Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied ribonucleic acid (RNA)-seq and genome-scale loss-offunction clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations. Atm-/-nu-/-lymphomas, which phenotypically resemble either activated B-cell-like or germinal center Bcell-like DLBCL, harbor a complex karyotype, and are characterized by MYC pathway activation. In Atm-/-nu-/-lymphomas, we discovered nucleotide biosynthesis as a MYCdependent cellular vulnerability that can be targeted through the synergistic nucleotidedepleting actions of mycophenolate mofetil (MMF) and the WEE1 inhibitor, adavosertib (AZD1775). The latter is mediated through a synthetically lethal interaction between RRM2 suppression and MYC dysregulation that results in replication stress overload in Atm-/-nu-/-lymphoma cells. Validation in cell line models of human DLBCL confirmed the broad applicability of nucleotide depletion as a therapeutic strategy for MYC-driven DLBCL independent of ATM mutation status. Our findings extend current understanding of lymphomagenic mechanisms underpinning ATM loss and highlight nucleotide metabolism as a targetable therapeutic vulnerability in MYC-driven DLBCL.

Ulva fasciata, a green alga, attenuates the kidney and liver dysfunctions in rats induced by acetaminophen.

Acetaminophen (AAP) is an analgesic-antipyretic drug which is considered safe at recommended dose, but its overuse may induce renal and hepatic injuries. Marine macro algae have great potential against drug-induced renal and hepatic dysfunctions. The present study described the reno-protective and hepato-protective effects of the ethanol extract of an edible green alga Ulva fasciata and its fractions (n-hexane, chloroform and methanol) against AAP toxicity. In the 1st set of experiment, rats were divided into five groups. Of which two were treatment groups beside three controls, the first treatment group was given ethanol extract of U. fasciata alone and the second group was given the same extract with AAP. In the 2nd set of experiment, rats were divided into nine groups, of which three treatment groups administered n-hexane, chloroform and methanol fractions of ethanol extract of U. fasciata respectively while other three treatment groups received the same fractions individually with AAP. On the 11th day, rats were decapitated after 12 h of fasting from both sets, blood samples were collected for assessment of biochemical parameters and kidney tissues were used for determination of oxidants and antioxidants. Histopathological assessment was also done in kidney tissues. A single dose of AAP (600 mg/kg) affected kidney markers including creatinine, urea and blood urea nitrogen (BUN) and hepatic enzymes. Ethanolic extract of U. fasciata normalized kidney and liver markers in AAP intoxicated rats. AAP also reduced glutathione (GSH) in kidney tissues and altered kidney architecture, which were improved by ethanolic extract and chloroform soluble fraction of U. fasciata. A total of 14 polyunsaturated fatty acids were identified from chloroform soluble fraction of U. fasciata by GC-MS and assumed these may be involved in protective activities of U. fasciata.

Ameliorative effect of Spatoglossum asperum and its solvent fractions against acetaminophen-induced liver dysfunction in rats.

Acetaminophen (APAP) is a widely consumed drug for pain management and treatment of pyrexia. However, beyond its recommended dose, it becomes harmful for health and may induce acute liver dysfunction. Current work is designed to ameliorate the APAP induced liver toxicity which was induced in rats by giving intra-peritoneal injection of APAP (800mg/kg) dissolved in 40% polyethylene glycol at day 1 and day 14. APAP dosed/intoxicated rats orally administered either with ethanol extract of Spatoglossum asperum (200mg/kg) and its fractions including n-hexane, chloroform and methanol soluble in a dose of 150mg/kg each daily for 14 days in their respective groups. APAP dosed rats showed remarkable elevation in hepatic biomarkers viz., alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenases, total bilirubin, pro-inflammatory cytokines interleukine-6 and apoptotic protein (caspase-3). In addition, hepatic oxidative stress (lipid per oxidation and indirect nitric oxide) and antioxidant biomarkers (glutathione peroxidase, catalase and reduced glutathione) were also altered. Whereas APAP dosed rats treated with ethanol extract of S. asperum and its fractions showed amelioration in concentration of hepatic enzymes, pro-inflammatory cytokines, apoptotic protein and reduction in hepatic oxidative stress by decreasing the lipid peroxidation, indirect nitric oxide and uplifting the activities of antioxidant enzymes and protein.

GPCR-styrene maleic acid lipid particles (GPCR-SMALPs): their nature and potential.

G-protein-coupled receptors (GPCRs) form the largest class of membrane proteins and are an important target for therapeutic drugs. These receptors are highly dynamic proteins sampling a range of conformational states in order to fulfil their complex signalling roles. In order to fully understand GPCR signalling mechanisms it is necessary to extract the receptor protein out of the plasma membrane. Historically this has universally required detergents which inadvertently strip away the annulus of lipid in close association with the receptor and disrupt lateral pressure exerted by the bilayer. Detergent-solubilized GPCRs are very unstable which presents a serious hurdle to characterization by biophysical methods. A range of strategies have been developed to ameliorate the detrimental effect of removing the receptor from the membrane including amphipols and reconstitution into nanodics stabilized by membrane scaffolding proteins (MSPs) but they all require exposure to detergent. Poly(styrene-co-maleic acid) (SMA) incorporates into membranes and spontaneously forms nanoscale poly(styrene-co-maleic acid) lipid particles (SMALPs), effectively acting like a 'molecular pastry cutter' to 'solubilize' GPCRs in the complete absence of detergent at any stage and with preservation of the native annular lipid throughout the process. GPCR-SMALPs have similar pharmacological properties to membrane-bound receptor, exhibit enhanced stability compared with detergent-solubilized receptors and being non-proteinaceous in nature, are fully compatible with downstream biophysical analysis of the encapsulated GPCR.

Ameliorative Effect of Marine Macroalgae on Carbon Tetrachloride-Induced Hepatic Fibrosis and Associated Complications in Rats

Objectives: Liver fibrosis is one of the serious health concern around the globe. Persistent exposure to drugs, toxicants, and pathogens may induce liver fibrosis. Marine macroalgae are globally consumed because of nutritive and medicinal value. This study was conducted to evaluate the protective role of two seaweeds Padina pavonia and Caulerpa racemosa in carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Materials and Methods: Animal model of hepatic fibrosis was developed by injecting 40% CCl4 dissolved in olive oil [2 mL/kg, body weight (b.w.), i.p.] on alternate days for 30 days. Water extracts (WE) [200 mg/kg b.w., p.o.] of P. pavonia and C. racemosa were given to rats daily for 30 days. On day 31, rats were sacrificed after 12 h fasting. Serum was used for biochemical estimation. 10% neutral buffered formalin was used to preserve the liver sample for histopathological examination, while the other portion was used for the preparation of tissue homogenate to estimate antioxidant enzymes and malondialdehyde levels. Results: WEs of both marine macro-algae significantly abrogate the elevated serum concentrations of aminotransferases (alanine aminotransferase and aspartate aminotransferases), alkaline phosphatase and lactate dehydrogenase along with a substantial (p<0.05) reduction in serum bilirubin levels. They also showed positive effects on oxidative stress, evident by improvement in reduced glutathione, catalase, and glutathione peroxidase activities and down regulation of lipid peroxidation level, with stabilizing the destructive cellular morphology of liver induced by repeated CCl4 injection. Both algal extracts also improved kidney function (urea and creatinine) along with lipid metabolism (triglycerides and cholesterol). Conclusion: Water extract of C. racemosa has shown great potential in attenuating liver fibrosis induced by CCl4.

An update on glass fiber dental restorative composites: a systematic review.

Dentistry is a much developed field in the last few decades. New techniques have changed the conventional treatment methods as applications of new dental materials give better outcomes. The current century has suddenly forced on dentistry, a new paradigm regarding expected standards for state-of-the-art patient care. Within the field of restorative dentistry, the incredible advances in dental materials research have led to the current availability of esthetic adhesive restorations. The chemistry and structure of the resins and the nature of the glass fiber reinforced systems in dental composites are reviewed in relation to their influence and properties including mechanical, physical, thermal, biocompatibility, technique sensitivity, mode and rate of failure of restorations on clinical application. It is clear that a deeper understanding of the structure of the polymeric matrix and resin-based dental composite is required. As a result of ongoing research in the area of glass fiber reinforced composites and with the development and advancement of these composites, the future prospects of resin-based composite are encouraging.