Ethanol extract of Butea monosperma bark modulates dyslipidemia in streptozotocin-induced diabetic rats

Context: Dyslipidemia is one of the major risk factors for cardiovascular disease in diabetes mellitus (DM). The availability of multiple lipid-lowering drugs and supplements provides new opportunities for patients to regulate lipid levels.

Objective: The present study was designed to evaluate the effect of Butea monosperma Lam. (Fabaceae) bark extract in diabetes-induced dyslipidemia.

Materials and methods: A daily dose of B. monosperma bark extract (BMBE, 500?mg/kg body weight) was given orally to streptozotocin (STZ)-induced diabetic rats for 60?d. Several indices such as blood glucose, insulin, glycosylated hemoglobin, TC, TG, high-density lipoprotein-cholesterol (HDL-C), apo A1, apo B, activities of lipogenic enzymes in tissues, liver function tests, and histopathology of liver were analyzed to assess the modulation of STZ-induced diabetic dyslipidemia by B. monosperma bark.

Results: BMBE significantly reduced blood glucose (40.79%) and increased plasma insulin (37.5%) levels in diabetic rats. Altered levels of serum lipids, lipoproteins, and activities of lipogenic enzymes in tissues were partially restored upon the administration of BMBE in diabetic rats. Liver function tests and histopathological examination revealed that consumption of BMBE at a dose of 500?mg/kg body weight had no toxic effects in experimental rats.

Conclusion: The findings suggest that BMBE supplementation could ameliorate dyslipidemia in DM.     

Do stand-alone interbody spacers with integrated screws provide adequate segmental stability for multilevel cervical arthrodesis?

Background contextSome postoperative complications after anterior cervical fusions have been attributed to anterior cervical plate (ACP) profiles and the necessary wide operative exposure for their insertion. Consequently, low-profile stand-alone interbody spacers with integrated screws (SIS) have been developed. Although SIS constructs have demonstrated similar biomechanical stability to the ACP in single-level fusions, their role as a stand-alone device in multilevel reconstructions has not been thoroughly evaluated.PurposeTo evaluate the acute segmental stability afforded by an SIS device compared with the traditional ACP in the setting of a multilevel cervical arthrodesis.Study designIn vitro human cadaveric biomechanical analysis.MethodsThirteen human cadaveric cervical spines (C2–T1) were nondestructively tested with a custom 6 df spine simulator under axial rotation, flexion-extension, and lateral bending loading. After intact analysis, eight single-levels (C4–C5/C6–C7) from four specimens were instrumented and tested with ACP and SIS. Nine specimens were tested with C5–C7 SIS, C5–C7 ACP, C4–C7 ACP, C4–C7 ACP+posterior fixation, C4–C7 SIS, and C4–C7 SIS+posterior fixation. Testing order was randomized with each additional level instrumented. Full range of motion (ROM) data were obtained and analyzed by each loading modality, using mean comparisons with repeated measures analysis of variance. Paired t tests were used for post hoc analysis with Sidak correction for multiple comparisons.ResultsNo significant difference in ROM was noted between the ACP and SIS for single-level fixation (p>.05). For multisegment reconstructions (two and three levels), the ACP proved superior to SIS and intact condition, with significantly lower ROM in all planes (p<.05). When either the three-level SIS or ACP constructs were supplemented with posterior lateral mass fixation, there was a greater than 80% reduction in ROM under all testing modalities (p<.05), with no significant difference between the ACP and SIS constructs (p>.05).ConclusionsThe SIS device may be a reasonable option as a stand-alone device for single-level fixation. However, SIS devices should be used with careful consideration in the setting of multilevel cervical fusion. However, when supplemented with posterior fixation, SIS devices are a sound biomechanical alternative to ACP for multilevel fusion constructs.     

Clinical safety profile of ticagrelor compared to clopidogrel in 1208 patients: Real world evidence

Introduction

Dual antiplatelet treatment is recommended by current clinical practice guidelines for patients undergoing PCI. The PLATO trial showed superiority of ticagrelor to clopidogrel in reducing the rate of death from vascular causes, myocardial infarction and stroke without increase in the rate of overall major bleeding in ACS patients. However, real world evidence in Indian patients is limited. The objective of this study is to compare safety profile of ticagrelor with clopidogrel in real world settings.

Predictors of changes in disease activity among children with juvenile dermatomyositis enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry

Determinants of changes in disease activity among patients with juvenile dermatomyositis (JDM) are unknown. Our objective was to develop predictive models to predict changes in disease activity using the CARRA Legacy Registry. The CARRA Legacy Registry included 658 subjects with definite or probably JDM with 297 subjects with a one follow-up visit after baseline, and we studied the 65 subjects with active disease at baseline. Linear regression models were used to build risk scores for changes in disease activity adjusted for baseline disease activity, age, sex, and disease duration. Disease activity improved from baseline to 6-month follow-up as measured by patient/parent global health score (median 4; p = 0.008), patient pain score (median 2; p = 0.014), physician global (median 4; p < 0.001), and Childhood Myositis Assessment Scale (CMAS) (median 41, p < 0.001). Anti-nuclear antibodies (p = 0.013) and hydroxychloroquine use (p = 0.045) were significant predictors of less improvement in patient/parent global and baseline patient/parent global. Anti-nuclear antibodies (p = 0.001) and V/shawl sign (p = 0.005) were significant predictors of less improvement in patient pain (R-square improved from 0.29 for adjustors alone to 0.46 for the full model). Small joint arthritis (p < 0.01) predicted less improvement and dysphagia/dysphonia (p = 0.033) predicted greater improvement in CMAS and baseline CMAS (R-square improved from 0.73 for adjustors alone to 0.86 for the full model). Disease characteristics can help identify patients who are less likely to improve over time. Risk scores to predict future changes in disease activity could be used to trigger more aggressive treatment earlier in the disease course.     

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Dichloroacetic acid (DCA), a water disinfection by-product, has attained emphasis due to its prospect for clinical use against different diseases including cancer along with negative impact on organisms. However, these reports are based on the toxicological as well clinical data using comparatively higher concentrations of DCA without much of environmental relevance. Here, we evaluate cellular as well as organismal effects of DCA at environmentally and mild clinically relevant concentrations (0.02–20.0 μg/ml) using an established model organism, Drosophila melanogaster. Flies were fed on food mixed with test concentrations of DCA for 12–48 h to examine the induction of reactive oxygen species (ROS) generation, oxidative stress (OS), heat shock genes (hsps) and cell death along with organismal responses. We also examined locomotor performance, ROS generation, glutathione (GSH) depletion, expression of GSH-synthesizing genes (gclc and gclm), and hsps at different days (0, 10, 20, 30, 40, 50) of the age in flies after prolonged DCA exposure. We observed mild OS and induction of antioxidant defense system in 20.0 μg/ml DCA-exposed organism after 24 h. After prolonged exposure to DCA, exposed organism exhibited improved survival, elevated expression of hsp27, gclc, and gclm concomitant with lower ROS generation and GSH depletion and improved locomotor performance. Conversely, hsp27 knockdown flies exhibited reversal of the above end points. The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA.     

Nocturnal variant of benign myoclonic epilepsy of infancy: a case series

Myoclonus is a brief, rapid, involuntary muscle jerk originating in the central nervous system that can be physiological or a symptom of disease. We report a group of five children with excessive myoclonic jerks, only during sleep, and abnormal EEG during the events. Although only one third of the events had EEG epileptiform correlate, the presence of myoclonus without epileptiform EEG correlate has been described in patients with benign myoclonic epilepsy of infancy. We hypothesize that these findings may represent a variant of benign myoclonic epilepsy of infancy.     

Medullary carcinoma of thyroid metastasis to breast: A cytological experience

Medullary carcinoma of thyroid is a relatively uncommon malignancy, which can be sporadic and syndromic in nature. It commonly spreads to regional lymph nodes followed by spreading to distant sites. Breast is an uncommon site of metastasis of this malignancy. Our case is a 38‐year‐old woman married parous woman presenting to the outpatient department with complaints of lump in both the breasts. Fine‐needle aspiration (FNA) was attempted, which revealed a malignancy more suggestive of a metastasis, which was confirmed on CT scan. A detailed history revealed that the patient is a known case of medullary carcinoma of thyroid. The report was given as metastatic medullary carcinoma to the breast after confirming with a calcitonin immunostain. Given the versatility of primary lesions in the breast, minimally invasive FNA cytology (FNAC) technique with adequate sampling helps in identifying metastatic lesions. Differentiating primary from metastatic lesions changes the course of management to the patient. Metastatic lesions should always be kept in mind in the occurrence of known malignancies, however rare the site of occurrence may be. Morphological clues and immunohistochemical work up aid in arriving at correct diagnosis.     

Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells

The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there is limited insight into its role in metastasis, when some cancer cells experience high levels of oxidative stress. To address this, we mutated the substrate binding site of glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, in patient-derived melanomas. G6PD mutant melanomas had significantly decreased G6PD enzymatic activity and depletion of intermediates in the oxidative pentose phosphate pathway. Reduced G6PD function had little effect on the formation of primary subcutaneous tumors, but when these tumors spontaneously metastasized, the frequency of circulating melanoma cells in the blood and metastatic disease burden were significantly reduced. G6PD mutant melanomas exhibited increased levels of reactive oxygen species, decreased NADPH levels, and depleted glutathione as compared to control melanomas. G6PD mutant melanomas compensated for this increase in oxidative stress by increasing malic enzyme activity and glutamine consumption. This generated a new metabolic vulnerability as G6PD mutant melanomas were more dependent upon glutaminase than control melanomas, both for oxidative stress management and anaplerosis. The oxidative pentose phosphate pathway, malic enzyme, and glutaminolysis thus confer layered protection against oxidative stress during metastasis.

The pentose phosphate pathway is an important source of NADPH for oxidative stress resistance (1–5). The oxidative branch of the pentose phosphate pathway contains two enzymes that generate NADPH from NADP⁺, glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (PGD) (SI Appendix, Fig. S1). NADPH is an important source of reducing equivalents for oxidative stress resistance because it is used by cells to convert oxidized glutathione (GSSG) to glutathione (GSH), an abundant redox buffer. Complete deficiency for G6PD is embryonic-lethal in mice (2, 6, 7) but hypomorphic G6PD mutations are common in certain human populations, perhaps because they protect against malaria (8, 9). These partial loss-of-function G6PD mutations are well tolerated in adults, though they sensitize red blood cells to hemolysis from oxidative stress under certain circumstances (10).Several studies have reported a lower incidence and mortality for certain cancers in people with hypomorphic mutations in G6PD (11–14), suggesting that cancer cells depend upon G6PD to manage oxidative stress. Cells experience high levels of oxidative stress during certain phases of cancer development and progression, including during metastasis (15–17). Antioxidant mechanisms thus promote the survival of cells during oncogenic transformation (18, 19) as well as during metastasis (15, 16). For example, relative to primary cutaneous tumors, metastasizing melanoma cells exhibit increased dependence upon the folate pathway (15), monocarboxylate transporter-1 (MCT1) (20), and glutathione peroxidase-4 (GPX4) (21), each of which directly or indirectly attenuate oxidative stress. By better understanding the mechanisms that confer oxidative stress resistance in cancer cells, it may be possible to develop pro-oxidant therapies that inhibit cancer progression by exacerbating the oxidative stress experienced by cancer cells.G6PD (22) or PGD deficiency (23–25) reduce the growth of some cancers, including melanoma, but G6PD deficiency has little effect on primary tumor formation by K-Ras–driven epithelial cancers (26). This is at least partly because loss of G6PD in these cancers leads to compensatory increases in the function of other NADPH-generating enzymes, including malic enzyme and isocitrate dehydrogenase (1, 27). Nonetheless, pentose phosphate pathway function may increase during metastasis (20, 28–30) and higher G6PD expression is associated with worse outcomes in several cancers (31–33), raising the question of whether metastasizing cells are particularly dependent upon G6PD. G6PD is not essential for metastasis in a breast cancer cell line but it reduces their capacity to form metastatic tumors (26).Melanoma cells show little evidence of oxidative stress in established primary tumors but exhibit increased levels of reactive oxygen species (ROS) and dependence upon antioxidant mechanisms during metastasis (15, 20, 21). To test if these cells are more dependent upon the pentose phosphate pathway during metastasis, we generated three G6PD mutant melanomas, including two patient-derived xenografts and one human melanoma cell line. Reduced G6PD function had little effect on the formation or growth of primary subcutaneous tumors but significantly increased ROS levels and reduced spontaneous metastasis. G6PD mutant melanomas compensated by increasing malic enzyme activity and glutamine consumption, both to increase oxidative stress resistance and to replenish tricarboxylic acid (TCA) cycle intermediates through anaplerosis. Melanoma cells thus have redundant layers of protection against oxidative stress during metastasis, including the abilities to alter fuel consumption and antioxidant pathway utilization.     

Current progress,challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer

The indazole core is an interesting pharmacophore due to its applications in medicinal chemistry. In the past few years, this moiety has been used for the synthesis of kinase inhibitors. Many researchers have demonstrated the use of indazole derivatives as specific kinase inhibitors, including tyrosine kinase and serine/threonine kinases. A number of anticancer drugs with an indazole core are commercially available, e.g. axitinib, linifanib, niraparib, and pazopanib. Indazole derivatives are applied for the targeted treatment of lung, breast, colon, and prostate cancers. In this review, we compile the current development of indazole derivatives as kinase inhibitors and their application as anticancer agents in the past five years.

The indazole core is an interesting pharmacophore due to its applications in medicinal chemistry.