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International Journal of Molecular... Apr 2024The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is...
The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.
Topics: Humans; Apoptosis; Hematologic Neoplasms; Cell Line, Tumor; Cell Survival; Antineoplastic Agents; Cytostatic Agents; Cell Proliferation; Hydroxamic Acids; HL-60 Cells; Matrix Metalloproteinase Inhibitors; Cell Cycle Checkpoints; MAP Kinase Signaling System; Leukemia, Myeloid, Acute; Phenylalanine; Thiophenes
PubMed: 38674139
DOI: 10.3390/ijms25084554 -
Frontiers in Microbiology 2024HIV-1 gp120 glycan binding to C-type lectin adhesion receptor L-selectin/CD62L on CD4 T cells facilitates viral attachment and entry. Paradoxically, the adhesion...
HIV-1 gp120 glycan binding to C-type lectin adhesion receptor L-selectin/CD62L on CD4 T cells facilitates viral attachment and entry. Paradoxically, the adhesion receptor impedes HIV-1 budding from infected T cells and the viral release requires the shedding of CD62L. To systematically investigate CD62L-shedding mediated viral release and its potential inhibition, we screened compounds specific for serine-, cysteine-, aspartyl-, and Zn-dependent proteases for CD62L shedding inhibition and found that a subclass of Zn-metalloproteinase inhibitors, including BB-94, TAPI, prinomastat, GM6001, and GI25423X, suppressed CD62L shedding. Their inhibition of HIV-1 infections correlated with enzymatic suppression of both ADAM10 and 17 activities and expressions of these ADAMs were transiently induced during the viral infection. These metalloproteinase inhibitors are distinct from the current antiretroviral drug compounds. Using immunogold labeling of CD62L, we observed association between budding HIV-1 virions and CD62L by transmission electron microscope, and the extent of CD62L-tethering of budding virions increased when the receptor shedding is inhibited. Finally, these CD62L shedding inhibitors suppressed the release of HIV-1 virions by CD4 T cells of infected individuals and their virion release inhibitions correlated with their CD62L shedding inhibitions. Our finding reveals a new therapeutic approach targeted at HIV-1 viral release.
PubMed: 38572241
DOI: 10.3389/fmicb.2024.1385775 -
Dental Materials Journal Aug 2023This study aimed to evaluate the effect of different matrix metalloproteinase inhibitors (MMPIs) on the microtensile bond strength (μTBS) and nanoleakage of universal...
This study aimed to evaluate the effect of different matrix metalloproteinase inhibitors (MMPIs) on the microtensile bond strength (μTBS) and nanoleakage of universal adhesives. One hundred twenty non-carious human molars were prepared and randomly assigned to two groups: Scotchbond Bond Universal (SBU) and Gluma Bond Universal (GBU). The samples in each group were assigned to five subgroups (n=12) based on one control (water) and four MMPIs (Benzalkonium-chloride (BAC), Batimastat (BB94), Chlorhexidine (CHX), and Epigallocatechin-gallate (EGCG)). Each adhesive was applied in self-etch (SE) mode or etch-and-rinse (ER) mode. Dentin/composite sticks were fabricated and subjected to the μTBS test after 24 h or 6 months. At 6 months, MMPIs did not affect the μTBS of the adhesives, regardless of etching mode. Nanoleakage was more pronounced in ER mode than in SE mode for all subgroups. All MMPIs, with the exception of CHX, decreased the nanoleakage of GBU in ER mode.
Topics: Humans; Acid Etching, Dental; Adhesives; Dental Bonding; Dental Cements; Dentin; Dentin-Bonding Agents; Materials Testing; Matrix Metalloproteinase Inhibitors; Resin Cements; Tensile Strength; Molar
PubMed: 37302822
DOI: 10.4012/dmj.2022-282 -
Frontiers in Cardiovascular Medicine 2023Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses...
Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ablation of Pax7 muscle progenitor cells (MPCs) in a model of hindlimb ischemia (HLI) inhibited muscle regeneration following ischemic injury, despite a lack of morphological or physiological changes in resting muscle. Compared to control mice (Pax7), the ischemic limb of Pax7-deficient mice (Pax7) was unable to generate significant force 7 or 28 days after HLI. A significant increase in adipose was observed in the ischemic limb 28 days after HLI in Pax7 mice, which replaced functional muscle. Adipogenesis in Pax7 mice corresponded with a significant increase in PDGFRα fibro/adipogenic progenitors (FAPs). Inhibition of FAPs with batimastat decreased muscle adipose but increased fibrosis. , Pax7 MPCs failed to form myotubes but displayed increased adipogenesis. Skeletal muscle from patients with critical limb threatening ischemia displayed increased adipose in more ischemic regions of muscle, which corresponded with fewer satellite cells. Collectively, these data demonstrate that Pax7 MPCs are required for muscle regeneration after ischemia and suggest that muscle regeneration may be an important therapeutic target in PAD.
PubMed: 36937923
DOI: 10.3389/fcvm.2023.1118738 -
RSC Advances Feb 2023Matrix metalloproteinases (MMPs) play roles in remodelling of the extracellular matrix that occurs during morphogenesis, repair, and angiogenesis. Dysregulation of... (Review)
Review
Matrix metalloproteinases (MMPs) play roles in remodelling of the extracellular matrix that occurs during morphogenesis, repair, and angiogenesis. Dysregulation of extracellular matrix remodelling can lead to cell proliferation, invasion, and tissue fibrosis. Identification of a specific MMP(s) in a disease has been challenging due to the presence of 24 closely-related human MMPs, each existing in three forms, of which only one is active and capable of catalysis. This review focuses on methods for MMP profiling, with particular emphasis on the batimastat affinity resin that binds only to the active forms of MMPs and related ADAMs (a disintegrin and metalloproteinases), which are then identified by mass spectrometry. Use of the batimastat affinity resin has identified targets for intervention in several human diseases.
PubMed: 36825288
DOI: 10.1039/d2ra07005g -
Turkish Neurosurgery 2023To investigate the efficacy of locally applied batimastat after laminectomy in preventing postoperative epidural fibrosis.
AIM
To investigate the efficacy of locally applied batimastat after laminectomy in preventing postoperative epidural fibrosis.
MATERIAL AND METHODS
Thirty-two Wistar albino male rats weighing 200?250 g were used. The rats were assigned to four different groups (I-Control group, II-sham group, III-Laminectomy+Batimastat group, and IV-Laminectomy+SpongostanTM group). The rats were euthanized 28 days after surgery before TNF-?, IL6, IL-1?, IL10, TGF-?1, and MMP9 gene expression levels of tissue in the surgical area were determined with qPCR. TNF-?, IL6, and IL10 protein levels were also measured in both tissue and plasma. In addition, the surgical area was evaluated by histopathological and immunohistochemical methods.
RESULTS
TNF-?, IL6, and IL-1? gene expression levels were higher in the batimastat group than in the control group. Whereas IL10 gene expression levels increased about two-fold in the sham and SpongostanTM groups, in the batimastat group, it was similar to that in the control group. TGF-?1 gene expression was three-fold higher in the sham group but was similar to that in the control group in both batimastat and SpongostanTM groups. MMP9 gene expression levels significantly decreased only in the batimastat group. In addition, fibrosis score, fibroblast cell count, inflammatory cell count, and CD105 expression decreased in the batimastat group relative to the control.
CONCLUSION
Molecular and pathological examination results suggested that batimastat is an effective agent in reducing the occurrence of epidural fibrosis after laminectomy.
Topics: Animals; Rats; Epidural Space; Fibrosis; Interleukin-1; Interleukin-10; Interleukin-6; Laminectomy; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Rats, Wistar
PubMed: 36482856
DOI: 10.5137/1019-5149.JTN.41841-22.2 -
Biosensors Aug 2022We have previously shown that human melanoma cells rapidly decrease human brain endothelial barrier strength. Our findings showed a fast mechanism of melanoma mediated...
We have previously shown that human melanoma cells rapidly decrease human brain endothelial barrier strength. Our findings showed a fast mechanism of melanoma mediated barrier disruption, which was localised to the paracellular junctions of the brain endothelial cells. Melanoma cells are known to release molecules which cleave the surrounding matrix and allow traversal within and out of their metastatic niche. Enzymatic families, such as matrix metalloproteinases (MMPs) and proteases are heavily implicated in this process and their complex nature in vivo makes them an intriguing family to assess in melanoma metastasis. Herein, we assessed the expression of MMPs and other proteases in melanoma conditioned media. Our results showed evidence of a high expression of MMP-2, but not MMP-1, -3 or -9. Other proteases including Cathepsins D and B were also detected. Recombinant MMP-2 was added to the apical face of brain endothelial cells (hCMVECs), to measure the change in barrier integrity using biosensor technology. Surprisingly, this showed no decrease in barrier strength. The addition of potent MMP inhibitors (batimastat, marimastat, ONO4817) and other protease inhibitors (such as aprotinin, Pefabloc SC and bestatin) to the brain endothelial cells, in the presence of various melanoma lines, showed no reduction in the melanoma mediated barrier disruption. The inhibitors batimastat, Pefabloc SC, antipain and bestatin alone decreased the barrier strength. These results suggest that although some MMPs and proteases are released by melanoma cells, there is no direct evidence that they are substantially involved in the melanoma-mediated disruption of the brain endothelium.
Topics: Blood-Brain Barrier; Brain; Endothelial Cells; Endothelium; Humans; Matrix Metalloproteinase 2; Melanoma; Peptide Hydrolases
PubMed: 36005056
DOI: 10.3390/bios12080660 -
Cancers Aug 2022Matrix metalloproteinases (MMPs) play a crucial role in tumour initiation, progression, and metastasis, including peritoneal carcinosis (PC) formation. MMPs serve as...
BACKGROUND
Matrix metalloproteinases (MMPs) play a crucial role in tumour initiation, progression, and metastasis, including peritoneal carcinosis (PC) formation. MMPs serve as biomarkers for tumour progression in colorectal cancer (CRC), and MMP overexpression is associated with advanced-stage metastasis and poor survival. However, the molecular mechanisms of PC from CRC remain largely unclear.
METHODS
We investigated the role of MMPs during peritoneal colonisation by CRC cell lines in a human ex vivo peritoneum model and in patient-derived CRC and corresponding PC samples. MMP2 and MMP9 were inhibited using the small-molecule inhibitors batimastat and the specific MMP2/9 inhibitor III.
RESULTS
MMP2 and MMP9 were strongly upregulated in patient-derived samples and following peritoneal colonisation by CRC cells in the ex vivo model. MMP inhibition with batimastat reduced colonisation of HT29 and Colo205 cells by 36% and 68%, respectively ( = 0.0073 and = 0.0002), while MMP2/9 inhibitor III reduced colonisation by 50% and 41%, respectively ( = 0.0003 and = 0.0051). Fibronectin cleavage was enhanced in patient-derived samples of PC and during peritoneal colonisation in the ex vivo model, and this was inhibited by MMP2/9 inhibition.
CONCLUSION
MMPs were upregulated in patient-derived samples and during peritoneal attachment of CRC cell lines in our ex vivo model. MMP2/9 inhibition prevented fibronectin cleavage and peritoneal colonisation by CRC cells. MMP inhibitors might thus offer a potential treatment strategy for patients with PC.
PubMed: 35954423
DOI: 10.3390/cancers14153760 -
Nature Communications Apr 2022Developing precise nanomedicines to improve the transport of anticancer drugs into tumor tissue and to the final action site remains a critical challenge. Here, we...
Developing precise nanomedicines to improve the transport of anticancer drugs into tumor tissue and to the final action site remains a critical challenge. Here, we present a bioorthogonal in situ assembly strategy for prolonged retention of nanomedicines within tumor areas to act as drug depots. After extravasating into the tumor site, the slightly acidic microenvironment induces the exposure of cysteine on the nanoparticle surface, which subsequently undergoes a bioorthogonal reaction with the 2-cyanobenzothiazole group of another neighboring nanoparticle, enabling the formation of micro-sized drug depots to enhance drug retention and enrichment. This in situ nanoparticle assembly strategy remarkably improves the antimetastatic efficacy of extracellular-targeted drug batimastat, and also leads to the simultaneous enhanced retention and sustained release of multiple agents for combined cocktail chemoimmunotherapy to finally elicit a potent antitumor immune response. Such in situ assembly of nanomedicines represents a generalizable strategy towards extracellular drug delivery and cocktail chemoimmunotherapy.
Topics: Antineoplastic Agents; Drug Delivery Systems; Drug Liberation; Humans; Nanomedicine; Nanoparticles; Neoplasms; Pharmaceutical Preparations; Tumor Microenvironment
PubMed: 35440570
DOI: 10.1038/s41467-022-29693-8 -
3 Biotech May 2021Matrix metalloproteinases (MMPs) are the major proteolytic enzymes which assist in regulating the metastatic process by degrading the extracellular matrix proteins. In...
UNLABELLED
Matrix metalloproteinases (MMPs) are the major proteolytic enzymes which assist in regulating the metastatic process by degrading the extracellular matrix proteins. In this study, we have investigated the anti-metastatic potential of major bioactive compounds in the medicinal plant targeting matrix metalloproteinases (MMP2 & MMP9) and it's in silico pharmacokinetic profiles using computational studies. (Sivanar vembu in Tamil) is a renowned medicinal herb in traditional Indian medicine which contains indigocarpan, mucronulatol, indigocarpan diacetate, erythroxydiol X and erythroxydiol Y as the major constituents. The 3-dimensional structure of MMP2 and MMP9 was designed by using and Modeller and it was validated by PROCHECK. The structures of mucronulatol and indigocarpan have been retrieved from PubChem and indigocarpan diacetate, erythroxydiol X & Y were drawn by using Chemdraw Ultra 6.0. Batimastat was used as a positive control. Molecular docking was performed by using AutoDock 4.2 tools and AutoDock vina, an open-source program which signifies an effective interaction between the phytoligands and MMP2 & MMP9. From the results, AutoDock 4.2 have showed that indigocarpan possesses strong binding energy (ΔG) of - 7.68 kcal/mol towards MMP2 and - 6.35 kcal/mol towards MMP9, whereas batimastat showed binding energy (ΔG) of - 6.34 kcal/mol for MMP2 and - 5.66 kcal/mol for MMP9, meanwhile the results from AutoDock vina indicates that indigocarpan possesses strong binding energy (ΔG) of - 8.0 kcal/mol towards MMP2 and - 8.2 kcal/mol towards MMP9, whereas batimastat showed binding energy (ΔG) of - 7.2 kcal/mol for MMP2 and - 7.6 kcal/mol for MMP9. Also, the ADME and toxicity results suggest that the indigocarpan compound possesses a druggable pharmacokinetic potentiality and does not have carcinogenicity and Ames mutagenesis compared with other phytoligands. Hence, it is evident from our results that both AutoDock platforms strongly revealed that the phytoligand, indigocarpan possesses strong inhibitory activity against MMP2 and MMP9 to control cancer metastasis.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s13205-021-02731-w.
PubMed: 33927994
DOI: 10.1007/s13205-021-02731-w