SOLUSYKLI

fredag 22 mars 2024

Serpiinit, seriiniproteaasi-inhibiittorit

Seriiniproteaasi-inhibiittori lääkkeissä on Trasylol. aprotiniini. Sitä joudutaan käyttämään sydämen ohituksleikkauksissa kun on hallittava verenkierron rheologiassa tapahtuvia suuria muutoksia proteolyyttisiä aktivaatioita : Pancreatic Trypsin Inhibitor Trasylol Trypsin inhibitor

Näistä vahvoista proteaaseista löydettiin ensimmäiset serpiinit ja siksi nimi seriiniproteaasi-inhibiittorit, serpins, mutta osa serpiinirakenteisista ei ole inhibitorisia. Niitä on luomakunnassa erittäinpaljon. Ihmisille tyypilliset on taulukoitu kirjaiminja numeroin sitä muiaa kun niitä löydettiin.

Kaikki serpiinit eivät kuitenkaan ole proteaasi-inhibiittoreita luonteeltaan ja niiden ominaisuuksiakin on taulukoitu . Ensimmäiset löydetyt olivat reologian alueen serpiineitä.

Uusia tietoja eri serpiineistä Pub Med artikkeleissa 2024:

https://en.wikipedia.org/wiki/Serpin

SERPIN E1, PAI-1 https://pubmed.ncbi.nlm.nih.gov/38500661/

SERPIN E2, PI7, Protease nexin 1 https://pubmed.ncbi.nlm.nih.gov/38407942/ Kay role in many tumors, lever ca metastases) ...SERPINE2 activated epidermal growth factor receptor (EGFR) and its downstream signaling pathways by interacting with EGFR. Mechanistically, SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase, c-Cbl. Additionally, EGFR was activated in liver cancer cells after sorafenib treatment, and SERPINE2 knockdown-induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer. Furthermore, we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment.

SERPIN F1, PEDF: https://pubmed.ncbi.nlm.nih.gov/38474001/

SERPIN B5, Maspin: https://pubmed.ncbi.nlm.nih.gov/38509770/

https://pubmed.ncbi.nlm.nih.gov/8290962/

SERPIN B9 ,PI9, Cytoplasmic Anti-Proteinase 9 , CAP9, ( intracellular inhibitor of granzyme B)

SERPIN B12, Yokopin https://pubmed.ncbi.nlm.nih.gov/38504347/

2024 mainitaan SERBP1, SERPIN mRNA-binding protein 1 https://pubmed.ncbi.nlm.nih.gov/38408537/

https://genomebiology.biomedcentral.com/articles/10.1186/gb-2006-7-5-216/tables/1

Table 1 Function and dysfunction of human serpins

From: An overview of the serpin superfamily

Serpin	Alternative name(s)	Protease target or function	Involvement in disease
SERPINA1	Antitrypsin	Extracellular; inhibition of neutrophil elastase	Deficiency results in emphysema: polymerization and retention in the ER results in cirrhosis [14,64,65]
SERPINA2	Antitrypsin-related protein	Not characterized, probable pseudogene
SERPINA3	Antichymotrypsin	Extracellular; inhibition of cathepsin G	Deficiency results in emphysema (see [61] for a review)
SERPINA4	Kallistatin (PI4)	Extracellular, inhibition of kallikrein [68]
SERPINA5	Protein C inhibitor (PAI-3)	Extracellular; inhibition of active protein C (see [69] for a review)	Angioedema
SERPINA6	Corticosteroid-binding globulin	Extracellular; non-inhibitory; cortisol binding	Deficiency linked to chronic fatigue [83,84]
SERPINA7	Thyroxine-binding globulin	Extracellular; non-inhibitory, thyroxine binding	Deficiency results in hypothyroidism [85]
SERPINA8	Angiotensinogen	Extracellular; non-inhibitory; amino-terminal cleavage by the protease renin results in release of the decapeptide angiotensin I	Certain variants linked to essential hypertension [86]
SERPINA9	Centerin	Extracellular; maintenance of naive B cells [70]
SERPINA10	Protein Z-dependent proteinase inhibitor	Extracellular; inhibition of activated factor Z and XI	Deficiency linked to venous thromboembolic disease [87]
SERPINA11	XP_170754.3	Not characterized
SERPINA12	Vaspin	Extracellular; insulin-sensitizing adipocytokine [71]
SERPINA13	XM_370772	Not characterized
SERPINB1	Monocyte neutrophil elastase inhibitor	Intracellular; inhibition of neutrophil elastase [72]
SERPINB2	Plasminogen activator inhibitor-2 (PAI2)	Intracellular; inhibition of uPA (see [73] for a review)
SERPINB3	Squamous cell carcinoma antigen-1	Intracellular; cross-class inhibition of cathepsins L and V [6]
SERPINB4	Squamous cell carcinoma antigen-2	Intracellular; cross-class inhibition of cathepsin G and chymase [74]
SERPINB5	Maspin	Intracellular; non-inhibitory; inhibition of metastasis through uncharacterized mechanism	Downregulation and/or intracellular location linked to tumor progression and overall prognosis [10]
SERPINB6	Proteinase inhibitor-6 (PI6)	Intracellular, inhibition of cathepsin G [75]
SERPINB7	Megsin	Intracellular; megakaryocyte maturation [76]	IgA nephropathy
SERPINB8	Cytoplasmic antiproteinase 8 (PI8)	Intracellular; inhibition of furin [77]
SERPINB9	Cytoplasmic antiproteinase 9 (PI9)	Intracellular, inhibition of granzyme B [78]
SERPINB10	Bomapin (PI10)	Intracellular; inhibition of thrombin and trypsin [79]
SERPINB11	Epipin	Intracellular
SERPINB12	Yukopin	Intracellular; inhibition of trypsin [80]
SERPINB13	Headpin (PI13)	Intracellular; inhibition of cathepsins L and K
SERPINC1	Antithrombin	Extracellular; thrombin and factor Xa inhibitor	Deficiency results in thrombosis (see [88] for review)
SERPIND1	Heparin cofactor II	Extracellular; thrombin inhibitor	May contribute to thrombotic risk when combined with other deficiencies [89]
SERPINE1	Plasminogen activator inhibitor I (PAI1)	Extracellular; inhibitor of thrombin, uPA, tPA and plasmin	Abnormal bleeding [90]
SERPINE2	Protease nexin I (PI7)	Extracellular; inhibition of uPA and tPA
SERPINE3	Hs.512272	Not characterized
SERPINF1	Pigment epithelium derived factor	Non-inhibitory; potent anti-angiogenic molecule [81]
SERPINF2	Alpha-2-antiplasmin	Extracellular; plasmin inhibitor	Unrestrained fibrinolytic activity, bleeding [91]
SERPING1	C1 inhibitor	C1 esterase inhibitor	Angioedema [92]
SERPINH1	47kDa heat-shock protein	Non-inhibitory molecular Chaperone for collagens [9]
SERPINI1	Neuroserpin (PI12)	Extracellular; inhibitor of tPA, uPA and plasmin	Polymerization results in dementia [17]
SERPINI2	Myoepithelium-derived serine proteinase inhibitor (PI14)	Extracellular; inhibition of cancer metastasis [82]

SERPINB5, MASPIN, normaalisti estää rintasyövän kasvua, invaasiota ja metastasoitumista

MASPIN in Cancer , PubMed Search:

https://pubmed.ncbi.nlm.nih.gov/?term=MASPIN++in+cancer&sort=date

741 results

GeneCards:

SERPIN B5, Maspin , https://www.genecards.org/cgi-bin/carddisp.pl?gene=SERPINB5&keywords=MASPIN

18q21.33 , Suositeltu proteiinin nimi, Recommended name: SERPIN B5

Protein attributes for SERPINB5 Gene

Size: 375 amino acids
Molecular mass:42100 Da
Quaternary structure: Interacts with IRF6.

Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to act upstream of or within several processes, including extracellular matrix organization; prostate gland morphogenesis; and regulation of epithelial cell proliferation. Located in cytoplasm. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

GeneCards Summary for SERPINB5 Gene

SERPINB5 (Serpin Family B Member 5) is a Protein Coding gene. Diseases associated with SERPINB5 include Pleomorphic Adenoma and Bone Squamous Cell Carcinoma. Among its related pathways are Validated transcriptional targets of TAp63 isoforms and Apoptosis and Autophagy. Gene Ontology (GO) annotations related to this gene include serine-type endopeptidase inhibitor activity. An important paralog of this gene is SERPINB1.

UniProtKB/Swiss-Prot Summary for SERPINB5 Gene

Tumor suppressor. It blocks the growth, invasion, and metastatic properties of mammary tumors. As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity. ( SPB5_HUMAN,P36952 )

Molecular function for SERPINB5 Gene according to UniProtKB/Swiss-Prot

Function:

Tumor suppressor.
It blocks the growth, invasion, and metastatic properties of mammary tumors.
As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity. SPB5_HUMAN,P36952

Molecular function for SERPINB5 Gene according to GENATLAS

Biochemistry:

tumor suppressor of breast and prostate carcinomas,inhibiting tumor motility,invasion and metastasis,expressed by a number of cell types of epithelial cells,located in the cell membrane and extracellular matrix,serine proteinase inhibitor,member of the serpin family,ovalbumin subgroup SERPINB5

SERPIN B5, (String kartan molekyylit)

Interacting Proteins for SERPINB5 Gene

STRING Interaction Network Preview (showing top 5 STRING interactants - click image to see top 25)

Your Current Organism:

Homo sapiens

NCBI taxonomy Id: 9606
Other names: H. sapiens, human, man

Your Input:
	SERPINB5	Serpin B5; Tumor suppressor. It blocks the growth, invasion, and metastatic properties of mammary tumors. As it does not undergo the S (stressed) to R (relaxed) conformational transition characteristic of active serpins, it exhibits no serine protease inhibitory activity; Belongs to the serpin family. Ov-serpin subfamily. (375 aa)
	HDAC1	Histone deacetylase 1; Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium st [...] (482 aa)
	PPIL3	Peptidyl-prolyl cis-trans isomerase-like 3; PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. May be involved in pre-mRNA splicing; Belongs to the cyclophilin-type PPIase family. PPIL3 subfamily. (165 aa)
	LACC1	Laccase domain-containing protein 1; Central regulator of the metabolic function and bioenergetic state of macrophages. In macrophages, promotes flux through de novo lipogenesis to concomitantly drive high levels of both fatty-acid oxidation and glycolysis. (430 aa)
	C11orf54	Ester hydrolase C11orf54; Exhibits ester hydrolase activity on the substrate p- nitrophenyl acetate. (315 aa)
	HMGCS1	Hydroxymethylglutaryl-CoA synthase, cytoplasmic; This enzyme condenses acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is the substrate for HMG-CoA reductase. (520 aa)
	GPR18	N-arachidonyl glycine receptor; Receptor for endocannabinoid N-arachidonyl glycine (NAGly). However, conflicting results about the role of NAGly as an agonist are reported. Can also be activated by plant-derived and synthetic cannabinoid agonists. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. May contribute to regulation of the immune system. Is required for normal homeostasis of CD8+ subsets of intraepithelial lymphocytes (IELs) (CD8alphaalpha and CD8alphabeta IELs)in small intstine by supporting preferential migration of CD8alphaalpha T-cells [...] (331 aa)
	EIF2A	Eukaryotic translation initiation factor 2A, N-terminally processed; Functions in the early steps of protein synthesis of a small number of specific mRNAs. Acts by directing the binding of methionyl- tRNAi to 40S ribosomal subunits. In contrast to the eIF-2 complex, it binds methionyl-tRNAi to 40S subunits in a codon-dependent manner, whereas the eIF-2 complex binds methionyl-tRNAi to 40S subunits in a GTP-dependent manner; Belongs to the WD repeat EIF2A family. (585 aa)
	VRK1	Serine/threonine-protein kinase VRK1; Serine/threonine kinase involved in Golgi disassembly during the cell cycle: following phosphorylation by PLK3 during mitosis, required to induce Golgi fragmentation. Acts by mediating phosphorylation of downstream target protein. Phosphorylates 'Thr-18' of p53/TP53 and may thereby prevent the interaction between p53/TP53 and MDM2. Phosphorylates casein and histone H3. Phosphorylates BANF1: disrupts its ability to bind DNA, reduces its binding to LEM domain- containing proteins and causes its relocalization from the nucleus to the cytoplasm. Phosph [...] (396 aa)
	KAT7	Histone acetyltransferase KAT7; Component of the HBO1 complex which has a histone H4-specific acetyltransferase activity, a reduced activity toward histone H3 and is responsible for the bulk of histone H4 acetylation in vivo. Involved in H3K14 (histone H3 lysine 14) acetylation and cell proliferation (By similarity). Through chromatin acetylation it may regulate DNA replication and act as a coactivator of TP53-dependent transcription. Acts as a coactivator of the licensing factor CDT1. Specifically represses AR-mediated transcription. Belongs to the MYST (SAS/MOZ) family. (611 aa)
	CALML5	Calmodulin-like protein 5; Binds calcium. May be involved in terminal differentiation of keratinocytes. (146 aa)
	BLMH	Bleomycin hydrolase; The normal physiological role of BLM hydrolase is unknown, but it catalyzes the inactivation of the antitumor drug BLM (a glycopeptide) by hydrolyzing the carboxamide bond of its B- aminoalaninamide moiety thus protecting normal and malignant cells from BLM toxicity. (455 aa)
	NAA50	N-alpha-acetyltransferase 50; N-alpha-acetyltransferase that acetylates the N-terminus of proteins that retain their initiating methionine. Has a broad substrate specificity: able to acetylate the initiator methionine of most peptides, except for those with a proline in second position. Also displays N-epsilon-acetyltransferase activity by mediating acetylation of the side chain of specific lysines on proteins. Autoacetylates in vivo. The relevance of N-epsilon-acetyltransferase activity is however unclear: able to acetylate H4 in vitro, but this result has not been confirmed in vivo. [...] (169 aa)
	PKP1	Plakophilin-1; Seems to play a role in junctional plaques. Contributes to epidermal morphogenesis. (747 aa)
	LGALS7B	Galectin-7; Could be involved in cell-cell and/or cell-matrix interactions necessary for normal growth control. Pro-apoptotic protein that functions intracellularly upstream of JNK activation and cytochrome c release. (136 aa)
	SYT16	Synaptotagmin-16; May be involved in the trafficking and exocytosis of secretory vesicles in non-neuronal tissues. Is Ca(2+)-independent. (645 aa)
	CCDC82	Coiled-coil domain containing 82. (544 aa)
	RBM24	RNA-binding protein 24; Multifunctional RNA-binding protein involved in the regulation of pre-mRNA splicing, mRNA stability and mRNA translation important for cell fate decision and differentiation. Plays a major role in pre-mRNA alternative splicing regulation. Mediates preferentially muscle-specific exon inclusion in numerous mRNAs important for striated cardiac and skeletal muscle cell differentiation. Binds to intronic splicing enhancer (ISE) composed of stretches of GU-rich motifs localized in flanking intron of exon that will be included by alternative splicing (By similarity). I [...] (236 aa)
	ALDH2	Aldehyde dehydrogenase, mitochondrial; Aldehyde dehydrogenase 2 family member; Belongs to the aldehyde dehydrogenase family. (517 aa)
	COL1A2	Collagen alpha-2(I) chain; Type I collagen is a member of group I collagen (fibrillar forming collagen); Belongs to the fibrillar collagen family. (1366 aa)
	UCHL5	Ubiquitin carboxyl-terminal hydrolase isozyme L5; Protease that specifically cleaves 'Lys-48'-linked polyubiquitin chains. Deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome. Putative regulatory component of the INO80 complex; however is inactive in the INO80 complex and is activated by a transient interaction of the INO80 complex with the proteasome via ADRM1. (355 aa)
	PRSS21	Testisin; Could regulate proteolytic events associated with testicular germ cell maturation. (314 aa)
	CUL9	Cullin-9; Core component of a Cul9-RING ubiquitin-protein ligase complex, a complex that mediates ubiquitination and subsequent degradation of BIRC5 and is required to maintain microtubule dynamics and genome integrity. Acts downstream of the 3M complex, which inhibits CUL9 activity, leading to prevent ubiquitination of BIRC5. Cytoplasmic anchor protein in p53/TP53-associated protein complex. Regulates the subcellular localization of p53/TP53 and subsequent function. (2517 aa)
	TRIM21	E3 ubiquitin-protein ligase TRIM21; E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B ('Thr-187' phosphorylated-form), thereby promoting its degrad [...] (475 aa)
	AKIRIN2	Akirin-2; Required for the innate immune response. Downstream effector of the Toll-like receptor (TLR), TNF and IL-1 beta signaling pathways leading to the production of IL-6. Forms a complex with YWHAB that acts to repress transcription of DUSP1 (By similarity); Belongs to the akirin family. (203 aa)
	BRD4	Bromodomain-containing protein 4; Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal- inducible genes by associating with the P-TEFb complex and re [...] (1362 aa)

Kaavaa sinkkiproteaasi superperheestä, johon kuuluvat MMP, matrixmetalloproteinaasit

Zn proteaasien superperhe

GLUZINCIN

INUZINCIN

METZINCIN

CARBOXYPEPTIDASE

DDCARBOXY

METZINCIN
genefamily https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036576/

MATRIXIN:

Matrixmetalloproteases MMPs, ( Tissue Inhibitors of MMP = TIMPs)

ASTACIN:https://www.frontiersin.org/articles/10.3389/fmolb.2022.1080836/full

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9848320/

Meprin

BMP1/TII

ADAMALYSIN:

ADAM

ADAMTS

Class III Snake Venoms

SERRALYSIN

MMP-inhibiittorit (matrix metalloproteasi estäjät). Missä vaiheessa on näiden lääkkeiden kehitys?

I Haku: matrix metalloprotease inhibitors. vastauksia 27 787.

II Haku human matrix metalloprotease inhibitors . Vastauksia 20 008

Katson artikkeleita ajallisesti tuoreimmasta päästä 10 ja siten otsikoita 30:een asti . Kaikki ovat tältä vuodelta 2024 tällä sivulla paitsi numero 30 on joulukuulta 2023. Muutamat artikkelit koskevat onkologisia lääkevalmisteita

SITAATTIA tiedoista joita on artikkeleissa 1-30.

Search Results

20,008 results

Page of 2,001

Dysregulated fibrinolysis and plasmin activation promote the pathogenesis of osteoarthritis.

Wang Q, Shao G, Zhao X, Wong HH, Chin K, Zhao M, Bai A, Bloom MS, Love ZZ, Chu CR, Cheng Z, Robinson WH. JCI Insight. 2024 Mar 19:e173603. doi: 10.1172/jci.insight.173603. Online ahead of print. PMID: 38502232 Free article.

Here we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA) and the uPA receptor (uPAR), were dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression in a destabilization of the medial meniscus (DMM) mouse model, while genetic deficiency of plasmin activator inhibitor (PAI-1), or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans, induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, PDK1, AKT, and ERK signaling cascades, and activates matrix metalloproteinases (pro-MMPs) to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.

LOX-1 and MMP-9 Inhibition Attenuates the Detrimental Effects of Delayed rt-PA Therapy and Improves Outcomes After Acute Ischemic Stroke.

Arkelius K, Wendt TS, Andersson H, Arnou A, Gottschalk M, Gonzales RJ, Ansar S. Circ Res. 2024 Mar 19. doi: 10.1161/CIRCRESAHA.123.323371. Online ahead of print. PMID: 38501247Acute ischemic stroke triggers endothelial activation that disrupts vascular integrity and increases hemorrhagic transformation leading to worsened stroke outcomes. rt-PA (recombinant tissue-type plasminogen activator) is an effective treatment; however, its use is limited due to a restricted time window and hemorrhagic transformation risk, which in part may involve activation of MMPs (matrix metalloproteinases) mediated through LOX-1 (lectin-like oxLDL [oxidized low-density lipoprotein] receptor 1). This study's overall aim was to evaluate the therapeutic potential of novel MMP-9 (matrix metalloproteinase 9) and LOX-1 inhibitors in combination with rt-PA to improve stroke outcomes. Results :Stroke and subsequent rt-PA treatment increased edema, hemorrhage, MMP-9 activity, LOX-1 expression, and worsened neurological outcomes. LOX-1 inhibition improved neurological function, reduced edema, and improved endothelial barrier integrity. Elevated MMP-9 activity correlated with increased edema, infarct volume, and decreased neurological function. MMP-9 inhibition reduced MMP-9 activity and LOX-1 expression. In human brain microvascular endothelial cells, LOX-1/MMP-9 inhibition differentially attenuated MMP-9 levels, inflammation, and activation following hypoxia plus glucose deprivation/R.

Multiple integrated computational approach to analyse wound healing potential of Symplocos racemosa bark as Matrix metalloproteinase inhibitors.

Rafey HA, Amin A, Ross SA, El-Shazly M, Zahid MA, Niaz SI, Ul Mahmood F, Ullah H. Nat Prod Res. 2024 Mar 18:1-10. doi: 10.1080/14786419.2024.2321488. Online ahead of print. PMID: 38497294

The healing of wounds is the flagging concern in chronic wound cases especially when accompanied by pathogenic, diabetic comorbidities. Matrix metalloproteinases are associated with widespread pathological ailments, and the selective inhibitors for metallo …

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1.

Rao S, He Z, Wang Z, Yin H, Hu X, Tan Y, Wan T, Zhu H, Luo Y, Wang X, Li H, Wang Z, Hu X, Hong C, Wang Y, Luo M, Du W, Qian Y, Tang S, Xie H, Chen C. Acta Pharm Sin B. 2024 Mar;14(3):1166-1186. doi: 10.1016/j.apsb.2023.12.009. Epub 2023 Dec 16. PMID: 38487008 Free PMC article.

Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases. This study demonstrates that extracellular vesicles from human urine-derived stem cells (USC-EVs) efficiently inhibit cellular senescence in vitro and in vivo. ..Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase (PLAU) and tissue inhibitor of metalloproteinases 1 (TIMP1). These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases, cyclin-dependent kinase inhibitor 2A (P16^INK4a), and cyclin-dependent kinase inhibitor 1A (P21^cip1). These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.

Relationship between the Expression of Matrix Metalloproteinases and Their Tissue Inhibitors in Patients with Brain Tumors.

Dibdiakova K, Majercikova Z, Galanda T, Richterova R, Kolarovszki B, Racay P, Hatok J. Int J Mol Sci. 2024 Mar 1;25(5):2858. doi: 10.3390/ijms25052858. PMID: 38474106 Free PMC article.Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) play critical roles in regulating processes associated with malignant behavior. These endopeptidases selectively degrade components of the extracellular matrix (ECM), growth factors, and their receptors, contributing to cancer cell invasiveness and migratory characteristics by disrupting the basal membrane. However, the expression profile and role of various matrix metalloproteinases remain unclear, and only a few studies have focused on differences between diagnoses of brain tumors. However, the expression profile and role of various matrix metalloproteinases remain unclear, and only a few studies have focused on differences between diagnoses of brain tumors. Using quantitative real-time PCR analysis, we identified the expression pattern of ECM modulators (n = 10) in biopsies from glioblastoma (GBM; n = 20), astrocytoma (AST; n = 9), and meningioma (MNG; n = 19) patients. We found eight deregulated genes in the glioblastoma group compared to the benign meningioma group, with only MMP9 (FC = 2.55; p = 0.09) and TIMP4 (7.28; p < 0.0001) upregulated in an aggressive form. The most substantial positive change in fold regulation for all tumors was detected in matrix metalloproteinase 2 (MNG = 30.9, AST = 4.28, and GBM = 4.12). Notably, we observed an influence of TIMP1, demonstrating a positive correlation with MMP8, MMP9, and MMP10 in tumor samples. Subsequently, we examined the protein levels of the investigated MMPs (n = 7) and TIMPs (n = 3) via immunodetection. We confirmed elevated levels of MMPs and TIMPs in GBM patients compared to meningiomas and astrocytomas. Even when correlating glioblastomas versus astrocytomas, we showed a significantly increased level of MMP1, MMP3, MMP13, and TIMP1. The identified metalloproteases may play a key role in the process of gliomagenesis and may represent potential targets for personalized therapy. However, as we have not confirmed the relationship between mRNA expression and protein levels in individual samples, it is therefore natural that the regulation of metalloproteases will be subject to several factors.

Matrix Metalloproteinases in the Periodontium-Vital in Tissue Turnover and Unfortunate in Periodontitis.

Radzki D, Negri A, Kusiak A, Obuchowski M. Int J Mol Sci. 2024 Feb 27;25(5):2763. doi: 10.3390/ijms25052763. PMID: 38474009 Free PMC article. Review.The extracellular matrix (ECM) is a complex non-cellular three-dimensional macromolecular network present within all tissues and organs, forming the foundation on which cells sit, and composed of proteins (such as collagen), glycosaminoglycans, proteoglycans, minerals, and water. The ECM provides a fundamental framework for the cellular constituents of tissue and biochemical support to surrounding cells.

The ECM is a highly dynamic structure that is constantly being remodeled. Matrix metalloproteinases (MMPs) are among the most important proteolytic enzymes of the ECM and are capable of degrading all ECM molecules. MMPs play a relevant role in physiological as well as pathological processes; MMPs participate in embryogenesis, morphogenesis, wound healing, and tissue remodeling, and therefore, their impaired activity may result in several problems. MMP activity is also associated with chronic inflammation, tissue breakdown, fibrosis, and cancer invasion and metastasis. The periodontium is a unique anatomical site, composed of a variety of connective tissues, created by the ECM. During periodontitis, a chronic inflammation affecting the periodontium, increased presence and activity of MMPs is observed, resulting in irreversible losses of periodontal tissues. MMP expression and activity may be controlled in various ways, one of which is the inhibition of their activity by an endogenous group of tissue inhibitors of metalloproteinases (TIMPs), as well as reversion-inducing cysteine-rich protein with Kazal motifs (RECK).

Matrix metalloproteinases are associated with severity of disease among COVID-19 patients: A possible pharmacological target.

Cavalcante GL, Bonifacio LP, Sanches-Lopes JM, Puga FG, de Carvalho FS, Bellissimo-Rodrigues F, Tanus-Santos JE. Basic Clin Pharmacol Toxicol. 2024 Mar 11. doi: 10.1111/bcpt.14001. Online ahead of print. PMID: 38468413

COVID-19 is a devastating disease and imbalanced matrix metalloproteinase (MMP) activity may contribute to its pathophysiology. This exploratory study examined whether increased circulating concentrations of MMP-2 and MMP-9, and their endogenous inhibitors, the tissue inhibitors of MMP (TIMP)-1, TIMP-2, TIMP-3 and TIMP-4 are persistently found in patients 2 weeks after their recovery from severe or critical COVID-19 as compared with those in healthy controls. Subjects who had severe (n = 26) or critical (n = 25) PCR-confirmed COVID-19 and healthy controls (n = 21) had blood samples drawn 2 weeks after recovery and serum MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 were determined using two Human Luminex® Discovery Assays. Circulating MMP activity was also determined by gel zymography. Patients who had severe or critical COVID-19 had increased circulating MMP-9 and MMP-2 concentrations, with increased MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios indicating increased MMP activity, confirmed by gel zymography (all p < 0.05). Higher circulating MMP-9 (but not MMP-2) concentrations were found in critical versus severe COVID-19 (p < 0.05). We found increased circulating MMP-9 and MMP-2 concentrations and activity many days after recovery from the acute disease, with MMP-9 levels associated with disease severity. These biochemical alterations suggest that MMP-2 and MMP-9 may be important pharmacological targets in COVID-19.

Serum levels of matrix metalloproteinases 1, 2, and 7, and their tissue inhibitors 1, 2, 3, and 4 in polytraumatized patients: Time trajectories, correlations, and their ability to predict mortality.

Negrin LL, Carlin GL, Ristl R, Hajdu S. PLoS One. 2024 Mar 8;19(3):e0300258. doi: 10.1371/journal.pone.0300258. eCollection 2024. PMID: 38457458 Free PMC article.

There has been limited research on assessing metalloproteinases (MMPs) 1, 2, and 7, as well as their tissue inhibitors (TIMPs) 1, 2, 3, and 4 in the context of polytrauma. These proteins play crucial roles in various physiological and pathological processes and could be a reliable tool in polytrauma care. We aimed to determine their clinical relevance. We assessed 24 blunt polytrauma survivors and 12 fatalities (mean age, 44.2 years, mean ISS, 45) who were directly admitted to our Level I trauma center and spent at least one night in the intensive care unit. We measured serum levels of the selected proteins on admission (day 0) and days 1, 3, 5, 7, and 10. The serum levels of the seven proteins varied considerably among individuals, resulting in similar median trend curves for TIMP1 and TIMP4 and for MMP1, MMP2, TIMP2, and TIMP3. We also found a significant interrelationship between the MMP2, TIMP2, and TIMP3 levels at the same measurement points. Furthermore, we calculated significant cross-correlations between MMP7 and MMP1, TIMP1 and MMP7, TIMP3 and MMP1, TIMP3 and MMP2, and TIMP4 and TIMP3 and an almost significant correlation between MMP7 and TIMP1 for a two-day-lag. The autocorrelation coefficient reached statistical significance for MMP1 and TIMP3. Finally, lower TIMP1 serum levels were associated with in-hospital mortality upon admission. The causal effects and interrelationships between selected proteins might provide new insights into the interactions of MMPs and TIMPs. Identifying the underlying causes might help develop personalized therapies for patients with multiple injuries. Administering recombinant TIMP1 or increasing endogenous production could improve outcomes for those with multiple injuries. However, before justifying further investigations into basic research and clinical relevance, our findings must be validated in a multicenter study using independent cohorts to account for clinical and biological variability.

Resistance training modifies of serum levels of matrix metalloproteinase 2 and tissue inhibitor of matrix metalloproteinases in multiple sclerosis women - a randomized controlled trail.

Nezhad NN, Parnow A, Khamoushian K, Eslami R, Baker JS. BMC Neurosci. 2024 Mar 4;25(1):13. doi: 10.1186/s12868-024-00856-1. PMID: 38438999 Free PMC article. Clinical Trial.

Fifteen healthy aged-matched women participated as a control group (HCON). The serum level of matrix metalloproteinase-2 (MMP-2), matrix metallopeptidase-9 (MMP-9), tissue metalloproteinase inhibitors-1 (TIMP-1), tissue metalloproteinase inhibitors-2 ( …

DOCK1 regulates the malignant biological behavior of endometrial cancer through c-Raf/ERK pathway.

Xie S, Jin Y, Wang J, Li J, Peng M, Zhu X. BMC Cancer. 2024 Mar 4;24(1):296. doi: 10.1186/s12885-024-12030-1. PMID: 38438882 Free PMC article.

The expression of E-cadherin was upregulated and those of MMP9, Ezrin, Bcl-2, p-c-RAF (S338) and p-ERK1/2 (T202/Y204) were downregulated after DOCK1 knockout, while DOCK1 overexpression played the opposite effect. Additionally, Raf inhibitor LY3009120 reversed the function … '