Synergistic effect of spices in a decoction regulates the energy metabolism in liver cancer cells

Lactic acid fermentation and not oxidative phosphorylation is reported to be one of the major bioenergetics mechanisms by which cancer cells thrive and proliferate with such rapidity in non-ambient hypoxic conditions. The objective of the study was to determine the synergistic effect of spices in a decoction; Turmeric (Curcuma longa), Pepper (Piper nigrum) and Garlic (Allium sativum) in combination, on the metabolism of Hep G2 liver cancer cells.The biochemical studies of 2 major enzymes involved in cellular metabolism of cells namely; Pyruvate dehydrogenase (PDH) and Lactate dehydrogenase A (LDHA) showed that the decoction down regulated the activity of LDHA and increased the activity of PDH in cancer cells, thereby shifting the metabolic mechanism towards normal functioning in the cancer cells. The expression studies of major molecules involved in regulating metabolic machinery in cells viz., tumour suppressor p53 and oncogene MYC mRNAs; and western blot analysis of Hypoxia inducible factor-1-alpha (HIF-1α) and Vascular endothelial growth factor (VEGF) showed that the decoction regulated the expression of these factors helping to revert the metabolism in cancer cells, which could be attributed to the effect of turmeric and also garlic, rich in pantothenic acid, that aids in turning on oxidative phosphorylation in cancer cells. With the above results, it could be concluded that the decoction alters the metabolic mechanism in a cancer cell from lactic acid fermentation to oxidative phosphorylation, like in any other normal cell, thus inhibiting further growth of the cancer

Synergistic effect of spices in a decoction regulates the energy metabolism in liver cancer cells

Lactic acid fermentation and not oxidative phosphorylation is reported to be one of the major bioenergetics mechanisms by which cancer cells thrive and proliferate with such rapidity in non-ambient hypoxic conditions. The objective of the study was to determine the synergistic effect of spices in a decoction; Turmeric (Curcuma longa), Pepper (Piper nigrum) and Garlic (Allium sativum) in combination, on the metabolism of Hep G2 liver cancer cells.The biochemical studies of 2 major enzymes involved in cellular metabolism of cells namely; Pyruvate dehydrogenase (PDH) and Lactate dehydrogenase A (LDHA) showed that the decoction down regulated the activity of LDHA and increased the activity of PDH in cancer cells, thereby shifting the metabolic mechanism towards normal functioning in the cancer cells. The expression studies of major molecules involved in regulating metabolic machinery in cells viz., tumour suppressor p53 and oncogene MYC mRNAs; and western blot analysis of Hypoxia inducible factor-1-alpha (HIF-1α) and Vascular endothelial growth factor (VEGF) showed that the decoction regulated the expression of these factors helping to revert the metabolism in cancer cells, which could be attributed to the effect of turmeric and also garlic, rich in pantothenic acid, that aids in turning on oxidative phosphorylation in cancer cells. With the above results, it could be concluded that the decoction alters the metabolic mechanism in a cancer cell from lactic acid fermentation to oxidative phosphorylation, like in any other normal cell, thus inhibiting further growth of the cancer

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A New Promising Anti-Infective Agent Inhibits Biofilm Growth by Targeting Simultaneously a Conserved RNA Function That Controls Multiple Genes

Combating single and multi-drug-resistant infections in the form of biofilms is an immediate challenge. The challenge is to discover innovative targets and develop novel chemistries that combat biofilms and drug-resistant organisms, and thwart emergence of future resistant strains. An ideal novel target would control multiple genes, and can be inhibited by a single compound. We previously demonstrated success against Staphylococcus aureus biofilms by targeting the tRNA-dependent regulated T-box genes, not present in the human host. Present in Gram-positive bacteria, T-box genes attenuate transcription with a riboswitch-like element that regulates the expression of aminoacyl-tRNA synthetases and amino acid metabolism genes required for cell viability. PKZ18, the parent of a family of compounds selected in silico from 305,000 molecules, inhibits the function of the conserved T-box regulatory element and thus blocks growth of antibiotic-resistant S. aureus in biofilms. The PKZ18 analog PKZ18-22 was 10-fold more potent than vancomycin in inhibiting growth of S. aureus in biofilms. In addition, PKZ18-22 has a synergistic effect with existing antibiotics, e.g., gentamicin and rifampin. PKZ18-22 inhibits the T-box regulatory mechanism, halts the transcription of vital genes, and results in cell death. These effects are independent of the growth state, planktonic or biofilm, of the bacteria, and could inhibit emergent strains

Granulomatous dermatitis related to silicone implant

Silicone in liquid and gel implantation may induce granuloma formation and migration. Although there are many complications associated with solid silicone implantation, there have been no published reports of distant granuloma formation. We present a case of a woman with clinical and serologic findings that are consistent with systemic lupus erythematosus and a histopathologic diagnosis of foreign body granulomatous dermatitis 20 years after solid silicone nasal implantation. We review the literature on silicone granulomas and their treatment and speculate on the potential etiologies of a challenging case presentation

Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts

The TREX (transcription/export) complex has been conserved throughout evolution from yeast to man and is required for coupled transcription elongation and nuclear export of mRNAs. The TREX complex in mammals and Drosophila is composed of the THO subcomplex (THOC1, THOC2, THOC5, THOC6, and THOC7), THOC3, UAP56, and Aly/THOC4. In human and Drosophila, various studies have shown that THO is required for the export of heat shock mRNAs, but nothing is known about other mRNAs. Our previous study using conditional THOC5 (or FMIP) knockout mice revealed that the presence of THOC5 is critical in hematopoietic cells but not for terminally differentiated cells. In this study, we describe the establishment of a mouse embryo fibroblast cell line (MEF), THOC5 flox/flox. Four days after infection of MEF THOC5 flox/flox with adenovirus carrying Cre-recombinase gene (Ad-GFP-Cre), THOC5 is down-regulated >95% at the protein level, and cell growth is strongly suppressed. Transcriptome analysis using cytoplasmic RNA isolated from cells lacking functional THOC5 reveals that only 2.9% of all genes were down-regulated more than twofold. Although we examined these genes in fibroblasts, one-fifth of all down-regulated genes (including HoxB3 and polycomb CBX2) are known to play a key role in hematopoietic development. We further identified 10 genes that are spliced but not exported to the cytoplasm in the absence of THOC5. These mRNAs were copurified with THOC5. Furthermore, Hsp70 mRNA was exported in the absence of THOC5 at 37°C, but not under heat shock condition (42°C), suggesting that THOC5 may be required for mRNA export under stress and/or upon signaling-induced conditions

Severity and mortality associated with COVID-19 among children hospitalised in tertiary care centres in India: a cohort studyResearch in context

Summary: Background: It is critical to identify high-risk groups among children with COVID-19 from low-income and middle-income countries (LMICs) to facilitate the optimum use of health system resources. The study aims to describe the severity and mortality of different clinical phenotypes of COVID-19 in a large cohort of children admitted to tertiary care hospitals in India. Methods: Children aged 0–19 years with evidence of SARS-CoV-2 infection (real time polymerase chain reaction or rapid antigen test positive) or exposure (anti-SARS-CoV-2 antibody, or history of contact with SARS-CoV-2) were enrolled in the study, between January 2021 and March 2022 across five tertiary hospitals in India. All study participants enrolled prospectively and retrospectively were followed up for three months after discharge. COVID-19 was classified into severe (Multisystem Inflammatory Syndrome in Children (MIS-C), severe acute COVID-19, ‘unclassified’) or non-severe disease. The mortality rates were estimated in different phenotypes. Findings: Among 2468 eligible children enrolled, 2148 were hospitalised. Signs of illness were present in 1688 (79%) children with 1090 (65%) having severe disease. High mortality was reported in MIS-C (18.6%), severe acute COVID-19 (13.3%) and the unclassified severe COVID-19 disease (12.3%). Mortality remained high (17.5%) when modified MIS-C criteria was used. Non-severe COVID-19 disease had 14.1% mortality when associated with comorbidity. Interpretation: Our findings have important public health implications for low resource settings. The high mortality underscores the need for better preparedness for timely diagnosis and management of COVID-19. Children with associated comorbidity or coinfections are a vulnerable group and need special attention. MIS-C requires context specific diagnostic criteria for low resource settings. It is important to evaluate the clinical, epidemiological and health system-related risk factors associated with severe COVID-19 and mortality in children from LMICs. Funding: Department of Biotechnology, Govt of India and Department of Maternal, Child and Adolescent Health and Aging, WHO, Geneva, Switzerland

Jet fragmentation transverse momentum distributions in pp and p-Pb collisions at s \sqrt{s} , sNN \sqrt{s_{\mathrm{NN}}} = 5.02 TeV

Jet fragmentation transverse momentum (j$_{T}$) distributions are measured in proton-proton (pp) and proton-lead (p-Pb) collisions at $\sqrt{s_{\mathrm{NN}}}$ = 5.02 TeV with the ALICE experiment at the LHC. Jets are reconstructed with the ALICE tracking detectors and electromagnetic calorimeter using the anti-k$_{T}$ algorithm with resolution parameter R = 0.4 in the pseudorapidity range |η| < 0.25. The j$_{T}$ values are calculated for charged particles inside a fixed cone with a radius R = 0.4 around the reconstructed jet axis. The measured j$_{T}$ distributions are compared with a variety of parton-shower models. Herwig and Pythia 8 based models describe the data well for the higher j$_{T}$ region, while they underestimate the lower j$_{T}$ region. The j$_{T}$ distributions are further characterised by fitting them with a function composed of an inverse gamma function for higher j$_{T}$ values (called the “wide component”), related to the perturbative component of the fragmentation process, and with a Gaussian for lower j$_{T}$ values (called the “narrow component”), predominantly connected to the hadronisation process. The width of the Gaussian has only a weak dependence on jet transverse momentum, while that of the inverse gamma function increases with increasing jet transverse momentum. For the narrow component, the measured trends are successfully described by all models except for Herwig. For the wide component, Herwig and PYTHIA 8 based models slightly underestimate the data for the higher jet transverse momentum region. These measurements set constraints on models of jet fragmentation and hadronisation

Measurements of the groomed and ungroomed jet angularities in pp collisions at s \sqrt{s} = 5.02 TeV

International audienceThe jet angularities are a class of jet substructure observables which characterize the angular and momentum distribution of particles within jets. These observables are sensitive to momentum scales ranging from perturbative hard scatterings to nonperturbative fragmentation into final-state hadrons. We report measurements of several groomed and ungroomed jet angularities in pp collisions at $\sqrt{s}$ = 5.02 TeV with the ALICE detector. Jets are reconstructed using charged particle tracks at midrapidity (|η| < 0.9). The anti-k$_{T}$ algorithm is used with jet resolution parameters R = 0.2 and R = 0.4 for several transverse momentum {p}_{\mathrm{T}}^{\mathrm{ch}} ^{jet} intervals in the 20–100 GeV/c range. Using the jet grooming algorithm Soft Drop, the sensitivity to softer, wide-angle processes, as well as the underlying event, can be reduced in a way which is well-controlled in theoretical calculations. We report the ungroomed jet angularities, λ$_{α}$, and groomed jet angularities, λ$_{α,g}$, to investigate the interplay between perturbative and nonperturbative effects at low jet momenta. Various angular exponent parameters α = 1, 1.5, 2, and 3 are used to systematically vary the sensitivity of the observable to collinear and soft radiation. Results are compared to analytical predictions at next-to-leading-logarithmic accuracy, which provide a generally good description of the data in the perturbative regime but exhibit discrepancies in the nonperturbative regime. Moreover, these measurements serve as a baseline for future ones in heavy-ion collisions by providing new insight into the interplay between perturbative and nonperturbative effects in the angular and momentum substructure of jets. They supply crucial guidance on the selection of jet resolution parameter, jet transverse momentum, and angular scaling variable for jet quenching studies.[graphic not available: see fulltext

Inclusive quarkonium production in pp collisions at s=5.02\sqrt{s} = 5.02 TeV

This article reports on the inclusive production cross section of several quarkonium states, $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, $\Upsilon\rm(2S)$, and $\Upsilon\rm(3S)$, measured with the ALICE detector at the LHC, in \pp collisions at $\sqrt{s} = 5.02$ TeV. The analysis is performed in the dimuon decay channel at forward rapidity ($2.5 < y < 4$). The measured cross sections, assuming unpolarized quarkonia, are: $\sigma_{\mathrm{J}/\psi} = 5.88 \pm 0.03 \pm 0.34\ \mu$b, $\sigma_{\psi {\rm (2S)}} = 0.87 \pm 0.06 \pm 0.10\ \mu$b, $\sigma_{\Upsilon\rm(1S)} = 45.5 \pm 3.9 \pm 3.5$ nb, $\sigma_{\Upsilon\rm(2S)} = 22.4 \pm 3.2 \pm 2.7$ nb, and $\sigma_{\Upsilon\rm(3S)} = 4.9 \pm 2.2 \pm 1.0$ nb, where the first (second) uncertainty is the statistical (systematic) one. The transverse-momentum ($p_{\rm T}$) and rapidity ($y$) differential cross sections for $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, and the $\psi {\rm (2S)}$-to-$\mathrm{J}/\psi$ cross section ratios are presented. For the first time, the cross sections of the three $\Upsilon$ states, as well as the $\psi {\rm (2S)}$ one as a function of $p_{\rm T}$ and $y$, are measured at $\sqrt{s} = 5.02$ TeV at forward rapidity. These measurements also significantly extend the $\mathrm{J}/\psi$$p_{\rm T}$ reach with respect to previously published results. A comparison with ALICE measurements in pp collisions at $\sqrt{s} = 2.76$, 7, 8, and 13 TeV is presented and the energy dependence of quarkonium production cross sections is discussed. Finally, the results are compared with the predictions from several production models