Comparison of the efficacy and safety of leflunomide versus mycophenolate mofetil in treating IgG4-related disease: a retrospective cohort study.

OBJECTIVE: Combination therapy of glucocorticoids (GCs) plus leflunomide (LEF) and GCs plus mycophenolate mofetil (MMF) was reported to have good efficacy and safety in the management of IgG4-RD. However, studies comparing the efficacy and safety of these two combination therapies were unavailable. Herein, this study aimed to compare the efficacy and safety of GCs plus LEF and GCs plus MMF in treating IgG4-RD. METHODS: This study included 130 newly diagnosed IgG4-RD patients who received the therapy of GCs plus LEF (group I) and GCs plus MMF (group II). Clinical data at baseline and after treatment, treatment response, relapse rate, and adverse effects were recorded and analyzed. RESULTS: Patients in both groups responded well to the treatment in the 1st-month follow-up, and 100% of patients achieved treatment response. However, at the 6th and 12th-month follow-up, the total response rate of group II was higher than that in group I (75.6 vs. 53.7%, p = 0.038 and 85.4% vs. 61.0%, p = 0.013, respectively). In addition, the duration of disease remission in group II was longer than that in group I (9 (6-9) vs. 6 (6-6) months, p = 0.014). Moreover, more patients in group I had adverse effects compared with group II (36.6 vs. 7.3%, p < 0.01); and the most common adverse events of LEF were rash (12.2%) and elevation of liver enzymes (9.8%). CONCLUSION: The combination therapy of GCs plus low-dose MMF had better efficacy and safety in the management of IgG4-RD compared with the therapy of GCs plus LEF.

Dietary patterns and life-styles of patients with gastrointestinal involvement of systemic lupus erythematosus: Questionnaire survey from a tertiary center of China.

OBJECTIVE: To investigate the dietary patterns and lifestyles of patients with lupus gastrointestinal (GI) involvement and to reveal the possible role of organ-specific involvement of systemic lupus erythematosus (SLE) on daily diet. METHODS: Patients with SLE complicated with gastrointestinal involvement (SLE-GI) admitted to Peking Union Medical College Hospital (PUMCH) from January 2010 to September 2021 were enrolled. Age- and sex-matched SLE patients with lupus nephritis (SLE-LN) but free of other internal organs involvement who were admitted during the same period were enrolled as disease controls at the ratio of 1:1. In addition, a group of age- and sex-matched healthy people were also included as healthy controls (HCs). Questionnaires were distributed to these patients and HC to collect their dietary patterns and lifestyle information. Clinical features, dietary and lifestyle habits were compared between the two groups of patients and HC. RESULTS: The questionnaire survey showed that compared with HC, the SLE-GI group had higher proportions of vegetarians (p = 0.014) and a lower proportion of omnivores (p = 0.058). A higher percentage of SLE-GI patients reported a traditional Chinese medicine (p = 0.018) taken history and surgical history (p = 0.014). They also less likely to take fried/pickled food (p = 0.042) and dietary supplements (p = 0.024) than HC. Higher percentages of SLE-GI patients and SLE-LN patients preferred self-catering (87.5% and 94.3%) over take-out food than HC (70.8%) (p = 0.127 and p = 0.016). No significant difference on drinking preference among the three groups, but it seemed more SLE-GI patients consumed yogurt than HC (p = 0.097). The SLE-LN patients were also found to have lower frequencies of staying up late (p = 0.005). The SLE-GI group also presented higher positivity rates for anti-SSA (69.6% vs. 45.7%, p = 0.020) and anti-SSB antibodies (32.6% vs. 10.9%, p = 0.011) but lower positivity rates for anti-dsDNA antibodies (30.4% vs. 82.6%, p < 0.001) compared with the SLE-LN group. CONCLUSION: The dietary patterns, life-styles and autoantibody spectrum of SLE-GI patients differed greatly from those of SLE-LN patients and healthy people. These factors may reflect the influence of disease and organ involvement modes on patients' daily life and may contribute partly to the systemic involvement in SLE.

Source tracing and health risk assessment of phthalate esters in household tap-water: A case study of the urban area of Quanzhou, Southeast China.

The occurrence of phthalate esters (PAEs) in household tap water has been investigated via the presence of their geochemical characteristics in the pretreatment and transfer processes of water plants in the urban and suburban areas of the subtropical medium-sized city of Quanzhou, southeast China. The results for all approximately 300 tap water samples collected from 6 sampling stations at household kitchens from Nov. 30, 2017, to Dec. 6, 2018, showed that dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutylphthaate (DIBP), di-n-butyl phthalate (DBP), and di(2-ethylhexyl) phthalate (DEHP) could be identified and quantified among the 16 PAE congeners with the developed gas chromatographymass spectrometry method. The levels of the sum of 5 PAE congeners (Σ5PAEs) for all tap water ranged from 780.0 ng/L to 9180 ng/L, while DIBP and DEHP were the most abundant congeners, accounting for 82.2% in the dry season, 89.9% in the normal season, and 89.3% in the wet season. Factors of the transferring process, such as the spatial distance from the sampling station to the water plant, the material of pipelines, and the storage time of tap water in the pipeline, affected the levels of PAE congeners in tap water from the correlation of Σ5PAEs levels and transferring distance according to hierarchical cluster analysis. The seasonal variations in Σ5PAEs and each congener had good agreement with the temperature, suggesting that PAEs in tap water mainly come from raw water, which should be further explored in future work. Health risk assessment of PAEs in tap water with the HQ method showed that the occurrence of DEP and DBP has no noncarcinogenic risk for adults and children, while the concentration of DEHP might cause potential noncarcinogenic risk for adults and children, which should be given considerably more attention.

Bifurcations of a Fractional-Order Four-Neuron Recurrent Neural Network with Multiple Delays.

This paper investigates the bifurcation issue of fractional-order four-neuron recurrent neural network with multiple delays. First, the stability and Hopf bifurcation of the system are studied by analyzing the associated characteristic equations. It is shown that the dynamics of delayed fractional-order neural networks not only depend heavily on the communication delay but also significantly affects the applications with different delays. Second, we numerically demonstrate the effect of the order on the Hopf bifurcation. Two numerical examples illustrate the validity of the theoretical results at the end.

The pathophysiological mechanisms underlying diabetic retinopathy.

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM), which can lead to visual impairment and even blindness in severe cases. DR is generally considered to be a microvascular disease but its pathogenesis is still unclear. A large body of evidence shows that the development of DR is not determined by a single factor but rather by multiple related mechanisms that lead to different degrees of retinal damage in DR patients. Therefore, this article briefly reviews the pathophysiological changes in DR, and discusses the occurrence and development of DR resulting from different factors such as oxidative stress, inflammation, neovascularization, neurodegeneration, the neurovascular unit, and gut microbiota, to provide a theoretical reference for the development of new DR treatment strategies.

Clinical characteristics and long-term outcome of patients with gastrointestinal involvement in eosinophilic granulomatosis with polyangiitis.

Objective: This study aims to investigate clinical characteristics, potential risk factors, as well as long-term outcome in EGPA patients with GI involvement. Methods: A total of 94 EGPA patients were included in this cohort study. We retrospectively reviewed the clinical data, treatment, and outcome of 21 EGPA patients with GI involvement and compared them with other 73 EGPA patients without GI involvement. Multivariate logistic regression was used to find potential risk factors associated with GI involvement in EGPA patients. Results: Compared with EGPA patients without GI involvement, EGPA patients with GI involvement had higher level of hs-CRP (65.1 (24.5-138.9) vs. 21.3 (5.7-39.1) mg/L, p=0.005), higher grades of Birmingham vasculitis activity score (BVAS) (20 (13-29.5) vs. 12 (16-19), p=0.022), higher Five Factor Score (FFS) (1 (1-2) vs. 0 (0-1), p<0.001), and were more likely to have weight loss (66.7% vs. 38.4%, p=0.021) at baseline. In EGPA patients with GI involvement, the most common gastrointestinal symptoms were abdominal pain (90.5%) and diarrhea (42.9%). Weight loss was identified as a potential risk factor for GI involvement in EGPA patients (OR = 4.304, 95% CI 1.339-13.841). During follow-up, EGPA patients with GI involvement showed lower 1-year cumulative survival rate (75.2% vs. 100.0%, P <0.0001) and 3-year cumulative survival rate (67.7% vs. 100.0%, P<0.0001), lower long-term remission rate (33.3% vs. 86.3%, P<0.001), but higher 1-year cumulative relapse rate (19.2% vs. 3.8%, P=0.03) and 3-year cumulative relapse rate (54.6% vs. 13.1%, P<0.001) compared with patients without GI involvement. Conclusion: EGPA patients with GI involvement had distinct features from those without GI involvement, including higher hs-CRP level, higher BVAS and FFS scores. EGPA patients with GI involvement showed lower cumulative survival rate, lower long-term remission rate and higher cumulative relapse rate compared with those without GI involvement.

Gut Microbiota in Lupus: a Butterfly Effect?

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that typically displays chronic inflammatory tissue damage and miscellaneous circulatory autoantibodies, as well as distinctive type 1 interferon signatures. The etiology of SLE is unclear and currently is attributed to genetic predisposition and environmental triggers. Gut microbiota has recently been considered a critical environmental pathogenic factor in immune-related disorders, and studies are ongoing to uncover the key pathogens and the imputative mechanisms. Fundamental advancements on the role of the microbiota in SLE pathology have been achieved in recent years and are summarized in this review. RECENT FINDINGS: Recent findings suggested that gut commensals could propagate autoimmunity via molecular mimicry in which ortholog-carrying microbes cross-activate autoreactive T/B cells and trigger the response against host autoantigens, or via bystander activation by stimulating antigen-presenting cells that present autoantigens and enhancing the expression of co-stimulatory molecules and cytokines, thus leading to the loss of self-tolerance and the production of autoantibodies. Additionally, the break of gut barrier and the translocation of gut commensals to inner organs can trigger immune dysregulation and inappropriate systemic inflammation. All these microbiota-mediated mechanisms could contribute to lupus immunopathogenesis and promote disease development in susceptible individuals. Evidence of the causative role of disturbed gut microbiome in SLE is still limited, and the related molecular mechanisms and pathways are largely elusive. However, the modification of gut microbiota, such as pathobiont vaccine, special diet, restricted consortium transplantation, as well as regulatory metabolites supplementation, might be promising strategies for lupus prophylaxis and treatment.

Preparation of enteric-coated microcapsules of astaxanthin oleoresin by complex coacervation.

Astaxanthin oleoresin (AO) has a number of beneficial physiological functions. However, its sensitivity to light, heat, oxygen and gastric fluids has limited its application. In this paper, we describe the preparation of AO enteric microcapsules by coacervation to improve its stability and enteric solubility, and evaluate their efficacy by measuring the drug loading, encapsulation efficiency, optical microscopic appearance, stability, in vitro release and bioavailability. The results obtained showed that the AO enteric microcapsules possessed a high encapsulation efficiency (85.9%), a satisfactory in vitro release profile, and the ability of the microencapsulated AO to resist the effects of light, heat and oxygen was improved by 2.2-fold, 3.1-fold and 2.4-fold, respectively, during storage. In addition, the bioavailability of AO microcapsules was approximately 1.29-fold higher than AO, which is important for pharmaceutical applications and as a functional food.

Spatial distribution and seasonal variation of phthalate esters in the Jiulong River estuary, Southeast China.

The spatial distribution and seasonal variation of 16 phthalate esters (PAEs) in water, suspended particulate matter (SPM) and sediment were investigated in the Jiulong River estuary, Fujian, Southeast China. Of the 16 PAE congeners analyzed, only six PAEs, including dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DIBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DINP), were identified and quantified. The total concentrations of the six PAEs (∑6PAEs) detected for all seasons ranged from 3.01 to 26.4µg/L in water, 1.56 to 48.7mg/kg in SPM, and 0.037 to 0.443µg/kg in sediment. DEHP, DIBP and DBP were the most abundant PAE congeners in all of the water, SPM and sediment phases. The spatial distributions of PAEs in the estuary were controlled not only by the riverine runoff, seasons, hydrodynamic condition and human activities but also the physicochemical properties of PAEs.

Ultradeformable Liposomes: a Novel Vesicular Carrier For Enhanced Transdermal Delivery of Procyanidins: Effect of Surfactants on the Formation, Stability, and Transdermal Delivery.

The aims of this work were to develop a novel vesicular carrier, procyanidins, ultradeformable liposomes (PUDLs), to expand the applications for procyanidins, and increase their stability and transdermal delivery. In this study, we prepared procyanidins ultradeformable liposomes using thin film hydration method and evaluated their encapsulation efficiency, vesicle deformability, storage stability, and skin permeation in vitro. The influence of different surfactants on the properties of PUDLs was also investigated. The results obtained showed that the PUDLs containing Tween 80 had a high entrapment efficiency (80.27 ± 0.99%), a small particle size (140.6 ± 19 nm), high elasticity, and prolonged drug release. Compared with procyanidins solution, the stability of procyanidins in PUDLs improved significantly when stored at 4, 25, and 30°C. The penetration rate of PUDLs was 6.25-fold greater than that of procyanidins solution. Finally, the results of our study suggested that PUDLs could increase the transdermal flux, prolong the release and improve the stability of procyanidins, and could serve as an effective dermal delivery system for procyanidins.

Occurrence, spatial distribution, historical trend and ecological risk of phthalate esters in the Jiulong River, Southeast China.

The occurrence and spatial distribution of phthalate esters (PAEs) in the Jiulong River of southeast China were investigated in water and sediment samples collected from 35 stations along the river in Mar. 2014. The historical trend of the past 26years was reconstructed with a sediment core collected in Dec. 2012 via a 210Pb dating technique. The potential ecological risk of PAEs was assessed using the risk quotient (RQ) method. Of the 16 PAE congeners analyzed, only 6 PAEs, including dimethyl phthalate (DMP), diethyl phthalate (DEP), diisobutyl phthalate (DIBP), di-n-butyl phthalate (DBP), di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DINP), were identified and quantified; the remaining 10 PAEs were below their respective limits of quantification (LOQs) for the analytical methods used here. The cumulative concentration of 6 PAEs (∑6PAEs) found in the samples spanned a range of 3.48-17.7µg/L in water and 0.046-1.65mg/kg in sediment. The most abundant PAEs in the water-phase were DEHP and DIBP, together accounting for 84.9% of ∑6PAEs in the North River, 82.8% of ∑6PAEs in the West River and 91.6% of ∑6PAEs in the estuary. DEHP and DINP were the richest congeners in the sediment-phase, with proportions of 84.9% in the North River, 81.0% in the West River and 65.4% in the estuary. The spatial distribution of ∑6PAEs in water and sediment phases showed that the riverside environment had influence on the distribution pattern. The reconstruction profile of the PAE congeners and the ∑6PAEs vs the depth of the sediment core indicated that PAEs became increasingly present pollutants around 2006 in the Jiulong River. The results of the potential ecological risk assessment of the RQ method revealed that DIBP and DEHP posed a high risk because of their relatively higher concentrations, while DBP and DINP posed a medium risk to the aquatic system. The baseline data of PAEs in this river will be benefits to the regulatory attention and future strategies of the pollutants control along the river network.

The preparation of Cistanche phenylethanoid glycosides liquid proliposomes: Optimized formulation, characterization and proliposome dripping pills in vitro and in vivo evaluation.

Water-soluble Cistanche phenylethanoid glycosides (CPhGs) have poor permeability and low bioavailability. However, liposomes can improve the permeability of such drugs and their poor stability, and proliposomes have been used to overcome these problems. Based on this, Cistanche phenylethanoid glycoside liquid proliposomes (CPhGsP) and dripping(?) pills were prepared and optimized using response surface methodology. The properties of CPhGsP were evaluated in terms of their encapsulation efficiency, particle size, zeta potential, and morphology. The results obtained showed that the optimal formulation was drug/soybean phospholipid/poloxamer-188/sodium deoxycholate/propylene glycol 1:22.38:3.52:0.84:80 (w/w/w/w/v). This resulted in an encapsulation efficiency, particle size, and zeta potential of hydrated proliposomes with phosphate buffer solution (pH7.4) of 51.97%, 671.7nm, and -25.49mV, respectively. Stability testing of CPhGsP and CPhGs ordinary liposomes was carried out for 3months at 4±2°C, 25±2°C, 40±2°C, 75±5% RH. The results obtained showed that the stability of the proliposomes was better than that of ordinary liposomes at the same temperature, while a lower temperature of 4°C is ideal for storage. Cistanche phenylethanoid glycoside liquid proliposomes dripping pills (CPhGsPD) are efficiently released in gastrointestinal solution as shown by in vitro release experiments and the structure of the liposomes does not destroy the proliposome dripping pills by hydration. In vivo experiments showed that the areas under the plasma level-time curves and peak concentrations of CPhGsPD and hydrated proliposomes were higher than those of CPhGs. Moreover, with CPhGsPD, the pharmacokinetic parameters were similar to those with hydrated proliposomes. These results showed that CPhGsPD offer a good way to improve the oral delivery of CPhGs.

Comprehensive identification of novel proteins and N-glycosylation sites in royal jelly.

BACKGROUND: Royal jelly (RJ) is a proteinaceous secretion produced from the hypopharyngeal and mandibular glands of nurse bees. It plays vital roles in honeybee biology and in the improvement of human health. However, some proteins remain unknown in RJ, and mapping N-glycosylation modification sites on RJ proteins demands further investigation. We used two different liquid chromatography-tandem mass spectrometry techniques, complementary N-glycopeptide enrichment strategies, and bioinformatic approaches to gain a better understanding of novel and glycosylated proteins in RJ. RESULTS: A total of 25 N-glycosylated proteins, carrying 53 N-glycosylation sites, were identified in RJ proteins, of which 42 N-linked glycosylation sites were mapped as novel on RJ proteins. Most of the glycosylated proteins were related to metabolic activities and health improvement. The 13 newly identified proteins were also mainly associated with metabolic processes and health improvement activities. CONCLUSION: Our in-depth, large-scale mapping of novel glycosylation sites represents a crucial step toward systematically revealing the functionality of N-glycosylated RJ proteins, and is potentially useful for producing a protein with desirable pharmacokinetic and biological activity using a genetic engineering approach. The newly-identified proteins significantly extend the proteome coverage of RJ. These findings contribute vital and new knowledge to our understanding of the innate biochemical nature of RJ at both the proteome and glycoproteome levels.

Proteome and phosphoproteome analysis of honeybee (Apis mellifera) venom collected from electrical stimulation and manual extraction of the venom gland.

BACKGROUND: Honeybee venom is a complicated defensive toxin that has a wide range of pharmacologically active compounds. Some of these compounds are useful for human therapeutics. There are two major forms of honeybee venom used in pharmacological applications: manually (or reservoir disrupting) extracted glandular venom (GV), and venom extracted through the use of electrical stimulation (ESV). A proteome comparison of these two venom forms and an understanding of the phosphorylation status of ESV, are still very limited. Here, the proteomes of GV and ESV were compared using both gel-based and gel-free proteomics approaches and the phosphoproteome of ESV was determined through the use of TiO2 enrichment. RESULTS: Of the 43 proteins identified in GV, < 40% were venom toxins, and >60% of the proteins were non-toxic proteins resulting from contamination by gland tissue damage during extraction and bee death. Of the 17 proteins identified in ESV, 14 proteins (>80%) were venom toxic proteins and most of them were found in higher abundance than in GV. Moreover, two novel proteins (dehydrogenase/reductase SDR family member 11-like and histone H2B.3-like) and three novel phosphorylation sites (icarapin (S43), phospholipase A-2 (T145), and apamin (T23)) were identified. CONCLUSIONS: Our data demonstrate that venom extracted manually is different from venom extracted using ESV, and these differences may be important in their use as pharmacological agents. ESV may be more efficient than GV as a potential pharmacological source because of its higher venom protein content, production efficiency, and without the need to kill honeybee. The three newly identified phosphorylated venom proteins in ESV may elicit a different immune response through the specific recognition of antigenic determinants. The two novel venom proteins extend our proteome coverage of honeybee venom.

Proteome analysis of hemolymph changes during the larval to pupal development stages of honeybee workers (Apis mellifera ligustica).

Hemolymph is vital for the flow and transportation of nutrients, ions, and hormones in the honey bee and plays role in innate immune defense. The proteome of the hemolymph changes over the life of a honey bee, but many of these changes are not well characterized, including changes during the life cycle transition from the larval to pupal stages of workers. We used two-dimensional gel electrophoresis, mass spectrometry, bioinformatics, and Western blot to analyze the proteome changes of the honeybee hemolymph during the transition from newly hatched larvae to five-day-old pupae. Of the 49 nonredundant proteins that changed in abundance (identified by 80 protein spots), 29 (59.2%) and 20 (40.8%) were strongly expressed in the larvae and the pupae, respectively. The larval hemolymph had high expressions of major royal jelly proteins and proteins related to metabolism of carbohydrates and energy, folding activities, development, and the cytoskeleton and antioxidant systems. Proteins involved in food storage and the metabolism of fatty acids and amino acids were abundantly expressed during the late larval to pupal development stages. The proteins expressed by the young larvae are used to enhance their development process and as a temporal innate immune protection mechanism until they gain immunity with age development. The pupae use more energy storage related proteins as they prepare for their non-diet-driven pupation. Our data provide new evidence that changes in the hemolymph at the proteome level match the processes during life transitions in the honeybee.

Towards posttranslational modification proteome of royal jelly.

Royal jelly (RJ) is a secretory protein from the hypopharyngeal glands of nurse honeybee workers, which contains a variety of proteins of which major royal jelly proteins (MRJPs) are some of the most important. It plays important roles both for honeybee and human. Each family of MRJP 1-5 displays a string of modified protein spots in the RJ proteome profile, which may be caused by posttranslational modifications (PTMs) of MRJPs. However, information on the RJ PTMs is still limited. Therefore, the PTM status of RJ was identified by using complementary proteome strategies of two-dimensional gel electrophoresis (2-DE), shotgun analysis in combination with high performance liquid chromatography-chip/electrospray ionization quadrupole time-of-flight/tandem mass spectrometry and bioinformatics. Phosphorylation was characterized in MRJP 1, MRJP 2 and apolipophorin-III-like protein for the first time and a new site was localized in venom protein 2 precursor. Methylation and deamidation were also identified in most of the MRJPs. The results indicate that methylation is the most important PTM of MRJPs that triggers the polymorphism of MRJP 1-5 in the RJ proteome. Our data provide a comprehensive catalog of several important PTMs in RJ and add valuable information towards assessing both the biological roles of these PTMs and deciphering the mechanisms underlying the beneficial effects of RJ for human health.