Kinase Signal Transduction Research Articles

Janus-kinase inhibitors in dermatology: A review of their use in psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease.

Recent studies on molecular pathways have elucidated novel therapeutic approaches in inflammatory and autoimmune skin disorders. Specifically, the dysregulation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) cascade plays a central role in the pathogenesis of many skin conditions. JAK inhibitors, with their ability to selectively target immune responses, are potential treatment options. Using the National Library of Medicine, we provide a comprehensive review of the use of United States Food and Drug Administration (FDA)-approved and emerging JAK or tyrosine kinase 2 (TYK2) inhibitors in a wide range of dermatologic conditions, including psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. In patients with psoriasis, oral deucravacitinib (TYK2 inhibitor) has been approved as a once-daily therapy with demonstrated superiority and efficacy over apremilast and placebo and tolerable safety profiles. In patients with vitiligo, topical ruxolitinib (JAK1 inhibitor) is approved as a twice-daily treatment for repigmentation. The efficacy of several other JAK inhibitors has also been demonstrated in several clinical trials and case studies for systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. Further investigations with long-term clinical trials are necessary to confirm their utility in treatment and safety for these diseases.

Tetramethylpyrazine promotes axonal remodeling and modulates microglial polarization via JAK2-STAT1/3 and GSK3-NFκB pathways in ischemic stroke

Ischemic stroke results in demyelination that underlies neurological disfunction. Promoting oligodendrogenesis will rescue the injured axons and accelerate remyelination after stroke. Microglia react to ischemia/hypoxia and polarize to M1/M2 phenotypes influencing myelin injury and repair. Tetramethylpyrazine (TMP) has neuroprotective effects in treating cerebrovascular disorders. This study aims to evaluate whether TMP promotes the renovation of damaged brain tissues especially on remyelination and modulates microglia phenotypes following ischemic stroke. Here magnetic resonance imaging (MRI)-diffusion tensor imaging (DTI) and histopathological evaluation are performed to characterize the process of demyelination and remyelination. Immunofluorescence staining is used to prove oligodendrogenesis and microglial polarization. Western blotting is conducted to examine interleukin (IL)-6, IL-10, transforming growth factor β (TGF-β) and Janus protein tyrosine kinase (JAK) 2-signal transducer and activator of transcription (STAT) 1/3-glycogen synthase kinase (GSK) 3-nuclear transcription factor κB (NFκB) signals. Results show TMP alleviates the injury of axons and myelin sheath, increases NG2+, Ki67+/NG2+, CNPase+, Ki67+/CNPase+, Iba1+/Arg-1+ cells and decreases Iba1+ and Iba1+/CD16+ cells in periinfarctions of rats. Particularly, TMP downregulates IL-6 and upregulates IL-10 and TGF-β expressions, besides, enhances JAK2-STAT3 and suppresses STAT1-GSK3-NFκB activation in middle cerebral artery occlusion (MCAo) rats. Then we demonstrate that TMP reverses M1/M2 phenotype via JAK2-STAT1/3 and GSK3-NFκB pathways in lipopolysaccharide (LPS) plus interferon-γ (IFN-γ)-stimulated BV2 microglia. Blocking JAK2 with AG490 counteracts TMP's facilitation on M2 polarization of microglia. This study warrants the promising therapy for stroke with TMP treatment.

Unraveling the dangerous duet between cancer cell plasticity and drug resistance

AbstractCancer cell plasticity is the ability of tumor cells to switch phenotypes and is one of the predominant requisites of cancer cells capable of undergoing metastasis. Cancer cell plasticity is also recognized as one of the major contributors to intratumoral heterogeneity, a critical factor underlying the progression of malignant tumors, which is known to modify tumor response and induce resistance against various modes of therapy, thus posing a barrier to efficient cancer management. Cancer cell plasticity is acquired by the subversion of cell signaling pathways like mitogen‐activated protein kinase pathway, phosphoinositide‐3‐kinase, signal transducer and activator of transcription 3, Wnt, Hedgehog and Notch as well as cellular programs such as epithelial to mesenchymal transition and phenotypic plasticity. This complex phenomenon has been studied in many cancer types like pancreatic cancer, colon cancer and breast cancer. This review will explore the current understanding we have in breast cancer on the intrinsic molecular mechanisms of cancer cell plasticity and the resistance to various types of cancer therapy that arise as a result of plasticity. We conclude by exploring the potential novel therapies that specifically target the pathways leading to plasticity and can be leveraged to treat patients living with the disease.

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth.

CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.

The therapeutic effect of Shenhua tablet against mesangial cell proliferation and renal inflammation in mesangial proliferative glomerulonephritis

Shenhua tablet (SH), a formulation of traditional Chinese medicine, exerts renoprotective effect on chronic kidney diseases, and it has been found to restrain inflammation, but the mechanism is still unclear. Here, we explored the potential renoprotection of SH in mesangial proliferative glomerulonephritis (MsPGN) rat model induced by anti-Thy1 antibody. Administration of SH reduced urinary albumin/creatinine ratio (UACR) and significantly attenuated mesangial cell proliferation and renal inflammation. Notably, SH protected rats against renal inflammation, which was associated with decreasing macrophage infiltration and promoting macrophage anti-inflammatory activity. Network analysis combined with arrays identified the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway as the main pathways of SH could target inflammation. Furthermore, it was confirmed that mesangial cell proliferation, which response to inflammation, were alleviated by ASS1 expression enhanced after SH administration both in vivo and in vitro. Collectively, SH has the beneficial on relieving the progression of MsPGN to alleviate inflammation and mesangial proliferation by inhibiting STAT3 phosphorylation and maintains the expression level of ASS1, might be an effective strategy for treating MsPGN.

Discovery of genome-wide genetic variations and development of first set of InDel markers for genetics research in cashew

Cashew nut is an edible tree nut having great industrial applications. Cashew and its products (nut shell liquid and kernel oil) are used in various food preparations, medicines, green energy feedstocks and polymer synthesis making it an industrially important tree. In spite of great economic importance, genetics and molecular studies in cashew are lagging due to a largely unexplored genome and scarcity of robust genome-wide molecular markers. Here, we resequenced the whole genome of Nethra Vaman, a commercial clone of cashew, and identified and characterized their genome-wide variants (GVs): 420,560 SNPs and 26,987 InDels by aligning with the reported draft genome of cashew cv. Bhaskara. The mean density of SNPs was 2,867.78 per Mb of the genome while the mean density of InDels was 184.02 per Mb. KEGG pathway analysis of the genes with GVs revealed that apart from the primary metabolic pathways, plant hormone signal transduction and Mitogen-activated protein kinase (MAPK) pathways were enriched. Besides, the first set of InDel markers (88) possessing advantages of both SSR and SNP markers was developed, and 87.5% of them were highly informative (PIC value ≥0.50). The PIC value of InDel markers ranged from 0.11 (AoINDL-16) to 0.85 (AoINDL-1) with a mean of 0.66. Cross-species amplification of InDel markers showed 84.68%, 79.84%, 74.19%, and 58.06% successful amplification in A. othonianum, A. microcarpum, A. pumilum and S. anacardium, respectively. Genetic diversity analysis using 14 informative InDel markers by UPGMA method clustered the 64 accessions into three main clusters and a total of 200 alleles were identified with a mean of 14.29. AMOVA analysis showed that 6% of genetic variations were attributable to among populations while 94% was attributable to individuals within and among populations. Further, InDel markers were assayed for hybridity ascertaining in A. occidentale × A. microcarpum progeny and the hybrid purity index of markers varied from 45.45 % (AoINDL-40) to 94.5% (AoINDL-77). Thus, the genomic resources, identification and annotation of GVs, and the new class of markers designed here will be valuable for molecular biology, genetics, and molecular breeding in cashew and related Anacardium species.

Synthesis and Biological Properties of Pyranocoumarin Derivatives as Potent Anti-Inflammatory Agents.

This study aimed to synthesize 23 coumarin derivatives and analyze their anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. A cytotoxicity test performed on LPS-induced RAW264.7 macrophages revealed that none of the 23 coumarin derivatives were cytotoxic. Among the 23 coumarin derivatives, coumarin derivative 2 showed the highest anti-inflammatory activity by significantly reducing nitric oxide production in a concentration-dependent manner. Coumarin derivative 2 inhibited the production of proinflammatory cytokines, including tumor necrosis factor alpha and interleukin-6, and decreased the expression level of each mRNA. In addition, it inhibited the phosphorylation of extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, nuclear factor kappa-B p65 (NF-κB p65), and inducible nitric oxide synthase. These results indicated that coumarin derivative 2 inhibited LPS-induced mitogen-activated protein kinase and NF-κB p65 signal transduction pathways in RAW264.7 cells, as well as proinflammatory cytokines and enzymes related to inflammatory responses, to exert anti-inflammatory effects. Coumarin derivative 2 showed potential for further development as an anti-inflammatory drug for the treatment of acute and chronic inflammatory diseases.

Research Progress on Gene Mutation and CHIP in Pathogenesis of MDS --Review

With the development of molecular biology techniques, the people's understanding of myelodysplastic syndromes (MDS) has greatly improved, a heterogeneous hematopoietic pre-malignant disorder of the stem cells. Gene mutations include RNA splicing, DNA methylation, chromosome modification, transcription factors, signal transduction kinases, RAS pathways, cohesion complexes, DNA repair, etc. Gene mutation is the determinant of diagnostic typing and therapeutic efficacy of MDS. The new concepts of CHIP and ICUS have aroused people's attention to the elderly patients with clonal hematopoiesis and non-clonal cytopenia but without MDS characteristics, who have the possibility of high-risk transformation to MDS and leukemia. In order to better understand the pathogenesis of MDS, the significance of gene mutations, CHIP and ICUS in the diagnosis and prognosis of MDS were reviewed in this paper.

Role of JAK-STAT signaling pathway in pathogenesis and treatment of primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully elucidated, B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients. It has long been identified that Janus kinases-signal transducer and activator of transcription (JAK-STAT) signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus. Recently, increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells. Signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development, respectively or synergically. These results reveal the potential application of Janus kinase inhibitors for treatment of pSS, which may fundamentally improve the quality of life and prognosis of patients with pSS.

Network models of protein phosphorylation, acetylation, and ubiquitination connect metabolic and cell signaling pathways in lung cancer

We analyzed large-scale post-translational modification (PTM) data to outline cell signaling pathways affected by tyrosine kinase inhibitors (TKIs) in ten lung cancer cell lines. Tyrosine phosphorylated, lysine ubiquitinated, and lysine acetylated proteins were concomitantly identified using sequential enrichment of post translational modification (SEPTM) proteomics. Machine learning was used to identify PTM clusters that represent functional modules that respond to TKIs. To model lung cancer signaling at the protein level, PTM clusters were used to create a co-cluster correlation network (CCCN) and select protein-protein interactions (PPIs) from a large network of curated PPIs to create a cluster-filtered network (CFN). Next, we constructed a Pathway Crosstalk Network (PCN) by connecting pathways from NCATS BioPlanet whose member proteins have PTMs that co-cluster. Interrogating the CCCN, CFN, and PCN individually and in combination yields insights into the response of lung cancer cells to TKIs. We highlight examples where cell signaling pathways involving EGFR and ALK exhibit crosstalk with BioPlanet pathways: Transmembrane transport of small molecules; and Glycolysis and gluconeogenesis. These data identify known and previously unappreciated connections between receptor tyrosine kinase (RTK) signal transduction and oncogenic metabolic reprogramming in lung cancer. Comparison to a CFN generated from a previous multi-PTM analysis of lung cancer cell lines reveals a common core of PPIs involving heat shock/chaperone proteins, metabolic enzymes, cytoskeletal components, and RNA-binding proteins. Elucidation of points of crosstalk among signaling pathways employing different PTMs reveals new potential drug targets and candidates for synergistic attack through combination drug therapy.

Promoter activity and transcriptome analyses decipher functions of CgbHLH001 gene (Chenopodium glaucum L.) in response to abiotic stress

BackgroundOur previous studies revealed that CgbHLH001 transcription factor (TF) played an important role in abiotic stress tolerance, suggesting that its promoter was a potential target in response to stress signals. In addition, the regulatory mechanism of CgbHLH001 TF is still limited.ResultsIn the present study, a 1512 bp of 5’-flanking sequence of CgbHLH001 gene was identified, and the sequence carried quite a few of cis-acting elements. The gene promoter displayed strong activity and was induced by multiple abiotic stress. A series of 5’-deletions of the promoter sequence resulted in a gradual decrease in its activity, especially, the 5’ untranslated region (UTR) was necessary to drive promoter activity. Further, CgbHLH001 promoter drove its own gene overexpression ectopically at the transcriptional and translational levels, which in turn conferred the stress tolerance to transgenic Arabidopsis. Transcriptome analysis showed that salt stress induced a large number of genes involved in multiple biological regulatory processes. Differentially expressed genes (DEGs) that mediate phytohormone signal transduction and mitogen-activated protein kinase (MAPK) signaling pathway were widely induced and mostly upregulated under salt stress, and the transcription levels in PbHLH::bHLH-overexpressing transgenic lines were higher than that of 35S::bHLH overexpression.ConclusionsThe CgbHLH001 promoter exhibited a positive response to abiotic stress and its 5’ UTR sequence enhanced the regulation of gene expression to stress. A few important pathways and putative key genes involved in salt tolerance were identified, which can be used to elucidate the mechanism of salt tolerance and decipher the regulatory mechanism of promoters to develop an adaptation strategy for desert halophytes.

Putative Role of Neutrophil Extracellular Trap Formation in Chronic Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) are hematologic malignancies characterized by gene mutations that promote myeloproliferation and resistance to apoptosis via constitutively active signaling pathways, with Janus kinase 2-signal transducers and the activators of transcription (JAK-STAT) axis as a core part. Chronic inflammation has been described as a pivot for the development and advancement of MPNs from early stage cancer to pronounced bone marrow fibrosis, but there are still unresolved questions regarding this issue. The MPN neutrophils are characterized by upregulation of JAK target genes, they are in a state of activation and with deregulated apoptotic machinery. Deregulated neutrophil apoptotic cell death supports inflammation and steers them towards secondary necrosis or neutrophil extracellular trap (NET) formation, a trigger of inflammation both ways. NETs in proinflammatory bone marrow microenvironment induce hematopoietic precursor proliferation, which has an impact on hematopoietic disorders. In MPNs, neutrophils are primed for NET formation, and even though it seems obvious for NETs to intervene in the disease progression by supporting inflammation, no reliable data are available. We discuss in this review the potential pathophysiological relevance of NET formation in MPNs, with the intention of contributing to a better understanding of how neutrophils and neutrophil clonality can orchestrate the evolution of a pathological microenvironment in MPNs.

Role of SOCS and VHL Proteins in Neuronal Differentiation and Development.

The basic helix-loop-helix factors play a central role in neuronal differentiation and nervous system development, which involve the Notch and signal transducer and activator of transcription (STAT)/small mother against decapentaplegic signaling pathways. Neural stem cells differentiate into three nervous system lineages, and the suppressor of cytokine signaling (SOCS) and von Hippel-Lindau (VHL) proteins are involved in this neuronal differentiation. The SOCS and VHL proteins both contain homologous structures comprising the BC-box motif. SOCSs recruit Elongin C, Elongin B, Cullin5(Cul5), and Rbx2, whereas VHL recruits Elongin C, Elongin B, Cul2, and Rbx1. SOCSs form SBC-Cul5/E3 complexes, and VHL forms a VBC-Cul2/E3 complex. These complexes degrade the target protein and suppress its downstream transduction pathway by acting as E3 ligases via the ubiquitin-proteasome system. The Janus kinase (JAK) is the main target protein of the E3 ligase SBC-Cul5, whereas hypoxia-inducible factor is the primary target protein of the E3 ligase VBC-Cul2; nonetheless, VBC-Cul2 also targets the JAK. SOCSs not only act on the ubiquitin-proteasome system but also act directly on JAKs to suppress the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway. Both SOCS and VHL are expressed in the nervous system, predominantly in brain neurons in the embryonic stage. Both SOCS and VHL induce neuronal differentiation. SOCS is involved in differentiation into neurons, whereas VHL is involved in differentiation into neurons and oligodendrocytes; both proteins promote neurite outgrowth. It has also been suggested that the inactivation of these proteins may lead to the development of nervous system malignancies and that these proteins may function as tumor suppressors. The mechanism of action of SOCS and VHL involved in neuronal differentiation and nervous system development is thought to be mediated through the inhibition of downstream signaling pathways, JAK-STAT, and hypoxia-inducible factor-vascular endothelial growth factor pathways. In addition, because SOCS and VHL promote nerve regeneration, they are expected to be applied in neuronal regenerative medicine for traumatic brain injury and stroke.

Magnesium Reduces Hepatic Lipid Accumulation in Yellow Catfish (Pelteobagrus fulvidraco) and Modulates Lipogenesis and Lipolysis via PPARA, JAK-STAT, and AMPK Pathways in Hepatocytes

BackgroundMagnesium influences hepatic lipid deposition in vertebrates, but the underlying mechanism is unknown. ObjectiveWe used yellow catfish and their isolated hepatocytes to test the hypothesis that magnesium influences lipid deposition by modulating lipogenesis and lipolysis. MethodsJuvenile yellow catfish (mean ± SEM weight: 3.43 ± 0.02 g, 3 mo old, mixed sex) were fed a 0.14- (low), 0.87- (intermediate) or 2.11- (high) g Mg/kg diet for 56 d. Primary hepatocytes were incubated for 48 h in control or MgSO4-containing medium with or without 2-h pretreatment with an inhibitor (AG490, GW6471, or Compound C). Growth performance, cell viability, triglyceride (TG) concentrations, and expression of enzymes and genes involved in lipid metabolism were measured. ResultsCompared with fish fed low magnesium, those fed intermediate or high magnesium had lower hepatic lipids (18%, 22%) and 6-phosphogluconate dehydrogenase (6PGD; 3.7%, 3.8%) and malic enzyme (ME; 35%, 48%) activities and greater mRNA levels of the lipolytic genes adipose triacylglyceride lipase (atgl; 82% and 1.7-fold) and peroxisome proliferator-activated receptor (ppara; 18% and 1.0-fold), respectively (P < 0.05). Relative mRNA levels of AMP-activated protein kinase (ampk) a1, ampka2, ampkb1, ampkb2, ampkg1a, ampkg1b, Janus kinase (jak) 2a, jak2b, and signal transducers and activators of transcription (stat) 3 in fish fed high magnesium were higher (24% to 3.1-fold, P < 0.05) than in those fed low or intermediate magnesium. Compared with cells incubated with MgSO4 alone, those incubated with MgSO4 and pretreated with AG490, GW6471, or Compound C had greater TG concentrations (42%, 31%, or 56%), g6pd (98%, 59%, or 51%), 6pgd (68%, 73%, or 32%) mRNA expression, and activities of G6PD (35%, 45%, or 16%) and ME (1.5-fold, 1.3-fold, or 13%), and reduced upregulation (61%, 25%, or 45%) of the lipolytic gene, atgl (P < 0.05). ConclusionsMagnesium reduced hepatic lipid accumulation in yellow catfish and the variation might be attributed to inhibited lipogenesis and increased lipolysis. PPARA, JAK-STAT, and AMPK pathways mediated the magnesium-induced changes in lipid deposition and metabolism. These results offer new insight into magnesium nutrition in vertebrates.

Quantitative fret studies of EphA2-Lyn interactions.

The regulation of the receptor tyrosine kinase (RTK) signal transduction pathways is critical for proper cellular function. RTK activation occurs in response to ligand binding, which induces RTK dimerization or oligomerization to allow cross-phosphorylation of specific tyrosines in the kinase domains of the RTK. Downstream signals are then propagated upon the recruitment of soluble kinases or adaptor proteins to these phoshorylated tyrosines. The EphA2 receptor tyrosine kinase is a member of the largest RTK family and has been reported to initiate downstream signaling by recruiting Lyn, a member of the Src family of non-receptor tyrosine kinases. Contrary to expectations, quantitative FRET experiments demonstrate that ligand-induced EphA2 tyrosine phosphorylation does not lead to Lyn recruitment to EphA2. In control experiments, Lyn is efficiently recruited by a different RTK, EGFR, upon ligand stimulation. The differential interactions of Lyn with EphA2 and EGFR may be a means of signal diversification. Current work is focused on the mechanism behind the unexpected lack of interactions between EphA2 and Lyn upon EphA2 clustering and phosphorylation.

Metabolomic and Transcriptome Analysis of the Inhibitory Effects of Bacillus subtilis Strain Z-14 against Fusarium oxysporum Causing Vascular Wilt Diseases in Cucumber

Controlling cucumber Fusarium wilt caused by Fusarium oxysporum f. sp. cucumerinum (FOC) with Bacillus strains is a hot research topic. However, the molecular mechanism of Bacillus underlying the biocontrol of cucumber wilt is rarely reported. In this study, B. subtilis strain Z-14 showed significant antagonistic activity against FOC, and the control effect reached 88.46% via pot experiment. Microscopic observations showed that strain Z-14 induced the expansion and breakage of FOC hyphae. The cell wall thickness was uneven, and the organelle structure was degraded. The combined analysis of metabolome and transcriptome showed that strain Z-14 inhibited the FOC infection by inhibiting the synthesis of cell wall and cell membrane, energy metabolism, and amino acid synthesis of FOC mycelium, inhibiting the clearance of reactive oxygen species (ROS) and the secretion of cell wall-degrading enzymes (CWDEs), thereby affecting mitogen-activated protein kinase (MAPK) signal transduction and inhibiting the transport function.

Protein content of blood-derived extracellular vesicles: An approach to the pathophysiology of cerebral hemorrhage.

Introduction: Extracellular vesicles (EVs) participate in cell-to-cell paracrine signaling and can be biomarkers of the pathophysiological processes underlying disease. In intracerebral hemorrhage, the study of the number and molecular content of circulating EVs may help elucidate the biological mechanisms involved in damage and repair, contributing valuable information to the identification of new therapeutic targets. Methods: The objective of this study was to describe the number and protein content of blood-derived EVs following an intracerebral hemorrhage (ICH). For this purpose, an experimental ICH was induced in the striatum of Sprague-Dawley rats and EVs were isolated and characterized from blood at baseline, 24 h and 28 days. The protein content in the EVs was analyzed by mass spectrometric data-dependent acquisition; protein quantification was obtained by sequential window acquisition of all theoretical mass spectra data and compared at pre-defined time points. Results: Although no differences were found in the number of EVs, the proteomic study revealed that proteins related to the response to cellular damage such as deubiquitination, regulation of MAP kinase activity (UCHL1) and signal transduction (NDGR3), were up-expressed at 24 h compared to baseline; and that at 28 days, the protein expression profile was characterized by a higher content of the proteins involved in healing and repair processes such as cytoskeleton organization and response to growth factors (COR1B) and the regulation of autophagy (PI42B). Discussion: The protein content of circulating EVs at different time points following an ICH may reflect evolutionary changes in the pathophysiology of the disease.

Effect on MAPK Signal Path of Lead, Nickel, Mercury, Cadmium and Chromium in Breast Cancer Cell Line

The harms of heavy metals such as cadmium and lead on human health have been identified in the literature. However, genetic mechanisms that show the relationship between heavy metals and cancer have not been identified up to now. In the proposed project, the effects of lead, nickel, mercury, cadmium, and chrome on the expression levels of mitogen-activated protein kinase signal transduction pathways in breast cancer cell lines will be quantified by the Real Time-Polymerase Chain Reaction method, comparatively. Mitogen-activated protein kinase signal transduction pathway, found in eukaryotic organisms, plays a significant role in information transfer from the cell membrane to the nucleus. Genes in this signal transfer regulate embryogenesis, reproduction, diversification, survival, and apoptosis functions. Most of these genes are well-known oncogenes and each of these is an important subject in cancer treatment. The changes of gene expression levels in this transduction pathway can be the reason of breast and some other cancer types. According to the findings, when the heavy metal-treated cells were compared with the heavy metal-untreated cells, significant changes were observed in the level of expression of 47 genes in the signal pathway. It has been determined that heavy metals cause changes in the expression level of genes in the signaling pathway according to the obtained data.

Analyzing the role of tofacitinib in treatment of alopecia areata: A retrospective analysis from a tertiary care center of North India

Background: Alopecia areata is a disease, in which patients’ loss hairs as random patches due to autoimmune complications. Tofacitinib acts as an inhibiter in the Janus kinase signal transducer and activator of transcription pathway and is an effective drug approved for the of rheumatoid arthritis treatment. Limited evidence is available on the role of tofacitinib in treatment of alopecia areata. Aim and Objective: The present study aims to evaluate the efficacy of tofacitinib in treatment of alopecia areata patients visiting the tertiary care center of North India. Materials and Methods: Total 17 patients with alopecia areata were recruited in this study and prescribed with the tofacitinib 5 mg twice daily for 6 months. Severity of alopecia tool (SALT) was used to analyze the severity of hair loss. The SALT score measures the total percent of hair loss in all area of scalp. A higher SALT score indicates higher hair loss. Results: The mean age of the patients was 27.88 ± 16.30 years with male-to-female sex ratio of 2.4:1. The mean duration of disease was 32.29 ± 22.14 months. There was a significant decrease in the SALT score (P = 0.0001) following the 6 months tofacitinib treatment. Conclusion: Tofacitinib was found to be effective in the treatment of alopecia areata. Further multicentric studies with ample sample size are required to establish tofacitinib as a standard treatment for the alopecia areata.

Upadacitinib-induced paradoxical face and scalp dermatitis: A case report of a novel sequela

Atopic dermatitis is a chronic, pruritic inflammatory cutaneous condition that can carry significant morbidity. Severe or recalcitrant atopic dermatitis is often treated with immunosuppressants, biologics, or immune-modulating small molecule therapies. The Janus kinase-signal transducer and activator of transcription pathway is highly implicated in atopic dermatitis pathogenesis, and agents that inhibit Janus kinase signalling are new to the atopic dermatitis landscape. Upadacitinib is a JAK1 inhibitor that has a good safety and efficacy profile and is increasingly being prescribed for atopic dermatitis. We report a case of a 35-year-old male with extensive atopic dermatitis that initially improved significantly on upadacitinib, then after 6 months developed a severe crusted dermatitic eruption on the head favouring a seborrheic distribution. While the pathogenesis of this paradoxical reaction is unclear, this phenomenon may involve a shift to a more Th1/Th17-mediated immune response.