Neutrophilic asthma (NA) refers to an asthma phenotype characterized by significantly elevated levels of neutrophils in induced sputum samples. It is typically associated with a poor response to glucocorticoid therapy and an increased frequency of disease exacerbations. Factors such as pathogen infections and oxidative stress are believed to be associated with the progression of the disease. Marsdenia tenacissima (Roxb.) Wight et Arn (MT), a traditional Chinese medicinal herb, has been extensively utilized for centuries in the treatment of airway inflammatory disorders, particularly asthma. Despite its prolonged clinical application, the specific molecular mechanisms responsible for its therapeutic effects remain inadequately elucidated.

AIM OF THE STUDY:

This study aims to reveal the molecular mechanisms underlying the therapeutic effects of MT in NA by an integrated approach of network pharmacology combined with in vivo and in vitro experiments.

MATERIAL AND METHODS:

We constructed a mouse model of NA using house dust mite (HDM) and lipopolysaccharide (LPS). The therapeutic effects of MT on NA were assessed through pulmonary function tests, histology, and enzyme-linked immunosorbent assay (ELISA). Using network pharmacology, we screened the key compounds of MT for treating NA and their potential targets, which were validated through molecular docking and molecular dynamics simulations. Using in vitro cytotoxicity assay, ELISA, real-time quantitative polymerase chain reaction (qPCR), transwell assay, Western blot (WB), cell thermal shift assay (CETSA), and in vivo experiments, we verified the therapeutic effects and potential mechanism of the key compound.

RESULTS:

The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the intersection between MT's targets and asthma targets revealed that MT acts on multiple biological processes and pathways related to NA. We demonstrated that MT alleviates asthma symptoms, neutrophil infiltration, and the release of inflammatory cytokines in vitro. Employing network pharmacology, we identified 17β-Tenacigenin B as the key compound of MT, targeting interleukin (IL)-6 and Janus kinase (JAK)1, thereby modulating the JAK/STAT and its downstream PI3K/AKT/mTOR pathway. Molecular docking, molecular dynamics simulations, and CETSA demonstrated stable binding between this compound and its targets. The therapeutic effects of the key compound and the key protein within these pathways were validated in vivo and in vitro. Furthermore, we confirmed the therapeutic effects of MT in NA by suppressing the IL-6/JAK/STAT pathway through the administration of LMT-28, the IL-6 inhibitor.

CONCLUSIONS:

This research revealed that MT treats NA through the IL-6/JAK/STAT and PI3K/AKT/mTOR pathways. It is worth noting that this is the first time that network pharmacology has been comprehensively used to explore the mechanism of MT in treating asthma. This finding advances our understanding of the pharmacological mechanisms underlying MT and lends support to its usage as a treatment agent for NA.

2026-01-01·Arthritis & Rheumatology

Expert Perspective: Diagnosis and Treatment of Castleman Disease

Review

作者: David C. Fajgenbaum ; Lu Zhang ; Luke Y. C. Chen

Castleman disease (CD) is a major diagnostic challenge for rheumatologists. Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions. Both UCD and MCD may exhibit a wide range of symptoms that overlap with other immune‐mediated conditions. MCD can be associated with excessive cytokine production due to a plasma cell neoplasm (MCD–polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes) or uncontrolled human herpesvirus‐8 infection (HHV‐8) (HHV‐8–positive MCD), but more than half of cases are idiopathic. Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6), patients with idiopathic MCD (iMCD) often present as a diagnostic mystery with heterogeneous symptomatology that can be classified into three subtypes. The three subtypes are iMCD–thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD–idiopathic plasmacytic lymphadenopathy (IPL); and iMCD–not otherwise specified (NOS). Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO. Patients with iMCD‐IPL present with subacute or chronic lymphadenopathy, anemia of inflammation, and polyclonal hypergammaglobulinemia, often with increased IgG4 in serum and lymph node tissue; these cases can be difficult to distinguish from IgG4‐related disease and histiocyte disorders. Those who have iMCD not meeting criteria for TAFRO or IPL have iMCD‐NOS, which often mimics indolent lymphoma or autoimmune conditions. Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD. Broadly speaking, treatments for CD can be considered in three categories: immunomodulators such as glucocorticoids, cytokine inhibitors, and sirolimus; antilymphoma therapies such as rituximab, cytotoxic chemotherapy, and BTK inhibitors; and antimyeloma therapies such as thalidomide and bortezomib. The first‐line therapy for all subtypes of iMCD is siltuximab, an IL‐6 antagonist. Patients with refractory disease have numerous treatment options and consulting treatment guidelines as well as consultation with a center with expertise in CD are recommended.image

2025-12-01·Journal of the Royal College of Physicians of Edinburgh

Tocilizumab vs bevacizumab in critically ill COVID-19 patients: Registry-based prospective study

Article

作者: Parihar, Gulam Mateen ; Sarwa, Pramod ; Sharma, Anil Kumar ; Gupta, Rajeev ; Khedar, Raghubir S ; Gupta, Yatendra Kumar

Background::

Tocilizumab, an interleukin-6 (IL-6) inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, have been used in critically ill COVID-19 patients for cytokine storm. We performed a registry-based prospective study to compare the efficacy of these two drugs.

Methods::

Virologically confirmed hospitalised patients with severe COVID-19 who received either tocilizumab or bevacizumab have been included. Management details and outcomes were recorded. The primary outcome was in-hospital deaths and secondary outcomes were 30-day deaths, changes in oxygen requirement at 48 h of drug administration and duration of intensive care unit stay. Descriptive statistics are reported.

Results::

One thousand three hundred forty-five COVID-19 patients were hospitalised during the study period, 87 with severe COVID-19 received tocilizumab ( n = 62) or bevacizumab ( n = 25). Patients in the tocilizumab group were older (62.6 ± 11 vs 53.2 ± 14, p = 0.001) with more cardiovascular disease and no significant differences in clinical features, laboratory investigations, or radiological and biochemical markers of disease severity. Oxygenation, ventilatory support and proning were similar as were supportive therapies (steroids, remdesivir, anticoagulants; p > 0.05). In-hospital deaths in tocilizumab vs bevacizumab group were 47 (75.8%) vs 12 (48.0%; p = 0.012) with unadjusted hazard ratio (HR) 1.91 (95% confidence interval (CI) 0.99–3.65, p = 0.050) and age-adjusted HR 1.76 (95% CI 0.90–3.44, p = 0.097). Secondary outcome of 30-day death was also more in tocilizumab group: 49 (79.0%) vs 13 (52.0%; p = 0.011). Within-group comparison showed that PaO 2 :FiO 2 at 48-h of drug administration was better in bevacizumab group ( p = 0.003) compared to tocilizumab ( p = 0.651).

Conclusion::

VEGF inhibitor bevacizumab led to significantly better ventilatory outcomes and lower in-hospital and 30-day deaths compared to IL-6 inhibitor tocilizumab in severely ill COVID-19 patients. Randomised studies are required to confirm these findings.

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