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PubMed2025

Efficacy of Janus kinase inhibitor combined with phototherapy in non-segmental vitiligo: systematic review and meta-analysis.

BACKGROUND: Vitiligo is a chronic autoimmune disease causing skin depigmentation and psychosocial issues. Non-segmental vitiligo often shows limited response to standard therapies. The IFN-γ-JAK-STAT pathway plays a key role, and combining JAK inhibitors with NB-UVB may improve repigmentation. AIM: To evaluate the efficacy of JAK inhibitors (baricitinib or tofacitinib) plus NB-UVB versus NB-UVB without JAK inhibitors in adult NSV. METHODS: PubMed, Cochrane, and ClinicalTrials.gov were searched till August 2024 for randomized controlled trials. Four studies, comprising 217 adults (121 in the combination group and 96 in the control group), were analyzed using RevMan 5.4. Bias was assessed via Newcastle-Ottawa, Cochrane ROB-2, and ROBINS-I tools. RESULTS: Combination therapy significantly reduced total VASI compared to controls (MD = -4.96, 95% CI [-9.29, -0.63], p = 0.02), with a greater effect on sensitivity analysis (MD = -6.84, p = 0.0007). Significant reductions were seen in face/neck (MD = -0.17, p = 0.002), trunk (MD = -3.62, p = 0.0001); acral (MD = -0.85, p = 0.0002) and extremity (MD = -4.61, p < 0.00001) regions after sensitivity analysis. Patients were more likely to achieve ≥50% (RR = 6.87, p < 0.00001) and ≥75% (RR = 15.13, p = 0.006) repigmentation. CONCLUSIONS: JAK inhibitor plus NB-UVB markedly improves the repigmentation in adult NSV compared to NB-UVB alone.

Humans↗

PubMed2004

Ubiquitin ligases in malignant lymphoma.

The highly controlled degradation of proteins via the ubiquitin-proteasome pathway represents a key mechanism for cell regulation and homeostasis. Ubiquitin-dependent proteolysis, carried out in large part by the E3 ubiquitin ligases, is a critical mode of post-translational modification that is important in regulation of cell cycle progression, signal transduction, gene transcription, antigen receptor signaling, immune response and cell differentiation. Recent studies demonstrate that increasing numbers of proteins with ubiquitin ligase activity are being characterized. Identification and characterization of their substrates indicate that they regulate the turnover of key cell cycle proteins (p27Kip1, p21Cip1, p57Kip2, cyclin E), tumor suppressor proteins (p53, RB), signaling kinases (Src, Zap70, PI-3 kinase), apoptosis regulators (Bcl-2, Bax, Bik) and transcription factors (Myc, NF-kappaB, E1F1), all of which have been implicated in the pathogenesis of malignant lymphoma. Studies to determine the functional role of ubiquitin ligases in the pathogenesis of malignant lymphoma represent potential areas of investigation.

Animals↗

PubMed2001

Role of ERK and p38 mitogen-activated protein kinase cascades in gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide.

The animal model of H. pylori lipopolysaccharide (LPS)-induced gastritis was used to study the role of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) in the mucosal release of tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1) in response to H. pylori infection. Rats, pretreated with specific inhibitors of p38 and ERK pathways, SB203580 and PD98059, were submitted to intragastric application of H. pylori LPS and maintained on the daily regimen of the inhibitors for 4 days. In the absence of inhibitors, the LPS elicited a pattern of mucosal inflammatory responses resembling that of acute gastritis, and reflected in a massive increase in the mucosal level of ET-1 and TNF-alpha. Administration of SB203580 led to a 63.4% reduction in the extent of inflammatory involvement, the level of ET-1 fell by a 42% and TNF-alpha declined by a 52.3%, whereas PD98059 elicited a 21.2% reduction in the extent of inflammatory involvement and a 22.7% decrease in TNF-alpha, but had no effect on the LPS-induced increase in ET-1. A combination of both inhibitors, while exerting additive effect on TNF-alpha, produced no additional reduction in ET-1 and the extent of inflammatory involvement achieved with SB203580 alone. The findings suggest that the p38 MAPK signaling pathway plays a key role in the mediation of gastric mucosal inflammatory reaction to H. pylori infection.

Animals↗

PubMed2000

Aberrant caveolin-1 expression in psoriasis: a signalling hypothesis.

A preliminary retrospective immunocytochemical study was conducted examining the expression of caveolin-1 in skin biopsies resected from clinically defined psoriatic subjects. These pilot investigations revealed a dramatic down-regulation of caveolin-1 (a protein product of the caveolin supergene family known to regulate signal transduction events and cell cycle dynamics) in the hyperproliferative basal regions of the epidermis in all psoriatic biopsies examined when compared to normal control samples. These results lead us to hypothesise that caveolin-1 negatively regulates key signal transduction pathways in epidermal keratinocytes and through it's reduced expression in psoriasis, pertubations in keratinocyte cell signalling and abnormal cell differentiation ensue, events fundamental to the development of the psoriatic phenotype. Novel therapeutic strategies for the treatment of psoriasis based upon caveolin-1 protein can be envisaged.

Biopsy↗

PubMed2003

Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1.

Profilaggrin is a large epidermal polyprotein that is proteolytically processed during keratinocyte differentiation to release multiple filaggrin monomer units as well as a calcium-binding regulatory NH2-terminal filaggrin S-100 protein. We show that epidermal deficiency of the transmembrane serine protease Matriptase/MT-SP1 perturbs lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation. Surprisingly, proteomic analysis of Matriptase/MT-SP1-deficient epidermis revealed the selective loss of both proteolytically processed filaggrin monomer units and the NH2-terminal filaggrin S-100 regulatory protein. This was associated with a profound accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum. The data identify keratinocyte Matriptase/MT-SP1 as an essential component of the profilaggrin-processing pathway and a key regulator of terminal epidermal differentiation.

Animals↗

PubMed1998

A novel sialic acid binding site on factor H mediates serum resistance of sialylated Neisseria gonorrhoeae.

Factor H (fH), a key alternative complement pathway regulator, is a cofactor for factor I-mediated cleavage of C3b. fH consists of 20 short consensus repeat (SCR) domains. Sialic acid binding domains have previously been localized to fH SCRs 6-10 and 13. To examine fH binding on a sialylated microbial surface, we grew Neisseria gonorrhoeae in the presence of 5'-cytidinemonophospho-N-acetylneuraminic acid, which sialylates lipooligosaccharide and converts to serum resistance gonococci previously sensitive to nonimmune serum killing. fH domains necessary for binding sialylated gonococci were determined by incubating organisms with recombinant human fH (rH) and nine mutant rH molecules (deletions spanning the entire fH molecule). rH and all mutant rH molecules that contained SCRs 16-20 bound to the sialylated strain; no mutant molecule bound to serum-sensitive nonsialylated organisms. Sialic acid was demonstrated to be the fH target by flow cytometry that showed a fourfold increase in fH binding that was reversed by neuraminidase-mediated cleavage of sialic acid off gonococci. Functional specificity of fH was confirmed by decreased total C3 binding and almost complete conversion to iC3b on sialylated gonococci. Sialic acid can therefore bind fH uniquely through SCRs 16-20. This blocks complement pathway activation for N. gonorrhoeae at the level of C3.

Antigens, Bacterial↗

PubMed2002

Role of protein-tyrosine kinase syk in oxidative stress signaling in B cells.

Oxidative stress induces the activation of multiple signaling pathways related to various cellular responses. In B cells, Syk has a crucial role in intracellular signal transduction induced by oxidative stress as well as antigen receptor engagement. Treatment of B cells with hydrogen peroxide (H(2)O(2)) induces enzymatic activation of Syk. Syk is essential for Ca(2+) release from intracellular pools through phospholipase C-gamma2 and the activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase-Akt survival pathway following H(2)O(2) stimulation. Oxidative stress-induced cellular responses in B cells follow different patterns, such as necrosis, apoptosis, and mitotic arrest, according to the intensity of H(2)O(2) stimulation. Syk is involved in the protection of cells from apoptosis and induction of G2/M arrest. Syk leads to the activation of the phosphatidylinositol 3-kinase-Akt survival pathway, thereby enhancing cellular resistance to oxidative stress-induced apoptosis. On the other hand, Syk-dependent phospholipase C-gamma2 activation is required for acceleration toward apoptosis following oxidative stress. These findings suggest that oxidative stress-induced Syk activation triggers the activation of several pathways, such as proapoptotic and survival pathways, and the balance among these various pathways is a key factor in determining the fate of a cell exposed to oxidative stress.

Animals↗

PubMed2002

Cross-species conservation of SEL1L, a human pancreas-specific expressing gene.

SEL1L is a recently cloned and organ-specific expressing human gene whose function is still at an embryonic stage but displays several interesting characteristics, among which a remarkable cross-species conservation. During evolution, the gene structural complexity increased, suggesting a diversification of its function; however, several amino acid motifs remain perfectly conserved from the bacteria to the human protein. SEL1L is the human ortholog of the C. elegans gene sel-1; the latter is implicated in the negative regulation of LIN-12/GLP-1/Notch receptor proteins. These receptor proteins play fundamental roles in signal transduction pathways and are key players in cell fate determination during the development of various organs. Studies in model organisms, such as C. elegans, helped to illuminate fundamental mechanisms involved in normal cellular functions and human diseases. This paper describes the conserved nature of SEL1L across a wide range of species suggesting, that the encoded protein most likely exerts a very important biological function; it may belong to a subclass of genes considered to be "essential."

Amino Acid Sequence↗

PubMed1993

Tissue-related and species-specific differences in the 2-5A oligomer size requirement for activation of 2-5A-dependent RNase.

2',5'-Oligoadenylate (2-5A)-dependent RNase (L or F) is the final enzyme in the 2-5A pathway and a key component in the molecular mechanism of interferon (IFN) action. Here we demonstrate differences in the 2-5A oligomer size requirement between rabbit 2-5A-dependent RNase from reticulocytes and from cultured kidney cells. The rabbit reticulocyte enzyme was activated by tetramer 2-5A, whereas the ribonuclease from rabbit kidney cells required only trimer 2-5A. Interestingly, in contrast to the 2-5A-dependent RNase from rabbit reticulocytes, that from murine reticulocytes could be activated by trimer 2-5A. Partial proteolysis of affinity-labeled, 80-kD 2-5A-dependent RNase from rabbit reticulocytes and rabbit kidney cells resulted in the same pattern of labeled peptides. However, the affinity labeling reaction with a 32P-labeled 2-5A analog did produce some different labeled polypeptides in rabbit kidney cell extract and rabbit reticulocyte lysate. These results could indicate specialized functions for the 2-5A system in different organ systems.

Adenine Nucleotides↗

PubMed1992

Angiotensin II regulates cytochrome P-450 steroid hydroxylase enzyme expression in human adrenal glomerulosa cells.

We have examined the regulation of cytochrome P-450 side chain cleavage enzyme (P-450SCC) and P-45011 beta (18) hydroxylase (P-450(11) beta) enzyme expression by angiotensin II (AII), the major regulator of aldosterone biosynthesis, in cultured human adrenal glomerulosa cells. We also examined the effect of lipoxygenase products of arachidonic acid on the expression of these enzymes since it has been previously shown that the 12-lipoxygenase pathway plays a key role in AII-induced aldosterone synthesis in rat and human adrenal glomerulosa cells. AII (10(-7) mol/L) induced a 3-fold stimulation of P-450SCC and over a 2-fold increase in P-450(11) beta protein expression. The 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid (12-HETE) caused a 2-fold increase in P-450(11) beta levels without altering P-450SCC levels. These results show for the first time that AII can directly increase the levels of P-450SCC and P-450(11) beta enzymes in glomerulosa cells. The results also suggest that 12-HETE may mediate long term effects of AII action by stimulating P-450(11) beta levels.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗

PubMed2004

Pharmacological background of EGFR targeting.

Epidermal growth factor receptor (EGFR) signaling pathways play a key role in the regulation of cell proliferation, survival and differentiation. As a consequence, EGFR is one of the best studied ligand-receptor system and specific EGFR inhibition approaches are currently among the most promising and the most advanced in the clinical setting. Monoclonal antibodies (mAbs) and specific tyrosine kinase inhibitors (TKIs) have been developed, among which C225 (Cetuximab) and ZD1839 (Iressa), respectively, are the most advanced. The aim of the present review was not to cover the field of EGFR inhibitors, but to compare at experimental and clinical levels the different key points governing the actions of mAbs and TKIs. In addition, combinations of conventional chemotherapies with EGFR targeting drugs, as well as resistance mechanisms of EGFR targeting, have been reviewed.

Antibodies, Monoclonal↗

PubMed2005

Low levels of pyrophosphate in transgenic potato plants expressing E. coli pyrophosphatase lead to decreased vitality under oxygen deficiency.

BACKGROUND AND AIMS: The aim of this study was to investigate the importance of pyrophosphate (PPi) for plant metabolism and survival under low oxygen stress. Responses of roots of wild-type potato plants were compared with roots of transgenic plants containing decreased amounts of PPi as a result of the constitutive expression of Escherichia coli pyrophosphatase in the cytosol. METHODS: For the experiments, roots of young wild-type and transgenic potato plants growing in nutrient solution were flushed for 4 d with nitrogen, and subsequently metabolite contents as well as enzyme activities of the glycolytic pathway were determined. KEY RESULTS AND CONCLUSIONS: In roots of transgenic plants containing 40% less PPi, UDPglucose accumulated while the concentrations of hexose-6-phosphate, other glycolytic intermediates and ATP were decreased, leading to a growth retardation in aerated conditions. Apart from metabolic alterations, the activity of sucrose synthase was increased to a lower extent in the transgenic line than in wild type during hypoxia. These data suggest that sucrose cleavage was inhibited due to PPi deficiency already under aerated conditions, which has severe consequences for plant vitality under low oxygen. This is indicated by a reduction in the glycolytic activity, lower ATP levels and an impaired ability to resume growth after 4 d of hypoxia. Interestingly, the phosphorylation of fructose-6-phosphate via PPi-dependent phosphofructokinase was not altered in roots of transgenic plants. Nevertheless, our data provide some evidence for the importance of PPi to maintain plant growth and metabolism under oxygen deprivation.

Blotting, Northern↗

PubMed1997

Inhibition by piroxicam of oxidative DNA damage, liver cirrhosis and development of enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats.

Previously, we have reported that aspirin, a cyclooxygenase (COX) inhibitor, can prevent the fibrosis, cirrhosis and generation of oxidative DNA damage, and the associated development of glutathione-S-transferase placental form (GST-P)-positive preneoplastic liver nodules, caused by a choline-deficient, L-amino acid-defined (CDAA) diet in rats. In the present study, in order to elucidate the role of COX pathway in liver lesion-induction by a CDAA diet, the modulatory effects of other distinct chemical classes of COX inhibitors were examined. A long-acting example, piroxicam (PIRO) (at doses of 0.01, 0.02, 0.04 and 0.06%) and the short-acting ibuprofen (IBU) (at doses of 0.02, 0.04 and 0.06%) and indomethacin (IND) (at doses of 0.005 and 0.008%) were administered in the CDAA diet to male F344 rats, and animals were killed after 12 and 30 weeks. In another experiment, IND was given in drinking water at doses of 0.001, 0.002 and 0.004%. None of the inhibitors affected the development of fatty liver caused by a CDAA diet, but PIRO at doses higher than 0.04%, strongly inhibited the development of GST-P-positive and neoplastic nodules as well as fibrosis, cirrhosis and formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts. IBU at the highest dose also exhibited similar but much less pronounced inhibitory effects. With IND, there was only a tendency for inhibition with no clear dose-dependence. The results together with our previous findings, indicate that relatively strong COX inhibitors, acting irreversibly like aspirin or for extended periods like PIRO, can prevent the endogenous hepatocarcinogenesis associated with a CDAA diet, although not the development of a fatty liver, suggesting that an augmented COX pathway might play key roles in the causation of liver lesions in this model.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2003

Comparative metabolism of N-nitrosopiperidine and N-nitrosopyrrolidine by rat liver and esophageal microsomes and cytochrome P450 2A3.

N-nitrosopiperidine (NPIP) is a potent esophageal carcinogen in rats whereas structurally similar N-nitrosopyrrolidine (NPYR) induces liver, but not esophageal tumors. NPIP is a possible causative agent for human esophageal cancer. Our goal is to explain mechanistically these differing carcinogenic activities in the esophagus. We hypothesize that differences in metabolic activation of these nitrosamines could be one factor accounting for their differing carcinogenicity. alpha-Hydroxylation is the key metabolic activation pathway leading to nitrosamine-induced carcinogenesis. In this study, we examined the alpha-hydroxylation rates of [3,4-(3)H]NPIP and [3,4-(3)H]NPYR by male F344 rat esophageal and liver microsomes. The major alpha-hydroxylation products of NPIP and NPYR, 2-hydroxytetrahydro-2H-pyran (2-OH-THP) and 2-hydroxytetrahydrofuran (2-OH-THF), respectively, were monitored by high performance liquid chromatography with radioflow detection. NPIP or NPYR (4 microM) was incubated with varying concentrations of esophageal microsomes and co-factors. Microsomes converted NPIP to 2-OH-THP with a 40-fold higher velocity than NPYR to 2-OH-THF. Similar results were observed in studies with NPIP and NPYR at substrate concentrations between 4 and 100 micro M. Kinetics of NPIP alpha-hydroxylation were biphasic; K(M) values were 312 +/- 50 and 1600 +/- 312 microM. Expressed cytochrome P450 2A3, found in low levels in rat esophagus, was a good catalyst of NPIP alpha-hydroxylation (K(M) = 61.6 +/- 20.5 microM), but a poor catalyst of NPYR alpha-hydroxylation (K(m) = 1198 +/- 308 micro M). Cytochrome P450 2A3 may play a role in the preferential activation of NPIP observed in rat esophagus. Liver microsomes metabolized NPYR to 2-OH-THF (V(max)/K(M) = 3.23 pmol/min/mg/ microM) as efficiently as NPIP to 2-OH-THP (V(max)/K(M) = 3.80-4.61 pmol/min/mg/ microM). We conclude that rat esophageal microsomes activate NPIP but not NPYR whereas rat liver microsomes activate NPIP and NPYR. These results are consistent with previous findings that tissue-specific activation of nitrosamines contributes to tissue-specific tumor formation.

Animals↗

PubMed2003

The reelin signaling pathway: some recent developments.

The Reelin signaling pathway plays a key role in the architectonic development of the central nervous system. Extracellular Reelin binds to receptors of the lipoprotein receptor family and induces tyrosine phosphorylation of the adaptor Dab1. In this paper, we discuss three recent developments. First, we show that the central part of Reelin is involved in receptor binding and signal activation as reflected in Dab1 phosphorylation. Second, we examine the genomic organization, alternative splicing and promoter use of the Dab1 gene, which hint at a particularly complex regulation. Third, we present preliminary studies by in situ hybridization that demonstrate regulated expression of Reelin receptors and Dab1 by radial precursors in the ventricular zone.

Cell Adhesion Molecules, Neuronal↗

PubMed1997

Mouse disabled (mDab1): a Src binding protein implicated in neuronal development.

Here, we identify a mouse homolog of the Drosophila Disabled (Dab) protein, mDab1, and show it is an adaptor molecule functioning in neural development. We find that mDab1 is expressed in certain neuronal and hematopoietic cell lines, and is localized to the growing nerves of embryonic mice. During mouse embryogenesis, mDab1 is tyrosine phosphorylated when the nervous system is undergoing dramatic expansion. However, when nerve tracts are established, mDab1 lacks detectable phosphotyrosine. Tyrosine-phosphorylated mDab1 associates with the SH2 domains of Src, Fyn and Abl. An interaction between mDab1 and Src is observed when P19 embryonal carcinoma (EC) cells undergo differentiation into neuronal cell types. mDab1 can also form complexes with cellular phosphotyrosyl proteins through a domain that is related to the phosphotyrosine binding (PTB) domains of the Shc family of adaptor proteins. The mDab1 PTB domain binds to phosphotyrosine-containing proteins of 200, 120 and 40 kDa from extracts of embryonic mouse heads. The properties of mDab1 and genetic analysis of Dab in Drosophila suggest that these molecules function in key signal transduction pathways involved in the formation of neural networks.

Amino Acid Sequence↗

PubMed2002

Mutational analysis reveals a role for the C terminus of the proteasome subunit Rpt4p in spindle pole body duplication in Saccharomyces cerevisiae.

The ubiquitin/proteasome pathway plays a key role in regulating cell cycle progression. Previously, we reported that a conditional mutation in the Saccharomyces cerevisiae gene RPT4/PCS1, which encodes one of six ATPases in the proteasome 19S cap complex/regulatory particle (RP), causes failure of spindle pole body (SPB) duplication. To improve our understanding of Rpt4p, we created 58 new mutations, 53 of which convert clustered, charged residues to alanine. Virtually all mutations that affect the N-terminal region, which contains a putative nuclear localization signal and coiled-coil motif, result in a wild-type phenotype. Nine mutations that affect the central ATPase domain and the C-terminal region confer recessive lethality. The two conditional mutations identified, rpt4-145 and rpt4-150, affect the C terminus. After shift to high temperature, these mutations generally cause cells to progress slowly through the first cell cycle and to arrest in the second cycle with large buds, a G2 content of DNA, and monopolar spindles, although this phenotype can vary depending on the medium. Additionally, we describe a genetic interaction between RPT4 and the naturally polymorphic gene SSD1, which in wild-type form modifies the rpt4-145 phenotype such that cells arrest in G2 of the first cycle with complete bipolar spindles.

Adenosine Triphosphatases↗

PubMed2006

Use of transgenic mice to study lung morphogenesis and function.

Successful transition to air breathing at birth depends on perinatal maturation of the gas exchange surface, resorption of fluid from the air spaces, and synthesis and secretion of pulmonary surfactant. Genetic mutations that alter lung development and/or cellular differentiation in the prenatal period, lung function in the perinatal period, or lung homeostasis in the postnatal period can lead to neonatal lethality or chronic lung disease. Current knowledge of the molecular pathways that regulate key prenatal, perinatal, and postnatal morphogenetic events has been shaped largely by remarkable advances in transgenic technologies. In this review, selected transgenic mouse models are highlighted to illustrate the power of this technology, which in many cases has provided important insights that otherwise could not have been obtained.

Animals↗