367 Matching Annotations
  1. Sep 2021
    1. In contrast , in adult mice TLR2 / TLR4 activation on pericryptal macrophages by exogenous HA or other TLR2 / TLR4 agonists results in CXCL12 production resulting in the migration of COX-2 expressing MSCs .

      TLR2 activates TLR4.

    2. TLR4 activation by LPS requires a TLR4-MD2 complex , LPS binding protein , and CD14 which delivers LPS to the TLR4-MD2 complex ( 33 , 34 ) .
    3. TLR4 activation by LPS and LMW-HA require different accessory molecules .
    4. Although both LMW-HA and LPS bind to TLR4 , the results of TLR4 activation by LMW-HA and LPS are not identical .
    5. Activation of TLR2 by LTA or activation of TLR4 by LPS or HA results in the release of the chemokine CXCL12 , which binds to CXCR4 on COX-2 expressing MSCs .
    6. Although there are differences in the accessory molecules involved in TLR4 activation by LPS and LMW - HA , TLR4 activation by either one promotes wound healing ( 12 , 27 , 28 , 33 ) .
    7. TLR4 activation by HA also plays a role in wound repair ( 22 ) .

      hyaluronic acid activates TLR4.

    8. TLR4 activation by HA also affects the immune response in ischemia - reperfusion injury in the kidney and in acute allograft rejection in a skin transplant model ( 8) .

      hyaluronic acid activates TLR4.

    9. Moreover , in contrast to wound repair where activation of TLRs by both microbial PAMPs and non-microbial agents , such as HA , play a role ( 11 , 12 ) , intestinal growth is driven only by TLR4 activation by the nonmicrobial agent , HA ( 17 ) .

      hyaluronic acid activates TLR4.

    1. PIK3CA promoted bladder cancer progression by activating EMT related makers - - Snail , beta-catenin , vimentin and E-cadherin .
    2. PIK3CA Promote Bladder Cancer Progression by Activating EMT Related Makers - - Snail , E-cadherin , Vimentin , and beta-Catenin Although the functional role of PIK3CA in EMT has been investigated in several cancers ( 39 ) , there are only a few reports in bladder cancer demonstrating involvement of PIK3CA in the process of EMT .
    3. In our study , we found activation of PIK3CA resulted in an increase in the expression of Snail and a decrease in the expression of E-cadherin at the mRNA and protein level , while inhibition of PIK3CA had the opposite effect .

      PIK3CA activates SNAI1.

    4. For example , the conclusion that CUX1 stimulates the expression of PIK3CA requires more experiments to further demonstrate .

      CUX1 activates PIK3CA.

    5. Together , the above results demonstrated that CUX1 stimulated transcription activity via direct interaction with the binding site of PIK3CA promoter .
    1. In line with these findings , gene ontology analysis of AR-ERG co-bound gene signature in VCaP cells indicated that the most striking transcriptional changes were linked to cellular differentiation and cell cycle arrest that are directly induced by DHT and repressed by ERG ( e.g ., HOXA genes , CDKN1A / p21 , Fig. 1d , Fig. 3b , and Supplementary Fig. 5d ) .

      ERG inhibits cell cycle.

    2. ZMYND11 induces AR signaling pathway and represses ERG activity Next , we assessed if ZMYND11 protein upregulation also contributed to the synthetic sick relationship .

      ZMYND11 inhibits ERG.

    3. ZMYND11 induces AR signaling pathway and represses ERG activity .

      ZMYND11 inhibits ERG.

    1. RPL11 and RPL5 suppress P53 degradation via binding to MDM2 .

      RPL5 inhibits TP53.

    2. The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector-transfected cells , indicating that RPL11 and RPL5 could inhibit P53 degradation ( Fig. 4e ) .

      RPL5 inhibits TP53.

    3. RPL11 and RPL5 suppress P53 degradation via binding to MDM2 .

      RPL11 inhibits TP53.

    4. The results showed that the half-life of P53 in cells transfected with RPL11 or RPL5 overexpression vector was prolonged compared with control vector-transfected cells , indicating that RPL11 and RPL5 could inhibit P53 degradation ( Fig. 4e ) .

      RPL11 inhibits TP53.

    5. These findings suggested that RPL11 and RPL5 could inhibit breast cancer cell proliferation and induce apoptosis .
    6. RPL11 and RPL5 inhibits breast cancer cell proliferation and induced apoptosis .
    1. Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

      RB1 activates BCL2.

    2. Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

      RB1 activates BCL2.

    3. Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

      RB1 activates PI3K.

    4. Moreover , Rb1 activated the PI3K / AKT pathway , down-regulated Cleaved caspase-3 and Bax , and up-regulated Bcl-2 expression .

      RB1 activates PI3K.

    1. Heme oxygenase ( HO ) is a stress-inducing enzyme that catalyzes heme to produce free iron , carbon monoxide ( CO ) , and biliverdin [ 7 ] .

      heme activates carbon monoxide.

    2. Heme oxygenase ( HO ) is a stress-inducing enzyme that catalyzes heme to produce free iron , carbon monoxide ( CO ) , and biliverdin [ 7 ] .

      heme activates biliverdin.

    1. Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

      PTEN inhibits ARID4B.

    2. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

      PTEN inhibits ARID4B.

    1. CKIotadelta promotes the interaction and degradation of LATS1 by SPOP It has been previously reported that proper substrate phosphorylation is necessary before substrate ubiquitination and degradation by SCF type of E3 ligases including FBW7 and beta-TRCP .

      SPOP activates LATS1.

  2. Aug 2021
    1. Dong et al. found that NLRP3 inhibits senescence and enables replicative immortality through regulating the Wnt / beta-catenin pathway via the thioredoxin-interacting protein ( TXNIP ) / NLRP3 axis ( 74 ) .
    2. The knockdown of NLRP3 significantly reduces the proliferation , clonogenicity , invasion and migration in both Ishikawa and HEC-1A cells , while in contrast , NLRP3 overexpression enhances the proliferation , migration and invasion in both Ishikawa and HEC-1A cells and furthermore , increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells .
    3. Inhibition of NLRP3 suppresses the proliferation , migration and invasion , and promotes apoptosis in glioma cells , while in contrast , increased expression of NLRP3 significantly enhances the proliferation , migration and invasion as well as attenuating apoptosis in glioma cells ( 56 ) ( Table 2 ) .
    4. The role of NLRP3 in promoting invasion has been demonstrated with human endometrial cancer cell lines such as Ishikawa and HEC-1A cells , where knockdown of NLRP3 significantly reduces proliferation , clonogenicity , invasion and migration .
    5. Collectively , these results indicate that upregulated NLRP3 expression promotes the progression of endometrial cancer ( 55 ) .

      NLRP3 activates Dientamoebiasis.

    6. Liu et al. concluded that the upregulation of NLRP3 expression promotes the progression of endometrial cancer ; therefore , NLPR3 inflammasome might be a new therapeutic target for endometrial cancer ( 55 ) .

      NLRP3 activates Dientamoebiasis.

    7. NLRP3 enhances IL-1beta , subsequently activating NF-kappaB , and initiates JNK signaling to cause proliferation and invasion in gastric cancer ( 21 ) .

      NLRP3 activates IL1B.

    8. Consistently , knockdown of NLRP3 induces cell apoptosis in MCF-7 cells and decreases cell migration ( 54 ) ; nevertheless , in other cell-types , NLRP3 inflammasome may pharmacologically repress proliferation and metastasis of hepatic cell carcinoma ( HCC ) ( 21 ) ( Table 4 ) .

      NLRP3 activates cell migration.

    9. NLRP3 enhances IL-1beta , subsequently activating NF-kappaB , and initiates JNK signaling to cause proliferation and invasion in gastric cancer ( 21 ) .

      NLRP3 activates NFkappaB.

    10. Moreover , NLRP3 downstream , IL-1beta , also stimulates the production of ROS that , in turn , induces DNA damage and cancer development in CRC ( 42 ) ( Table 2 ) .
    1. KLK8 degrades VE-cadherin , thereby promoting plakoglobin nuclear translocation The KLK family is considered to cleave kininogens to release kinin 15 .

      KLK8 inhibits CDH5.

    2. As shown in Figure 11A , it was found that high glucose led to a significant increase in the association of plakoglobin with p53 , which was blocked by KLK8 knockdown .

      KLK8 activates TP53.

    3. We then generated a KLK8 report gene by cloning the promoter of human KLK8 into the pGL3 vector , thereby further confirming that high glucose stimulates KLK8 expression through the Sp-1 site in the KLK8 gene .

      glucose activates KLK8.

    4. It was found that the mRNA and protein expression levels of KLK8 were significantly upregulated in a dose-dependent manner in high glucose-treated HCAECs compared with those of normal glucose-treated HCAECs ( Figure 8A-B ) , suggesting that high glucose stimulated KLK8 expression at the transcriptional level .

      glucose activates KLK8.

    1. Downregulation of PTEN expression or inhibiting its biologic activity improves heart function , promotes cardiomyocytes proliferation , reduces cardiac fibrosis as well as dilation , and inhibits apoptosis following ischemic stress such as myocardial infarction .

      PTEN activates apoptotic process.

  3. Jul 2021
    1. The C2 domain ( amino acids 186-351 ) can bind phospholipid membrane independent of calcium because it lacks the canonical Ca2 + chelating residues in vitro , which makes PTEN inhibit cell migration [ 31 ] .

      PTEN inhibits cell migration.

    2. Recently , it has been found that the impairment of PARK2 can induce the suppression of PTEN by S-nitrosylation through increase the level of NO [ 55 ] .

      PRKN activates PTEN.

    3. The C2 domain ( amino acids 186-351 ) can bind phospholipid membrane independent of calcium because it lacks the canonical Ca2 + chelating residues in vitro , which makes PTEN inhibit cell migration [ 31 ] .

      PTEN inhibits cell migration.

    4. Recently , it has been found that the impairment of PARK2 can induce the suppression of PTEN by S-nitrosylation through increase the level of NO [ 55 ] .

      PRKN activates PTEN.

    1. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .
    2. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .
    3. However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .
    4. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .
    5. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .
    6. However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .
    1. Our study showed that hypoxia increased the production of S100A8 in microglia .

      Hypoxia activates S100A8.

    2. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

      Hypoxia activates S100A8.

    3. In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

      S100A8 activates IL1B.

    4. Our study showed that hypoxia increased the production of S100A8 in microglia .

      Hypoxia activates S100A8.

    5. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

      Hypoxia activates S100A8.

    6. In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

      S100A8 activates IL1B.

    7. Our study showed that hypoxia increased the production of S100A8 in microglia .

      Hypoxia activates S100A8.

    8. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

      Hypoxia activates S100A8.

    9. In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

      S100A8 activates IL1B.

    1. Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

      PTEN inhibits ARID4B.

    2. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

      PTEN inhibits ARID4B.

    3. Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

      PTEN inhibits ARID4B.

    4. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

      PTEN inhibits ARID4B.

    5. Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

      PTEN inhibits ARID4B.

    6. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

      PTEN inhibits ARID4B.

    1. Increased mitochondrial Ca2 + concentration ( [ Ca2 + ] ) , in addition to augmented ROS production , induces a reduction of the mitochondrial membrane potential ( DeltaPsim ) in melanocytes and the circulating mononuclear cells of vitiligo patients ( 44 , 72 ) .

      CA2 inhibits Melanocytes.

    2. These events can thus result in the alteration of the Treg / cytotoxic T cell ratio , impaired Treg differentiation , and increased inflammation in vitiligo .
    3. Increased mitochondrial Ca2 + concentration ( [ Ca2 + ] ) , in addition to augmented ROS production , induces a reduction of the mitochondrial membrane potential ( DeltaPsim ) in melanocytes and the circulating mononuclear cells of vitiligo patients ( 44 , 72 ) .
    4. High concentrations of H2O2 disrupt melanin synthesis by inhibiting tyrosinase and dihydropteridine reductase ( 71 ) .
    5. IFN-gamma is also responsible for stimulating the production of CXCL9 and CXCL10 in keratinocytes , which engages the chemokine receptor CXCR3 on melanocytes and triggers apoptosis , further contributing to the disease ( 127 ) .
    6. In vitiligo , stressed melanocytes increase the expression of Hsp70 , which binds and transports potentially immunogenic antigens to the MHC complex , allowing for their presentation on the cell surface to cytotoxic T cells ( 109 ) .

      Melanocytes activates HSPA.

    7. Interestingly , keratinocytes in vitiligo lesions aberrantly produce IL-1 , IL-6 , and TNF-alpha , which inhibit melanocyte function ( 65 , 66 ) and elicit an inflammatory response .
    8. Blockade of IL-15Rbeta ( CD122 ) reduces IFN-gamma production and can eliminate skin TRM and reverse vitiligo ( 133 ) .

      IL2RB activates IFNG.

    9. In this case , NKG2D enhances TCR activation and thus , T cell function ( 18-20 ) .

      KLRK1 activates TCR.

    10. ROS production is also increased by TNF-alpha , further promoting stress signals in vitiligo melanocytes .
    11. These events , in combination with reduced suppression by dysfunctional Treg cells , result in the onset , perpetuation , and spreading of vitiligo .

      event activates Vitiligo.

    12. Exposure to UV light and its absorption by melanocytes causes photo-oxidation of melanin , generating superoxide radicals ( 54 ) , which in turn induce melanin biosynthesis ( 56 ) .
    13. Calreticulin , an endoplasmic reticulum ( ER ) protein that regulates Ca2 + homeostasis and signaling , is also modulated by H2O2 , which increases calreticulin expression and translocation to the cell surface of melanocytes .

      hydrogen peroxide activates CALR.

    14. Calreticulin , an endoplasmic reticulum ( ER ) protein that regulates Ca2 + homeostasis and signaling , is also modulated by H2O2 , which increases calreticulin expression and translocation to the cell surface of melanocytes .
    1. In addition , resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS-stimulated human umbilical vein endothelial cells ( HUVECs ) as determined by electrophoretic mobility shift assay [ 87 ] .
    2. In addition , resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS-stimulated human umbilical vein endothelial cells ( HUVECs ) as determined by electrophoretic mobility shift assay [ 87 ] .
    3. Similarly , other polyphenols , such as luteolin , chrysin , hesperidin , naringin and kaempferol have been shown to reduce inflammation by interfering with MAPKs pathways [ 107-109 ] .
    4. In addition , resveratrol as well as oleuropein aglycone and hydroxytyrosol significantly reduce the activation of NFkappaB in LPS-stimulated human umbilical vein endothelial cells ( HUVECs ) as determined by electrophoretic mobility shift assay [ 87 ] .
    5. Polyphenols in the treatment of autoimmune diseases In addition to protecting body from infections and diseases , the immune system produces auto-antibodies that can cause complex autoimmune disorders , such as Type I diabetes , primary biliary cirrhosis , rheumatoid arthritis , and multiple sclerosis , to name a few .
    6. However , under certain circumstances , the immune system may produce auto-antibodies against its own cells , leading to autoimmune diseases .
    7. Curcumin has also been reported to reactivate the neprilysin gene ( a strong inhibitor of Akt ) through CpG demethylation , leading to Akt inhibition and the subsequent inhibition of NFkappaB in mouse neuroblastoma N2a cells [ 132 ] .

      curcumin activates MME.

    8. Also , resveratrol induced neuroprotection in rats undergoing ischemia / reperfusion induced cerebral damage by activating the PI3K / Akt survival pathway [ 119 ] .
    9. Among the various polyphenols , resveratrol has been shown to be a strong activator of SIRT1 , resulting in the inhibition of NFkappaB and its downstream genes , such as COX-2 and iNOS [ 123 , 124 ] .

      resveratrol activates SIRT1.

    10. Once in the cytoplasm , AA is targeted by various enzymes such as COX and LOX to generate prostaglandins ( PGs ) and thromboxanes A2 or hydroxyeicosatetraenoic acids ( HETEs ) and leukotrienes ( LTs ) , respectively [ 69 ] .
    1. The retention of tissue-resident memory T cells is mediated by TGF-beta , which up-regulates CD103 expression and down-regulates CCR7 expression .

      TGFB inhibits CCR7.

    2. High-fat diet upregulated E-FABP expression and promote skin inflammation , suggesting the role of lipid metabolism in immune regulation ( 105 ) .
    3. High-fat diet upregulated E-FABP expression and promote skin inflammation , suggesting the role of lipid metabolism in immune regulation ( 105 ) .

      Diet, High-Fat activates FABP5.

    4. Endothelial cells increase the expression of adhesion molecules ; CD54 ( ICAM-1 ) and CD106 ( VCAM-1 ) , which guide T cell entry into the tissue .
    5. These mediators stimulate keratinocytes to produce TNF-alpha , IL-8 , and vascular endothelial growth factor , thereby promoting inflammation , neutrophil recruitment , and angiogenesis ( 129 ) .

      Keratinocytes activates CXCL8.

    6. These mediators stimulate keratinocytes to produce TNF-alpha , IL-8 , and vascular endothelial growth factor , thereby promoting inflammation , neutrophil recruitment , and angiogenesis ( 129 ) .
    7. These mediators stimulate keratinocytes to produce TNF-alpha , IL-8 , and vascular endothelial growth factor , thereby promoting inflammation , neutrophil recruitment , and angiogenesis ( 129 ) .

      Keratinocytes activates VEGF.

    8. Thus , CD8 + CD103 + TRM cells efficiently produce IL-17A .

      ITGAE activates IL17A.

    9. In contrast , in the xenotransplantation model of psoriasis , blocking CD49a inhibits T cell migration into the epidermis , resulting in a decrease of TRM cells and prevention of psoriasis development ( 76 ) .

      ITGA1 activates T cell migration.

    10. Th17-derived cytokines , IL-17A , IL-17F and IL-22 , induce epidermal acanthosis , which represents an intriguing histological finding of psoriasis and results from the proliferation of epidermal keratinocytes .
    11. Th17-derived cytokines , IL-17A , IL-17F and IL-22 , induce epidermal acanthosis , which represents an intriguing histological finding of psoriasis and results from the proliferation of epidermal keratinocytes .
    12. Th17-derived cytokines , IL-17A , IL-17F and IL-22 , induce epidermal acanthosis , which represents an intriguing histological finding of psoriasis and results from the proliferation of epidermal keratinocytes .
    13. They sense autoantigen in the skin long after stabilization of disease and produce IFN-gamma , which further induces CXCL9 , and CXCL10 production .

      IP-10 production activates CXCL9.

    14. TGF-beta induces CD103 expression on activated CD8 + T cells , but not CD4 + T cells , and leads to CD103-mediated adhesion of CD8 + T cells , but not CD4 + T cells , to monolayer human keratinocyte cultures ( 68 ) .

      TGFB activates ITGAE.

    15. The retention of tissue-resident memory T cells is mediated by TGF-beta , which up-regulates CD103 expression and down-regulates CCR7 expression .

      TGFB activates ITGAE.

    16. Since IL-12 can induce IFN-gamma production and CD49a expression , it is tempting to speculate that in the psoriasis context , IL-17A-producing TRM cells , which preferentially express IL-23R ( 74 ) , downregulate their CD49a due to a greater influence of IL-23 over IL-12 .

      IL12 activates ITGA1.

    17. Since IL-12 can induce IFN-gamma production and CD49a expression , it is tempting to speculate that in the psoriasis context , IL-17A-producing TRM cells , which preferentially express IL-23R ( 74 ) , downregulate their CD49a due to a greater influence of IL-23 over IL-12 .

      IL12 activates IFNG.

    18. Thus , CD8 + CD103 + TRM cells efficiently produce IL-17A .

      CD8 activates IL17A.

    19. The ligand for CCR8 , CCL1 , is preferentially expressed in human skin , and keratinocyte-derived prostaglandin E2 and vitamin D3 can induce CCR8 expression by CD8 + T cells , suggesting that it may involve in TRM localization in skin ( 62 , 63 ) .

      calciol activates CCR8.

    1. BP patient samples and the murine models of PDs indicate that GzmB is produced in PDs by TBO-positive mast cells and / or basophils .

      Basophils activates GZMB.

    2. Double immunostaining of GzmB and a mouse basophil-specific marker , mouse mast cell protease-8 ( mMCP-8 ) 22 , in WT mice with EBA , showed a subset of GzmB-positive cells was also mMCP-8 positive , which supported our findings with TBO staining that not only mast cells but also basophils were major sources of GzmB ( Fig. 1e ) .

      Basophils activates GZMB.

    3. Double immunostaining of GzmB and mMCP-8 in mast cell-deficient mice ( diphtheria toxin ( DT ) - treated Mcpt5-Cre iDTR mice ) with EBA further confirmed that basophils were a source of GzmB ( Supplementary Fig. 1b ) .

      Basophils activates GZMB.

    4. These findings suggested that mast cells but not basophils were a significant source of GzmB in this neonatal BP model .

      Basophils activates GZMB.

    5. Mast cells and / or basophils produce GzmB to degrade hemidesmosomal proteins .

      Basophils activates GZMB.

    6. GzmB deficiency hinders neutrophil infiltration through impeded secretion of chemoattractant macrophage inflammatory protein-2 / IL-8 Next , the effects of GzmB on the inflammatory response in the EBA murine model were assessed .
    7. Granzyme B ( GzmB ) promotes neutrophil infiltration , increased macrophage inflammatory protein-2 ( MIP-2 ) / IL-8 levels , and elevated elastase activity .
    8. Indeed , a recent work revealed that GzmB activates caspase 3 in secretory lysosomes of mast cells , a mechanism which possibly contributes to enhanced caspase 3-dependent proteolytic cleavage in the extracellular space39 .

      GZMB activates CASP3.

    9. As proteolytic degradation of alpha6 integrin by other proteases has been reported31 , we hypothesized that GzmB augments inflammation to increase the activity of other proteases to degrade alpha6 integrin .
    10. In this traditional dogma , GzmB was considered to be exclusively released from the granules of cytotoxic T and natural killer cells and internalized into target cells through perforin-mediated pores to initiate apoptosis .

      GZMB activates apoptotic process.

  4. May 2021
    1. The loss of AR increased NGF expression in our study , suggesting that the AR may act as an upstream regulator that downregulates the NGF in the absence of ADT .

      AR inhibits NGF.

    2. ZBTB46 directly binds to the regulatory sequence of the NGF and upregulates NGF expression We hypothesized that ZBTB46 upregulates NGF expression in prostate cancer cells by acting as a transcriptional activator and binding to a ZBTB46-binding element ( ZBE ) in the NGF regulatory sequence .

      ZBTB46 activates NGF.

    3. Moreover , ZBTB46-binding signals were enriched in C4-2 and LNCaP cells in response to CSS-containing medium or MDV3100 ( Fig. 2e , f ) , supporting the hypothesis that ADT-increased ZBTB46 upregulates NGF expression .

      ZBTB46 activates NGF.

  5. Apr 2021
    1. In this study , we demonstrate that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation can be partially reversed by Wnt10b , and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP / Smad signaling at least .

      PTEN inhibits WNT10B.

    2. Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs ( Huang et al ., 2014 ) .

      GDF2 inhibits PTEN.

    3. In this study , we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs .

      GDF2 inhibits PTEN.

    4. In this study , we demonstrate that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation can be partially reversed by Wnt10b , and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP / Smad signaling at least .

      PTEN inhibits WNT10B.

    5. Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs ( Huang et al ., 2014 ) .

      GDF2 inhibits PTEN.

    6. In this study , we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs .

      GDF2 inhibits PTEN.

    1. On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

      MDM2 inhibits TP53.

    2. p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

      TP53 inhibits PROM1.

    3. For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

      TP53 inhibits PROM1.

    4. With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .
    5. Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

      TP53 activates MIR34A.

    6. Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

      TP53 activates MIR34A.

    7. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

      TP53 activates isoxaflutole.

    8. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

      TP53 activates isoxaflutole.

    9. On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

      MDM2 inhibits TP53.

    10. p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

      TP53 inhibits PROM1.

    11. For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

      TP53 inhibits PROM1.

    12. With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .
    13. Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

      TP53 activates MIR34A.

    14. Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

      TP53 activates MIR34A.

    15. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

      TP53 activates isoxaflutole.

    16. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

      TP53 activates isoxaflutole.

    1. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .
    2. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .
    3. However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .
    4. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .
    5. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .
    6. However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .
    1. In the case of high calcium / phosphate treatment , the expression of P53 was decreased , while PLG increased the expression of PTEN .

      PLG activates PTEN.

    2. PLG promotes PTEN expression by increasing P53 signaling .

      PLG activates PTEN.

    3. Western blotting and qRT-PCR analyses showed that high calcium / phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group .

      PLG activates TP53.

    4. These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation .

      PLG activates TP53.

    5. PLG upregulates P53 signaling in vivo and in vitro .

      PLG activates TP53.

    6. In the case of high calcium / phosphate treatment , the expression of P53 was decreased , while PLG increased the expression of PTEN .

      PLG activates PTEN.

    7. PLG promotes PTEN expression by increasing P53 signaling .

      PLG activates PTEN.

    8. Western blotting and qRT-PCR analyses showed that high calcium / phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group .

      PLG activates TP53.

    9. These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation .

      PLG activates TP53.

    10. PLG upregulates P53 signaling in vivo and in vitro .

      PLG activates TP53.

    1. Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

      PTEN inhibits ARID4B.

    2. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

      PTEN inhibits ARID4B.

    3. Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

      PTEN inhibits ARID4B.

    4. PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

      PTEN inhibits ARID4B.

    1. Furthermore , IR induced RAC1 expression and activity via the activation of PI3K / AKT signaling pathway , and then enhancing cell proliferation , survival , migration and metastasis and increasing levels of epithelial-to-mesenchymal transition ( EMT ) markers , which facilitated the cell survival and invasive phenotypes .
    2. Furthermore , IR induced RAC1 expression and activity via the activation of PI3K / AKT signaling pathway , and then enhancing cell proliferation , survival , migration and metastasis and increasing levels of epithelial-to-mesenchymal transition ( EMT ) markers , which facilitated the cell survival and invasive phenotypes .
    1. Our study showed that hypoxia increased the production of S100A8 in microglia .

      Hypoxia activates S100A8.

    2. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

      Hypoxia activates S100A8.

    3. In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

      S100A8 activates IL1B.

    4. Our study showed that hypoxia increased the production of S100A8 in microglia .

      Hypoxia activates S100A8.

    5. FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

      Hypoxia activates S100A8.

    6. In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

      S100A8 activates IL1B.

    1. Previous studies have demonstrated that beta-catenin signaling helps VEGF regulate angiogenesis , and that FBXW7 promotes the degradation of beta-catenin ( 42,43 ) .

      FBXW7 inhibits CTNNB1.

    2. FBXW7 inhibits VEGF expression through inactivation of beta-catenin signaling To further elucidate the potential molecular mechanism by which FBXW7 mediates its antitumor effects in OC , western blot analysis was performed to detect the expression levels of key proteins in beta-catenin signaling .

      FBXW7 inhibits VEGF.

    3. Collectively , these results suggested that FBXW7 may inhibit VEGF expression through inactivation of beta-catenin signaling in SKOV3 cells .

      FBXW7 inhibits VEGF.

    4. Mechanistically , FBXW7 suppressed VEGF expression by inactivating beta-catenin signaling .

      FBXW7 inhibits VEGF.

    5. Overall , the current results suggested that FBXW7 may inhibit VEGF expression through inactivation of beta-catenin signaling in SKOV3 cells .

      FBXW7 inhibits VEGF.

    1. At the same time , limonin down-regulated the expression of NQO1 , indicating that limonin may indirectly act on the apoptosis pathway by regulating the expression activity of antioxidant enzymes in vivo , thus exerting its inhibitory effect on tumor cells , which provides an idea for the molecular mechanism that natural products can indirectly exert their anticancer effect by regulating the activity of antioxidant enzymes .

      limonin inhibits NQO1.

    2. At the same time , limonin down-regulated the expression of NQO1 , indicating that limonin may indirectly act on the apoptosis pathway by regulating the expression activity of antioxidant enzymes in vivo , thus exerting its inhibitory effect on tumor cells , which provides an idea for the molecular mechanism that natural products can indirectly exert their anticancer effect by regulating the activity of antioxidant enzymes .

      limonin inhibits NQO1.

    1. Dong et al. found that NLRP3 inhibits senescence and enables replicative immortality through regulating the Wnt / beta-catenin pathway via the thioredoxin-interacting protein ( TXNIP ) / NLRP3 axis ( 74 ) .
    2. Inhibition of NLRP3 suppresses the proliferation , migration and invasion , and promotes apoptosis in glioma cells , while in contrast , increased expression of NLRP3 significantly enhances the proliferation , migration and invasion as well as attenuating apoptosis in glioma cells ( 56 ) ( Table 2 ) .
    3. The role of NLRP3 in promoting invasion has been demonstrated with human endometrial cancer cell lines such as Ishikawa and HEC-1A cells , where knockdown of NLRP3 significantly reduces proliferation , clonogenicity , invasion and migration .
    4. The knockdown of NLRP3 significantly reduces the proliferation , clonogenicity , invasion and migration in both Ishikawa and HEC-1A cells , while in contrast , NLRP3 overexpression enhances the proliferation , migration and invasion in both Ishikawa and HEC-1A cells and furthermore , increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells .
    5. Liu et al. concluded that the upregulation of NLRP3 expression promotes the progression of endometrial cancer ; therefore , NLPR3 inflammasome might be a new therapeutic target for endometrial cancer ( 55 ) .

      NLRP3 activates Dientamoebiasis.

    6. Collectively , these results indicate that upregulated NLRP3 expression promotes the progression of endometrial cancer ( 55 ) .

      NLRP3 activates Dientamoebiasis.

    7. NLRP3 enhances IL-1beta , subsequently activating NF-kappaB , and initiates JNK signaling to cause proliferation and invasion in gastric cancer ( 21 ) .

      NLRP3 activates IL1B.

    8. Consistently , knockdown of NLRP3 induces cell apoptosis in MCF-7 cells and decreases cell migration ( 54 ) ; nevertheless , in other cell-types , NLRP3 inflammasome may pharmacologically repress proliferation and metastasis of hepatic cell carcinoma ( HCC ) ( 21 ) ( Table 4 ) .

      NLRP3 activates cell migration.

    9. NLRP3 enhances IL-1beta , subsequently activating NF-kappaB , and initiates JNK signaling to cause proliferation and invasion in gastric cancer ( 21 ) .

      NLRP3 activates NFkappaB.

    10. Moreover , NLRP3 downstream , IL-1beta , also stimulates the production of ROS that , in turn , induces DNA damage and cancer development in CRC ( 42 ) ( Table 2 ) .
    1. TLR4 - / - mice are more susceptible to SARS-CoV-1 than wild-type mice with higher viral titers [ 113 ] , which means that there was impairment in the innate immune response due to the lack of TLR4 , and hence difficulty in fighting the virus .
    2. TLR4 - / - mice are more susceptible to SARS-CoV-1 than wild-type mice with higher viral titers [ 113 ] , which means that there was impairment in the innate immune response due to the lack of TLR4 , and hence difficulty in fighting the virus .
    3. In addition , SARS-CoV-2 may activate TLR4 to increase PI3K / Akt signalling in infected cells , preventing apoptosis and thus increasing time for viral replication .
    4. Hence , a possible model for the interaction of SARS-CoV-2 and TLR4 is outlined in Section 11 and the graphical abstract ( Figure 1 ) in which SARS-CoV-2 may activate TLR4 in the heart and lungs to cause aberrant TLR4 signalling in favour of the proinflammatory MyD88-dependent ( canonical ) pathway rather than the alternative TRIF / TRAM-dependent anti-inflammatory and interferon pathway .

      SARS-CoV-2 activates TLR4.

    5. We can confidently extrapolate the above findings in Sections 8.1 and 8.2 from SARS-CoV-1 to SARS-CoV-2 ; hence , we propose that SARS-CoV-2 would activate TLR4 directly , probably via its spike protein binding to TLR4 ( and / or MD2 ) .

      SARS-CoV-2 activates TLR4.