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1.
Chem Biodivers ; : e202302080, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578653

RESUMO

Numerous chemical pesticides were employed for a long time to manage pests, but their uncontrolled application harmed the health and the environment. Accurately quantifying pesticide residues is essential for risk evaluation and regulatory purposes. Numerous analytical methods have been developed and utilized to achieve sensitive and specific detection of pesticides in intricate sampl es like water, soil, food, and air. Electrochemical sensors based on amperometry, potentiometry, or impedance spectroscopy offer portable, rapid, and sensitive detection suitable for on-site analysis. This study examines the potential of electrochemical sensors for the accurate evaluation of various effects of pesticides. Emphasizing the use of Graphene (GR), Graphene Oxide (GO), Reduced Graphene Oxide (rGO), and Graphdiyne composites, the study highlights their enhanced performance in pesticide sensing by stating the account of many actual sensors that have been made for specific pesticides. Computational studies provide valuable insights into the adsorption kinetics, binding energies, and electronic properties of pesticide-graphene complexes, guiding the design and optimization of graphene-based sensors with improved performance. Furthermore, the discussion extends to the emerging field of biopesticides. While the GR/GO/rGO based sensors hold immense future prospects, and their existing limitations have also been discussed, which need to be solved with future research.

2.
Am J Hematol ; 99(6): 1040-1055, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38440831

RESUMO

Myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocytosis, and primary myelofibrosis, are clonal hematopoietic neoplasms driven by mutationally activated signaling by the JAK2 tyrosine kinase. Although JAK2 inhibitors can improve MPN patients' quality of life, they do not induce complete remission as disease-driving cells persistently survive therapy. ERK activation has been highlighted as contributing to JAK2 inhibitor persistent cell survival. As ERK is a component of signaling by activated RAS proteins and by JAK2 activation, we sought to inhibit RAS activation to enhance responses to JAK2 inhibition in preclinical MPN models. We found the SHP2 inhibitor RMC-4550 significantly enhanced growth inhibition of MPN cell lines in combination with the JAK2 inhibitor ruxolitinib, effectively preventing ruxolitinib persistent growth, and the growth and viability of established ruxolitinib persistent cells remained sensitive to SHP2 inhibition. Both SHP2 and JAK2 inhibition diminished cellular RAS-GTP levels, and their concomitant inhibition enhanced ERK inactivation and increased apoptosis. Inhibition of SHP2 inhibited the neoplastic growth of MPN patient hematopoietic progenitor cells and exhibited synergy with ruxolitinib. RMC-4550 antagonized MPN phenotypes and increased survival of an MPN mouse model driven by MPL-W515L. The combination of RMC-4550 and ruxolitinib, which was safe and tolerated in healthy mice, further inhibited disease compared to ruxolitinib monotherapy, including extending survival. Given SHP2 inhibitors are undergoing clinical evaluation in patients with solid tumors, our preclinical findings suggest that SHP2 is a candidate therapeutic target with potential for rapid translation to clinical assessment to improve current targeted therapies for MPN patients.


Assuntos
Janus Quinase 2 , Transtornos Mieloproliferativos , Nitrilas , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Pirazóis , Pirimidinas , Janus Quinase 2/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Animais , Transtornos Mieloproliferativos/tratamento farmacológico , Humanos , Camundongos , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia
3.
New Phytol ; 242(5): 2251-2269, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38501480

RESUMO

The plant cuticle is a hydrophobic barrier, which seals the epidermal surface of most aboveground organs. While the cuticle biosynthesis of angiosperms has been intensively studied, knowledge about its existence and composition in nonvascular plants is scarce. Here, we identified and characterized homologs of Arabidopsis thaliana fatty acyl-CoA reductase (FAR) ECERIFERUM 4 (AtCER4) and bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferase 1 (AtWSD1) in the liverwort Marchantia polymorpha (MpFAR2 and MpWSD1) and the moss Physcomitrium patens (PpFAR2A, PpFAR2B, and PpWSD1). Although bryophyte harbor similar compound classes as described for angiosperm cuticles, their biosynthesis may not be fully conserved between the bryophytes M. polymorpha and P. patens or between these bryophytes and angiosperms. While PpFAR2A and PpFAR2B contribute to the production of primary alcohols in P. patens, loss of MpFAR2 function does not affect the wax profile of M. polymorpha. By contrast, MpWSD1 acts as the major wax ester-producing enzyme in M. polymorpha, whereas mutations of PpWSD1 do not affect the wax ester levels of P. patens. Our results suggest that the biosynthetic enzymes involved in primary alcohol and wax ester formation in land plants have either evolved multiple times independently or undergone pronounced radiation followed by the formation of lineage-specific toolkits.


Assuntos
Ceras , Ceras/metabolismo , Álcoois/metabolismo , Filogenia , Marchantia/genética , Marchantia/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Bryopsida/genética , Bryopsida/metabolismo , Briófitas/genética , Briófitas/metabolismo , Aldeído Oxirredutases/metabolismo , Aldeído Oxirredutases/genética , Vias Biossintéticas/genética , Evolução Molecular , Regulação da Expressão Gênica de Plantas , Aciltransferases/metabolismo , Aciltransferases/genética , Evolução Biológica , Arabidopsis/genética , Arabidopsis/metabolismo , Mutação/genética
4.
Am J Trop Med Hyg ; 109(1): 50-52, 2023 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-37188342

RESUMO

Leprosy is a chronic cutaneous infection. It is usually characterized by thickened nerves and maculo-anesthetic patches. Leprosy often has an unusual presentation, which is a diagnostic challenge. In this case report, we present a case of an elderly male who presented with fever and chronic pus-draining axillary, cervical, and inguinal lymph nodes. He also had a weak left foot for the previous 5 months. During his hospital stay, he developed additional papular lesions over his extremities. We performed fine needle aspiration from the lymph nodes and skin biopsy, which were suggestive of lepromatous leprosy. We initiated him on antileprosy medication. On follow-up, he was responsive to therapy. Although skin and nerve involvement in leprosy is common, this case had an atypical presentation of discharging lymph nodes.


Assuntos
Hanseníase Virchowiana , Hanseníase , Linfadenite , Humanos , Masculino , Idoso , Hanseníase Virchowiana/diagnóstico , Hanseníase Virchowiana/tratamento farmacológico , Hanseníase Virchowiana/patologia , Pele/patologia , Hanseníase/patologia , Linfadenite/diagnóstico , Linfadenite/tratamento farmacológico , Linfadenite/patologia , Supuração/patologia
5.
Eur J Immunol ; 52(11): 1842-1858, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36074916

RESUMO

IL-17-producing Th17 cells play an important role in pathogenesis of rheumatoid arthritis (RA). Aberrant immune activation due to an imbalance between Th17 and regulatory T (Treg) cells is associated with the development of RA and other autoimmune diseases. Targeting pathogenic Th17 cells and their associated molecules is emerging as a promising strategy to treat and reverse RA. Here, we demonstrate that IL-3 inhibits the differentiation of Th17 cells and promotes the development of Treg cells in IL-2-dependent manner. In IL-2 KO mice, we observed that IL-3 has no effect on differentiation of both Th17 and Treg cells. In addition, IL-3 decreases pathogenic IL-17A+ TNF-α+ , IL-17A+ IFN-γ+ and IL-23R+ Th17 cells, secretion of GM-CSF and IFN-γ, and osteoclastogenesis when presented in the culture together with Th17 polarizing cytokines. Mechanistically, IL-3 regulates the development of Th17 cells through the inhibition of STAT3 phosphorylation. IL-3 treatment significantly decreases the pathogenic Th17 cell responses and arthritic scores in the mouse model of RA. Importantly, IL-3 inhibits the differentiation of human Th17 cells. Thus, our results suggest a novel therapeutic role of IL-3 in the regulation of Th17 cell-mediated pathophysiology of RA.


Assuntos
Artrite Reumatoide , Diferenciação Celular , Interleucina-3 , Células Th17 , Animais , Humanos , Camundongos , Interleucina-17/metabolismo , Interleucina-2/metabolismo , Interleucina-3/metabolismo , Linfócitos T Reguladores/citologia , Células Th17/citologia
6.
J Exp Bot ; 73(22): 7450-7466, 2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36112045

RESUMO

The formation of a hydrophobic cuticle layer on aerial plant parts was a critical innovation for protection from the terrestrial environment during the evolution of land plants. However, little is known about the molecular mechanisms underlying cuticle biogenesis in early terrestrial plants. Here, we report an APETALA2/Ethylene Response Factor (AP2/ERF) transcriptional activator, PpWIN1, involved in cutin and cuticular wax biosynthesis in Physcomitrium patens and Arabidopsis. The transcript levels of PpWIN1 were 2.5-fold higher in gametophores than in the protonema, and increased by approximately 3- to 4.7-fold in the protonema and gametophores under salt and osmotic stresses. PpWIN1 harbouring transcriptional activation activity is localized in the nucleus of tobacco leaf epidermal cells. Δppwin1 knockout mutants displayed a permeable cuticle, increased water loss, and cutin- and wax-deficient phenotypes. In contrast, increased total cutin and wax loads, and decreased water loss rates were observed in PpWIN1-overexpressing Arabidopsis plants. The transcript levels of genes involved in cutin or wax biosynthesis were significantly up-regulated in PpWIN1-overexpressing Arabidopsis lines, indicating that PpWIN1 acts as a transcriptional activator in cuticle biosynthesis. This study suggests that Arabidopsis WIN1/SHN1 orthologs may be functionally conserved from early to vascular land plants.


Assuntos
Arabidopsis , Fatores de Transcrição , Fatores de Transcrição/genética , Arabidopsis/genética
7.
Blood Cancer J ; 12(1): 13, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-35082276

RESUMO

The Philadelphia chromosome negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocytosis, and myelofibrosis, are driven by hyper activation of the JAK2 tyrosine kinase, the result of mutations in three MPN driving genes: JAK2, MPL, and CALR. While the anti-inflammatory effects of JAK2 inhibitors can provide improved quality of life for many MPN patients, the upfront and persistent survival of disease-driving cells in MPN patients undergoing JAK2 inhibitor therapy thwarts potential for remission. Early studies indicated JAK2 inhibitor therapy induces heterodimeric complex formation of JAK2 with other JAK family members leading to sustained JAK2-dependent signaling. Recent work has described novel cell intrinsic details as well as cell extrinsic mechanisms that may contribute to why JAK2 inhibition may be ineffective at targeting MPN driving cells. Diverse experimental strategies aimed at uncovering mechanistic details that contribute to JAK2 inhibitor persistence have each highlighted the role of MEK/ERK activation. These approaches include, among others, phosphoproteomic analyses of JAK2 signaling as well as detailed assessment of JAK2 inhibition in mouse models of MPN. In this focused review, we highlight these and other studies that collectively suggest targeting MEK/ERK in combination with JAK2 inhibition has the potential to improve the efficacy of JAK2 inhibitors in MPN patients. As MPN patients patiently wait for improved therapies, such studies should further strengthen optimism that pre-clinical research is continuing to uncover mechanistic insights regarding the ineffectiveness of JAK2 inhibitors, which may lead to development of improved therapeutic strategies.


Assuntos
Janus Quinase 2/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Transtornos Mieloproliferativos/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Ativação Enzimática/efeitos dos fármacos , Humanos , Janus Quinase 2/metabolismo , Transtornos Mieloproliferativos/metabolismo , Policitemia Vera/tratamento farmacológico , Policitemia Vera/metabolismo , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/metabolismo
8.
Mater Today Proc ; 51: 939-946, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34189058

RESUMO

In this paper, the determined economic impact of the Medicine industry of the Coronavirus pandemic for aggravating items with a ramp-type demand with inflation effects in two-warehouse storage devices and wastewater treatment cost using PSO is developed. The owned warehouse has a fixed capacity of W units; rented warehouse has unlimited capacity. Here, we hypothesized that the Block chain Economic Impact of the Coronavirus Pandemic Medicine Industry in Inventory Cost of Inventory in RW is greater than that in OW using PSO. The shortcomings of the economic impact of the Coronavirus pandemic Medicine industry are allowed and partially lagged behind, and it is assumed that Block chain's economic impact of the Coronavirus medicine pandemic industry decreases over time with a variable deterioration rate and wastewater treatment cost using PSO. The effect of inflation was also considered due to the different costs associated with Blockchain applying the Economic Impact of the Coronavirus Medicine Industry Inventory System and wastewater treatment cost using PSO. The numerical sample is also used to study the behavior of the model using particle size optimization. The cost minimization technique is used to obtain expressions for total costs and other parameters.

9.
J Assoc Physicians India ; 70(11): 11-12, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37355943

RESUMO

OBJECTIVE: To study the prevalence of trigger factors and associated disorders in tension-type headache (TTH). Trigger factors have been widely studied in the context of migraine, but very few studies have investigated trigger factors in the context of TTH. MATERIALS AND METHODS: A total of 400 patients above the age of 15 years fulfilling the third edition of the International Classification of Headache Disorders (ICHD 3) criteria of frequent episodic tension-type headache (FETTH) and chronic tension-type headache (CTTH) were enrolled and evaluated using a questionnaire. Details regarding demographics, headache characteristics, triggers, and associated symptoms were obtained. Associated psychiatric disorders were also recorded. Data were analyzed using Microsoft Excel and statistical analysis was done using SPSS 22 trial version. Chi-square test and Fischer's exact test were used for statistical analysis and subgroup comparison. RESULTS: Out of 400 patients, 360 (90%) were found to have triggers. The mean headache intensity on visual analog scale (VAS) was 6.7. The most common trigger factor was emotional stress among both males and females. There was a statistically significant difference in the frequency of trigger factors between men and women for emotional stress, sunlight, sleep deprivation/insomnia, noise, weather change, studying, fried food, and hypersomnia. Psychiatric comorbidity was found in 29% of individuals, with sleep disorder being the most common. CONCLUSIONS: TTH has been an underrated diagnosis despite being an extremely common disorder. The trigger factors are less studied and their interactions are lesser known. The diagnostic criteria as per ICHD 3 make TTH a diagnosis of exclusion, rather than a positive diagnosis of inclusion. The trigger factors must be included in the diagnostic criteria in future versions of ICHD and associated psychiatric disorders should be sought for and treated simultaneously for better management and quality of life.


Assuntos
Cefaleia do Tipo Tensional , Masculino , Humanos , Feminino , Adolescente , Cefaleia do Tipo Tensional/epidemiologia , Cefaleia do Tipo Tensional/complicações , Cefaleia do Tipo Tensional/diagnóstico , Prevalência , Qualidade de Vida , Inquéritos e Questionários , Cefaleia
10.
ChemMedChem ; 16(12): 1927-1932, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33713036

RESUMO

A set of novel hydrazone derivatives were synthesized and analyzed for their biological activities. The compounds were tested for their inhibitory effect on the phosphorylating activity of the protein kinase CK2, and their antioxidant activity was also determined in three commonly used assays. The hydrazones were evaluated for their radical scavenging against the DPPH, ABTS and peroxyl radicals. Several compounds have been identified as good antioxidants as well as potent protein kinase CK2 inhibitors. Most hydrazones containing a 4-N(CH3 )2 residue or perfluorinated phenyl rings showed high activity in the radical-scavenging assays and possess nanomolar IC50 values in the kinase assays.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antioxidantes/farmacologia , Caseína Quinase II/antagonistas & inibidores , Fluorocarbonos/farmacologia , Hidrazonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Doença de Alzheimer/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Caseína Quinase II/metabolismo , Fluorocarbonos/síntese química , Fluorocarbonos/química , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Picratos/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ácidos Sulfônicos/antagonistas & inibidores
11.
Anal Methods ; 12(35): 4327-4333, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32840506

RESUMO

A novel, simple, sensitive and rapid spectrophotometric method for the determination of selenium(iv) in an acidic medium using rhodamine B hydrazide (RBH) has been developed. The method is based on the micellar mediated oxidation of RBH by Se(iv) in an acidic medium to produce a pinkish violet color of rhodamine B, which was monitored spectrophotometrically at λmax 585 nm. The sensitivity of the method was found to increase when the reaction was performed in a micellar medium. Beer's law was obeyed in the concentration range of 0.002-0.032 µg mL-1. The reaction variables such as time, temperature, reagent concentration, and acidity have been optimized for the reaction. Sandell's sensitivity and molar absorptivity for the reaction system were found to be 0.00004 µg cm-2 and 42.52 × 106 L mol-1 cm-1, respectively. The developed method was successfully applied for the determination of Se(iv) in several real samples with quantitative results.

12.
Cancers (Basel) ; 12(8)2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32823910

RESUMO

Myelofibrosis (MF) is a myeloproliferative neoplasm hallmarked by the upregulation of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway with associated extramedullary hematopoiesis and a high burden of disease-related symptoms. While JAK inhibitor therapy is central to the management of MF, it is not without limitations. In an effort to improve treatment for MF patients, there have been significant efforts to identify combination strategies that build upon the substantial benefits of JAK inhibition. Early efforts to combine agents with additive therapeutic profiles have given way to rationally designed combinations hoping to demonstrate clinical synergism and modify the underlying disease. In this article, we review the preclinical basis and existing clinical data for JAK inhibitor combination strategies while highlighting emerging strategies of particular interest.

13.
Turk J Obstet Gynecol ; 17(1): 46-51, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32341830

RESUMO

OBJECTIVE: Malignant melanoma of the genital tract comprises 3% of all melanomas afflicting females. They are characterized by poor prognosis with 5-year survival of 0-25% and high incidence for distant metastasis. This study was performed to assess various clinical features, treatment options, and thre management of genital melanomas. MATERIALS AND METHODS: This was a retrospective analysis where records of patients with genital melanomas between 2005 to 2018 were reviewed to obtain demographic and clinical information, including age of diagnosis, presenting symptoms, performance status, pathology reports, treatment, follow-up, and survival. RESULTS: Between 2005 and 2018, 31 women were analyzed. The median age was 53.5 (range: 28.5-85) years. Vaginal bleeding was the most common presenting symptom (80.6%), followed by discharge (29%), mass in the vagina/perineum (19.3%), pain (16.1%), and difficulty in micturition (9.6%). The most common site of origin was the vagina (67.7%), followed by that vulva (19.3%) and cervix (12.9%). Tumor diameter was more than 3 cm in 74.2% (23/31). Out of 31 patients, only 16 opted for treatment. Four patients underwent surgery, 10 received primary chemotherapy, and two needed palliative radiotherapy for heavy bleeding. The median survival in the treatment group was 5 (range: 2.5-28) months, almost similar to patients not receiving any treatment (5 months, range: 2-11). CONCLUSION: Genital melanoma are rare but aggressive tumors. Diagnosis is usually made with biopsy. No effective treatment strategy is yet available. However, surgery is the preferred first- line treatment, radiotherapy and chemotherapy have been used in adjuvant settings.

14.
New Phytol ; 225(6): 2468-2483, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31691980

RESUMO

During the evolution of land plants from aquatic to terrestrial environments, their aerial surfaces were surrounded by cuticle composed of cutin and cuticular waxes to protect them from environmental stresses. Glycerol-3-phosphate acyltransferase (GPAT) harboring bifunctional sn-2 acyltransferase/phosphatase activity produces 2-monoacylglycerol, a precursor for cutin synthesis. Here, we report that bifunctional sn-2 GPATs play roles in cuticle biosynthesis and gametophore development of Physcomitrella patens. Land plant-type cuticle was observed in gametophores but not in protonema. The expression of endoplasmic reticulum-localized PpGPATs was significantly upregulated in gametophores compared with protonema. Floral organ fusion and permeable cuticle phenotypes of Arabidopsis gpat6-2 petals were rescued to the wild type (WT) by the expression of PpGPAT2 or PpGPAT4. Disruption of PpGPAT2 and PpGPAT4 caused a significant reduction of total cutin loads, and a prominent decrease in the levels of palmitic and 10,16-dihydroxydecanoic acids, which are major cutin monomers in gametophores. Δppgpat2 mutants displayed growth retardation, delayed gametophore development, increased cuticular permeability, and reduced tolerance to drought, osmotic and salt stresses compared to the WT. Genome-wide analysis of genes encoding acyltransferase or phosphatase domains suggested that the occurrence of sn-2 GPATs with both domains may be a key event in cuticle biogenesis of land plants.


Assuntos
Bryopsida , Glicerol-3-Fosfato O-Aciltransferase/genética , Aciltransferases/genética , Aciltransferases/metabolismo , Bryopsida/genética , Bryopsida/metabolismo , Regulação da Expressão Gênica de Plantas , Glicerol , Fosfatos
15.
Blood Adv ; 3(22): 3503-3514, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31725895

RESUMO

Aberrant JAK2 tyrosine kinase signaling drives the development of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. However, JAK2 kinase inhibitors have failed to significantly reduce allele burden in MPN patients, underscoring the need for improved therapeutic strategies. Members of the PIM family of serine/threonine kinases promote cellular proliferation by regulating a variety of cellular processes, including protein synthesis and the balance of signaling that regulates apoptosis. Overexpression of PIM family members is oncogenic, exemplified by their ability to induce lymphomas in collaboration with c-Myc. Thus, PIM kinases are potential therapeutic targets for several malignancies such as solid tumors and blood cancers. We and others have shown that PIM inhibitors augment the efficacy of JAK2 inhibitors by using in vitro models of MPNs. Here we report that the recently developed pan-PIM inhibitor INCB053914 augments the efficacy of the US Food and Drug Administration-approved JAK1/2 inhibitor ruxolitinib in both in vitro and in vivo MPN models. INCB053914 synergizes with ruxolitinib to inhibit cell growth in JAK2-driven MPN models and induce apoptosis. Significantly, low nanomolar INCB053914 enhances the efficacy of ruxolitinib to inhibit the neoplastic growth of primary MPN patient cells, and INCB053914 antagonizes ruxolitinib persistent myeloproliferation in vivo. These findings support the notion that INCB053914, which is currently in clinical trials in patients with advanced hematologic malignancies, in combination with ruxolitinib may be effective in MPN patients, and they support the clinical testing of this combination in MPN patients.


Assuntos
Inibidores de Janus Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirazóis/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Xenoenxertos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Nitrilas , Pirimidinas , Transdução de Sinais/efeitos dos fármacos
16.
Am J Cancer Res ; 9(12): 2634-2649, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31911851

RESUMO

AML, the second most common childhood leukemia is also one of the deadliest cancers. High mortality rate in AML is due to high incidence of relapse after complete remission with chemotherapy and inadequate prognostic assessment of patients. Moreover, there is dearth of therapeutic targets for treatment of this malignancy. Previous pilot study (n = 24) by our group revealed strong association between cathepsin B (CTSB) overexpression in peripheral blood mononuclear cells (PBMCs) and poor survival outcome in pediatric AML patients. To further explore the clinical utility and role of this protease in pediatric AML, we measured its enzymatic activity and mRNA expression in PBMCs as well as bone marrow mononuclear cells (BMMCs) of patients (n = 101) and PBMCs of healthy controls. Our results revealed elevated CTSB activity (P < 0.01) and overexpression of its mRNA (P < 0.01) in AML patients. Interestingly CTSB in BMMCs of patients emerged as an independent prognostic marker when compared with other known risk factors. Moreover, chemical inhibition of CTSB activity compromised survival, and induced apoptosis in an AML cell line THP-1. We further demonstrate the inhibition of CTSB activity by chemotherapeutic agent doxorubicin in these cells. Docking and simulation studies suggested the binding of doxorubicin to CTSB with higher affinity than its known specific inhibitor CA-074 Me, thereby indicating that cell death induced by this drug may at least partly be mediated by CTSB inhibition. CTSB, therefore, may serve as a prognostic marker and an attractive chemotherapeutic target in pediatric AML.

17.
Adv Biochem Eng Biotechnol ; 164: 237-261, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29356846

RESUMO

The genetic material DNA in association with histone proteins forms the complex structure called chromatin, which is prone to undergo modification through certain epigenetic mechanisms including cytosine DNA methylation, histone modifications, and small RNA-mediated methylation. Alterations in chromatin structure lead to inaccessibility of genomic DNA to various regulatory proteins such as transcription factors, which eventually modulates gene expression. Advancements in high-throughput sequencing technologies have provided the opportunity to study the epigenetic mechanisms at genome-wide levels. Epigenomic studies using high-throughput technologies will widen the understanding of mechanisms as well as functions of regulatory pathways in plant genomes, which will further help in manipulating these pathways using genetic and biochemical approaches. This technology could be a potential research tool for displaying the systematic associations of genetic and epigenetic variations, especially in terms of cytosine methylation onto the genomic region in a specific cell or tissue. A comprehensive study of plant populations to correlate genotype to epigenotype and to phenotype, and also the study of methyl quantitative trait loci (QTL) or epiGWAS, is possible by using high-throughput sequencing methods, which will further accelerate molecular breeding programs for crop improvement. Graphical Abstract.


Assuntos
Epigênese Genética , Epigenômica , Plantas/genética , Metilação de DNA , Histonas/metabolismo
18.
Leuk Lymphoma ; 59(9): 2175-2187, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29345177

RESUMO

Overexpression of cathepsin L (CTSL), an endolysosomal cysteine protease, is associated with inferior survival of patients with various human malignancies. We evaluated the expression/activity of CTSL in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of 103 pediatric acute myeloid leukemia (AML) patients to assess its prognostic significance in this malignancy. Thirty-five healthy siblings of patients served as controls. Our results revealed significantly higher CTSL activity (p < .0001), protein (p < .05), and mRNA levels (p < .01) in both PBMCs and BMMCs of patients as compared with controls. BMMCs displayed higher activity of CTSL than PBMCs (p < .01). A dramatic reduction in CTSL activity was recorded after chemotherapy in a significant proportion (74%) of patients (p < .0001). By multivariate analysis, CTSL in BMMCs emerged as a strong independent prognostic marker for overall survival (OS) (p = .004). Thus, our results suggest the potential utility of CTSL in predicting the outcome of pediatric AML.


Assuntos
Células da Medula Óssea/enzimologia , Catepsina L/metabolismo , Leucemia Mieloide Aguda/enzimologia , Leucócitos Mononucleares/enzimologia , Adolescente , Células da Medula Óssea/metabolismo , Catepsina L/genética , Criança , Pré-Escolar , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucócitos Mononucleares/metabolismo , Masculino , Análise Multivariada , Prognóstico
19.
J Ayurveda Integr Med ; 9(3): 169-176, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29102462

RESUMO

BACKGROUND: The quality of herbal medicine is determined by its secondary metabolites, which may vary according to growth, season and altitude etc. OBJECTIVE: We studied the variation in phytochemistry and biological activities of Thalictrum foliolosum (TF) roots collected from four sites at different altitudes. MATERIAL AND METHODS: The berberine content in different extracts of T. foliolosum roots collected from various altitudes was estimated using HPTLC. Total phenolic and flavonoid contents were determined using Folin-Ciocalteau reagent and aluminum chloride method respectively. The sensitivity of microbes for the extracts was studied using disc diffusion and the MIC was estimated using broth dilution method. Antioxidant capacity of the plant was studied using ß-carotene bleaching assay, lipid peroxidation assay using goat liver, reducing power assay and DPPH free radical scavenging activity. RESULTS: Berberine content varied inversely with altitude; while phenol and flavonoid content of TF increased at higher altitudes. All the TF extracts showed moderate to high activity against Candida albicans, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Extracts with high berberine content were most effective against C. albicans and S. aureus and also showed relatively significant anti-lipid peroxidation, ß-carotene bleaching and reducing power. TF extracts with higher phenol and flavonoid content showed better scavenging of DPPH free radicals. Berberine was used as a standard in all the antioxidant and antimicrobial experiments performed. CONCLUSION: Thalictrum from lower elevations can be explored as an alternate source of berberine and the plant has high antioxidant and antimicrobial properties owing to its berberine content.

20.
Front Microbiol ; 8: 1897, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29021789

RESUMO

A plant growth promoting bacterial endophyte designated as AL2-14B isolated from the leaves of Achyranthes aspera L. was identified as Pseudomonas aeruginosa based on its phenotypic and physiological features, and 16S rRNA gene sequence analysis. AL2-14B had plant growth stimulating attributes including siderophore and indole acetic acid release, inorganic phosphate solubilization, along with nitrogenase, ammonification, and protease activities. It also exhibited antifungal property against Rhizoctonia solani. The plantlets grown in germ-free condition were inoculated with AL2-14B and studied for the colonization of endophyte. Significant increase in population of AL2-14B between 3rd and 5th days after inoculation was recorded. The treatment of plants with endophytic P. aeruginosa AL2-14B increased nitrogen, phosphorus, potassium (NPK) contents in plant by 3.8, 12.59, and 19.15%, respectively. Significant enhancement of shoot and root length, dry leaf, dry shoot and dry root weight, and leaf surface area as compared to control (P < 0.05) was recorded in AL2-14B inoculated plants. The antioxidant activities increased in plants grown in germ-free conditions and inoculated with AL2-14B. The present study emphasizes on the role of diazotrophic endophyte P. aeruginosa AL2-14B in stimulating growth of A. aspera L. and improvement of its medicinal properties. Significant increase in growth and antioxidant content of P. aeruginosa AL2-14B treated plants suggests the possibility of an economical and eco-friendly mean of achieving antioxidants rich, healthier A. aspera plants.

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