Although renal fibrosis is predominantly driven by the accumulated inflammatory cells that secrete proinflammatory factors within the kidney, the key mechanisms underlying macrophage clearance from the kidney are not well understood. The interaction of hyaluronan with lymphatic endothelial hyaluronan receptor 1 (LYVE1) constitutes a critical initial step in macrophage adhesion and removal by lymphatic vessels. This study investigates alterations in LYVE1 during kidney disease and elucidates its role in macrophage trafficking. Three renal fibrosis models demonstrated a reduction in full-length LYVE1 and an increase in the soluble LYVE1 fragment. Immunostaining of fibrotic kidneys showed significantly reduced expression of soluble LYVE1 compared with the intracellular fragment (Cyto-LYVE1), demonstrating ectodomain shedding of LYVE1 in vivo and in vitro. Functionally, human lymphatic endothelial cells exposed to TGF-β1 exhibited a significant decrease in macrophage adhesion and transendothelial migration compared with controls. Mechanistic analyses identified increased matrix metalloproteinase 9 (MMP9) in renal injury as a key upstream regulator of LYVE1 shedding. MMP9 inhibitors reduced LYVE1 shedding, enhanced macrophage adhesion and trafficking, and mitigated macrophage accumulation and disease progression. In conclusion, MMP9-induced LYVE1 shedding is linked to progressive kidney fibrosis and macrophage accumulation. LYVE1 shedding inhibitors offer potential as therapeutic agents for mitigating immune overload and kidney fibrosis.

2025-09-01·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Network pharmacology analysis and biological validation of molecular targets regulated by glaucocalyxin a in periodontitis

Article

作者: Li, Quan ; Xin, Yuqi ; Jiang, Qingkun ; Hua, Chenhan ; Zheng, Junjie ; Fan, Jianlin ; Xu, Zichen ; Guan, JiaYing

BACKGROUND AND AIM:

Isodon japonicus (Nakai) Hara var. Japonicus (Japanese blue basil) has been widely used in traditional medicine to treat diarrhea. Glaucocalyxin A (Gla-A), one of its primary active constituents, has demonstrated anti-inflammatory, antitumor, antioxidant, and antifibrotic properties. Periodontitis, an inflammatory disease triggered by biofilm, leads to the destruction of periodontal supporting tissues. This study employed network pharmacology and biological experiments to elucidate the anti-periodontitis effects of Gla-A.

METHODS:

Network pharmacology combined with biological experiments was employed to identify key targets linking periodontitis and Gla-A and to investigate the related signaling pathways.

RESULTS:

Key targets identified included HIF1A, MMP9, mTOR, NFKB1, PTGS2, and STAT3. Notably, Gla-A exhibited the highest binding affinity and stability with MMP9, suggesting its potential as an MMP9 inhibitor. Furthermore, Gla-A suppressed phosphorylation in the PI3K-AKT pathway and inhibited the secretion of pro-inflammatory cytokines, thereby mitigating the progression of periodontitis.

CONCLUSION:

These findings provide novel insights into the mechanism underlying traditional Chinese medicine-adjunctive therapy for periodontitis, offering a promising therapeutic strategy for the disease.

2025-08-01·BIOORGANIC CHEMISTRY

Unveiling Tetrahydroberberine–1,3,4-Oxadiazole hybrids as potent anticancer agents and MMP-9 inhibitors with comprehensive insights from in silico, in vitro, and ex vivo permeation studies

Article

作者: Ikhe, Akansha Sanjayrao ; Makhal, Priyanka N ; Mourya, Atul ; Sharma, Anamika ; Kumar, Ashish ; Chilvery, Shrilekha ; Godugu, Chandraiah ; Shaikh, Arbaz Sujat ; Madan, Jitender ; Kaki, Venkata Rao ; Patil, Saurav

Overexpression of the MMP9 enzyme is a critical biomarker in colorectal cancer (CRC) and a key promoter of metastasis, contributing to mortality rates. Thus, a novel series of Tetrahydroberberine-1,3,4-oxadiazole series was synthesized to halt CRC progression via MMP9 inhibition. The designed molecules were incorporated with pharmacophoric features observed in MMP9 inhibitors. All the newly synthesized hybrids (10a-i) and (12a-e) were subjected to antiproliferative activity using the MTT assay against different cancer cell lines. Among them, compound 10 g was found to be 16-fold selective towards the HCT-116 cancer cell line with an IC₅₀ value of 1.54 ± 0.06 μM compared to a non-cancerous cell line, i.e., HEK293. Compound 10 g mediated apoptosis was observed in cellular and nuclear morphology of cancerous cells. Quantitative analysis was performed using PI staining to validate its apoptotic potential. Target-based study for compound 10 g revealed excellent inhibition of MMP9, as evidenced by Western blotting, Immunofluorescence study and MMP9 enzyme inhibition assay. In-silico studies, including molecular docking and molecular dynamics simulations, corroborated the experimental results by demonstrating strong binding interaction and stability at the MMP9 active site. Additionally, solubility and ex-vivo permeation studies concluded the improved pharmacokinetic properties of compound 10 g over berberine. Collectively, these finding highlights compound 10 g as a promising lead candidate for further development as an anticancer agent targeting MMP9 in colorectal cancer.

项与 MMP9 inhibitors(Trinity College) 相关的新闻（医药）

2022-10-04

·Science Daily

Mechanism used by metastatic cancer cells to infiltrate the liver found

Metastasis -- when cancer spreads to form new tumors -- causes approximately 90% of cancer-related deaths. Because metastatic cancer cells circulate in the blood, the liver -- which filters the blood -- is considered the most vulnerable organ, so treatments that prevent liver metastasis are urgently needed. A team of researchers discovered a mechanism that allows metastatic cancer cells to infiltrate the liver, and how that infiltration can be blocked by inhibiting a related protein. Approximately 90% of cancer-related deaths are due to metastasis when cancer spreads and forms new tumors. The liver is considered the most vulnerable organ to metastatic cancer: the 5-year survival rate after surgery to remove liver metastases is as low as 30-50%, so developing treatments to prevent liver metastasis is urgently needed. A group of researchers including graduate student Truong Huu Hoang and Professor Norifumi Kadawa from the Osaka Metropolitan University Graduate School of Medicine, and Associate Professor Misako Matsubara from the Graduate School of Veterinary Science, has identified an alternative pathway for liver metastasis, showing that cancer cells invade via intracellular gap formation in endothelial cells, and clarified the molecular mechanism involved. The results of their research are expected to lead to the development of drugs to prevent and treat metastatic liver cancer. Metastasizing cancer cells are known to change the microenvironment of liver cells in ways that promote metastasis, but the extent of these interactions has not been fully investigated. Cancer cells carried in the bloodstream come into contact with liver sinusoidal endothelial cells (LSECs), which line the blood vessels of the liver to form a protective barrier. LSECs are responsible for the detoxification functions of the liver and have numerous small pores, through which the liquid components of blood and small particles -- but not cancer cells -- can enter the liver. LSECs are constantly exposed to toxic substances carried by the blood that can disrupt these small pores under stressful conditions; this causes larger intracellular gaps to form in the LSECs, weakening the protective barrier. This led the research group to consider that the LSECs' intracellular gaps may be involved in liver metastasis. The research group created a mouse model of liver metastasis -- by injecting cancer cells into the spleen -- and performed omics analysis to observe changes in the LSECs. They found that when cancer cells moved from the spleen to the liver, they induced the LSECs to produce multiple proteins. The expression of one of these proteins -- matrix metalloproteinase 9 (MMP9) -- in LSECs caused the intracellular gaps to form. Furthermore, using electron microscopy and 3D tomography reconstruction, the researchers showed that cancer cells extended their projections directly into the intracellular gaps of LSECs, allowing them to infiltrate the liver tissue. They found a positive correlation between the number of intracellular gaps in the LSECs and the number of new metastatic liver tumors that formed in the mice. However, new tumors could be prevented from forming by treating the mice with a MMP9 inhibitor, suggesting that MMP9 is a promising therapeutic target to prevent liver metastasis. Professor Matsubara concluded, "In this study, we discovered a new phenomenon related to metastasis: cancer cells induce LSEC intracellular gap formation and infiltrate the liver through those gaps. With these results we are continuing our research to develop new treatments for liver metastasis, targeting intracellular gap formation in LSECs."

100 项与 MMP9 inhibitors(Trinity College) 相关的药物交易

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