LukS-PV,a component of Panton-Valentine leukocidin,exerts potent activity against acute myeloid leukemia in vitro and in vivo

LukS-PV, a component of Panton-Valentine leukocidin (PVL) secreted by Staphylococcus aureus, has been shown to inhibit proliferation and induce apoptosis in acute myeloid leukemia (AML) THP-1 cells. Here we investigated anti-leukemia activities of LukS-PV in HL-60 cells, using in vitro assays to assess the ability of LukS-PV to mediate cell viability, apoptosis and differentiation; and developing a Severe Combined Immunodeficiency (SCID) mouse model of disseminated AML with the HL-60 cells to examine in vivo anti-leukemia activity. LukS-PV inhibited viability and induced differentiation and apoptosis in the HL-60 AML cell line. In the SCID mice, LukS-PV potently inhibited tumor growth, decreased tumor cell infiltration into peripheral blood and tissues, and significantly increased mean survival time. No severe adverse effects, such as death, weight loss, or pathological changes in livers or spleens were observed in the toxicity test group. These results indicate that LukS-PV may be a novel and effective chemotherapeutic agent against AML.     

Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation

Chronic ethanol ingestion mildly damages liver through oxidative stress and lipid oxidation, which is ameliorated by dietary supplementation with the anti-inflammatory β-amino acid taurine. Kidney, like liver, expresses cytochrome P450 2E1 that catabolizes ethanol with free radical formation, and so also may be damaged by ethanol catabolism. Sudden loss of kidney function, and not liver disease itself, foreshadows mortality in patients with alcoholic hepatitis [J. Altamirano, Clin. Gastroenterol. Hepatol. 2012, 10:65]. We found that ethanol ingestion in the Lieber-deCarli rat model increased kidney lipid oxidation, 4-hydroxynonenal protein adduction, and oxidatively truncated phospholipids that attract and activate leukocytes. Chronic ethanol ingestion increased myeloperoxidase-expressing cells in kidney and induced an inflammatory cell infiltrate. Apoptotic terminal deoxynucleotidyl transferase nick-end labeling-positive cells and active caspase-3 increased in kidney after ethanol ingestion, with reduced filtration with increased circulating blood urea nitrogen (BUN) and creatinine. These events were accompanied by release of albumin, myeloperoxidase, and the acute kidney injury biomarkers kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, and cystatin c into urine. Taurine sequesters HOCl from myeloperoxidase of activated leukocytes, and taurine supplementation reduced renal lipid oxidation, reduced leukocyte infiltration, and reduced the increase in myeloperoxidase-positive cells during ethanol feeding. Taurine supplementation also normalized circulating BUN and creatinine levels and suppressed enhanced myeloperoxidase, albumin, KIM-1, and cystatin c in urine. Thus, chronic ethanol ingestion oxidatively damages kidney lipids and proteins, damages renal function, and induces acute kidney injury through an inflammatory cell infiltrate. The anti-inflammatory nutraceutical taurine effectively interrupts this ethanol-induced inflammatory cycle in kidney.     

Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK–NF-κB pathway

Acute lung injury (ALI) is a serious disease with unacceptably high mortality and morbidity rates. Up to now, no effective therapeutic strategy for ALI has been established. Rutin, quercetin-3-rhamnosyl glucoside, expresses a wide range of biological activities and pharmacological effects, such as anti-inflammatory, antihypertensive, anticarcinogenic, vasoprotective, and cardioprotective activities. Pretreatment with rutin inhibited not only histopathological changes in lung tissues but also infiltration of polymorphonuclear granulocytes into bronchoalveolar lavage fluid in lipopolysaccharide (LPS)-induced ALI. In addition, LPS-induced inflammatory responses, including increased secretion of proinflammatory cytokines and lipid peroxidation, were inhibited by rutin in a concentration-dependent manner. Furthermore, rutin suppressed phosphorylation of NF-κB and MAPK and degradation of IκB, an NF-κB inhibitor. Decreased activities of antioxidative enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 caused by LPS were reversed by rutin. At the same time, we found that ALI amelioration by chelation of extracellular metal ions with rutin is more efficacious than with deferoxamine. These results indicate that the protective mechanism of rutin is through inhibition of MAPK–NF-κB activation and upregulation of antioxidative enzymes.     

Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

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Prognostic implications of changes in cardiac troponin I levels in patients with non-ST elevation acute coronary syndrome

Abstract

Objective: Information is limited on the prognostic implications of cardiac troponin I (cTnI) changes during the first days of non-ST elevation acute coronary syndrome (NSTE-ACS).

Methods: High-sensitivity cTnI levels were measured at study inclusion and after 48?h in 1615 conservatively managed NSTE-ACS patients from the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO) IV trial.

Results: Patients with moderately increased cTnI levels and without a relevant decrease over time had a significantly raised mortality at 30 days and 1 year. No relevant associations between cTnI changes and recurrent myocardial infarction were seen.

Conclusion: The cTnI change is predictive for subsequent mortality in selected conservatively managed NSTE-ACS patients.     

Opposing roles of IL-10 in acute bacterial infection

Interleukin-10 (IL-10) is recognized as an anti-inflammatory cytokine that downmodulates inflammatory immune responses at multiple levels. In innate cells, production of this cytokine is usually triggered after pathogen recognition receptor (PRR) engagement by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patters (DAMPs), as well as by other soluble factors. Importantly, IL-10 is frequently secreted during acute bacterial infections and has been described to play a key role in infection resolution, although its effects can significantly vary depending on the infecting bacterium. While the production of IL-10 might favor host survival in some cases, it may also result harmful for the host in other circumstances, as it can prevent appropriate bacterial clearance. In this review we discuss the role of IL-10 in bacterial clearance and propose that this cytokine is required to recover from infection caused by extracellular or highly pro-inflammatory bacteria. Altogether, we propose that IL-10 drives excessive suppression of the immune response upon infection with intracellular bacteria or in non-inflammatory bacterial infections, which ultimately favors bacterial persistence and dissemination within the host. Thus, the nature of the bacterium causing infection is an important factor that needs to be taken into account when considering new immunotherapies that consist on the modulation of inflammation, such as IL-10. Indeed, induction of this cytokine may significantly improve the host’s immune response to certain bacteria when antibiotics are not completely effective.     

Isocitrate dehydrogenase variants in cancer — Cellular consequences and therapeutic opportunities

Abnormal metabolism is common in cancer cells and often correlates with mutations in genes encoding for enzymes involved in small-molecule metabolism. Isocitrate dehydrogenase 1 (IDH1) is the most frequently mutated metabolic gene in cancer. Cancer-associated substitutions in IDH1 and IDH2 impair wild-type production of 2-oxoglutarate and reduced nicotinamide adenine dinucleotide phosphate (NADPH) from isocitrate and oxidised nicotinamide adenine dinucleotide phosphate (NADP⁺ ), and substantially promote the IDH variant catalysed conversion of 2-oxoglutarate to d-2-hydroxyglutarate (d-2HG). Elevated d-2HG is a biomarker for some cancers, and inhibition of IDH1 and IDH2 variants is being pursued as a medicinal chemistry target. We provide an overview of the types of cancer-associated IDH variants, discuss some of the proposed consequences of altered metabolism as a result of elevated d-2HG, summarise therapeutic efforts targeting IDH variants and identify areas for future research.     

Timing and magnitude of lumbar spine contribution to trunk forward bending and backward return in patients with acute low back pain

Alterations in the lumbo-pelvic coordination denote changes in neuromuscular control of trunk motion as well as load sharing between passive and active tissues in the lower back. Differences in timing and magnitude aspects of lumbo-pelvic coordination between patients with chronic low back pain (LBP) and asymptomatic individuals have been reported; yet, the literature on lumbo-pelvic coordination in patients with acute LBP is scant. A case-control study was conducted to explore the differences in timing and magnitude aspects of lumbo-pelvic coordination between females with (n=19) and without (n=19) acute LBP. Participants in each group completed one experimental session wherein they performed trunk forward bending and backward return at preferred and fast paces. The amount of lumbar contribution to trunk motion (as the magnitude aspect) as well as the mean absolute relative phase (MARP) and deviation phase (DP) between thoracic and pelvic rotations (as the timing aspect) of lumbo-pelvic coordination were calculated. The lumbar contribution to trunk motion in the 2nd and the 3rd quarters of both forward bending and backward return phases was significantly smaller in the patient than the control group. The MARP and the DP were smaller in the patient vs. the control group during entire motion. The reduced lumbar contribution to trunk motion as well as the more in-phase and less variable lumbo-pelvic coordination in patients with acute LBP compared to the asymptomatic controls is likely the result of a neuromuscular adaptation to reduce painful deformation and to protect injured lower back tissues.     

DDT induced ethological changes in estuarine fish

Synopsis Experiments were carried out to study the feeding rates of the predator fish Therapon jarbua (Forsk) on mullet juveniles, before and after treatment with DDT. Mullet juveniles treated with a subacute concentration, were refused by the control predators, whereas predators treated with a subacute concentration consumed more mullet juveniles. In the present study crescent perch T. jarbua were exposed to subacute and acute concentrations of DDT, and their behaviour was compared with that of the control predators. There were changes in oriented behaviour and co-ordinated movements, and in feeding, aggression and comfort behaviour of the fish. Inflammation in the gills, and caudal fin serration, were noticed in treated fishes. The findings presented here throw light on fundamental pathways by which pollutants interact with the behaviour of fishes.     

Acute and long-lasting effects of peripheral injection of caerulein and CCK-8 on the central GABAergic system in mice

Acute and long-lasting effects of peripheral injection of caerulein (CLN) and cholecystokinin octapeptide (CCK-8) on the gamma-aminobutylic acid (GABA) content and the GABA accumulation by aminooxyacetic acid (AOAA) in the discrete brain regions of mice were examined. The content and accumulation of GABA in the striatum, hypothalamus, and frontal cortex was measured with high performance liquid chromatography with electrochemical detection (HPLC-ECD). The GABA content slightly decreased in the striatum 60 min after CLN and CCK-8 were administered, whereas it slightly increased in the hypothalamus and frontal cortex. Moreover, with CLN and CCK-8, the GABA accumulation after AOAA treatment decreased in the striatum and hypothalamus 30 min after injection. Meanwhile, when administering CLN, the GABA content as well as the GABA accumulation after AOAA treatment increased in the striatum and frontal cortex 1 day after injection, and continued to increase the second and third day in the striatum. These results showed that peripheral injection of CLN and CCK-8 had effects on the central GABAergic system with local specific actions, and also the long-lasting and time-dependent biphasic effects of CLN.