Microenvironmental Enzyme-Responsive Methotrexate Modified Quercetin Micelles for the Treatment of Rheumatoid Arthritis.

Purpose: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease involving synovial inflammation and joint destruction. Although therapeutic drugs for RA have some efficacy, they usually cause severe side effects and are expensive. RA is characterized by synovial hyperplasia, intra-articular hypoxia, upregulated expression of matrix metalloproteinases, and excessive accumulation of reactive oxygen species. The adverse microenvironment further aggravates activated macrophage infiltration. Therefore, controlling the microenvironment of diseased tissues and targeting the activated macrophages have become new therapeutic targets in RA patients. Methods: Here, microenvironment-targeting micelles (PVGLIG-MTX-Que-Ms) were synthesized using the thin film hydration method. In the inflammatory microenvironment, PVGLIG was cleaved by the highly expressed MMP-2, PEG5000 was eliminated, MTX was exposed, macrophage activation was targeted, and Que enrichment was enhanced. The cytotoxicity, targeting, antioxidant, and anti-inflammatory properties of drug-loaded micelles were tested in vitro. The drug-loaded micelles were used to treat CIA rats. In vivo targeting, expression of serum inflammatory factors, immunohistochemistry of the articular cartilage, and changes in immunofluorescence staining were observed. Results: The developed micelles had a particle size of (89.62 ±1.33) nm and a zeta potential of (-4.9 ±0.53) mV. The IC50 value of PVGLIG-MTX-Que-Ms (185.90 ±6.98) µmol/L was significantly lower than that of free Que (141.10 ±6.39) µmol/L. The synthesized micelles exhibited slow-release properties, low cytotoxicity, strong targeting abilities, and significant anti-inflammatory effects in vitro. In vivo, the drug-loaded micelles accumulated at the joint site for a long time. PVGLIG-MTX-Que-Ms significantly reduced joint swelling, improved bone destruction, and decreased the expression of serum inflammatory factors in CIA rats. Conclusion: The smart-targeting micelles PVGLIG-MTX-Que-Ms with strong targeting, anti-inflammatory, cartilage-protective, and other multiple positive effects are a promising new tool for RA treatment.

Preparation and evaluation of dual drug-loaded nanofiber membranes based on coaxial electrostatic spinning technology.

Wound healing is a complicated process consisting of wound bleeding, inflammatory response, cell proliferation and tissue remodeling. During this long-term period, wound is vulnerable to infection by bacteria or microbes. Therefore, we prepared a novel centella total glucoside-ciprofloxacin dual-loaded coaxial nanofiber membrane (CDCNM) by using coaxial electrostatic spinning technique. To satisfy personalized therapeutic demands by adjusting release behaviors, we loaded centella total glucoside (CTG) and ciprofloxacin (CIP) into different positions of the fibers and the morphology and coaxial structure of the nanofiber membranes were analyzed by SEM and TEM. In addition, water contact angle, water absorption capacity, breathability and in vitro drug release were tested. In vitro cell experiments demonstrated that CDCNM can promote fibroblast proliferation. CDCNM demonstrated excellent antimicrobial activity through the agar flat dish diffusion method. Furthermore, rat scald experiments showed that CDCNM significantly accelerated scald healing, meanwhile immunohistochemical staining showed that CDCNM promoted the expression of CD31 and VEGF during early wound healing, which accelerated scald healing by promoting neovascularization and endothelial cell proliferation. As a topical multifunctional wound dressing, this dual drug-loaded nanofiber membrane achieved scald healing effect and continuous bacterial inhibition, which provides new ideas for existing trauma treatment tools and dual drug delivery systems.

A novel alginate/gelatin sponge combined with curcumin-loaded electrospun fibers for postoperative rapid hemostasis and prevention of tumor recurrence.

Surgical resection of the tumor remains the preferred treatment for most solid tumors at an early stage, but surgical treatment often leads to massive bleeding and residual tumor cells. Therefore, a novel alginate/gelatin sponge combined with curcumin-loaded electrospun fibers (CFAGS) for rapid hemostasis and prevention of tumor recurrence was prepared by using an electrospinning and interpenetrating polymer network (IPN) strategy. The present results show that alginate/gelatin sponge display excellent hemostatic properties and possess more advantages than commercial gelatin hemostasis sponge. More importantly, CFAGS could control the release of curcumin, inducing curcumin to accumulate at the surgical site of the tumor, thereby inhibiting local tumor recurrence in the subcutaneous postoperative recurrence model. In addition, the sponge was safe to implant in the body and did not cause toxicity to normal tissues and organs. This approach represents a new strategy to implant a dual functional sponge at the postoperative site as an adjuvant to the surgical treatment of cancer.

The Dysfunction of the Cerebellum and Its Cerebellum-Reward-Sensorimotor Loops in Chronic Spontaneous Urticaria.

Chronic spontaneous urticaria (CSU) is a common itchy skin disease. Despite its prevalence, the neuropathology of CSU is uncertain. In this study, we explored resting state functional connectivity (rs-FC) changes in CSU, as well as how the symptom changes following intervention can modulate rs-FC. Forty patients and 40 healthy controls (HCs) were recruited. Following an intervention, 32 patients participated in a second scan approximately 6 weeks after the first scan. Compared with healthy controls, CSU subjects exhibited higher regional homogeneity (ReHo) values in the cerebellum, which were positively associated with urticaria activity scores over 7 days (UAS7) at baseline. After an intervention accompanied with clinical improvement, we found that ReHo values decreased at the cerebellum and increased at the bilateral primary somatosensory cortex (SI)/primary motor cortex (MI)/supplementary motor area (SMA). Using the cerebellum as a seed, CSU subjects exhibited increased rs-FC with reward regions when compared with HCs and exhibited decreased rs-FC at the right orbitofrontal cortex and right sensorimotor region following the intervention. The improvement rate values were positively associated with reduced rs-FC values in the two regions. Using the cluster of SI/MI/SMA as a seed, CSU patients exhibited decreased rs-FC with the left putamen, caudate, accumbens, and thalamus following the intervention. These results demonstrate the altered cerebellar activity and cerebellum-reward-sensorimotor loops in CSU.

The functional and structural alterations of the striatum in chronic spontaneous urticaria.

The brain has long been known to be the regulation center of itch, but the neuropathology of chronic itch, such as chronic spontaneous urticaria (CSU), remains unclear. Thus, we aimed to explore the brain areas involved in the pathophysiology of CSU in hopes that our results may provide valuable insights into the treatment of chronic itch conditions. 40 CSU patients and 40 healthy controls (HCs) were recruited. Urticaria activity scores 7 (UAS7) were collected to evaluate patient's clinical symptoms. Amplitude of low frequency fluctuations (ALFF), voxel-based morphometry (VBM), and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess brain activity and related plasticity. Compared with HCs, CSU patients exhibited 1) higher ALFF values in the right ventral striatum / putamen, which were positively associated with clinical symptoms as measured by UAS7; 2) gray matter volume (GMV) increase in the right ventral striatum and putamen; and 3) decreased rs-FC between the right ventral striatum and the right occipital cortex and between the right putamen and the left precentral gyrus. Using multiple-modality brain imaging tools, we demonstrated the dysfunction of the striatum in CSU. Our results may provide valuable insights into the neuropathology and development of chronic itch.

[Clinical observation on effect of compound E-bei ointment in treating plaque psoriasis].

OBJECTIVE: To observe the efficacy oand safety of Compound E-Bei ointment (CEBO) in treating plaque psoriasis. METHODS: Adopting block-randomized, open, positive Western medicine and placebo parallel group controlled method, a total of 120 enrolled patients were administered orally with Saoxuan Pill, and randomized into three groups respectively treated with external application of CEBO, Daivonex, or vehicle control twice a day for 4 weeks. The changes of erythema, infiltration, scaly eruption, pruritus and the area of lesion were evaluated, the safety and the initiating time of symptom improvement (ITSI) were observed as well. RESULTS: Observation on local lesion showed that the scores of erythema, infiltration, scaly eruption, pruritus were significantly improved in difference between the CEBO group and the Daivonex group (P < 0.01). But in the placebo control group, significant improvement was only shown in scaly eruption scores (P < 0.01), so, the improvement in skin lesion in the placebo group was significantly inferior to that in the other two groups (P < 0.01). The ITSI of pruritus was shorter in CEBO group than that in the Daivonex group and the placebo group (P < 0.01), but that of other symptoms showed insignificant difference between the CEBO group and the Daivonex group, as for comparing in ITSI of erythema, infiltration, scaly eruption and pruritus, it was significantly shorter in the CEBO group and Daivonex group than that in the placebo group respectively (P < 0.01). The occurrence of adverse events in the CEBO group had insignificant difference to that in the Daivonex group, but the recurrence rate in the former was significantly lower than that in the latter (P < 0.05). CONCLUSION: CEBO can effectively improve the symptoms of skin lesion in patients with plaque psoriasis, the clinical efficacy is not inferior to that of positive Western medicine.