Conjugating doxorubicin to polymannose: a new strategy for target specific delivery to lung cancer cells

Abstract

As mannose receptors are known to be over-expressed in cancer cells, we synthesized polymannose-doxorubicin (PM-DOX) conjugates with the objective of targeting the drug to cancer cells. DOX was conjugated to oxidized PM through Schiff’s linkages to obtain PM-DOX conjugates. In order to examine the superior targeting efficacy of PM-DOX conjugate, sodium alginate (SA) was conjugated to DOX by similar chemistry and compared with PM-DOX conjugate. The cytotoxicity of the conjugates was investigated in A549 cell lines using MTT Assay and the cell uptake and retention studies, were performed using flow cytometry and cell imaging. In vitro drug release studies with both PM-DOX and SA-DOX conjugates showed an initial burst release of DOX up to 37–39% at 1?h, followed by a steady release up to 58–62% at 24?h in human plasma while negligible release was observed in phosphate buffered saline. The conjugates exhibited negligible hemolytic potential to human erythrocytes compared to free DOX. The PM-DOX conjugate showed better cytotoxic potential against A549 cells at lower concentration (equivalent to 0.27?μg/mL of DOX) at 72?h compared to free DOX and SA-DOX conjugate. Further, PM-DOX conjugate showed enhanced uptake by the cells in comparison with SA-DOX conjugate thereby confirming the target specificity of PM to the cancer cells.     

E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity

Protein aggregation and ordered fibrillar amyloid deposition inside and outside of the central nervous system cells is the common pathologic hallmark of most aging-related neurodegenerative disorders. Dominant mutations in the gene encoding superoxide dismutase 1 (SOD1) protein are linked to familial amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to muscle paralysis and death. The major histochemical hallmark in the remaining motor neurons of ALS is the intracellular accumulation of ubiquitinated inclusions consisting of insoluble aberrant protein aggregates. However, the molecular pathomechanisms underlying the process have been elusive. Here for the first time, we report that E6-AP, a homologous to E6-AP C terminus-type E3 ubiquitin ligase depleted in ALS mouse models before neurodegeneration. E6-AP coimmunoprecipitates with the SOD1 protein and is predominantly mislocalized in mutant SOD1-containing inclusion bodies. Overexpression of E6-AP increases the ubiquitination and facilitates degradation of SOD1 proteins. Finally, we show that the overexpression of E6-AP suppresses the aggregation and cell death mediated by mutated SOD1 proteins and cellular protective effect is more prominent when E6-AP is overexpressed along with Hsp70. These data suggest that enhancing the activity of E6-AP ubiquitin ligase might be a viable therapeutic strategy to eliminate mutant SOD1-mediated toxicity in ALS.     

Pediatric maxillofacial injuries and its management

BackgroundPediatric facial injuries are common due to children's high level of activity which gradually decreases as age advances. Main etiology in cases of pediatric age group are self-fall, sports related injuries, interpersonal violence and lastly road traffic accident. Pattern and management of facial fracture in pediatric age group is different to that of adult population.Material and methodsThis study included 87 patients who had facial injuries and who reported at dental institute RIMS, Ranchi over a period of three years from 2017 to 2020. Initial assessment diagnosis and management were given to the patients.ResultsSelf-fall accounted as the leading cause of fracture (47.1%). Most frequent age group with facial injuries were from 7 to 12 years age group (49.1%). Dentoalveolar pattern of facial fracture was most common accounting for (39.1%) followed by mandible fracture in 33.3%. Closed reduction of the fracture was the most common way of treatment. Open reduction and fixation was carried out in 3.4% patients.ConclusionSelf-fall was the main etiology in our study and younger age group patients were more involved. Conservative treatment are generally given to pediatric age group, with open reduction in few cases on the basis of displacement. Close monitoring and follow up is mandatory in these age group.     

A simple technique to reinforce kinked South Pole RAE tracheal tube

Journal of Clinical Monitoring and Computing -     

Protective effects of Eugenia jambolana extract versus N‐acetyl cysteine against cisplatin‐induced damage in rat testis

To assess the protective effects of Eugenia jambolana extract (EJE) or N‐acetyl cysteine (NAC) on testis, cisplatin (CIS, 5 mg kg^?1 bw, single dose) was administered either alone or along with EJE (25 mg kg^?1 bw, alternate day) or NAC (150 mg kg^?1 bw, Day 1 and 4) for 7 days. Significant alterations in serum LH, FSH and testosterone were observed in CIS group which were effectively modulated by EJE or NAC supplementation. Upregulation of 3β‐HSD gene indicated the rise in functional Leydig cells. This was further confirmed from the identical improvement in hCG‐stimulated testosterone production in isolated Leydig cells. Reduction in oxidative stress was associated with restoration of total antioxidant capacity and glutathione levels, and activation of antioxidant enzymes, SOD, catalase, glutathione s‐transferase (GST) and glutathione reductase (GR). CIS‐induced apoptosis of germ and Leydig cells was contained by both NAC and EJE intervention by effective modulation of apoptotic markers in the extrinsic, intrinsic and other pathways of metazoan apoptosis. Taken together, the study findings establish the potential of EJE as a therapeutically better antioxidant than NAC for use in curtailing the adverse effects of anticancer drugs on testicular function.     

The RAD3 gene of Saccharomyces cerevisiae encodes a DNA-dependent ATPase.

The RAD3 gene of the yeast Saccharomyces cerevisiae is required for excision repair of damaged DNA and for cell viability. A protein of approximately equal to 89 kDa was purified to near homogeneity from yeast strains harboring multicopy plasmids that overproduce RAD3 protein; this protein corresponds closely to the expected size of the RAD3 protein and cross-reacts with the antiserum raised against a truncated RAD3 protein produced in Escherichia coli. The purified RAD3 protein shows a single-stranded DNA-dependent ATPase activity that catalyzes hydrolysis of ATP to ADP and Pi. The ATPase activity was coincident with the RAD3 protein during purification and is inhibited by anti-RAD3 antibodies, indicating that the RAD3 gene encodes this activity.