Graphene oxide quantum dots-loaded sinomenine hydrochloride nanocomplexes for effective treatment of rheumatoid arthritis via inducing macrophage repolarization and arresting abnormal proliferation of fibroblast-like synoviocytes.

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.

Sex-related differences in safety profiles, pharmacokinetics and tissue distribution of sinomenine hydrochloride in rats.

Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum (Thunb.) Rehd. et Wils which exhibits significant analgesic, anti-inflammatory, and immunosuppressive effects. Sinomenine hydrochloride (SH) preparations, classified as natural disease-modifying antirheumatic drugs, are currently available for the treatment of rheumatoid arthritis and other rheumatic diseases. Our toxicity evaluation demonstrated that the median lethal dose of SH in female Sprague-Dawley (SD) rats was over 11 times greater than that in male SD rats, revealing striking sex-linked differences in the safety profile of SH. The present study was designed to investigate differences in the pharmacokinetics (PKs) and tissue distribution of SH between male and female SD rats after a single oral dose of 25 mg/kg. PK and tissue distribution studies were performed using a validated UPLC-MS/MS method. The results showed that SH-treated SD female rats displayed markedly greater drug exposure, and SH exhibited a longer half-life and slower clearance rate than comparable studies in male rats. Moreover, the tissue distribution study confirmed that the sinomenine concentration in female rats was considerably greater in the internal organs than in male rats. Our study demonstrates, for the first time, significant sex-related differences in the safety profile and PKs of SH, which may be associated with a distinct sex-dependent metabolic mechanism of sinomenine.

Multifunctional nanoparticles of sinomenine hydrochloride for treat-to-target therapy of rheumatoid arthritis via modulation of proinflammatory cytokines.

Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant of Sinomenium acutum (Thunb.) Rehd.et Wils. Currently, sinomenine hydrochloride (SIN) preparations, classified as a natural disease-modifying anti-rheumatic drug (nDMARD), have been used for therapy of rheumatoid arthritis (RA); however, the efficacy of SIN was seriously limited by its short half-life, low bioavailability, and dose-dependent adverse reactions. In this study, a biomimetic nanocomplex based on Prussian blue nanoparticles (PB NPs) was developed for overcoming clinical limitations of SIN and accordingly improving its efficacy. In vitro studies showed that the nanocomplexes significantly inhibited abnormal proliferation of fibroblast-like synoviocytes (FLSs) by scavenging reactive oxygen species (ROS) and inhibiting secretion of proinflammatory cytokines. In vivo imaging demonstrated that the improved immune-escape properties of the nanocomplexes resulted in markedly increased half-life of circulation and levels of accumulated drugs at arthritic sites of adjuvant-induced arthritis (AIA) rats. Notably, the nanocomplexes significantly suppressed joint inflammation and protected against bone destruction of AIA rats by inhibiting inflammatory cytokine secretion of the synovial macrophages and FLSs. These results indicate that the nanocomplexes provide an excellent carrier for controlled release and targeted accumulation of SIN within the arthritic sites, which consequently achieve disease-remitting effects of SIN on RA.

Lactate metabolism in rheumatoid arthritis: Pathogenic mechanisms and therapeutic intervention with natural compounds.

BACKGROUND: Rheumatoid arthritis (RA) is a common chronic and systemic autoimmune disease characterized by persistent inflammation and hyperplasia of the synovial membrane, the degradation of cartilage, and the erosion of bones in diarthrodial joints. The inflamed joints of patients with RA have been recognized to be a site of hypoxic microenvironment which results in an imbalance of lactate metabolism and the accumulation of lactate. Lactate is no longer considered solely a metabolic waste product of glycolysis, but also a combustion aid in the progression of RA from the early stages of inflammation to the late stages of bone destruction. PURPOSE: To review the pathogenic mechanisms of lactate metabolism in RA and investigate the potential of natural compounds for treating RA linked to the regulation of imbalance in lactate metabolism. METHODS: Research advances in our understanding of lactate metabolism in the pathogenesis of RA and novel pharmacological approaches of natural compounds by targeting lactate metabolic signaling were comprehensively reviewed and deeply discussed. RESULTS: Lactate produced by RA synovial fibroblasts (RASFs) acts on targeted cells such as T cells, macrophages, dendritic cells and osteoclasts, and affects their differentiation, activation and function to accelerate the development of RA. Many natural compounds show therapeutic potential for RA by regulating glycolytic rate-limiting enzymes to limit lactate production, and affecting monocarboxylate transporter and acetyl-CoA carboxylase to inhibit lactate transport and conversion. CONCLUSION: Regulation of imbalance in lactate metabolism offers novel therapeutic approaches for RA, and natural compounds capable of targeting lactate metabolic signaling constitute potential candidates for development of drugs RA.

A pH-Driven indomethacin-loaded nanomedicine for effective rheumatoid arthritis therapy by combining with photothermal therapy.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by inflammatory micro-environments in the joints. Indomethacin (IND), a conventional nonsteroidal anti-inflammatory drug (NSAID), has been used for the therapy of RA. However, the poor solubility and serious side effects of oral administration of IND significantly limit its efficacy. In this study, we have synthesized biomimetic IND-loaded Prussian blue (PB) nanoparticles (IND@PB@M@HA) with hyaluronic acid (HA) modification for increasing the solubility and targeting the ability of IND to the inflamed joints. The application of hybrid cell membranes on the NPs endowed immune escape of IND@PB@M@HA NPs, which accordingly extended the circulation time in the blood. In vitro assay demonstrated that the combination of nanomedicine and photothermal therapy produced a powerful anti-inflammatory effect by reducing the levels of inflammatory factors and cell viability of activated macrophages and NPs possessed obvious pH-responsiveness. In vivo assay demonstrated that the nanomedicine for synergistic photothermal therapy exhibited desirable pharmacodynamics and pharmacokinetic properties at ultra-low drug dosage in a rat model of adjuvant-induced arthritis, which was confirmed by inflammatory suppression, bone erosion remission, and negligible adverse effects. In summary, the proposed nanomedicine has the potential role for targeted anti-inflammatory therapy of RA.

Overview of human clonorchiasis sinensis in China.

The objective of the survey was to determine the current status, trends and transmission factors for Clonorchis sinensis infection in China and to provide updated information for development control strategies. This was part of a nationwide survey of major human parasitic diseases carried out during 2000-2002 sampled by the stratified randomized cluster sampling method. Fecal examination was conducted using the Kato-Katz thick smear method and egg count per gram of feces (EPG) was determined for the egg-positive patients. A questionnaire and a case-control study were applied to analyze the transmission factors for C. sinensis infection. The overall prevalence rate of C. sinensis infection was 0.58% in 356,629 residents from 688 sampled pilot sites in 31 provinces, autonomous regions and municipalities (PAM) of China. The infection rates of C. sinensis in Guangdong, Jilin, Guangxi Zhuang autonomous region, Anhui and Heilongjiang were higher than the other PAM, they were 5.35, 4.77, 3.71, 0.67 and 0.48%, respectively. In Guangxi, moderate and heavy infections were found in 29.14% and 11.52%, respectively, of the total infected. Heavy infections were not found in any of the other provinces except for 2 heavily infected cases in Heilongjiang. The prevalence rate increased with age for residents aged < 35 years and remained at high levels in those aged 25-60 years. The infection rate in males was 1.64 times that of females. The C. sinensis egg positivity rates in fishermen, businessmen, physicians and teachers were higher than others. Among the 38 ethnic groups, the prevalences in the Han (3.20%) and the Zhuang (3.15%) were the highest; no cases were found among the Zang, Miao, Man and other 29 ethnic groups. Significant differences in prevalences were also found among counties of different economic levels. C. sinensis infection is prevalent in hilly and plains regions of northeast and southcentral China, representing two highly endemic areas in the North and the South. An increasing trend in prevalence was seen in endemic areas. The infection was mainly detected in young and middle aged males. A higher prevalence was observed in those with a better education and a higher income. Consumption of raw (or under-cooked) fresh water fish or shrimp were the main risk factors responsible for transmission of the parasite.

[Study on 5S rDNA sequence of two isolates of Trichinella from Guangxi].

OBJECTIVE: To analyze 5S ribosomal DNA (5S rDNA) sequences of two Trichinella isolates from Guangxi. METHODS: The fragments of 5S rDNA were obtained by PCR from the isolates of Debao and Nandan, and sequencing was made for the PCR products. Homogeneity, genetic distance matrix and phylogenetic tree were analyzed by related software. 5S rDNA sequences of the two isolates were compared separately with those of Trichinella species in GenBank. RESULTS: 5S rDNA sequences of three Trichinella isolates (Debao, Nandan and T. spiralis) showed the same length at 695 bp. There were 4 variable positions. The homogeneities of Debao and Nandan isolates with T. spiralis were 99.0% and 99.1% respectively. The homogeneities between Debao isolate and Nandan isolate was 98.8%. Compared with other Trichinella isolates in GenBank, they were all less than 94.2%. The evolutionary distance among isolates of Debao and Nandan and T. spiralis was 0.014. Meanwhile, the evolutionary distances between the Guangxi isolates and other Trichinella isolates in GenBank were more than 0.056. Phylogenetic tree analysis revealed that two isolates of Guangxi and T. spiralis located at the same node, revealing a close relationship. Bootstrap confidence values in two phylogenetic trees were 96 and 99, respectively. CONCLUSION: The two Trichinella isolates of Guangxi show a high homogeneity with T. spiralis, locate at the same nodes in phylogenetic tree,suggesting that the Debao and Nandan Trichinella isolates be identified as T. spiralis.