Xuebifang (XBF), a potent Chinese herbal formula, has been employed in managing diabetic peripheral neuropathy (DPN). Nevertheless, the precise mechanism of its action remains enigmatic.

The primary objective of this investigation is to employ a bioinformatics-driven approach combined with network pharmacology to comprehensively explore the therapeutic mechanism of XBF in the context of DPN.

The active chemicals and their respective targets of XBF were sourced from the TCMSP and BATMAN databases. Differentially expressed genes (DEGs) related to DPN were obtained from the GEO database. The targets associated with DPN were compiled from the OMIM, GeneCards, and DrugBank databases. The analysis of GO, KEGG pathway enrichment, as well as immuno-infiltration analysis, was conducted using the R language. The investigation focused on the distribution of therapeutic targets of XBF within human organs or cells. Subsequently, molecular docking was employed to evaluate the interactions between potential targets and active compounds of XBF concerning the treatment of DPN.

The study successfully identified a total of 122 active compounds and 272 targets associated with XBF. 5 core targets of XBF for DPN were discovered by building PPI network. According to GO and KEGG pathway enrichment analysis, the mechanisms of XBF for DPN could be related to inflammation, immune regulation, and pivotal signalling pathways such as the TNF, TLR, CLR, and NOD-like receptor signalling pathways. These findings were further supported by immune infiltration analysis and localization of immune organs and cells. Moreover, the molecular docking simulations demonstrated a strong binding affinity between the active chemicals and the carefully selected targets.

In summary, this study proposes a novel treatment model for XBF in DPN, and it also offers a new perspective for exploring the principles of traditional Chinese medicine (TCM) in the clinical management of DPN.

Niosomes are drug delivery systems with widespread applications in pharmaceutical research and the cosmetic industry. Niosomes are vesicles of one or more bilayers made of non-ionic surfactants, cholesterol, and charge inducers. Because of their bilayer characteristics, similar to liposomes, niosomes can be loaded with lipophilic and hydrophilic cargos. Therefore, they are more stable and cheaper in preparation than liposomes. They can be classified into four categories according to their sizes and structures, namely small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs,), multilamellar vesicles (MLVs), and multivesicular vesicles (MVVs). There are many methods for niosome preparation, such as thin-film hydration, solvent injection, and heating method. The current study focuses on the preparation methods and pharmacological effects of niosomes loaded with natural and chemical anti-inflammatory compounds in kinds of literature during the past decade. We found that most research was carried out to load anti-inflammatory agents like non-steroidal anti-inflammatory drugs (NSAIDs) into niosome vesicles. The studies revealed that niosomes could improve anti-inflammatory agents' physicochemical properties, including solubility, cellular uptake, stability, encapsulation, drug release and liberation, efficiency, and oral bioavailability or topical absorption. See also the graphical abstract(Fig. 1).

Introduction: Rheumatoid arthritis (RA) is an immune-mediated disease associated with chronic inflammation of numerous joints. Nyctanthes arbor-tristis (NAT) is a traditional remedy for RA, a chronic inflammatory disorder. Aim: The current project aims to demonstrate the role of the NAT extracts in sub-acute toxicity, pharmacovigilance, and anti-rheumatic biomarkers. Method: Hydroethanolic extract (1:1) of plant leaves was prepared by using the reflux method. The safety of the dose was evaluated in Sprague-Dawley rats, and the anti-inflammatory effects of NAT on RA symptoms, including paw volumes, body weight, arthritic index, withdrawal latency, hematology and serological test, radiology, and histopathology, were evaluated in Freund's complete adjuvant (FCA)-induced arthritis Sprague-Dawley rat models. The inflammatory (TNF-α and COX-2) and anti-inflammatory markers (IL-10) were analyzed in control and experimental groups. Result: The study showed that 500 mg/kg BW NAT leaf extract was found to be least toxic without showing any subacute toxicity symptoms. The pharmacovigilance study highlighted the potential side effects of NAT, such as drowsiness, sedation, and lethargy, at high dosages. Treatment with the plant extract mitigated paw edema, restored the immune organ and body weights, and ameliorated the level of blood parameters such as hemoglobin, red blood cells, platelets, white blood cells, aspartate aminotransferase (AST), alanine transaminase (ALT), C-reactive proteins, and rheumatoid factor. Treatment with the plant extracts also reduced the level of cyclooxygenase 2 and TNF-α and increased the level of IL-10 in the serum of arthritic rats dose-dependently. Radiographic analysis of the ankle joint showed an improvement in the hind legs. Histological examination of the ankle joints revealed that the plant extract treatment decreased pannus formation, inflammation, and synovial hyperplasia in arthritic animals. Conclusion: NAT 500 mg/kg could serve as a promising therapeutic option for the treatment of inflammatory arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation, joint tissue damage, pain, and synovitis. It leads to deformity of joints, disability, and even premature death. Markers of inflammation are highly expressed in synovium fluid and serum of arthritic patients and play an important role in the pathophysiology of RA. These transcription factors promote the fabrication of type I interferons and inflammatory cytokines. In RA, degradation of synovial cartilage and bone results from stimulation of proinflammatory cytokines. Citronellol (Ct), a monoterpene alcohol, is found in citrus fruits and essential oils of many aromatic plants. It possesses numerous pharmacological properties such as antioxidant activity and potential antinociceptive and anti-inflammatory effects. Keeping in view the significant anti-inflammatory role of Ct, a trial of 28 days was conducted. Ct was administered orally at three different doses (25, 50, and 100) mg/kg in Freund's adjuvant-induced arthritic rats, and the results were compared with piroxicam, chosen as the standard drug. The antiarthritic activity of the compound was evaluated through measurements of arthritic scoring and plethysmometry before and after treatment. The blood biochemical and hematological parameters and histopathological analyses were performed. Additionally, qPCR was conducted to analyze the mRNA expression levels of TNF-α, IL-1β, NF-κB, MMP3, IL-6, and IL-4 in the blood. ELISA was performed to evaluate the levels of PGE2. The results demonstrated that Ct showed significant results at all doses, but the highest dose proved to be most significant in terms of decreasing arthritic scoring and paw edema, indicating the antiarthritic potential of Ct. Furthermore, the compound was found to downregulate all the proinflammatory cytokines (TNF-α, IL-1β, NF-κB, MMP3, and IL-6) and upregulate the anti-inflammatory cytokine (IL-4). The levels of PGE2 were also reduced which further supported the antiarthritic effects of Ct and validated it as a potential antiarthritic candidate.

Sarcococca saligna plant is commonly used as traditional therapy for arthritis especially in Asian countries. The current study is designed to explore the anti-arthritic potential of S. saligna aqueous methanolic extract (SSME). Preliminary proximate study and HPLC analysis were performed to investigate the phytochemical characterization and quality control. The safety of the SSME was evaluated by performing an acute oral toxicity study (OECD guidelines 425). The anti-arthritic potential of SSME was explored by in vivo formaldehyde-induced arthritis model. The antiarthritic effect of the SSME was determined through paw diameter, arthritic index, body weight, biochemical and haematological parameters. Radiographic and histopathological studies were also carried out to evaluate the results. qRT-PCR was performed to determine the upregulation and downregulation of anti- and pro-inflammatory cytokines in rats while ELISA was done to determine the concentration of HSP-70, IL-6 and TNF-α in the serum. Results of acute oral toxicity showed no abnormality and mortality. There was no noticeable change in haematological and biochemical parameters. Histopathological examination exhibited the normal structure of vital organs. So, SSME might be safe at a 2000 mg/kg dose, proposing that LD₅₀ was higher than 2000 mg/kg body weight. Gallic acid, catechin, hydroxyl benzoic acid, sinapic acid, caffeic acid, ferulic acid and p-cumaric acid were identified by HPLC. The outcomes of in vivo formaldehyde-induced arthritic model showed that SSME significantly reduced paw inflammation and arthritic index and improved haematological and biochemical parameters. Moreover, the SSME influentially down-regulated the gene expression of IL-1β, IL-6, COX-2, PGE2, TNF-α and NF-κB, and up-regulated the expression of IL-4, and IL-10. The results of the undertaken study suggest that S. saligna have strong anti-arthritic activity supporting its conventional application as the remedy of rheumatoid arthritis.

Clinically, Wangbi Capsule (WBC) is widely used in the treatment of Rheumatoid arthritis (RA) because of its remarkable therapeutic effect. To reveal the mechanism, a pharmacokinetic-pharmacodynamic (PK-PD) model was developed for the first time to assess the relationship between time-concentration (dose)-effect. Freund's Complete Adjuvant was used to induce the adjuvant-induced arthritis model. Multi-indices were used to evaluate the therapeutic effect and an S-I_max PK-PD model was established based on the concentrations of osthole, 5-O-methylvisamminoside, cimifugin, albiflorin, paeoniflorin and icariin and the levels of interleukin-1β and prostaglandin E₂ using a two-compartment PK model together with a PD model with an effect-site compartment. The results suggest that WBC can treat RA by regulating the levels of prostaglandin E₂ and interleukin-1β. For the PK-PD model, the parameters indicated that WBC had a large safety margin and all six bioactive ingredients of WBC have therapeutic effects on RA. Among them icariin, osthole and 5-O-methylvisamminoside may be the main effective substances. This study provided a scientific basis for further study of population pharmacokinetics / population pharmacodynamics (PPK/PPD), to develop a reasonable administration plan and improve individualized drug therapy.

Rheumatoid arthritis (RA) is an autoimmune disease that underlies chronic inflammation of the synovial membrane. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat RA. However, a long list of adverse events associated with long-term treatment regimens with NSAIDs negatively influences patient compliance and therapeutic outcomes.

The aim of this work was to achieve site-specific delivery of celecoxib-loaded spanlastic nano-vesicle-based delivery system to the inflamed joints, avoiding systemic administration of large doses.

To develop spanlastic nanovesicles for transdermal delivery of celecoxib, modified injection method was adopted using Tween 80 or Brij as edge activators. Entrapment efficiency, vesicle size, ex vivo permeation, and morphology of the prepared nano-vesicles were characterized. Carbopol-based gels containing the selected formulations were prepared, and their clarity, pH, rheological performance, and ex vivo permeation were characterized. Celecoxib-loaded niosomes and noisome-containing gels were developed for comparison. The in vivo efficacy of the selected formulations was evaluated in a rat model of Freund's complete adjuvant-induced arthritis. Different inflammatory markers including TNF-α, NF-кB and COX-2 were assessed in paw tissue before and after treatment.

The size and entrapment efficiency of the selected spanlastic nano-vesicle formulation were 112.5 ± 3.6 nm, and 83.6 ± 2.3%, respectively. This formulation has shown the highest transdermal flux and permeability coefficient compared to the other investigated formulations. The spanlastics-containing gel of celecoxib has shown transdermal flux of 6.9 ± 0.25 µg/cm2/hr while the celecoxib niosomes-containing gel and unprocessed celecoxib-loaded gel have shown 5.2 ± 0.12 µg/cm2/hr and 0.64 ± 0.09 µg/cm2/hr, respectively. In the animal model of RA, the celecoxib-loaded spanlastics-containing gel significantly reduced edema circumference and significantly suppressed TNF-α, NF-кB and COX-2 levels compared to the niosomes-containing gel, the marketed diclofenac sodium gel, and unprocessed celecoxib-loaded gel.

The spanlastic nano-vesicle-containing gel represents a more efficient site-specific treatment for topical treatment of chronic inflammation like RA, compared to commercial and other conventional alternatives.

Alternanthera bettzickiana is being used as a folk remedy for treating arthritis by conventional healers in Thailand. The current research was undertaken to explore the antiarthritic potential of A. bettzickiana ethanolic extract (ABEE). Plant characterization, molecular docking, and in vitro and in vivo (ABEE at 250, 500, and 1000 mg/kg was administered orally to rats once daily for 28 days) studies to explore the antiarthritic effect and enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR) analyses were performed. Oxidative stress biomarkers (superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA)) in the serum and histopathological and radiographic assessment of joints were also carried out. Gallic acid, catechin, chlorogenic acid, sinapic acid, quercetin, and γ- and α-tocopherol were identified in high-performance liquid chromatography (HPLC). Molecular docking revealed a strong interaction between these compounds and cyclooxygenase (COX) enzymes. The extract significantly subdued paw swelling and arthritic scoring, inhibited cachexia, and considerably improved biochemical and hematological modifications. SOD and CAT levels increased and the MDA level decreased in ABEE-treated rats dose-dependently. Radiographic and histopathological analyses also supported the antiarthritic effect of ABEE, which was linked with the downregulation of nuclear factor (NF)-kB, COX-2, interleukin (IL)-6, tumour necrosis factor (TNF)-α, and IL-1β and upregulation of IL-10, I-kB, and IL-4 as compared to disease control rats. Results suggested that A. bettzickiana possessed antiarthritic potential, supporting its folkloric use for treating rheumatoid arthritis.

Aim: Methotrexate (Mtx) is prescribed to reduce pain and inflammation in arthritis patients; however, improved repair and mobility of joints still are the major concerns. Magnesium oil (MO) improves joint mobility and repair; therefore, MO-assisted transdermal delivery of Mtx was aimed.Methods: MO integrated Mtx nanoemulsion (Mtx-MONE) was prepared with uniform size (175 ± 35.4 nm), pH (6.15 ± 0.3) near to skin pH, and high entrapment efficiency (65 ± 8.6%). Mtx-MONE was transformed to nanogel (Mtx-MONEG) with semisolid consistency (43,408 ± 77.72 cP) and good spreadability (3.63 ± 0.033 mJ).Results: Mtx-MONEG showed significant reduction in oedema, arthritic scores, level of inflammatory cytokines, and improved walking as compared to diseased control. MO offered additional improvements in joints, mobility, and repair.Conclusion: Transdermal delivery of Mtx has been successfully achieved by Mtx-MONEG. Tremendous recovery from inflammation, improved joints mobility and repair, and reduced pain strongly support the use of MO as an adjutant of Mtx for improved transdermal application.

The treatment of adult refractory idiopathic membranous nephropathy with steroid and other immunosuppressant-resistant nephrotic syndromes can be a significant challenge. We evaluated the efficacy and safety of the traditional Chinese medicine Jian Pi Qu Shi Formula (JPQSF) as a promising regimen.

We analyzed 15 consecutive patients with biopsy-proven idiopathic membranous nephropathy who failed immunosuppressive therapy from October 2013 to January 2017. JPQSF was administered orally two times per day, respectively, in the morning and at night for 6 months. All patients had at least 1 year of follow-up. The primary endpoints included complete or partial remission. Secondary endpoints included change of clinical parameters and adverse events after 12 months of treatment.

After 12 months, complete remission was achieved in 13.3% of patients and partial remission in 66.7%, yielding a response rate of 80%. Proteinuria, serum albumin, and cholesterol were improved significantly (P<0.001, P<0.001, and P<0.05, respectively). After 1 year of treatment, proteinuria (mean ± SD) decreased from 5.93 ± 2.54 g per 24 h to 1.99 ± 1.17 g per 24 h (P<0.001). No serious adverse events occurred during the observation.

JPQSF may be an alternative therapeutic option for steroid and general immunosuppressant-resistant membranous nephrotic syndrome patients, with a favorable safety profile. Larger and longer follow-up studies evaluating this regimen are warranted.