementation in improving circulating 25-hydroxyvitamin D [25(OH)D] levels. Methods: Three databases including Medline, EMBASE, and the Cochrane Library were systematically searched up to 10 November 2020. The risk of bias was evaluated according to Cochrane Collaboration's tool for rating methodological quality assessment. Direct and indirect comparisons between interventions and controls were performed by a Bayesian network meta-analysis (NMA), where the mean difference (MD) and its 95% confidence interval (CI) were used to indicate the efficacy. Results: This NMA analysis included 116 RCTs with a total of 11,376 participants. Generally, we observed that 25(OH)D concentrations were significantly elevated regardless of vitamin D supplementation frequency. Although the findings of SUCRA indicated that daily vitamin D supplementation had a higher rank value than intermittent supplementation when the supplement dosage was similar, no statistically significant pooled mean differences of 25(OH)D concentration were noted between the daily supplementation group and intermittent supplementation group. Additionally, weekly supplementation with a total of 600,000 IU vitamin D supplementation during 3 months had the best efficacy in elevating 25(OH)D concentration (pooled MD = 63 nmol/L, 95%CI: 49-77). To achieve optimal 25(OH)D concentration (>75 nmol/L), we recommend 60,000 IU vitamin D supplementation monthly (~2,000 IU/day). Conclusion: The efficacy of intermittent vitamin D supplementation was similar to daily supplementation. Coupled with its convenience, the frequency and dosage of intermittent vitamin D supplements were recommended to reach the optimal 25(OH)D level.Systematic review registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=257257, PROSPERO CRD42021257257.

Mechanosensitive TRPV4 is required for crystal-induced inflammation.

Crystal structures activate innate immune cells, especially macrophages and initiate inflammatory responses. We aimed to understand the role of the mechanosensitive TRPV4 channel in crystal-induced inflammation. Real-time RT-PCR, RNAscope in situ hybridisation, and Trpv4eGFP mice were used to examine TRPV4 expression and whole-cell patch-clamp recording and live-cell Ca2+ imaging were used to study TRPV4 function in mouse synovial macrophages and human peripheral blood mononuclear cells (PBMCs). Both genetic deletion and pharmacological inhibition approaches were used to investigate the role of TRPV4 in NLRP3 inflammasome activation induced by diverse crystals in vitro and in mouse models of crystal-induced pain and inflammation in vivo. TRPV4 was functionally expressed by synovial macrophages and human PBMCs and TRPV4 expression was upregulated by stimulation with monosodium urate (MSU) crystals and in human PBMCs from patients with acute gout flares. MSU crystal-induced gouty arthritis were significantly reduced by either genetic ablation or pharmacological inhibition of TRPV4 function. Mechanistically, TRPV4 mediated the activation of NLRP3 inflammasome by diverse crystalline materials but not non-crystalline NLRP3 inflammasome activators, driving the production of inflammatory cytokine interleukin-1ß which elicited TRPV4-dependent inflammatory responses in vivo. Moreover, chemical ablation of the TRPV1-expressing nociceptors significantly attenuated the MSU crystal-induced gouty arthritis. In conclusion, TRPV4 is a common mediator of inflammatory responses induced by diverse crystals through NLRP3 inflammasome activation in macrophages. TRPV4-expressing resident macrophages are critically involved in MSU crystal-induced gouty arthritis. A neuroimmune interaction between the TRPV1-expressing nociceptors and the TRPV4-expressing synovial macrophages contributes to the generation of acute gout flares.

O/W Nanoemulsion as an Adjuvant for an Inactivated H3N2 Influenza Vaccine: Based on Particle Properties and Mode of Carrying.

BACKGROUND AND PURPOSE: Adjuvant can reduce vaccine dosage and acquire better immune protection to the body, which helps to deal with the frequent outbreaks of influenza. Nanoemulsion adjuvants have been proved efficient, but the relationship between their key properties and the controlled release which greatly affects immune response is still unclear. The present work explores the role of factors such as particle size, the polydispersity index (PDI), stability and the safety of nanoemulsions by optimizing the water concentration, oil phase and modes of carrying, to explain the impact of those key factors above on adjuvant effect. METHODS: Isopropyl myristate (IPM), white oil, soybean oil, and grape-kernel oil were chosen as the oil phase to explore their roles in emulsion characteristics and the adjuvant effect. ICR mice were immunized with an emulsion-inactivated H3N2 split influenza vaccine mixture, to compare the nanoemulsion's adjuvant with traditional aluminium hydroxide or complete Freund's adjuvant. RESULTS: Particle size of all the nanoemulsion formed in our experiment ranged from 20 nm to 200 nm and did not change much when diluted with water, while the PDI decreased obviously, indicating that the particles tended to become more dispersive. Formulas with 80% or 85.6% water concentration showed significant higher HAI titer than aluminium hydroxide or complete Freund's adjuvant, and adsorption rather than capsule mode showed higher antigen delivery efficiency. As mentioned about oil phase, G (IPM), F (white oil), H (soybean oil), and I (grape-kernel oil) showed a decreasing trend in their adjuvant efficiency, and nanoemulsion G was the best adjuvant with smaller and uniform particle size. CONCLUSION: Emulsions with a smaller, uniform particle size had a better adjuvant effect, and the adsorption mode was generally more efficient than the capsule mode. The potential adjuvant order of the different oils was as follows: IPM > white oil > soybean oil > grape-kernel oil.

Analysis of the dose-sparing effect of adjuvanted Sabin-inactivated poliovirus vaccine (sIPV).

Sabin-based inactivated poliovirus vaccine(sIPV) is gradually replacing live-attenuated oral polio vaccine(OPV). Sabin-inactivated poliovirus vaccine(sIPV) has played a vital role in reducing economic burden of poliomyelitis and maintaining appropriate antibody levels in the population. However, due to its high cost and limited manufacturing capacity, sIPV cannot reach its full potential for global poliovirus eradication in developing countries. Therefore, to address this situation, we designed this study to evaluate the dose-sparing effects of AS03, CpG oligodeoxynucleotides (CpG-ODN) and polyinosinic:polycytidylic acid (PolyI:C) admixed with sIPV in rats. Our results showed that a combination of 1/4-dose sIPV adjuvanted with AS03 or AS03 with BW006 provides a seroconversion rate similar to that of full-dose sIPV without adjuvant and that, this rate is 5-fold higher than that of 1/4-dose sIPV without adjuvant after the first immunization. The combination of AS03 or AS03 with BW006 as an adjuvant effectively reduced sIPV dose by at least 4-fold and induced both humoral and cellular immune responses. Therefore, our study revealed that the combination of AS03 or AS03 with BW006 is a promising adjuvant for sIPV development.

Optimizing the conditions for hydrothermal liquefaction of barley straw for bio-crude oil production using response surface methodology.

The present paper examines the conversion of barley straw to bio-crude oil (BO) via hydrothermal liquefaction. Response surface methodology based on central composite design was utilized to optimize the conditions of four independent variables including reaction temperature (factor X1, 260-340°C), reaction time (factor X2, 5-25min), catalyst dosage (factor X3, 2-18%) and biomass/water ratio (factor X4, 9-21%) for BO yield. It was found that reaction temperature, catalyst dosage and biomass/water ratio had more remarkable influence than reaction time on BO yield by analysis of variance. The predicted BO yield by the second order polynomial model was in good agreement with experimental results. A maximum BO yield of 38.72wt% was obtained at 304.8°C, 15.5min, 11.7% potassium carbonate as catalyst and 18% biomass (based on water). GC/MS analysis revealed that the major BO components were phenols and their derivatives, acids, aromatic hydrocarbon, ketones, N-contained compounds and alcohols, which makes it a promising material in the applications of either bio-fuel or as a phenol substitute in bio-phenolic resins.

Trends in culprit drugs and clinical entities in cutaneous adverse drug reactions: a retrospective study.

PURPOSE: Morbidity due to cutaneous adverse drug reactions (CADRs) is quite common. The specific culprit drugs change over time and clinicians must be kept informed with updated knowledge, thus preventing potential CADRs. This retrospective study is a survey of CADRs encountered in a hospital-based population in Southern China during three time intervals, from 1984 to 2015. MATERIALS AND METHODS: The clinical records were review of 306 patients with CADRs who were admitted to our hospital from 2011 to 2015. These data were compared with patients visiting our hospital during 1984-1994 and 2003-2010. RESULTS: From 2011 to 2015, the most common CADRs were exanthematous reactions (40.8%) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN; 17.0%). There were eight cases (2.6%) of CADRs related to targeted therapy in oncology. In the 205 CADR cases that were due to single medications, the most common offending drugs were allopurinol (21.5%), cephalosporins (10.7%) and carbamazepine (10.2%). The percentages of CADR cases due to allopurinol, carbamazepine, or epidermal growth factor receptor inhibitors were significantly higher from 2011 to 2015 compared with 1984-1994 or 2003-2010. The rate of SJS/TEN occurrence was significantly higher in the two recent periods compared with 1984-1994. CONCLUSIONS: Changes in drug prescriptions are a major factor that affects the CADRs seen in clinical records. Newer drugs can be culpable for CADRs, and more CADRs are now documented with increased severity at clinical presentation. Reliable screening tests for specific drugs are urgently required to eliminate possible fatalities.

Astragaloside IV inhibits pathological functions of gastric cancer-associated fibroblasts.

AIM: To investigate the inhibitory effect of astragaloside IV on the pathological functions of cancer-associated fibroblasts, and to explore the underlying mechanism. METHODS: Paired gastric normal fibroblast (GNF) and gastric cancer-associated fibroblast (GCAF) cultures were established from resected tissues. GCAFs were treated with vehicle control or different concentrations of astragaloside IV. Conditioned media were prepared from GNFs, GCAFs, control-treated GCAFs, and astragaloside IV-treated GCAFs, and used to culture BGC-823 human gastric cancer cells. Proliferation, migration and invasion capacities of BGC-823 cells were determined by MTT, wound healing, and Transwell invasion assays, respectively. The action mechanism of astragaloside IV was investigated by detecting the expression of microRNAs and the expression and secretion of the oncogenic factor, macrophage colony-stimulating factor (M-CSF), and the tumor suppressive factor, tissue inhibitor of metalloproteinase 2 (TIMP2), in different groups of GCAFs. The expression of the oncogenic pluripotency factors SOX2 and NANOG in BGC-823 cells cultured with different conditioned media was also examined. RESULTS: GCAFs displayed higher capacities to induce BGC-823 cell proliferation, migration, and invasion than GNFs (P < 0.01). Astragaloside IV treatment strongly inhibited the proliferation-, migration- and invasion-promoting capacities of GCAFs (P < 0.05 for 10 µmol/L, P < 0.01 for 20 µmol/L and 40 µmol/L). Compared with GNFs, GCAFs expressed a lower level of microRNA-214 (P < 0.01) and a higher level of microRNA-301a (P < 0.01). Astragaloside IV treatment significantly up-regulated microRNA-214 expression (P < 0.01) and down-regulated microRNA-301a expression (P < 0.01) in GCAFs. Reestablishing the microRNA expression balance subsequently suppressed M-CSF production (P < 0.01) and secretion (P < 0.05), and elevated TIMP2 production (P < 0.01) and secretion (P < 0.05). Consequently, the ability of GCAFs to increase SOX2 and NANOG expression in BGC-823 cells was abolished by astragaloside IV. CONCLUSION: Astragaloside IV can inhibit the pathological functions of GCAFs by correcting their dysregulation of microRNA expression, and it is promisingly a potent therapeutic agent regulating tumor microenvironment.

The FDA-approved drug sofosbuvir inhibits Zika virus infection.

The rapidly expanding Zika virus (ZIKV) epidemic has affected thousands of individuals with severe cases causing Guillain-Barré syndrome, congenital malformations, and microcephaly. Currently, there is no available vaccine or therapy to prevent or treat ZIKV infection. We evaluated whether sofosbuvir, an FDA-approved nucleotide polymerase inhibitor for the distantly related hepatitis C virus, could have antiviral activity against ZIKV infection. Cell culture studies established that sofosbuvir efficiently inhibits replication and infection of several ZIKV strains in multiple human tumor cell lines and isolated human fetal-derived neuronal stem cells. Moreover, oral treatment with sofosbuvir protected against ZIKV-induced death in mice. These results suggest that sofosbuvir may be a candidate for further evaluation as a therapy against ZIKV infection in humans.

Combination with intravenous iron supplementation or doubling erythropoietin dose for patients with chemotherapy-induced anaemia inadequately responsive to initial erythropoietin treatment alone: study protocol for a randomised controlled trial.

INTRODUCTION: Erythropoietin (EPO) is a commonly used option in the treatment of chemotherapy-induced anaemia (CIA). However, ∼30-50% of patients fail to achieve an adequate response after initial treatment. Prior studies have demonstrated that intravenous iron might synergistically improve therapeutic response to EPO treatment in this patient population. METHODS AND ANALYSIS: We will perform this multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study to compare the two combination therapies of EPO plus intravenous iron regimen versus doubling the dose of EPO in patients with CIA who have an inadequate response to initial EPO treatment at a routine dose. A total of 603 patients with an increase in haemoglobin (Hb) <1 g/dL will be enrolled and randomised to one of the three study treatment groups at a 1:1:1 ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose without preplanned iron supplementation. The primary outcome measure to compare is the Hb response rate at week 15 and the secondary end points involve therapeutic blood transfusions. Time-to-progression, adverse events and quality of life will also be evaluated. ETHICS AND DISSEMINATION: All participants will provide informed consent; the study protocol has been approved by the independent ethics committee of Shanghai East Hospital. This study would clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China. TRIAL REGISTRATION NUMBER: NCT02731378.

Puerarin Exerts an Antiinflammatory Effect by Inhibiting NF-kB and MAPK Activation in Staphylococcus aureus-Induced Mastitis.

Mastitis is defined as the inflammation of the mammary gland. There is generally no effective treatment for mastitis in animals. Puerarin, extracted from Radix puerariae, has been proven to possess many biological activities. The present study aims to reveal the potential mechanism that is responsible for the antiinflammatory action of puerarin in Staphylococcus aureus (S. aureus)-induced mastitis in mice. Histopathological changes showed that puerarin ameliorated the inflammatory injury induced by S. aureus. Quantitative real-time polymerase chain reaction and ELISA analysis indicated that puerarin not only suppressed the production of pro-inflammatory cytokines such as TNF-α, IL-1ß, and IL-6 but also promoted the secretion of IL-10. Toll-like receptor 2 (TLR2) is important in the immune defense against S. aureus infection. Research in molecular biology has shown that the expression of TLR2 was inhibited with administration of puerarin. Further studies were performed on NF-kB and mitogen-activated protein kinase signaling pathways using western blot. The results demonstrated that puerarin suppressed phosphorylated IkBα, p65, p38, extracellular signal-regulated kinase 1and 2 (ERK), and c-Jun N-terminal kinase (JNK) in a dose-dependent manner. All of the results suggested that puerarin may be a potential therapy for treating mastitis. Copyright © 2016 John Wiley & Sons, Ltd.

Plantamajoside ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation.

Despite developments in the knowledge and therapy of acute lung injury in recent decades, mortality remains high, and there is usually a lack of effective therapy. Plantamajoside, a major ingredient isolated from Plantago asiatica L. (Plantaginaceae), has been reported to have potent anti-inflammatory properties. However, the effect of plantamajoside on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice has not been investigated. The present study aimed to reveal the potential mechanism responsible for the anti-inflammatory effects of plantamajoside on LPS-induced acute lung injury in mice and in RAW264.7 cells. The results of histopathological changes as well as the lung wet-to-dry ratio and myeloperoxidase (MPO) activity showed that plantamajoside ameliorated the lung injury that was induced by LPS. qPCR and ELISA assays demonstrated that plantamajoside suppressed the production of IL-1ß, IL-6 and TNF-α in a dose-dependent manner. TLR4 is an important sensor in LPS infection. Molecular studies showed that the expression of TLR4 was inhibited by plantamajoside administration. Further study was conducted on nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) using pathways using western blots. The results showed that plantamajoside inhibited the phosphorylation of IκBα, p65, p38, JNK and ERK. All results indicated that plantamajoside has protective effect on LPS-induced ALI in mice and in RAW264.7 cells. Thus, plantamajoside may be a potential therapy for the treatment of pulmonary inflammation.

A Comparative Pharmacokinetic Study of Myrislignan by UHPLC-MS After Oral Administration of a Monomer and Myristica fragrans Extract to Rats.

An ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) method was developed and validated to quantify myrislignan in rat plasma using podophyllotoxin as an internal standard (IS). The chromatographic separation of myrislignan and IS was performed on a 3.0 µm Hypersil C18 column (50 mm × 4.6 mm) with methanol and water containing 0.1% acetic acid (80:20, v/v) as the mobile phase at a flow rate of 0.3 mL/min. An electrospray ionization was used in the positive selective-ion monitoring mode for the target ions at m/z 397 and m/z 437 for the quantification of myrislignan and IS. The total run time was 3.6 min for each run. The calibration curve was linear over the range of 0.75-300 ng/mL (r> 0.995) with the lower limit of quantitation at 0.75 ng/mL. Intra- and interday precision was below 11.49%, and the mean accuracy ranged from -9.75 to 7.45%. The proposed method was successfully applied to evaluate the pharmacokinetic properties of myrislignan after oral administration of the myrislignan monomer and Myristica fragrans extract in rats. Statistical analyses indicate that the pharmacokinetic properties of myrislignan in rats have significant differences between two groups.