Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7, 12-dimethyl benz{a}anthracene (DMBA) induced breast cancer rats

<p>Abstract</p> <p>Background</p> <p>Antineoplastic drug cisplatin remains the drug of choice for various solid tumours including breast cancer. But dose dependent nephrotoxicity is the major drawback in majority of platinum based chemotherapy regimens. Recent reports have shown that inflammatory pathways are the main offender for cisplatin induced nephrotoxicity. The present study was undertaken to assess the effect of rosiglitazone, a PPARγ agonist and an anti-inflammatory agent, on cisplatin induced nephrotoxicity, and its anticancer activity in DMBA induced breast cancer rats.</p> <p>Methods</p> <p>Mammary tumours were induced in female Sprague-Dawley rats by feeding orally with dimethylbenz [a]anthracene (DMBA) (60 mg/kg). Cisplatin induced nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Posttranslational modifications of histone H3, mitogen-activated protein (MAP) kinase p38 expression and PPAR-γ expression were examined by western blotting.</p> <p>Results</p> <p>Our data shows involvement of TNF-α in preventing cisplatin induced nephrotoxicity by rosiglitazone. Rosiglitazone pre-treatment to cisplatin increases the expression of p38, PPAR-γ in mammary tumours and shows maximum tumour reduction. Furthermore, cisplatin induced changes in histone acetylation, phosphorylation and methylation of histone H3 in mammary tumours was ameliorated by pre-treatment of rosiglitazone. Suggesting, PPAR-γ directly or indirectly alters aberrant gene expression in mammary tumours by changing histone modifications.</p> <p>Conclusion</p> <p>To best of our knowledge this is the first report which shows that pre-treatment of rosiglitazone synergizes the anticancer activity of cisplatin and minimizes cisplatin induced nephrotoxicity in DMBA induced breast cancer.</p

Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy &gt;3&nbsp;months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P &lt;0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

Partial loss of actin nucleator actin-related protein 2/3 activity triggers blebbing in primary T lymphocytes

T lymphocytes utilize amoeboid migration to navigate effectively within complex microenvironments. The precise rearrangement of the actin cytoskeleton required for cellular forward propulsion is mediated by actin regulators, including the actin‐related protein 2/3 (Arp2/3) complex, a macromolecular machine that nucleates branched actin filaments at the leading edge. The consequences of modulating Arp2/3 activity on the biophysical properties of the actomyosin cortex and downstream T cell function are incompletely understood. We report that even a moderate decrease of Arp3 levels in T cells profoundly affects actin cortex integrity. Reduction in total F‐actin content leads to reduced cortical tension and disrupted lamellipodia formation. Instead, in Arp3‐knockdown cells, the motility mode is dominated by blebbing migration characterized by transient, balloon‐like protrusions at the leading edge. Although this migration mode seems to be compatible with interstitial migration in three‐dimensional environments, diminished locomotion kinetics and impaired cytotoxicity interfere with optimal T cell function. These findings define the importance of finely tuned, Arp2/3‐dependent mechanophysical membrane integrity in cytotoxic effector T lymphocyte activities

Early paleocene paleoceanography and export productivity in the Chicxulub crater

The Chicxulub impact caused a crash in productivity in the world''s oceans which contributed to the extinction of ~75% of marine species. In the immediate aftermath of the extinction, export productivity was locally highly variable, with some sites, including the Chicxulub crater, recording elevated export production. The long-term transition back to more stable export productivity regimes has been poorly documented. Here, we present elemental abundances, foraminifer and calcareous nannoplankton assemblage counts, total organic carbon, and bulk carbonate carbon isotope data from the Chicxulub crater to reconstruct changes in export productivity during the first 3 Myr of the Paleocene. We show that export production was elevated for the first 320 kyr of the Paleocene, declined from 320 kyr to 1.2 Myr, and then remained low thereafter. A key interval in this long decline occurred 900 kyr to 1.2 Myr post impact, as calcareous nannoplankton assemblages began to diversify. This interval is associated with fluctuations in water column stratification and terrigenous flux, but these variables are uncorrelated to export productivity. Instead, we postulate that the turnover in the phytoplankton community from a post-extinction assemblage dominated by picoplankton (which promoted nutrient recycling in the euphotic zone) to a Paleocene pelagic community dominated by relatively larger primary producers like calcareous nannoplankton (which more efficiently removed nutrients from surface waters, leading to oligotrophy) is responsible for the decline in export production in the southern Gulf of Mexico. © 2021. American Geophysical Union. All Rights Reserved

Drilling-induced and logging-related features illustrated from IODP-ICDP Expedition 364 downhole logs and borehole imaging tools

Expedition 364 was a joint IODP and ICDP mission-specific platform (MSP) expedition to explore the Chicxulub impact crater buried below the surface of the Yucatán continental shelf seafloor. In April and May 2016, this expedition drilled a single borehole at Site M0077 into the crater's peak ring. Excellent quality cores were recovered from ~ 505 to ~1335m below seafloor (m b.s.f.), and high-resolution open hole logs were acquired between the surface and total drill depth. Downhole logs are used to image the borehole wall, measure the physical properties of rocks that surround the borehole, and assess borehole quality during drilling and coring operations. When making geological interpretations of downhole logs, it is essential to be able to distinguish between features that are geological and those that are operation-related. During Expedition 364 some drilling-induced and logging-related features were observed and include the following: effects caused by the presence of casing and metal debris in the hole, logging-tool eccentering, drilling-induced corkscrew shape of the hole, possible re-magnetization of low-coercivity grains within sedimentary rocks, markings on the borehole wall, and drilling-induced changes in the borehole diameter and trajectory

TRAIP/RNF206 is required for recruitment of RAP80 to sites of DNA damage

RAP80 localizes to sites of DNA insults to enhance the DNA-damage responses. Here we identify TRAIP/RNF206 as a novel RAP80-interacting protein and find that TRAIP is necessary for translocation of RAP80 to DNA lesions. Depletion of TRAIP results in impaired accumulation of RAP80 and functional downstream partners, including BRCA1, at DNA lesions. Conversely, accumulation of TRAIP is normal in RAP80-depleted cells, implying that TRAIP acts upstream of RAP80 recruitment to DNA lesions. TRAIP localizes to sites of DNA damage and cells lacking TRAIP exhibit classical DNA-damage response-defect phenotypes. Biochemical analysis reveals that the N terminus of TRAIP is crucial for RAP80 interaction, while the C terminus of TRAIP is required for TRAIP localization to sites of DNA damage through a direct interaction with RNF20-RNF40. Taken together, our findings demonstrate that the novel RAP80-binding partner TRAIP regulates recruitment of the damage signalling machinery and promotes homologous recombinationopen

A Porcine Adenovirus with Low Human Seroprevalence Is a Promising Alternative Vaccine Vector to Human Adenovirus 5 in an H5N1 Virus Disease Model

Human adenovirus 5 (AdHu5) vectors are robust vaccine platforms however the presence of naturally-acquired neutralizing antibodies may reduce vector efficacy and potential for re-administration. This study evaluates immune responses and protection following vaccination with a replication-incompetent porcine adenovirus 3 (PAV3) vector as an alternative vaccine to AdHu5 using an avian influenza H5N1 disease model. Vaccine efficacy was evaluated in BALB/c mice following vaccination with different doses of the PAV3 vector expressing an optimized A/Hanoi/30408/2005 H5N1 hemagglutinin antigen (PAV3-HA) and compared with an AdHu5-HA control. PAV3-HA rapidly generated antibody responses, with significant neutralizing antibody titers on day 21, and stronger cellular immune responses detected on day 8, compared to AdHu5-HA. The PAV3-HA vaccine, administered 8 days before challenge, demonstrated improved survival and lower virus load. Evaluation of long-term vaccine efficacy at 12 months post-vaccination showed better protection with the PAV3-HA than with the AdHu5-HA vaccine. Importantly, as opposed to AdHu5, PAV3 vector was not significantly neutralized by human antibodies pooled from over 10,000 individuals. Overall, PAV3-based vector is capable of mediating swift, strong immune responses and offer a promising alternative to AdHu5

Ocean Drilling Perspectives on Meteorite Impacts

Extraterrestrial impacts that reshape the surfaces of rocky bodies are ubiquitous in the solar system. On early Earth, impact structures may have nurtured the evolution of life. More recently, a large meteorite impact off the Yucatán Peninsula in Mexico at the end of the Cretaceous caused the disappearance of 75% of species known from the fossil record, including non-avian dinosaurs, and cleared the way for the dominance of mammals and the eventual evolution of humans. Understanding the fundamental processes associated with impact events is critical to understanding the history of life on Earth, and the potential for life in our solar system and beyond. Scientific ocean drilling has generated a large amount of unique data on impact pro- cesses. In particular, the Yucatán Chicxulub impact is the single largest and most sig- nificant impact event that can be studied by sampling in modern ocean basins, and marine sediment cores have been instrumental in quantifying its environmental, cli- matological, and biological effects. Drilling in the Chicxulub crater has significantly advanced our understanding of fundamental impact processes, notably the formation of peak rings in large impact craters, but these data have also raised new questions to be addressed with future drilling. Within the Chicxulub crater, the nature and thickness of the melt sheet in the central basin is unknown, and an expanded Paleocene hemipelagic section would provide insights to both the recovery of life and the climatic changes that followed the impact. Globally, new cores collected from today’s central Pacific could directly sample the downrange ejecta of this northeast-southwest trending impact. Extraterrestrial impacts have been controversially suggested as primary drivers for many important paleoclimatic and environmental events throughout Earth history. However, marine sediment archives collected via scientific ocean drilling and geo- chemical proxies (e.g., osmium isotopes) provide a long-term archive of major impact events in recent Earth history and show that, other than the end-Cretaceous, impacts do not appear to drive significant environmental changes

Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes

Sirtuin 1 (Sirt1), a NAD[superscript +]-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.Japan. Ministry of Education, Culture, Sports, Science and Technology (Grant 22790800