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Background: The advent and increased use of high-resolution ultrasonography has resulted in improved detection of thyroid nodules. Even with the use of various Thyroid Imaging-Reporting and Data System, accurate imaging diagnosis of malignant thyroid nodules has been suboptimal, which necessitated use of newer modalities like contrast-enhanced ultrasonography alone and in combination for this purpose. Although the combined use of various Thyroid Imaging-Reporting and Data System and contrast-enhanced ultrasonography has turned out to be accurate in many studies, the ideal way to integrate contrast-enhanced ultrasonography into the Thyroid Imaging-Reporting and Data System algorithm is under-investigated. Purpose: To estimate and compare the diagnostic accuracy of American College of Radiology Thyroid Imaging-Reporting and Data System and contrast-enhanced ultrasonography in differentiating benign and malignant nodules alone and in combination. To estimate the diagnostic accuracy of contrast-enhanced ultrasonography in re-categorisation of Thyroid Imaging-Reporting and Data System 3 and Thyroid Imaging-Reporting and Data System 4 thyroid nodules. Materials and methods: This was a prospective cohort study performed in a tertiary care university-based hospital for 3 years. Adult patients with clinical or previous sonographic diagnosis of thyroid nodules were selected. Each of the nodules were assessed using ultrasonography and categorised using American College of Radiology Thyroid Imaging-Reporting and Data System criteria. The lesion was then assessed for contrast-enhanced ultrasonography features. The final diagnosis of the nodules was made using fine needle aspiration cytology. The diagnostic accuracy in diagnosis of malignant thyroid nodules for each of the American College of Radiology Thyroid Imaging-Reporting and Data System and contrast-enhanced ultrasonography alone and in combination was assessed. The diagnostic accuracy of contrast-enhanced ultrasonography in diagnosis of malignant thyroid nodules categorised as Thyroid Imaging-Reporting and Data System 3 and Thyroid Imaging-Reporting and Data System 4 was also assessed. Results: American College of Radiology Thyroid Imaging-Reporting and Data System had a sensitivity, specificity, negative predictive value, positive predictive value and diagnostic accuracy of 86.6%, 54.5%, 17.4%, 97.3% and 57.7%, respectively, in diagnosis of malignant thyroid nodules. Contrast-enhanced ultrasonography had a sensitivity, specificity, negative predictive value, positive predictive value and diagnostic accuracy of 86.6%, 95.4%, 67.9%, 98.4% and 94.4%, respectively, in diagnosis of malignant thyroid nodules. Contrast-enhanced ultrasonography had sensitivity, specificity, negative predictive value, positive predictive value and diagnostic accuracy of 93.3%, 100.0%, 100.0%, 99.2% and 99.3%, respectively, in re-categorisation of Thyroid Imaging-Reporting and Data System 3 and Thyroid Imaging-Reporting and Data System 4 nodules. Conclusion: Contrast-enhanced ultrasonography can play a key role in diagnosis of malignant thyroid nodules which are categorised as indeterminate on grey-scale ultrasound.
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BACKGROUND: Muscle diseases are of various types, viz., muscular dystrophies, inflammatory myopathies, myotonic disorders, congenital myopathies, and metabolic myopathies. They all present with muscle weakness, be it proximal or distal. The assessment of muscle biopsy with the help of enzyme histochemistry, histopathological, and immunohistochemical methods is an essential component in the diagnosis of neuromuscular disorders. The authors outline brief data on muscle diseases prevalent in the North Indian region. METHODS: Muscle biopsy was done, and the biopsy was freshly frozen in liquid nitrogen and sections were taken on a cryostat. Slides were then stained with hematoxylin and eosin (H&E), modified Gomori trichome (MGT), nicotinamide adenine dinucleotide hydrogenase (NADH), and succinic dehydrogenase (SDH) stains. Further specific immunohistochemistry tests were also done. RESULT: Out of n=16 cases, three cases were diagnosed as Becker's muscular dystrophy, two cases were diagnosed as inflammatory myopathy, four cases were diagnosed as Facioscapulohumeral muscular dystrophy, and one each case of dysferlinopathy and alpha sarcoglycanopathy. CONCLUSION: Muscle diseases can cause different levels of physical disability and thus it is important to diagnose at the appropriate time to ensure proper treatment.
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Arachis hypogea L. protein fraction-2 (AHP-F2) from the Peanut shell was extracted and characterized and its potent immunomodulatory and anti-leishmanial role was determined in this present study. AHP-F2 was found to be a glycoprotein as the presence of carbohydrates were confirmed by the analysis of high-performance liquid chromatography (HPLC) yielded glucose, galactose, mannose, and xylose. AHP-F2 molecular mass was found to be â¼28 kDa as indicated in MALDI-TOF and peptide mass fingerprinting analysis followed by Mascot search. The peptide matches revealed the similarity of the mannose/glucose binding lectin with 71.07% in the BLAST analysis. After that, the 3D structure of the AHP-F2 model was designed and validated by the Ramachandran plot. The immunomodulatory role of AHP-F2 was established in murine peritoneal macrophages as induction of nitric oxide (NO), and stimulation of proinflammatory cytokines (IL-12 and IFN-γ) in a dose-dependent manner was observed. Interestingly, it was also found that AHP-F2 has interacted with the innate immune receptor, toll-like receptors (TLRs) as established in molecular docking as well as mRNA expression. The anti-leishmanial potential of AHP-F2 was revealed with a prominent inhibition of amastigote growth within the murine macrophages with prompt induction of nitrite release. Altogether, the isolated AHP-F2 from Arachis hypogea L. has strong immunomodulatory and anti-leishmanial potential which may disclose a new path to treat leishmaniasis.
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Arachis , Leishmania donovani , Animales , Ratones , Manosa , Activación de Macrófagos , Simulación del Acoplamiento Molecular , Glicoproteínas , Glucosa , Leishmania donovani/metabolismo , Óxido Nítrico/metabolismo , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Oct4 has critical role in maintaining pluripotency, proliferative potential, and self-renewal capacity in embryonic stem and germ cells. Although Oct4 has been shown to be upregulated in many cancers, its clinical significance in gallbladder carcinoma is poorly understood. METHODS: We studied the expression profile of Oct4 in 61 GBC and 30 chronic cholecystitis (as control) using real time RT-PCR, western blotting, and immunohistochemistry. The expression data was correlated with clinico-pathological parameters. The diagnostic utility was assessed through ROC curve, and prognostic value was analyzed by Kaplan-Meier method. RESULTS: Oct4 was significantly upregulated at mRNA as well as protein levels. The higher mRNA expression shows significant association with late stage, late T stage, and higher grade of tumor. A significant positive correlation was also observed with stage, T stage, and tumor grade. Sum score analysis of protein expression shows positive correlation with stage and the presence or absence of gallstone in tumor samples. The ROC curve analysis revealed the moderate diagnostic potential of Oct4. Kaplan-Meier analysis showed that patients having higher expression of Oct4 were having low mean survival compared with the patients with lower Oct4 expression. CONCLUSION: In conclusion, our data suggests that higher expression of Oct4 may serve as potential biological indicator for tumor aggressiveness and poor prognosis of GBC.
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Neoplasias de la Vesícula Biliar , Factor 3 de Transcripción de Unión a Octámeros , Humanos , Neoplasias de la Vesícula Biliar/diagnóstico , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/patología , Factor 3 de Transcripción de Unión a Octámeros/genética , Colecistitis/genética , Biomarcadores de Tumor/genética , Pronóstico , India , Análisis de SupervivenciaRESUMEN
BACKGROUND: Previously, we have reported that PARP1 rs1136410 is significantly associated with increased the risk of gallbladder cancer. AIM: We aimed to investigate the association of PARP1 rs1805405 and rs3219088 polymorphisms with risk of GBC and also association of the haplotype and combined effect of PARP1 SNPs (rs1805405 G/A, rs3219088 G/T and rs1136410 A/G). We have also investigated the expression profile of PARP1 and its correlation with polymorphisms, clinical parameters and overall survival. METHODS: PARP1 polymorphisms were genotyped by PCR-RFLP and the expression profile of PARP1 at mRNA level was analyzed by semi-quantitative PCR. Overall survival was analyzed using Kaplan-Meier plot and Cox-regression analysis. RESULTS: Haplotype analysis of the PARP1 polymorphisms revealed that AGG, AAG and GGT haplotypes are significantly associated with decreased risk of GBC, while AAT, AGT, GGG and GAG haplotypes are significantly associated with increased risk of GBC. Patients with T1+T2 and treated with chemotherapy having risk genotypes of rs1805405 have decreased overall survival. Upregulation of PARP1 is significantly associated with longer overall survival in patients with GBC with different clinical parameters. SNPs rs1136410 and rs1805405 genotypes are significantly associated with PARP1 expression. CONCLUSION: Haplotype analysis suggests that PARP1 may have a potential role in gallbladder carcinogenesis.
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Carcinoma in Situ , Neoplasias de la Vesícula Biliar , Humanos , Haplotipos , Neoplasias de la Vesícula Biliar/genética , Desequilibrio de Ligamiento , Predisposición Genética a la Enfermedad , Genotipo , Polimorfismo de Nucleótido Simple , Poli(ADP-Ribosa) Polimerasa-1/genéticaRESUMEN
The ectopic ureter and paraureteric diverticulum are 2 known common urological anomalies of pediatric patients. Another rare entity is inverted-Y ureteric duplication. We report a case of a 3-month-old boy presented with bladder outlet obstruction, where surgical excision of large bladder diverticulum with left ureter and small kidney was done. Histopathology confirmed the presence of inverted-Y ureteric duplication with left dysplastic kidney. The report defines the first case of infantile bladder outlet obstruction having the co-existing congenital genitourinary anomaly of inverted Y-partial ureteric duplication with obstructive ectopic ureter and ipsilateral paraureteric diverticula.
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Divertículo , Uréter , Obstrucción Ureteral , Obstrucción del Cuello de la Vejiga Urinaria , Masculino , Humanos , Lactante , Niño , Obstrucción del Cuello de la Vejiga Urinaria/etiología , Obstrucción del Cuello de la Vejiga Urinaria/complicaciones , Pelvis Renal/patología , Uréter/anomalías , Riñón/patología , Obstrucción Ureteral/diagnóstico , Obstrucción Ureteral/etiología , Obstrucción Ureteral/cirugía , Divertículo/complicaciones , Divertículo/diagnóstico , Divertículo/cirugíaRESUMEN
The present study aimed to validate the potential of a novel serine protein protease inhibitor (PPI), purified from marine Oceanimonas sp. BPMS22, induced M2 to M1 repolarization of the macrophages to treat visceral leishmaniasis (VL). Peptide mass fingerprint of the purified trypsin digested PPI peptide was obtained using matrix-assisted laser desorption ionization-time of flight combined with tandem mass spectrometry (MALDI-TOF MS/MS) and the sequence was used to construct a 3D protein model by homology modelling. The IC50 of PPI were 25.28 ± 1.675 µg/mL and 0.415 ± 0.015 µg/mL against promastigotes and intracellular amastigotes, respectively, indicating the host-directed therapy using PPI. The PPI enhanced the effector molecule i.e., nitric oxide (NO), and dampened the arginase activity in a dose-dependent manner. In vitro studies revealed that the BPMS22-derived PPI significantly (p < 0.05) decreased the mRNA expressions of M2 markers (FIZZ-1, YM-1, CD206, Arg-1) and increased the mRNA expressions of M1 markers (iNOS, IL-1ß, IL-12) in rIL-4 + rIL-10 induced M2 macrophages. Interestingly, the BPMS22-derived PPI also significantly (p < 0.05) decreased the FIZZ-1, YM-1, CD206, and Arg-1; significantly (p < 0.05) increased iNOS, IL-12, and IFN-γ mRNA expression in L. donovani -infected murine macrophages, alongside the decreased parasite load in it. Hence, PPI has the potential to repolarize the cytokines (rIL-4 + rIL-10) pre-stimulated and L. donovani-infected M2 macrophages to M1 phenotype in vitro. A decrease in parasite burden after treatment with PPI indicated the acceleration of the parasite killing by enhancing the macrophage effector functions. Further, in vivo PPI treatment reduced hepatic and splenic Leishman donovan units (LDU) up to 93.34 % and 87.63 %, respectively. This was followed by a surge in pro-inflammatory cytokines and dampening anti-inflammatory cytokines (p < 0.01), which exhibited anti-VL immunity. These observations might open new perspectives on PPI in macrophage repolarization to treat VL.
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Leishmania donovani , Leishmaniasis Visceral , Ratones , Animales , Óxido Nítrico/metabolismo , Arginasa/metabolismo , Inhibidores de Proteasas/metabolismo , Tripsina/metabolismo , Espectrometría de Masas en Tándem , Macrófagos , Citocinas/metabolismo , Interleucina-12/metabolismo , Inmunidad , Serina/metabolismo , ARN Mensajero/metabolismoRESUMEN
Angiogenesis is a critical step of wound healing, and its failure leads to chronic wounds. The idea of restoring blood flow to the damaged tissues by promoting neo-angiogenesis is lucrative and has been researched extensively. Vascular endothelial growth factor (VEGF), a key dynamic molecule of angiogenesis has been investigated for its functions. In this review, we aim to appraise its biology, the comprehensive role of this dynamic molecule in the wound healing process, and how this knowledge has been translated in clinical application in various types of wounds. Although, most laboratory research on the use of VEGF is promising, its clinical applications have not met great expectations. We discuss various lacunae that might exist in making its clinical application unsuccessful for commercial use, and provide insight to the foundation for future research.
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Factor A de Crecimiento Endotelial Vascular , Cicatrización de Heridas , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial VascularRESUMEN
White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.
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Tejido Adiposo Blanco , Atlas como Asunto , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedades Metabólicas , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/metabolismo , Adiposidad , Animales , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Ratones , Obesidad/metabolismoRESUMEN
BACKGROUND: Epigenetic alterations have been reported as one of the risk factors of gallbladder cancer. Promoter hypermethylation is associated with high incidence and poor prognosis of GBC. Bcl-2/adenovirus E1B 19 kDa interacting protein 3 is a pro-apoptotic protein member of Bcl-2 family. AIMS: Present study was aimed to investigate expression profile and promoter methylation status of BNIP3 in GBC and its correlation with clinico-pathological parameters. METHODS: The expression analysis and methylation status of BNIP3 was performed by semi-quantitative reverse transcription polymerase chain reaction and Methylation-specific polymerase chain reaction respectively in 84 GBC patients and 29 gallstone tissues (used as normal controls). RESULTS: We demonstrate down regulation of BNIP3 in 56% of the GBC samples. BNIP3 promoter is also frequently hypermethylated (69%) in GBC samples. Interestingly, we found that 69% (40/58) of the BNIP3 promoter hypermethylated samples had also reduced expression of BNIP3. Our data demonstrate significant correlation of the mRNA expression and promoter hypermethylation with late stage and nodal metastasis. Hypermethylation of BNIP3 promoter is associated with low overall survival period. CONCLUSION: Our results suggest that promoter hypermethylation is an early event and can be a frequent mechanism for downregulation of BNIP3 in GBC.
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Neoplasias de la Vesícula Biliar , Metilación de ADN , Regulación hacia Abajo , Humanos , Proteínas de la Membrana , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
Background: The use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors for breast cancer (BC) therapy is the subject of debate, and there is an urgent need to understand much the expression and prognostic role of the PARP1 protein. In this study, we have compared the expression of PARP between BC and benign breast disease (BBD) patients and also analyzed the association of PARP expression with clinicopathological parameters in BC. Methods: The study consists of 30 patients with newly diagnosed operable BC who were planned for surgery without neoadjuvant chemotherapy and 15 patients of BBD as a control between 2019 and 2021. Immunohistochemical analyses were performed prospectively on tissue samples. Anti-human PARP1 rabbit polyclonal antibody gives strong nuclear positivity. Internal control was the adipose tissue and the BBD acted as the external control. PARP1 expression was evaluated using the multiplicative quickscore method. Results: The mean age for BC patients was 51.30 ± 10.694 years (range: 25-75 years) while BBD was below 30 years. Overexpression of PARP was present in 25 (83.3%) and weak expression in 5 (16.7%) of BC patients compared to BBD, only 2 (13.3%) patients demonstrated an overexpression of PARP, and 13 (86.6%) patients showed weak expression which showed significant association (P < 0.001). In BC, nuclear PARP (nPARP) overexpression was seen in 22 (73.3%) patients and weak expression of nPARP in 8 (26.7%), whereas 5 (16.7%) patients showed cytoplasmic overexpression. On comparing expression of PARP with clinicopathological parameters, PARP overexpression was significantly associated with older population (age >50 years) (P = 0.002), postmenopausal women (P = 0.029), higher TNM stage (Stage II and III) (P = 0.014), higher histological grade (grade 2) (P = 0.043), and presence of lymphovascular invasion (P = 0.015). Enhanced PARP1 expression is closely correlated with positive estrogen receptor status (P = 0.001) and PR status (P = 0.001). Overall PARP and nPARP overexpression was significantly associated with ER- (P = 0.006 and P = 0.008) and PR-positive (P = 0.006 and P = 0.008) patients. The PARP and nPARP overexpression was significantly associated with nontriple-negative BC patients (P = 0.001 and P = 0.001). Conclusion: We have not come across any study in the literature to compare PARP expression in BC and BBD patients. On the basis of our observations, we concluded that PARP overexpression is a poor prognostic marker in BC.
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OBJECTIVES: Leukemia is one of the severe cancer types all around the globe. Even though some chemotherapeutic drugs are available for treating leukemia, they have various side effects. As an alternative approach, herbal drugs are focused on current research to overcome leukemia. The present work was conducted to investigate the antileukemic mechanism of active phytochemical vitexin, which was isolated from ethno-medicine (Prosopis cineraria leaf) used by traditional healers of West Bengal, India. METHODS: Antiproliferative mechanisms of selected phyto-compound against K-562 cells were evaluated using cellular uptake, morphological changes, DNA fragmentation, mitochondrial membrane potential and signaling pathways analysis. KEY FINDINGS: Vitexin exhibited cytotoxicity by reducing mitochondrial membrane potential (32.40%) and causing DNA fragmentation (84.15%). The western blotting study indicated inhibition of cell survival proteins (BCR, ABL, H-RAS, N-RAS, K-RAS and RAF) and expression of apoptotic proteins (p38, BAX and caspase-9) in leukemia cells upon treatment with vitexin. CONCLUSIONS: Based on the results, presently investigated phyto-compound vitexin could be considered for developing safe and natural drugs to treat leukemia after conducting suitable preclinical and clinical trials.
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Apigenina/farmacología , Proteínas Oncogénicas v-abl/metabolismo , Prosopis , Proteínas Proto-Oncogénicas c-bcr/metabolismo , Quinasas raf/metabolismo , Proteínas ras/metabolismo , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fitoquímicos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
INTRODUCTION: Down regulation of DLC1 is associated with poor prognosis in many cancers, however, its role in gallbladder cancer (GBC) is still unclear. In present study, we investigated the expression profile and promoter methylation status of DLC1. METHODS: Expression profiles of DLC1 in 55 GBC and their paired adjacent control samples were analyzed through real time RT-PCR and immunohistochemistry. The mRNA data was correlated with clinico-pathological parameters. Promoter hypermethylation was analyzed through MSP. RESULTS: DLC1 shows downregulation in 76.4%, upregulation in 10.9% whereas no change in 12.7% of GBC samples. Its underexpression shows significant correlation with tumor grade and nodal spread. IHC shows cytoplasmic expression of DLC1 in normal as well as tumor samples. IHC result was concordant to mRNA result. Samples having downregulated DLC1 expression show heterozygous methylation in 83.3% of samples and homozygous methylation in 9.5% of samples whereas 7% of samples have no methylation. Kaplan-Meier analysis shows patient with decreased mRNA of DLC1 have significant low mean survival compared to patients with higher mRNA expression of DLC1. CONCLUSION: Our findings suggested that dysregulated expression of DLC1 and its hypermethylation may be one of the events playing roles in tumorigenesis of GBC and may serve as a potential target for development of future GBC gene therapy.
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Proteínas Activadoras de GTPasa , Neoplasias de la Vesícula Biliar , Proteínas Supresoras de Tumor , Línea Celular Tumoral , Metilación de ADN , Regulación hacia Abajo , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Pronóstico , Regiones Promotoras Genéticas , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Immune metabolic adaptation in macrophages by intracellular parasites is recognized to play a crucial role during Leishmania infection. However, there is little accessible information about changes in a metabolic switch in L. donovani infected macrophages. In previous studies, we have reported on the anti-leishmanial synergic effect of eugenol oleate with amphotericin B. In the present study, we demonstrated that glycolytic enzymes were highly expressed in infected macrophages during combinatorial treatment of eugenol oleate (2.5 µM) and amphotericin B (0.3125 µM). Additionally, we found that the biphasic role in arachidonic acid metabolite, PGE2, and LTB4, is released during this treatment. In vitro data showed that COX-2 mediated PGE2 synthesis increased significantly (p<0.01) in infected macrophages. Not only was the level of prostaglandin synthesis decreased 4.38 fold in infected macrophages after treatment with eugenol oleate with amphotericin B. The mRNA expression of PTGES, MPGES, and PTGER4 were also moderately expressed in infected macrophages, and found to be decreased in combinatorial treatment. In addition, NOS2 expression was activated by the phosphorylation of p38MAPK when combination-treated macrophages were promoted to kill intracellular parasites. The findings of the present study indicate that the synergism between eugenol oleate and amphotericin B could play an important role in immune metabolism adaptation with a concomitant increase in host immune response against the intracellular pathogen, L. donovani.
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Leishmania donovani , Leishmaniasis , Anfotericina B/farmacología , Animales , Eugenol/farmacología , Ratones , Ratones Endogámicos BALB C , Ácido OléicoRESUMEN
Myricitrin, a naturally occurring flavonoid in Madhuca longifolia, possesses several medicinal properties. Even though our earlier work revealed its role against the proliferation of acute myelogenous leukemia cells (HL-60), its molecular mechanisms have not yet been revealed. The current study aims to explore the molecular mechanisms of myricitrin (isolated from an ethnomedicinal drug Madhuca longifolia) to induce apoptosis in HL-60 cells. Treatment with IC-50 dose of myricitrin (353 µM) caused cellular shrinkage and cell wall damage in HL-60 cells compared to untreated control cells. Myricitrin treatment reduced the mitochondrial membrane potential (22.95%), increased DNA fragmentation (90.4%), inhibited the cell survival proteins (RAS, B-RAF, & BCL-2) and also induced pro-apoptotic proteins (p38, pro-caspase-3, pro-caspase-9 and caspase-3) in the HL-60 cells. The present study provides scientific evidence for the apoptosis caused by myricitrin in HL-60 leukemia cells. Hence, the phytochemical myricitrin could be considered as a potential candidate to develop an anticancer drug after checking its efficacy through suitable pre-clinical and clinical studies.
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Flavonoides/farmacología , Leucemia/metabolismo , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Flavonoides/metabolismo , Células HL-60 , Humanos , Leucemia/tratamiento farmacológico , Madhuca/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Extractos Vegetales/farmacología , Hojas de la Planta/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Conventional therapy of visceral leishmaniasis (VL) remains challenging with the pitfall of toxicity, drug resistance, and expensive. Hence, urgent need for an alternative approach is essential. In this study, we evaluated the potential of combination therapy with eugenol oleate and miltefosine in Leishmania donovani infected macrophages and in the BALB/c mouse model. The interactions between eugenol oleate and miltefosine were found to be additive against promastigotes and amastigotes with xΣFIC 1.13 and 0.68, respectively. Significantly (p < 0.001) decreased arginase activity, increased nitrite generation, improved pro-inflammatory cytokines, and phosphorylated p38MAPK were observed after combination therapy with eugenol oleate and miltefosine. >80% parasite clearance in splenic and hepatic tissue with concomitant nitrite generation, and anti-VL cytokines productions were observed after orally administered miltefosine (5 mg/kg body weight) and eugenol oleate (15 mg/kg body weight) in L. donovani-infected BALB/c mice. Altogether, this study suggested the possibility of an oral combination of miltefosine with eugenol oleate against visceral leishmaniasis.
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Citocinas/metabolismo , Eugenol/uso terapéutico , Inmunidad , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/inmunología , Óxido Nítrico/biosíntesis , Fosforilcolina/análogos & derivados , Administración Oral , Animales , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Interacciones Farmacológicas , Quimioterapia Combinada , Eugenol/administración & dosificación , Eugenol/farmacología , Femenino , Inmunidad/efectos de los fármacos , Concentración 50 Inhibidora , Leishmania donovani/efectos de los fármacos , Leishmania donovani/crecimiento & desarrollo , Leishmania donovani/inmunología , Leishmania donovani/ultraestructura , Leishmaniasis Visceral/parasitología , Estadios del Ciclo de Vida/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/parasitología , Macrófagos/ultraestructura , Masculino , Ratones Endogámicos BALB C , Óxido Nítrico Sintasa de Tipo II/metabolismo , Parásitos/efectos de los fármacos , Parásitos/crecimiento & desarrollo , Parásitos/inmunología , Parásitos/ultraestructura , Fosforilación/efectos de los fármacos , Fosforilcolina/administración & dosificación , Fosforilcolina/farmacología , Fosforilcolina/uso terapéutico , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Asthma is a chronic inflammatory disease of the airways, which is characterized by infiltration of inflammatory cells, airway hyperresponsiveness (AHR), and airway remodeling. This study aimed to explore the role and mechanism of tannic acid (TA), a naturally occurring plant-derived polyphenol, in murine asthma model. BALB/c mice were given ovalbumin (OVA) to establish an allergic asthma model. The results revealed that TA treatment significantly decreased OVA-induced AHR, inflammatory cells infiltration, and the expression of various inflammatory mediators (Th2 and Th1 cytokines, eotaxin, and total IgE). Additionally, TA treatment also attenuated increases in mucins (Muc5ac and Muc5b) expression, mucus production in airway goblet cells, mast cells infiltration, and airway remodeling induced by OVA exposure. Furthermore, OVA-induced NF-κB (nuclear factor- kappa B) activation and cell adhesion molecules expression in the lungs was suppressed by TA treatment. In conclusion, TA effectively attenuated AHR, inflammatory response, and airway remodeling in OVA-challenged asthmatic mice. Therefore, TA may be a potential therapeutic option against allergic asthma in clinical settings.
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Asma/tratamiento farmacológico , Hipersensibilidad/tratamiento farmacológico , Taninos/uso terapéutico , Remodelación de las Vías Aéreas (Respiratorias) , Alérgenos/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Mucinas/metabolismo , Nueces/inmunología , Hipersensibilidad Respiratoria , Células TH1 , Células Th2RESUMEN
Artemisinin is the frontline fast-acting anti-malarial against P. falciparum. Emergence and spread of resistant parasite in eastern-India poses a threat to national malaria control programs. Therefore, the objective of our study is to evaluate the artesunate-sulfadoxine-pyrimethamine efficacy in Central India. 180 monoclonal P. falciparum-infected patients received standard ASSP therapy during August 2015-January 2017, soon after diagnosis and monitored over next 42-days. Artemisinin-resistance was assessed through in-vivo parasite clearance half-life (PC1/2), ex-vivo ring-stage survivability (RSA), and genome analysis of kelch13 and other candidate gene (pfcrt, pfmdr1, pfatpase 6, pfdhfr and pfdhps). Of 180 P. falciparum positive patients, 9.5% showed increased PC1/2 (> 5.5 h), among them eleven isolates (6.1%) showed reduced sensitivity to RSA. In 4.4% of cases, parasites were not cleared by 72 h and showed prolonged PC1/2(5.6 h) (P < 0.005) along with significantly higher RSA (2.2%) than cured patients (0.4%). None of day-3 positive isolates contained the pfkelch13 mutation implicated in artemisinin resistance. Parasite recrudescence was observed in 5.6% patients, which was associated with triple dhfr-dhps (A16I51R59N108I164-S436G437K540G581T613) combination mutation. Emergence of reduced sensitivity to artesunate-sulfadoxine-pyrimethamine, in central India highlighted the risk toward spread of resistant parasite across different parts of India. Day-3 positive parasite, featuring the phenotype of artemisinin-resistance without pfkelch13 mutation, suggested kelch13-independent artemisinin-resistance.
Asunto(s)
Artemisininas/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Adolescente , Adulto , Antimaláricos/farmacología , Artemisininas/metabolismo , Resistencia a Medicamentos/genética , Quimioterapia Combinada/métodos , Femenino , Humanos , India/epidemiología , Secuencia Kelch/genética , Malaria/tratamiento farmacológico , Malaria/parasitología , Malaria Falciparum/parasitología , Masculino , Persona de Mediana Edad , Mutación/efectos de los fármacos , Fenotipo , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidad , Polimorfismo Genético/genética , Proteínas Protozoarias/genética , Pirimetamina/uso terapéutico , Sulfadoxina/uso terapéutico , Tetrahidrofolato Deshidrogenasa/genética , Resultado del TratamientoRESUMEN
Context: As propranolol has emerged as first-line therapy for problematic infantile hemangioma, the number of non-responders and partial responders to propranolol therapy is also increasing. Aims: The study was conducted to evaluate the response of intralesional bleomycin, triamcinolone, and a combination of both as second line of treatment for the residual hemangioma following propranolol therapy. Settings and Design: A prospective comparative study was conducted in patients who were either non-responders or partial responders to previous propranolol treatment. Materials and Methods: The patients randomly received injection bleomycin, injection triamcinolone, and combination of both bleomycin and triamcinolone. The response to treatment was recorded clinically by using photographs. The pathological response was assessed by calculating pre-treatment and post-treatment microvessel density in biopsy of lesion from the non-cosmetic sites using immunohistochemistry. Statistical Analysis Used: χ2 test was used to test the association between the variables. The utility of microvessel diameter (MVD) in terms of clinical response to the therapy was predicted by using receiver operating characteristic (ROC) curve. Results: Out of the 134 patients, 42 received bleomycin and 44 received triamcinolone and were treated with a combination of both. The overall clinical response was better in the combination group compared with the bleomycin group (P = 0.018) and triamcinolone group (P = 0.0005), respectively, after 6 months of follow-up. There was no difference in clinical response between the triamcinolone and bleomycin groups. Change in MVD correlated with the clinical response. Conclusion: The combination of bleomycin and triamcinolone is effective and safe for the treatment of residual hemangioma.