We focused on BMPRIB-mediated P38-MAPK activation, the potential contribution of BMPRII downregulation cannot be excluded

The gap

Evidence profile

Sourced from the future work and limitations section of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 2 journals. Those papers have been cited 35 times in total.

Supporting evidence — 3 representative gaps

• Current understanding of macrophages in intracranial aneurysm: relevant etiological manifestations, signaling modulation and therapeutic strategies (2024) · Frontiers in Immunology · cited 20× · doi

  IA is a devastating disease with high fate death ratio, as well as limited prevention and treatment approaches. In recent years, achievements have been made in our understanding of dysregulated macrophages in IA initiation and progression, whereas detailed mechanisms remain fragmentary. The macrophages were ubiquitously detected in both ruptured and unruptured IA walls. Intriguingly, the macrophages accumulation not merely lead to endothelial degeneration and hyperactive inflammatory signals, but also show a protect effect in ruptured IA under certain conditions. Hence, we summarized the regulation mechanisms regarding the roles of macrophages that may play. Particularly, through modulating polarization phenotypes, lipids metabolism, cellular signaling and inflammation stimulation, macrophages will help to clarify the IA process and provide insights to therapeutic strategies. Severe morphological changes in IA were associated with higher numbers of pro-inflammatory macrophages activation and infiltration, wherein the polarization tendency and inflammatory cytokines generation can provide some speculative insight into the nature of IA formation and rupture. Meanwhile, compelling evidences revealed NF-kB, STAT1 and TLR4 signaling cascade have an essential role in macrophages inflammatory response during IA lesion deterioration. Noteworthy, the lipid metabolism has controversial effects in macrophages, while its function in macrophages relevant IA is not negligible. The pros and cons of macrophages immune inflammatory modulation in IA pathogenesis and progression should be further elucidated. In general, most of the macrophages intra/inter-cellular modulation has been linked to macrophages pathogenic reaction and promotes IA lesion. The nutritional restriction and anti- inflammation treatments are mild and safe approaches for IA, but clinical evidence is still lacking. According to current knowledge, suppression of pro-inflammatory macrophages accumulation and cytokines generation through modulating key molecules is crucial in prevent IA progression. The macrophages specific signaling intervention like NF-kB and STAT1 cascades showed a great potential in ameliorating IA structural changes and inflammation condition. However, due to the controversial signaling interaction between inflammation, macrophages and complex IA pathological conditions, underlying regulation mechanisms are yet to be fully clarified. Distinguishing the mechanisms of macrophages heterogeneities and hyperactivation will facilitate our understanding of personalized rupture and unruptured IA therapeutic strategies. In this regard, it will be interesting to determine the diverse abilities of macrophages in the complex context of IA lesion and develop innovative therapeutic strategies to improve clinical outcomes.

  generalfuture workevidence 5/5
  Keywords: macrophages ammatory mechanisms signaling ammation progression therapeutic strategies lesion approaches understanding ruptured unruptured accumulation conditions
• Macrophage polarization in disease therapy: insights from astragaloside IV and cycloastragenol (2025) · Frontiers in Pharmacology · cited 15× · doi

  7.1 Therapeutic potential and mechanisms of action of AS-IV and CAG natural function. These AS-IV and its hydrolysate, CAG, have demonstrated broad therapeutic potential across a range of diseases by modulating macrophage exhibit compounds including anti-inflammatory, significant pharmacological effects, anti-tumor, anti-aging, and antioxidant properties, as evidenced by in vitro studies and mouse disease models. Notably, AS-IV and CAG play a pivotal role in regulating macrophage behavior, influencing their fate and functionality. By restoring macrophage inhibiting dysfunctional activation and polarization balance, reducing inflammatory infiltration, aberrant migration, and promoting autophagy, these compounds effectively improve the repair inflammatory inflammatory microenvironment, tissue damage, and regulate TME. These effects are primarily mediated through the including TLR4/NF-κB, modulation of key signaling pathways, PI3K-STAT, PPARγ, AMPK, and mTORC1. The therapeutic potential of AS-IV and CAG has been validated in various encompassing preclinical models, diseases, autoimmune disorders, ischemic injuries, metabolic conditions, neuroinflammation, and cancers. Interestingly, the combination of AS-IV with tanshinone IIA exhibits a marked synergistic effect in conditions such as atherosclerosis, enhancing the stabilization of vulnerable plaques while significantly amplifying antioxidant and anti-inflammatory activity. in nanotechnology have addressed the challenges posed by the low solubility and bioavailability of AS-IV and CAG, offering novel avenues and therapeutic efficacy. In recent years, advancements applicability enhance clinical their to 7.2 Challenges in clinical translation of AS-IV and CAG this dose daily 10 mg, At present, no marketed drugs containing AS-IV are available. Investigational products currently in development include AS-IV glucose injection and AS-IV sodium chloride injection (Acceptance numbers: X0408491 and X0408490), both targeting angina pectoris in coronary heart disease. However, their development remains at the completed Phase III clinical trial stage, with no subsequent updates reported (Chinese Clinical Trial Registry, 2015). In contrast, CAG has a commercially available formulation: Cycloastragenol 10 mg hard capsules, manufactured by Auzzie Lab. With a recommended formulation of demonstrates potential to support cellular function and promote overall health and wellbeing (Australian Government Department of Health and Aged Care, 2018). Nevertheless, it is exclusively a single-compound drug. Comparatively, on 1 November 2019, ProBLEN introduced Telomere-DNA, a novel spray formulation. This product transiently enhances the body’s capacity to maintain or rebuild telomere length, support cellular function, and protect against DNA damage (U.S. Food and Drug Administration, n.d.). However, it remains an unapproved homeopathic product under current regulatory standards. Nevertheless, there are still certain challenges in clinical development. One of the primary obstacles lies in the incomplete understanding of their molecular mechanisms, particularly in regulating macrophage polarization. Macrophage polarization is a complex and dynamic process, involving the interplay of multiple signaling pathways and effector genes. Current research predominantly focuses on classical pathways, yet a comprehensive understanding of the binding interactions between specific ligands and receptors, as well as the multilayered regulation of downstream signal lacking. Modern gene-editing technologies, such as CRISPR-Cas9, offer powerful tools to elucidate these mechanisms. For instance, by constructing a single-guide RNA (sgRNA) library targeting 2,398 genes and applying genome-wide CRISPR-Cas9 screening identified protein tyrosine researchers in B16 tumor cells, phosphatase cancer 2 type immunotherapy target. This study also highlighted the potential critical of CRISPR-Cas9 transduction, non-receptor identifying screening is still novel in as a

  generalfuture workevidence 5/5
  Keywords: potential macrophage ammatory clinical therapeutic anti mechanisms function polarization pathways challenges novel development formulation crispr
• Macrophage BMPRIB mediates p38-dependent inflammatory reprogramming and chemotaxis during ventilator-induced lung injury (2026) · Frontiers in Immunology · doi

  although we focused on BMPRIB-mediated P38-MAPK activation, the potential contribution of BMPRII downregulation cannot be excluded. LDN193189 is a non-selective BMPRI inhibitor that targets ACVR1, BMPRIA, and BMPRIB. the precise role of canonical SMAD signaling in BMP4-mediated macrophage polarization during VILI remains to be fully characterized, and the potential crosstalk between SMAD and non-canonical pathways warrants systematic investigation. while RAW264.7 cells are widely used for macrophage signaling studies, future experiments using primary alveolar macrophages or human monocyte-derived macrophages would further strengthen the translational relevance of our findings.

  generallimitations sectionevidence 5/5
  Keywords: although focused bmprib-mediated p38-mapk activation potential contribution bmprii

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