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Introduction: Despite the ability of cancer cells to survive glucose deprivation, most studies on anti-cancer effect of metformin explored its impact on glucose metabolism. No study ever examined whether its anti-cancer effect is reversible. Existing evidences warrant understanding of glucose-independent non-cytotoxic anti-proliferative effect of metformin to rationalize its role in liver cancer. Objectives: Characterization of glucose-independent anti-proliferative metabolic effects of metformin as well as analysis of their reversibility in liver cancer cells. Methodology: The dose-dependent effects of metformin on HepG2 cells were examined in presence and absence of glucose. The longitudinal evolution of metabolome was analyzed along with gene and protein expression as well as their correlations with and reversibility of cellular phenotype and metabolic signatures. Results: Metformin concentrations up to 2.5 mM were found to be anti-proliferative irrespective of presence of glucose without significant increase in cytotoxicity. Apart from mitochondrial impairment, derangement of fatty acid desaturation, one-carbon, glutathione, and polyamine metabolism were associated with metformin treatment irrespective of glucose supplementation. Depletion of pantothenic acid, downregulation of essential amino acid uptake and metabolism alongside purine salvage were identified as novel glucose-independent effects of metformin. These were significantly correlated with cMyc expression and reduction in proliferation. Rescue experiments established reversibility upon metformin withdrawal and tight association between proliferation, metabotype, and cMyc expression. Conclusions: The derangement of multiple glucose-independent metabolic pathways, which are often upregulated in therapy-resistant cancer, and concomitant cMyc downregulation coordinately contribute to the anti-proliferative effect of metformin in liver cancer cells. These are reversible and may influence its therapeutic utility. [ABSTRACT FROM AUTHOR]

Abstract The menstrual cycle is a well-known physiological model used to study working memory (WM) function. The present study examined auditory and visuospatial WM during proliferative and secretory phases of three consecutive menstrual cycles.Forty young adult females with a mean age of 23.4 ± 4.2 years and a history of regular menstrual cycle were selected for this study. Computerized software-based dual-task n-back WM tasks were performed by each participant during the proliferative (day 10th – 14th) and secretory phases (day 21st – 25th) of the menstrual cycle. The above tasks were repeated for three consecutive menstrual cycles during follow-up.Data from the three menstrual cycles were pooled and compared between the proliferative and secretory phases. Significant differences were observed in the hit rate (p = 0.006), Z score (p = 0.004) and parametric sensitivity (p = 0.005) of visuospatial targets and Z score (p = 0.037) and parametric sensitivity (p = 0.028) of auditory targets with better performance during the secretory phase. However, no significant differences were found across the three proliferative or three secretory phases, indicating that the results were consistent across consecutive cycles.This study concluded that visuospatial and auditory WM skills were significantly improved during the secretory phase compared to the proliferative phase of the menstrual cycle. [ABSTRACT FROM AUTHOR]

Introduction: The menstrual cycle is a well known physiological model to study the ovarian steroid hormones, influencing cognitive functions like Working Memory (WM). Hormonal fluctuation during the menstrual cycle also affects menstrual distress-related symptoms, which indecently could the cognitive functions. However, the data were inconclusive regarding the change in WM functions during different phases of the menstrual cycle and the correlation of various WM functions with menstrual distress-related symptoms. Aim: To examine the verbal and visuospatial WM functions during the proliferative (day 10-14) and secretory phase (day 21-25) of the menstrual cycle and to correlate various WM functions with menstrual distress symptoms scores. Materials and Methods: A cross-sectional, observational study was carried out in the Department of Physiology at VMMC and Safdarjung Hospital, New Delhi, India, over a period of 18 months, from November 2020 to May 2022. A total of 40 young adult females with a history of regular menstrual cycles were selected for the study. Computerised software-based dual-task n-back WM tasks were given twice in the same menstrual cycle: first, the proliferative (day 10-14) and second, the secretory phase (day 21-25). In addition, a standardised Menstrual Distress Questionnaire (MDQ) based on various menstrual distress symptoms was also administered to each subject after completion of the WM task, first in the proliferative (day 10-14) and second, in the secretory phase (day 21-25). Based on MDQ, a score was calculated, a Menstrual Distress Score (MDS). Descriptive statistics such as mean, median, standard deviation, and mode were calculated and Pearson's coefficient/Spearman's rank correlation coefficient was used to assess the correlation WM parameters with MDS. Data was compiled and analysed using the statistical software Graph PadPrism. Results: The mean age of the study population was 23.4 years with an average menstrual cycle length of 30 days. In the WM task, the 'overall proportion of correct' responses across all the tasks were significantly better in the secretory phase of the menstrual cycle than in the proliferative phase (p-value=0.040). Similarly, significantly improved performance in WM tasks during the secretory phase was also seen in the overall 'hit rate' of the visual target (p-value=0.020) and auditory targets (p-value=0.044). On the other hand, the correlation of WM parameters with MDS did not show any statistical significance except a significant negative correlation (r-value -0.369; p-value=0.019) between the 'parametric sensitivity' (subject's ability to correctly distinguishing a target from a non target) of auditory WM of secretory phase and MDS of the proliferative phase. Conclusion: The visual and auditory WM skills were significantly improved during the secretory phase compared to the menstrual cycle's proliferative phases in terms of the target 'hit rate'. However, increased MDS had no significant detrimental effect on the performance of WM tasks during the normal menstrual cycle. [ABSTRACT FROM AUTHOR]

Depletion of glutathione (GSH) is considered a critical pathogenic event promoting alcohol-induced lipotoxicity. We recently show that systemic GSH deficiency in mice harboring a global disruption of the glutamate-cysteine ligase modifier subunit (Gclm) gene confers protection against alcohol-induced steatosis. While several molecular pathways have been linked to the observed hepatic protection, including nuclear factor erythroid 2-related factor 2 and AMP-activated protein kinase pathways, the precise mechanisms are yet to be defined. In this study, to gain insights into the molecular mechanisms underpinning the protective effects of loss of GCLM, global profiling of hepatic polar metabolites combined with liver microarray analysis was carried out. These inter-omics analyses revealed both low GSH- and alcohol-driven changes in multiple cellular pathways involving the metabolism of amino acids, fatty acid, glucose and nucleic acids. Notably, several metabolic changes were uniquely present in alcohol-treated Gclm -null mouse livers, including acetyl-CoA enrichment and diversion of acetyl-CoA flux from lipogenesis to alterative metabolic pathways, elevation in glutamate concentration, and induction of the glucuronate pathway and nucleotide biosynthesis. These metabolic features reflect low GSH-elicited cellular response to chronic alcohol exposure, which is beneficial for the maintenance of hepatic redox and metabolic homeostasis. The current study indicates that fine-tuning of hepatic GSH pool may evoke metabolic reprogramming to cope with alcohol-induced cellular stress. Image 1 • GSH-deficient (Gclm -KO) liver is acetyl-CoA and glutamate enriched. • Low GSH promotes pyruvate and fatty acid oxidation and inhibits lipogenesis. • Ethanol-exposed WT and KO liver show differential changes in acetyl-CoA metabolism. • Transcriptional and post-transcriptional mechanisms underlie metabolic adaptions. [ABSTRACT FROM AUTHOR]

Graphical abstract Two tetranuclear Schiff base coordinated copper(II) complexes have been synthesized and structurally characterized. The catecholase-like activity and the interaction of the complexes with DNA/proteins were studied using spectroscopic techniques. Abstract Two tetranuclear Schiff base copper(II) complexes, namely [Cu 4 (L) 2 (LH) 2 (H 2 O) 2 ](ClO 4) 2 ·3H 2 O (1) and [Cu 4 (L) 2 (LH) 2 (H 2 O) 2 ](ClO 4)·(tp) 0.5 ·3H 2 O (2) (where H 2 L = 2-[(2-hydroxy-ethylimino)-methyl]-6-methoxy-phenol, tp = terephthalate), were synthesized and characterized by X-ray single crystal diffraction. Both complexes 1 and 2 are comprised of structurally similar tetranuclear cationic [Cu 4 (L) 2 (LH) 2 (H 2 O) 2 ]2+ species with a double open cubane core, in which two metal centers possess a square pyramidal environment and the other two exhibit a slightly distorted octahedral coordination geometry. The interaction of complexes 1 and 2 with calf thymus DNA (CT-DNA) was investigated using electronic absorption and fluorescence studies, and the results showed that the complexes interact with CT-DNA with the related intrinsic binding constants (K ib) of 1.8 × 106 and 1.1 × 107 L mol−1 for 1 and 2 , respectively. Their interactions with bovine serum albumin (BSA) and human serum albumin (HSA) were also investigated and spectroscopic techniques showed that both complexes interact with these proteins through a ground state association process. Using 3,5-di-tertbutylcatechol (3,5-DTBC) as a model substrate, both complexes show catecholase-like activity, being able to oxidase 3,5-DTBC to 3,5-di-tert-butylquinone (3,5-DTBQ) in the presence of oxygen. [ABSTRACT FROM AUTHOR]

Abstract: Two novel copper(II) complexes, [Cu4(L)2(LH)2(H2O)2]2(NO3)2. (pydc).9H2O (1) and {[Cu4(L)2(LH)2(H2O)2(ppda)].5H2O}n (2) [H2L=2‐[(2‐hydroxy‐ethylimino)‐methyl]‐6‐methoxy‐phenol, pydc=pyridine‐3,5‐dicarboxylate, ppda=phenylene‐1,4‐diacrylate]have been synthesized and characterised by X‐ray single crystal diffraction analysis and low temperature magnetic study. The structural determination reveals for complex 1 a tetranuclear species exhibiting a double‐open cubane like core framework, whereas use of ppda anions results 1D coordination polymer where tetranuclear double‐open cubane cores are connected by bridging ppda ligands. In both the complexes, hydrogen bonding interactions lead to 3D supramolecular structures. Low temperature magnetic study indicates antiferromagnetic coupling in both the complexes. A model based on an effective square tetramer of Heisenberg spins was used to determine exchange strengths of 174(2) K for 1 and 107.4(4) K for 2. [ABSTRACT FROM AUTHOR]

Understanding the molecular mechanism(s) of small compounds in cellular growth control are essential for using those against the disease(s). Oral cancers exhibit a very high mortality rate due to higher metastatic potential. Aberrant EGFR, RAR, HH signalling, enhanced [Ca2+] and oxidative stress are some of the important characteristics of oral cancer. So, we target these for our study. Herein, we tested the effect of fendiline hydrochloride (FH) as an LTCC Ca2+-channel inhibitor, erismodegib (a SMO inhibitor of HH-signalling) and all-trans retinoic acid (RA) inducer of RAR signalling that causes cellular differentiation. OCT4 activating compound (OAC1) counters differentiation and induces stemness properties. Cytosine β-D arabinofuranoside (Cyto-BDA), a DNA replication inhibitor was used to reduce high proliferative capacity. Treatment of FaDu cells with OAC1, Cyto-BDA and FH increase G0/G1 population by 3%, 20% and 7% respectively, and lead to reduction of cyclin D1, CDK4/6 levels. Erismodegib arrests the cells in S-phase with reduced cyclin-E1&A1 levels, whereas RA-treatment causes G2/M phase arrest with reduced cyclin-B1. There was a decrease in the expression of EGFR and mesenchymal markers, Snail/Slug/Vim/Zeb/Twist, and increased E-cadherin expression in all the drug treatments, indicating a reduction in proliferative signal and EMT. Enhanced MLL2 (Mll4) and reduced EZH2 expression associated overexpression of p53 and p21 were traced out. We conclude that these drugs impact expression of epigenetic modifiers by modulating signalling pathways and the epigenetic modifiers then controls the expression of cell cycle control genes, including p53 and p21. [Display omitted] • Hedgehog, Calcium and Retinoic acid signaling modulate EGFR mediated signaling, cell cycle and EMT in OSCC. • H3K4me3 methyltransferases – MLL1/2 expression was enhanced and KDM5A was reduced; H3K27me methyltransferase EZH2 was reduced following drug treatments. • Increased expression of E-cadherin, Cyc-D1 and tumor suppressor gene expression has epigenetic basis. [ABSTRACT FROM AUTHOR]

A six-coordinate Mn(IV) complex, [Mn(H2L)2] (1) [H4L = 2-methoxy-6-(tris(hydroxymethyl)methyliminomethyl)phenol], was synthesized and characterized by elemental analysis, single-crystal X-ray crystallography, FTIR, UV–Vis electronic absorption, and EPR spectroscopy. The single-crystal structural determination reveals that the complex crystallizes in tetragonal space groupP41212 and the tridentate Schiff base ligands are arranged inmerconfiguration chelating manganese, which exhibits as slightly distorted octahedral coordination sphere with a N2O4chromophore. Weak hydrogen bonding interactions of uncoordinated hydroxyl groups result in a 2-D supramolecular structure. The UV–Vis electronic absorption and IR spectral data of1have been compared with the results obtained by employing DFT and time-dependent density functional theory calculation using B3LYP, B3PW91, and MPW1PW91 functionals, with 6-31G (d-p) and LanL2MB basis sets. The results of these calculations are functional-dependent and, among those used, B3PW91 proved to better reproduce the experimental results. [ABSTRACT FROM AUTHOR]

Introduction: Coronary Heart Disease (CHD) is one of the leading causes of mortality in India, due to high consumption of mustard oil and ghee among urban population. Aim: To find out the relationship of mustard oil and ghee consumption on CHD history. Materials and Methods: By a random cross-sectional, houseto- house survey in North India, 137 people aged between 40- 80 years (70 males and 67 females) were selected by dietary history of Mustard Oil (MO) and Ghee consumption (G), but having no other CHD precipitating factor. Using food frequency questionnaire, the study population was divided into two groups based on the amount of MO and G consumption; Group A (n = 75): MO >1L/month, but G <0.5Kg/month and Group B (n = 62): MO =0.2 to 0.5L/month but G >1.25Kg/month. Serum lipid profile estimation and resting ECGs recording were done from all the subjects. Results: There was no statistical significant difference in CHD history between the two groups. Mustard Oil had positive correlation with CHD history. CHD was higher by 50.9% in Group A and was independent of gender. However, the odds of CHD history were higher among males by 32.2% irrespective of the groups. Conclusion: The results demonstrated that CHD history was associated with higher relative consumption of mustard oil than ghee and CHD is positively correlated with increase mustard oil intake, blood level of TG, TC, LDL, VLDL, TC/HDL and LDL/ HDL ratio. [ABSTRACT FROM AUTHOR]

The copper(II) complex, {[Cu(2,5-pdc)(H2O)4]·H2O} (1) [2,5-pdc = pyridine-2,5-dicarboxylate], has been synthesized and characterized by elemental analysis, IR spectroscopy, and X-ray crystallography. The metal shows a distorted octahedral coordination sphere and in solid state the complex forms a 3-D supramolecular network via hydrogen bonding and off-center anti-parallelπ–πstacking interactions between py rings. At room temperature,1exhibits fluorescence in methanolic solution [λex = 226 nm,λem = 309, 330, and 341 nm]. The geometry optimization at the B3LYP/LanL2DZ level led to a five-coordinate copper having a distorted square pyramidal geometry. The electronic spectrum of this compound is compared with the results obtained by employing density functional theory (DFT) and time dependent density functional theory calculations. [ABSTRACT FROM AUTHOR]

Abstract: The effects of the divalent alkaline-earth metal ions (Ca2+ and Mg2+) on the substrate binding affinity, spin-state transition at the heme active site, conformational properties as well as the stability of the active form of cytochrome P450cam (CYP 101) have been investigated using various spectroscopic and kinetic methods. The divalent cations were found to have two types of effects on the enzyme. At the initial stage the alkaline-earth metal ion facilitated enhanced binding of the substrate and formation of the high-spin form of the heme active center of the enzyme compared to that in absence of any metal ion. However, analogous to many other mono-valent metal ions, the alkaline-earth metal ions were also less efficient than K+ in promoting the substrate binding and spin-transition properties of the enzyme. The auxiliary metal ions were shown to cause small but distinct change in the circular dichroism spectra of the substrate-free enzyme in the visible region, indicating that the tertiary structure around the heme was perturbed on binding of the auxiliary metal ion to the enzyme. The effect of the auxiliary metal ion was found to be more prominent in the WT enzyme compared to the Y96F mutant of P450cam suggesting that the Tyr 96 residue plays an important role in mediating the effects of the auxiliary metal ions to the active site of the enzyme. At the second stage of interaction, the alkaline-earth metal ions were found to slowly convert the enzyme into an inactive P420 form, which could be reversibly re-activated by addition of KCl. The results have been discussed in the light of understanding the mechanism of inactivation of certain mammalian P450 enzymes by these alkaline-earth metal ions. [Copyright &y& Elsevier]

Abstract: Cytochrome c and myoglobin have been used as two representative proteins for assessing three parameters for protein encapsulation in mesoporous silica, specifically protein purity, protein secondary structure and morphology of the host structure. These aspects have been evaluated in order to determine the factors that control adsorption onto mesoporous silicas (MPS). Among the various MPS evaluated, those with rod like structures exhibited the highest loading amount ca. 408mgg−1 and 177mgg−1 for unpurified and ca. 241mgg−1 and 106mgg−1 for purified cytochrome c and myoglobin, respectively. These proteins were also found to be strongly adsorbed onto the silicas as indicated by low levels of leaching even after 10h of extraction. The stability of proteins during the course of encapsulation experiments was confirmed by evaluating their secondary structure and moreover, the structural integrity of MPS before and after encapsulation was monitored by XRD. The results indicated at least a partial degradation of the mesoporous structure in case of protein bound MPS. In view of these observations, the accessibility of MPS channel structure is evaluated and their promise as hosts for biomolecule adsorption is assessed. [Copyright &y& Elsevier]

The role of the threonine 101 residue that resides close to the heme propionic acid side chain of cytochrome P450cam on the conformational properties of the active site of the enzyme has been investigated by circular dichroism (CD) spectroscopy. Site-specific mutation of the threonine by valine has been carried out that does not affect the size of the residue but significantly alters the hydropathy index. The TI01V mutant of cytochrome P450cam showed distinct differences in the CD spectra near the heme region, indicating a subtle effect of the mutation on the properties of the heme active site. Thermal stabilities of the mutant and wild-type enzyme have been studied by temperature dependence of the ellipticity (intensity of the CD band) in the far-UV region for the secondary structure and at different wavelengths in the visible region that arise from the heme moiety for the tertiary structure around the prosthetic group. The thermal unfolding data from variations of the CD intensity at different wavelengths were analyzed using a generalized multistep unfolding model, and two distinct equilibrium intermediate conformational states of the enzyme were identified. The mutation of the TI01 residue by vatine was found to decrease the thermal stability of both the intermediates in the presence of the substrate. On the other hand, this mutation had no apparent effect on the thermal stability of the enzyme in the absence of the substrate. These results suggested that the threonine residue stabilizes the protein cavity around the heme center in the case of the substrate-bound species, possibly by hydrogen bonding with one of the propionate side chains of the heme moiety. Such hydrogen bonding of the heme propionate with threonine is absent in the substrate-free form of the enzyme. [ABSTRACT FROM AUTHOR]

Gene expression is influenced at many layers by a fine-tuned crosstalk between multiple extrinsic signalling pathways and intrinsic regulatory molecules that respond to environmental stimuli. Epigenetic modifiers like DNA methyltransferases, histone modifying enzymes and chromatin remodellers are reported to act as triggering factors in many scenarios by exhibiting their control over most of the cellular processes. These epigenetic players can either directly regulate gene expression or interact with some effector molecules that harmonize the expression of downstream genes. One such epigenetic regulator which exhibits multifaceted regulation over gene expression is KDM5A. It is classically a transcriptional repressor acting as H3K4me3 demethylase, but also is reported to act as an activator in many contexts either by loss of activity due to inhibition manifested by other interacting proteins or by downregulating the negative players of a given physiological process thereby escalating the framework. Through this review, we draw attention to the remarkable modes of functioning laid by KDM5A on transcriptional and translational processes, affecting gene expression during differentiation and development and finally summing up on role in disease causation (Fig. 1). We also shed light on different orthologs of KDM5A and their organism specific roles, along with comparison of the sequence similarity to extrapolate some unanswered questions about this protein. [ABSTRACT FROM AUTHOR]

Two cadmium(II)-azido complexes, [Cd(H 4 L1)(N 3) 2 ] n (1) and [Cd 2 (L2)(N 3) 2 ]·(H 2 O) (2) (H 4 L1 = 2-((2-hydroxy-3-methoxybenzylidene)amino)-2-(hydroxymethyl)-propane-1,3-diol; and H 2 L2 = bis((3-methoxysalicylidene)ethyl)ethylamine) were synthesized and structurally characterized. Both the complexes are active for photocatalytic degradation of methylene blue (MB) in presence of UV light. Two Schiff base coordinated cadmium(II) complexes, namely [Cd(H 4 L1)(N 3) 2 ] n (1) and [Cd 2 (L2)(N 3) 2 ]·(H 2 O) (2) (where H 4 L1 = 2-((2-hydroxy-3-methoxybenzylidene)amino)-2-(hydroxymethyl)-propane-1,3-diol; and H 2 L2 = bis((3-methoxysalicylidene)ethyl)ethylamine), were synthesized and characterized by X-ray single crystal diffraction. Both the complexes 1 and 2 crystallize in monoclinic system with space group P 2 1 /n. Complex 1 is a 1D coordination polymer where Cd(H 4 L1) species are doubly connected by bridging μ-1,1 azide anions. Complex 2 is a discrete dinuclear compound where the double deprotonated Schiff base (L2)2− acts as a two compartmental ligand coordinating two cadmium atoms. Photocatalytic activity of the complexes has been studied using UV–vis absorption spectroscopic technique and the results show that both the complexes are active for photocatalytic degradation of methylene blue (MB) in presence of UV light, and within 180 min MB decomposed by 37.64% and 32.60% in presence of complexes 1 and 2 , respectively. [ABSTRACT FROM AUTHOR]

Cellular physiology is critically regulated by multiple signaling nexuses, among which cell death mechanisms play crucial roles in controlling the homeostatic landscape at the tissue level within an organism. Apoptosis, also known as programmed cell death, can be induced by external and internal stimuli directing the cells to commit suicide in unfavourable conditions. In contrast, stress conditions like nutrient deprivation, infection and hypoxia trigger autophagy, which is lysosome-mediated processing of damaged cellular organelle for recycling of the degraded products, including amino acids. Apparently, apoptosis and autophagy both are catabolic and tumor-suppressive pathways; apoptosis is essential during development and cancer cell death, while autophagy promotes cell survival under stress. Moreover, autophagy plays dual role during cancer development and progression by facilitating the survival of cancer cells under stressed conditions and inducing death in extreme adversity. Despite having two different molecular mechanisms, both apoptosis and autophagy are interconnected by several crosslinking intermediates. Epigenetic modifications, such as DNA methylation, post-translational modification of histone tails, and miRNA play a pivotal role in regulating genes involved in both autophagy and apoptosis. Both autophagic and apoptotic genes can undergo various epigenetic modifications and promote or inhibit these processes under normal and cancerous conditions. Epigenetic modifiers are uniquely important in controlling the signaling pathways regulating autophagy and apoptosis. Therefore, these epigenetic modifiers of both autophagic and apoptotic genes can act as novel therapeutic targets against cancers. Additionally, liquid-liquid phase separation (LLPS) also modulates the aggregation of misfolded proteins and provokes autophagy in the cytosolic environment. This review deals with the molecular mechanisms of both autophagy and apoptosis including crosstalk between them; emphasizing epigenetic regulation, involvement of LLPS therein, and possible therapeutic approaches against cancers. [Display omitted] • Apoptosis and autophagy both are interconnected by several crosslinking intermediates. • Epigenetic chromatin modifications play pivotal roles in regulating genes involved in autophagy and apoptosis. • Liquid-liquid phase separation (LLPS) also modulates aggregation of misfolded proteins and provokes autophagy in the cytosolic environment. • Epigenetic modifiers (enzymes) of autophagic and apoptotic genes can be novel therapeutic targets. [ABSTRACT FROM AUTHOR]

The mechanisms by which deregulated nuclear factor erythroid-2-related factor 2 (NRF2) and kelch-like ECHassociated protein 1 (KEAP1) signaling promote cellular proliferation and tumorigenesis are poorly understood. Using an integrated genomics and 13C-based targeted tracer fate association (TTFA) study, we found that NRF2 regulates miR-1 and miR-206 to direct carbon flux toward the pentose phosphate pathway (PPP) and the tricarboxylic acid (TCA) cycle, reprogramming glucose metabolism. Sustained activation of NRF2 signaling in cancer cells attenuated miR-1 and miR-206 expression, leading to enhanced expression of PPP genes. Conversely, overexpression of miR-1 and miR-206 decreased the expression of metabolic genes and dramatically impaired NADPH production, ribose synthesis, and in vivo tumor growth in mice. Loss of NRF2 decreased the expression of the redox-sensitive histone deacetylase, HDAC4, resulting in increased expression of miR-1 and miR-206, and not only inhibiting PPP expression and activity but functioning as a regulatory feedback loop that repressed HDAC4 expression. In primary tumor samples, the expression of miR-1 and miR-206 was inversely correlated with PPP gene expression, and increased expression of NRF2-dependent genes was associated with poor prognosis. Our results demonstrate that microRNA-dependent (miRNA-dependent) regulation of the PPP via NRF2 and HDAC4 represents a novel link between miRNA regulation, glucose metabolism, and ROS homeostasis in cancer cells. [ABSTRACT FROM AUTHOR]

In this study, a liquid chromatography mass spectrometry (LC/MS)-based metabolomics protocol was optimized for quenching, harvesting, and extraction of metabolites from the human pancreatic cancer cell line Panc-1. Trypsin/ethylenediaminetetraacetic acid (EDTA) treatment and cell scraping in water were compared for sample harvesting. Four different extraction methods were compared to investigate the efficiency of intracellular metabolite extraction, including pure acetonitrile, methanol, methanol/chloroform/HO, and methanol/chloroform/acetonitrile. The separation efficiencies of hydrophilic interaction chromatography (HILIC) and reversed-phase liquid chromatography (RPLC) with UPLC-QTOF-MS were also evaluated. Global metabolomics profiles were compared; the number of total detected features and the recovery and relative extraction efficiencies of target metabolites were assessed. Trypsin/EDTA treatment caused substantial metabolite leakage proving it inadequate for metabolomics studies. Direct scraping after flash quenching with liquid nitrogen was chosen to harvest Panc-1 cells which allowed for samples to be stored before extraction. Methanol/chloroform/HO was chosen as the optimal extraction solvent to recover the highest number of intracellular features with the best reproducibility. HILIC had better resolution for intracellular metabolites of Panc-1 cells. This optimized method therefore provides high sensitivity and reproducibility for a variety of cellular metabolites and can be applicable to further LC/MS-based global metabolomics study on Panc-1 cell lines and possibly other cancer cell lines with similar chemical and physical properties. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract Two dinuclear azido bridged Ni(II) complexes [Ni 2 (HL1) 2 (N 3)(C 8 H 7 O 3)]·(H 2 O) (1) and [Ni 2 (L2) 2 (N 3) 2 (H 2 O)](2) [H 2 L1 and HL2 are Schiff bases, obtained from the condensation of 2-hydroxy-3-methoxy-benzaldehyde with 2-amino-2-methyl-1-propanol and N, N -diethylethylene diamine, respectively; C 8 H 7 O 3 = 3-methoxy-2-oxo-benzaldehyde] have been synthesized and their crystal structures have been determined. Complex 1 , C 32 H 39 N 5 Ni 2 O 10 , crystallizes in a triclinic system, space group P- 1 with a = 10.0846 (6), b = 12.5179 (7), c = 14.1176 (8) Å, α = 74.3873 (7), β = 83.9553 (7), γ = 83.1921 (7) º and Z = 2; complex 2 , C 28 H 44 N 10 Ni 2 O 5 , crystallizes in an orthorhombic system, space group Pbca with a = 12.4197 (1), b = 21.4737 (4), c = 24.4569 (5) Å, and Z = 8. X-ray single crystal structure determination reveals that both the complexes are dinuclear with μ 2 -(1,1-azido) and μ 2 -(penoxido) bridges. Variable temperature magnetic studies indicate overall ferromagnetic interaction between nickel (II) centers in both the complexes. The experimental magnetic data of the complexes were fitted using PHI program and the Ĥ = - JŜ 1 Ŝ 2 - D (Ŝ 1z 2 + Ŝ 2z 2) - gβH (Ŝ 1 + Ŝ 2) Hamiltonian, where S 1 = S 2 = S Ni , J is the intramolecular magnetic exchange constant and D is the zero-field splitting parameter. An intermolecular interaction term (zJ′) was also considered in the model and a good agreement between experimental and simulated curves was found by using the following parameters: g Ni = 2.13, D Ni = 5.83 cm−1, J Ni-Ni = 14.61 cm−1 and zJ' = −0.1 cm−1 for 1 , and g Ni = 2.15, D Ni = 2.33 cm−1, J Ni-Ni = 13.09 cm−1and zJ' = −0.07 cm−1 for 2. Graphical abstract Two μ 2 -(1,1-azido) and μ 2 -(1,1-phenoxido) bridged dinuclear nickel (II) complexes have been synthesized and structurally characterized. Variable temperature magnetic studies indicate overall ferromagnetic interaction between nickel (II) centers in both the complexes. Image 1 Highlights • Schiff base coordinated two Ni(II) complexes have been synthesised and characterised. • Both the complexes are dinuclear with μ 1,1 -azido and μ-phenoxido bridge. • Magnetic property study show overall intramolecular ferromagnetic exchange interaction between the Ni(II) centers. [ABSTRACT FROM AUTHOR]

Introduction: Nitric oxide (NO), different haematological and biochemical parameters, play an important role in the pathogenesis of Acute Ischaemic Stroke (AIS) (<24 hour). Aim: To establish a correlation between NO with haematological and biochemical parameters in AIS patients. Materials and Methods: A hospital based, cross-sectional study was done in 50 patients of AIS and 25 healthy controls. Serum NO level was measured by ELISA. Complete lipid profile, Random Blood Sugar (RBS), serum Blood Urea Nitrogen (BUN), creatinine and haemogram were assessed by automated devices. Pearson's correlation coefficients were analysed to look for the relationship between NO with biochemical and haematological parameters. The p-value was considered significant if p<0.05. Results: Statistically highly significant (p<0.001) elevation in mean serum NO levels were observed in cases (32.06 µmol/L) as compared to controls (24.41 µmol/L). NO was positively correlated with elevated levels of Triacylglycerol (TAG), T-Chol, Low Density Lipoprotein (LDL-C), VLDL-C, RBS, and negatively correlated with High Density Lipoprotein (HDL-C), BUN, serum creatinine, Total Leukocyte Count (TLC), ESR, but none of the correlation coefficient was found to be statistically significant. Conclusion: Elevated NO and derangement of biochemical and haematological parameters may be linked to pathogenesis of AIS. [ABSTRACT FROM AUTHOR]

Abstract: Vitamin D is an essential micronutrient required for normal physiological function and recognized for its role regulating calcium metabolism. Recent work is beginning to emerge demonstrating a role for vitamin D in chronic illnesses, such as cancer. Circulating serum levels of 25(OH)D2/3 were quantitatively measured using sensitive ultraperformance liquid chromatography coupled to tandem mass spectrometry (UPLC‐MS/MS) in 406 lung cancer cases and 437 population controls, while 1,25(OH)2D2/3 levels were measured in a subset of 90 cases and 104 controls using the same method, from the NCI‐MD case–control cohort. 25(OH)D3 levels were inversely associated with lung cancer status across quartiles (Q2 vs. Q1: ORadjusted = 0.5, 95% CI = 0.3–0.8; Q3 vs. Q1: ORadjusted = 0.5, 95% CI = 0.3–0.8; Q4 vs. Q1: ORadjusted = 0.5, 95% CI = 0.2–0.9; Ptrend = 0.004). Levels of 1,25(OH)2D3 were also inversely associated with lung cancer status (Q2 vs. Q1: ORadjusted = 0.2, 95% CI = 0.03–0.7; Q3 vs. Q1: ORadjusted = 0.1, 95% CI = 0.01–0.4; Q4 vs. Q1: ORadjusted = 0.04, 95% CI = 0.01–0.3; Ptrend<0.0001). Although the observed trends were similar for the 25(OH)D2 (Ptrend = 0.08), no significant associations were seen between vitamin D2 and lung cancer status. Additionally, genotyping of 296 SNPs in the same subjects resulted in findings that 27 SNPs, predominantly in CYP24A1 and VDR genes, were significantly associated with lung cancer status, affected mRNA expression, and modulated vitamin D levels. These findings suggest a protective role for vitamin D3 in lung cancer, with similar trends but insignificant findings for D2. Vitamin D3 levels appeared to be modulated by genetic variation in CYP24A1 and VDR genes. Additional research to illuminate the mechanism(s) through which vitamin D exacerbates effects against lung carcinogenesis is warranted. [ABSTRACT FROM AUTHOR]

Background: Ghee (G) is attributed with numerous health benefits in Ayurveda. However, due to the high saturated fat content, it has been predicted to increase the cardiovascular disease risk. Hence, the current study was performed to evaluate the effect of G consumption as compared to mustard oil (MO) on lipid profile. Methods: Two hundred (100 males) apparently healthy adults (=40 years) were randomly selected out of the total individuals interviewed in a house-to-house survey. They were divided into three groups based on G and MO consumption: (A) MO >1 L/month, G<0.5 kg/month; (B) MO 1-0.5 L/month, G 1.25-0.5 kg/month; and (C) MO <0.5-0.2 L/month, G>1.25 kg/month. Serum lipid parameters were compared among the groups. Results: Group C had the significantly lowest triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), TC/HDL and LDL/HDL and highest high-density lipoprotein (HDL). A similar finding was found when analysis was done separetely for male and female. Conclusions: A favorable lipid profile might suggest a possible beneficial effect of predominantly G consumption over MO. [ABSTRACT FROM AUTHOR]

Introduction: Family history of hypertension in medical students is an important, non-modifiable risk factor for Hypertension (HTN) in future. Aim: To determine the prevalence of sustained hypertension in young asymptomatic medical students with a parental history of hypertension. Materials and Methods: A cross-sectional study was conducted in a medical college of Dehradun. A total of 104 medical students with parental history of hypertension (Group A) and 100 medical students without a parental history of hypertension (Group B) were included. Electronically blood pressures were recorded on two separate occasions at an interval of 15 days. Comparison was done using Chi-square test/Likelihood ratio, Un-paired t-test and ANCOVA. Results: Overall, Group A had significantly higher percentage of prehypertensive (56.7%) and hypertensive (17.3%) students as compared to Group B which were 19% and 1%, respectively. Group A students had significantly higher Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) as compared to Group B, even after controlling for the differences in Body Mass Index (BMI) and gender (p<0.001). Conclusion: Hypertension was significantly higher in asymptomatic, healthy medical students with parental history of hypertension as compared to those with normotensive parents. We need to orient medical students to improve their knowledge, attitude and lifestyle practices early in life to prevent, treat hypertension and prevent its subsequent morbidity and mortality. [ABSTRACT FROM AUTHOR]

Aberrant DNA hypermethylation is associated with oral carcinogenesis. Procaine, a local anesthetic, is a DNA methyltransferase (DNMT) inhibitor that activates anticancer mechanisms. However, its effect on silenced tumor suppressor gene (TSG) activation and its biological role in oral squamous cell carcinoma (OSCC) remain unknown. Here, we report procaine inhibited DNA methylation by suppressing DNMT activity and increased the expression of PAX9, a differentiation gene in OSCC cells. Interestingly, the reactivation of PAX9 by procaine found to inhibit cell growth and trigger apoptosis in OSCC in vitro and in vivo. Likely, the enhanced PAX9 expression after exposure to procaine controls stemness and differentiation through the autophagy-dependent pathway in OSCC cells. PAX9 inhibition abrogated procaine-induced apoptosis, autophagy, and inhibition of stemness. In OSCC cells, procaine improved anticancer drug sensitivity through PAX9, and its deficiency significantly blunted the anticancer drug sensitivity mediated by procaine. Additionally, NRF2 activation by procaine facilitated the antitumor response of PAX9, and pharmacological inhibition of NRF2 by ML385 reduced death and prevented the decrease in the orosphere-forming potential of OSCC cells. Furthermore, procaine promoted antitumor activity in FaDu xenografts in athymic nude mice, and immunohistochemistry data showed that PAX9 expression was significantly enhanced in the procaine group compared to the vehicle control. In conclusion, PAX9 reactivation in response to DNMT inhibition could trigger a potent antitumor mechanism to provide a new therapeutic strategy for OSCC. [Display omitted] • Inhibition of DNA methyltransferase increases PAX9 expression in OSCC. • Procaine-mediated activation of PAX9 triggers apoptosis and autophagy in OSCC. • Procaine inhibits stemness and induces differentiation is PAX9-dependent in OSCC. • NRF2 activation by procaine facilitates PAX9-mediated antitumor activity. • PAX9 reactivation enhances chemotherapeutics sensitivity in OSCC. [ABSTRACT FROM AUTHOR]

Arsenic (As) is a ubiquitous carcinogenic metalloid that enters into human food chain, through rice consumption. To unravel the conundrum of oxidative vs. reductive stress, the differential root-system architecture (RSA) was studied under As (a ROS producer) and thiourea (TU; a ROS scavenger) alone treatments, which indicated 0.80- and 0.74-fold reduction in the number of lateral roots (NLR), respectively compared with those of control. In case of As+TU treatment, NLR was increased by 4.35-fold compared with those of As-stress, which coincided with partial restoration of redox-status and auxin transport towards the root-tip. The expression levels of 16 ROS related genes, including RBOHC , UPB-1 C , SHR1 , PUCHI , were quantified which provided the molecular fingerprint, in accordance with endogenous ROS signature. LC-MS based untargeted and targeted metabolomics data revealed that As-induced oxidative stress was metabolically more challenging than TU alone-induced reductive stress. Cis/trans-ferruloyl putrescine and γ-glutamyl leucine were identified as novel As-responsive metabolites whose levels were decreased and increased, respectively under As+TU than As-treated roots. In addition, the overall amino acid accumulation was increased in As+TU than As-treated roots, indicating the improved nutritional availability. Thus, the study revealed dynamic interplay between "ROS-metabolites-RSA", to the broader context of TU-mediated amelioration of As-stress in rice. [Display omitted] • Arsenic and thiourea alone treatments abolish root system architecture in rice. • Thiourea partially restored arsenic-induced loss in root phenotype. • In planta ROS scavenging activity of thiourea is linked with thiol accumulation. • Oxidative stress is metabolically more challenging than reductive stress. • Thiourea boost amino acid metabolism to provide arsenic stress tolerance. [ABSTRACT FROM AUTHOR]

Lung cancer remains the most common cause of cancer deaths worldwide, yet there is currently a lack of diagnostic noninvasive biomarkers that could guide treatment decisions. Small molecules (<1,500 Da) were measured in urine collected from469 patients with lung cancer and 536 population controls using unbiased liquid chromatography/mass spectrometry. Clinical putative diagnostic and prognostic biomarkers were validated by quantitation and normalized to creatinine levels at two different time points and further confirmed in an independent sample set, which comprises 80 cases and 78 population controls, with similar demographic and clinical characteristics when compared with the training set. Creatine riboside (IUPAC name: 2-{2-[(2R,3R,4S,5R)- 3,4-dihydroxy-5-(hydroxymethyl)-oxolan-2-yl]-1-methylcarbamimidamido}acetic acid), a novel molecule identified in this study, and N-acetylneuraminic acid (NANA) were each significantly (P < 0.00001) elevated in non-small cell lung cancer and associated with worse prognosis [HR = 1.81 (P = 0.0002), and 1.54 (P = 0.025), respectively]. Creatine riboside was the strongest classifier of lung cancer status in all and stage I-II cases, important for early detection, and also associated with worse prognosis in stage I-II lung cancer (HR = 1.71, P = 0.048). All measurements were highly reproducible with intraclass correlation coeficients ranging from 0.82 to 0.99. Both metabolites were significantly (P < 0.03) enriched in tumor tissue compared with adjacent nontumor tissue (N = 48), thus revealing their direct association with tumor metabolism. Creatine riboside and NANA may be robust urinary clinical metabolomic markers that are elevated in tumor tissue and associated with early lung cancer diagnosis and worse prognosis. [ABSTRACT FROM AUTHOR]

Cytochrome P450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of many low molecular weight toxicants and also an important contributor to oxidative stress. A noninvasive method to monitor CYP2E1 activity in vivo would be of great value for studying the role of CYP2E1 in chemical-induced toxicities and stress-related diseases. In this study, a mass spectrometry–based metabolomic approach was used to identify a metabolite biomarker of CYP2E1 through comparing the urine metabolomes of wild-type (WT), Cyp2e1-null, and CYP2E1-humanized mice. Metabolomic analysis with multivariate models of urine metabolites revealed a clear separation of Cyp2e1-null mice from WT and CYP2E1-humanized mice in the multivariate models of urine metabolomes. Subsequently, 2-piperidone was identified as a urinary metabolite that inversely correlated to the CYP2E1 activity in the three mouse lines. Backcrossing of WT and Cyp2e1-null mice, together with targeted analysis of 2-piperidone in mouse serum, confirmed the genotype dependency of 2-piperidone. The accumulation of 2-piperidone in the Cyp2e1-null mice was mainly caused by the changes in the biosynthesis and degradation of 2-piperidone because compared with the WT mice, the conversion of cadaverine to 2-piperidone was higher, whereas the metabolism of 2-piperidone to 6-hydroxy-2-piperidone was lower in the Cyp2e1-null mice. Overall, untargeted metabolomic analysis identified a correlation between 2-piperidone concentrations in urine and the expression and activity of CYP2E1, thus providing a noninvasive metabolite biomarker that can be potentially used in to monitor CYP2E1 activity. [ABSTRACT FROM PUBLISHER]

The recent pandemic of SARS-CoV-2 infection has affected more than 3.0 million people worldwide with more than 200 thousand reported deaths. The SARS-CoV-2 genome has the capability of gaining rapid mutations as the virus spreads. Whole-genome sequencing data offers a wide range of opportunities to study mutation dynamics. The advantage of an increasing amount of whole-genome sequence data of SARS-CoV-2 intrigued us to explore the mutation profile across the genome, to check the genome diversity, and to investigate the implications of those mutations in protein stability and viral transmission. We have identified frequently mutated residues by aligning ~660 SARS-CoV-2 genomes and validated in 10,000 datasets available in GISAID Nextstrain. We further evaluated the potential of these frequently mutated residues in protein structure stability of spike glycoprotein and their possible functional consequences in other proteins. Among the 11 genes, surface glycoprotein, nucleocapsid, ORF1ab, and ORF8 showed frequent mutations, while envelop, membrane, ORF6, ORF7a and ORF7b showed conservation in terms of amino acid substitutions. Combined analysis with the frequently mutated residues identified 20 viral variants, among which 12 specific combinations comprised more than 97% of the isolates considered for the analysis. Some of the mutations across different proteins showed co-occurrences, suggesting their structural and/or functional interaction among different SARS-COV-2 proteins, and their involvement in adaptability and viral transmission. Analysis of protein structure stability of surface glycoprotein mutants indicated the viability of specific variants and are more prone to be temporally and spatially distributed across the globe. A similar empirical analysis of other proteins indicated the existence of important functional implications of several variants. Identification of frequently mutated variants among COVID-19 patients might be useful for better clinical management, contact tracing, and containment of the disease. • We cataloged the frequently mutated residues in all proteins of SARS-CoV-2 genome. • Spike glycoprotein, ORF1ab, Nucleocapsid, ORF8 and ORF3a showed frequent mutations. • Combined analysis of frequently mutated residues identified 12 most abundant variants. • Stabilizing S protein mutants showed spatio-temporal distribution of the viral variants. • Identification of genotypes may help to assess the stability and viral transmission [ABSTRACT FROM AUTHOR]