Metformin and thymoquinone co-treatment enhance 5-fluorouracil cytotoxicity by suppressing the PI3K/mTOR/HIF1α pathway and increasing oxidative stress in colon cancer cells.

This study investigated the chemotherapeutic effects of 5-fluorouracil (5-FU), metformin (Met), and/or thymoquinone (TQ) single/dual/triple therapies in the HT29, SW480 and SW620 colon cancer (CRC) cell lines. Cell cycle/apoptosis were measured by flow cytometry. The gene and protein expression of apoptosis (PCNA/survivin/BAX/Cytochrome-C/Caspase-3) and cell cycle (CCND1/CCND3/p21/p27) molecules, the PI3K/mTOR/HIF1α oncogenic pathway, and glycolysis regulatory enzymes were measured by quantitative-PCR and Western blot. Markers of oxidative stress were also measured by colorimetric assays. Although all treatments induced anti-cancer effects related to cell cycle arrest and apoptosis, the triple therapy showed the highest pro-apoptotic actions that coincided with the lowest expression of CCND1/CCND3/PCNA/survivin and the maximal increases in p21/p27/BAX/Cytochrome-C/Caspase-3 in all cell lines. The triple therapy also revealed the best suppression of the PI3K/mTOR/HIF1α pathway by increasing its endogenous inhibitors (PTEN/AMPKα) in all cell lines. Moreover, the lowest expression of lactate dehydrogenase and pyruvate dehydrogenase kinase-1 with the highest expression of pyruvate dehydrogenase were seen with the triple therapy, which also showed the highest increases in oxidative stress markers (ROS/RNS/MDA/protein carbonyl groups) alongside the lowest antioxidant levels (GSH/CAT) in all cell lines. In conclusion, this is the first study to reveal enhanced anti-cancer effects for metformin/thymoquinone in CRC that were superior to all monotherapies and the other dual therapies. However, the triple therapy approach showed the best tumoricidal actions related to cell cycle arrest and apoptosis in all cell lines, possibly by enhancing oxidative glycolysis and augmenting oxidative stress through stronger modulation of the PI3K/mTOR/HIF1α oncogenic network.

Thermal degradation kinetics and pyrolysis GC-MS study of curcumin.

The objective of this work was to study kinetics of thermal degradation of curcumin in ambient-1023 K range and identify degradation products by GC-MS. No weight loss was observed up to ∼470 K and two major weight losses occurred beyond this. Sixteen degradation products were identified by GC-MS. Pharmacological properties, including LD50, LC50, gastrointestinal absorption, blood-brain barrier permeation and effect on cytochromes, of the products were calculated using standard software. The LD50 values indicated that the degradation products are more toxic than curcumin. All the decomposition products, except 2-methyl-6-(4-methylphenyl)-hept-2-en-4-one, have the potential to cross the blood-brain barrier that can affect brain functions. Twelve of the compounds showed the potential to inhibit the metabolism of xenobiotics and all the compounds appeared to be non-inhibitors of CYP2C9 and CYP3A4 in contrast to curcumin. Thus, this study suggests that the food materials containing curcumin when heated beyond 470 K will produce toxic substances.

Synthesis of gold and silver nanoparticles by use of arabinoglucan from Lallemantia royleana.

Highly stable gold and silver nanoparticles were synthesized by use of an arabinoglucan from Lallemantia royleana seeds without additional use of reducing or stabilizing agents. The mechanism involved the reduction potential of the hemicellulose as verified by cyclic voltammetry. The arabinoglucan used was substantially free from ferulic acid and phenolic content, suggesting the inherent reducing potential of arabinoglucan for gold and silver ions. The synthesized nanoparticles exhibited surface plasmon resonance maxima at 515 nm (gold) and 397 nm (silver) corresponding to sizes of 10 nm and 8 nm, respectively. The zeta potential values were -24.1 mV (gold) and -22.3 mV (silver). The silver nanoparticles showed potential for application in surface-enhanced Raman spectroscopy. Gold nanoparticles were found to be non-toxic, whereas silver nanoparticles exhibited dose-dependent biological activities and found to be cytotoxic against brine shrimps and HeLa cell lines and the tumours caused by A. tumefaciens.

Potential Predictors of Poor Prognosis among Severe COVID-19 Patients: A Single-Center Study.

BACKGROUND: Timely detection of the progression of the highly contagious coronavirus disease (COVID-19) is of utmost importance for management and intervention for patients in intensive care (ICU). AIM: This study aims to better understand this new infection and report the changes in the various laboratory tests identified in critically ill patients and associated with poor prognosis among COVID-19 patients admitted to the ICU. METHODS: This was a retrospective study that included 160 confirmed SARS-CoV-2-positive patients. RESULTS: Elevated serum ferritin, D-dimer, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and nonconjugated bilirubin levels were present in 139 (96%), 131 (96%), 107 (68%), 52 (34%), and 89 (70%) patients, respectively. Renal parameters were abnormal in a significant number of cases with elevated creatinine and blood urea nitrogen in 93 (62%) and 102 (68%) cases, respectively. Hematological profiles revealed lower red blood cell count, hemoglobin, eosinophils, basophils, monocytes, and lymphocytes in 90 (57%), 103 (65%), 89 (62%), 105 (73%), 35 (24%), and 119 (83%) cases, respectively. The neutrophil count was found to increase in 71.3% of the cases. There was significantly higher mortality (83%) among patients older than 60 years (p=0.001) and in female patients (75%) (p=0.012). Patients with lung diseases had a poor outcome compared to patients with other comorbidities (p=0.002). There was a significant association between elevated D-dimer levels and increased mortality (p=0.003). Elevated levels of AST, creatinine, blood urea nitrogen, and bilirubin were significantly associated with unfavorable outcomes. CONCLUSION: Different parameters can be used to predict disease prognosis, especially the risk of poor prognosis. Accurate diagnosis and monitoring of disease progression from the early stages will help in reducing mortality and unfavorable outcomes.

Pulmonary Mucormycosis: A Case Report of a Rare Infection with Potential Diagnostic Problems.

Pulmonary mucormycosis is a relatively rare pulmonary fungal disease, which is difficult to diagnose early and lacks effective treatment. It is seen in patients with hematological malignancies, diabetes mellitus, and immunocompromised states. The diagnosis depends primarily on the detection of fungi in lung tissue. Here, we present a case of a 52-year-old male who has type 2 diabetes mellitus and a past history of treated pulmonary tuberculosis. Clinical diagnosis is difficult in pulmonary mucormycosis, and early diagnosis is needed for this life-threatening infection. Histopathological examination of a resected cavity confirmed the diagnosis of pulmonary mucormycosis. This report highlights the difficulty of diagnosis and the importance of histological examination in detecting mucormycosis which will help for early management.

New Classification System for Cleft Alveolus: A Computed Tomography-based Appraisal.

AIM: The present study proposed a new classification system based on computed tomography (CT) scan appraisal; this enables the surgeon to identify the extent of the defect and helps to execute the proper treatment plan. BACKGROUND: Various terminologies and classifications were proposed to understand developmental defects. But none of the existing classifications/nomenclatures used the preoperative radiographic evaluation (i.e., computed tomography scan-CT scan) in the management and prognosis. Various treatments were advocated and practiced successfully for the surgical correction of lip and palate. MATERIALS AND METHODS: The available CT scans from archives of the Department of Radiology and Oral and Dental Surgery were evaluated (retrospectively) for cleft alveolus and its morphology as per the proposal. The English language literature was searched in the MEDLINE database without date restriction to revise existing literature on numerous classification systems/nomenclatures using MeSH keywords related to cleft lip, palate, alveolus, developmental disturbance, facial clefts, and classification. Existing classification systems were revisited with a note on the drawbacks. After careful examination of morphological patterns of all clefts, the new CT scan-based alveolar cleft classification is proposed depending on the extent of cleft. RESULTS: The literature revealed a total of twenty-nine classifications of cleft lip and palate starting from the year 1922 to the year 2015, but none exclusively classified the cleft alveolus based on CT scan observations. The observation of three thousand CT scans showed five types of cleft alveolus, depending on the extent of involvement. CONCLUSION: The CT scan-based classification is essential to the surgeon for successful surgical planning of cleft alveolus. The proposed classification is clinically relevant in this digital era for relating surgical outcomes. The three-dimensional viewing of a defect is essential for the surgeon for virtual planning. This paper provides a CT scan-based classification for universal acceptance in this era of digital technology, and CT scan aids in achieving these goals. CLINICAL SIGNIFICANCE: The new proposal is based on preoperative evaluation of cleft using a CT scan. CT scan imaging provides a clear picture of the cleft in three dimensions for the operating surgeon. Advanced technology-enhanced surgical management modalities like CAD/CAM guided templates to support graft for successful management. The classification system will help the medical and surgical fraternity in various aspects. The three-dimensional modeling of defect and printing of a defect model using additive manufacturing technology helps the surgeon for presurgical visualization and virtual planning in a better way. This strategy of defect classification using a CT scan will help obtain better clinical outcomes and patient satisfaction.

Synthesis and Biodistribution Study of Biocompatible 198Au Nanoparticles by use of Arabinoxylan as Reducing and Stabilizing Agent.

Radioactive gold-198 is a useful diagnostic and therapeutic agent. Gold in the form of nanoparticles possesses even more exciting properties. This work aimed at arabinoxylan-mediated synthesis and biodistribution study of radioactive gold nanoparticles (198AuNPs). The particles were synthesized by mixing suspension of arabinoxylan with H198AuCl4 without use of any additional reducing and stabilizing agents. An aqueous suspension of arabinoxylan was added to a H198AuCl4 solution, which resulted in reduction of Au3+ to 198AuNPs. Biodistribution was studied in vitro and in rabbit. The particles having exceptional stability were readily formed. Highest radioactivity was recorded in spleen after 3 h followed by liver, heart, kidney, and lungs after i.v. administration. After 24 h, the activity was not detectable in the spleen; it accumulated in the liver. However, after oral administration, the activity mainly accumulated in the colon. In serum proteins, the distribution was α1-globulin 6.5%, α2-globulin ~ 2%, ß-globulin ~ 1%, γ-globulin 0.7%, and albumin 0.7% of the administered dose. This indicates a low protein binding implying high bioavailability of the particles. The cytotoxicity study showed that the particles were inactive against HeLa cell line and Agrobacteriumtumefaciens. Highly stable 198AuNPs reported in this work have the potential for targeting the colon. They show affinity for globulins, the property that can be used in the study of the immune system.

Correction to: Synthesis and Biodistribution Study of Biocompatible 198Au Nanoparticles by use of Arabinoxylan as Reducing and Stabilizing Agent.

The original version of this article unfortunately contained a mistake.

Ligand Exchange/Scrambling Study of Gold(I)-Phosphine Complexes in the Solid Phase by DESI-MS Analysis.

Only a few analytical techniques are available for the characterization of mechanochemical synthetic reaction products. We demonstrate here that DESI-MS is a powerful technique for this purpose, combining the selectivity of MS-based assays with the simplicity and in situ analysis capability of ambient ionization methods. In this work, we report that auranofin, a gold-based drug, and its precursor triethylphosphine gold(I) chloride undergo a complex array of ligand exchange/scrambling reactions with thiol-containing amino acids in the solid state. The products were readily characterized by DESI-MS analysis from the solid-phase reaction, clearly exhibiting ligand exchange and scrambling, with independent confirmation by solid state 13C-NMR. The thioglucose and triethylphosphine moieties exchanged with cysteine and its derivatives, whereas the glutathione replaced 2,3,4,6-tetra-o-acetyl-ß-1-D-glucopyranose only. It was concluded that ligand exchange and scrambling reactions can be carried out in the solid state, and some of the unique products reported in this study can be conveniently prepared through mechanochemical synthesis in good yields (> 98%), as demonstrated by synthesis of (L-cysteinato-S)-triethylphosphine gold(I) from triethylphosphine gold(I) chloride and L-cysteine.

A Spectroscopic Study of Interaction of Auricyanide with n-Acetylcysteine.

Interaction of auricyanide, an important metabolite of anti-arthritic gold-based drug auranofin, was studied in vitro with a pharmacologically active ligand n-acetylcysteine with a view to understand reactivity of gold in vivo. Formation of reduction product aurocyanide occurred through mono- and di-n-acetylcysteine-substituted intermediates. The product and intermediates were identified and monitored spectrophotometrically and by electrospray ionization mass spectrometry. This study suggests successive substitution with n-acetylcysteine through trans effect. At equimolar concentrations of auricyanide and n-acetylcysteine, only mono-substituted mixed-ligand complex was formed. Substitution of the data obtained to various kinetic models suggested that the reaction orders are 0.6 in terms of n-acetylcysteine, 1.5 in terms of auricyanide, and 2 overall. The intermediates detected in this work may help to synthesize more effective and less toxic gold drugs.

A structural study of Acacia nilotica and Acacia modesta gums.

Superficially similar carbohydrate polymers from similar sources can have dramatically different characteristics. This work seeks to examine the molecular properties responsible for these differences. Protons responsible for cross-polarization in the anomeric region of Acacia nilotica (AN) were replaced easily by deuterium, but not for Acacia modesta (AM). Time constants describing the mobility and cross-polarization transfer were both found to be lower for AM. Variable contact time experiments showed poorer fits and more heterogeneity for AN. Solution state HSQC experiments showed a lower number of environments in the anomeric region for AM. The relaxation time T2 of AM solutions had a lower value consistent with a higher viscosity. The Tg' of solutions were -14.5°C AN and -18.5°C AM. These results form a largely self-consistent picture of molecular differences between AN and AM, suggesting a more compact but heterogeneous structure for AN and more branching in the case of AM.

Glucoxylan-mediated green synthesis of gold and silver nanoparticles and their phyto-toxicity study.

A green synthesis of gold and silver nanoparticles having exceptional high stability is reported. The synthesis involves the use of glucoxylans isolated from seeds of Mimosa pudica and excludes the use of conventional reducing and capping agents. The average particle sizes were 40 and 6 nm for gold and silver, respectively. The size of gold particles obtained in this work is suitable for drug delivery as they are non-cytotoxic. In phyto-toxicity tests the gold and silver nanoparticles did not show any significant effect on germination of radish seeds, whereas in radish seedling root growth assay the two particles behaved differently. The silver nanoparticles exhibited a concentration-dependent stimulatory effect on root length, whereas the gold nanoparticles had no significant effect in this test. The likely mechanism of these effects is discussed.

Thermal analysis of some natural polysaccharide materials by isoconversional method.

Isoconversional thermal analysis of some important polysaccharides from functional foods is reported. Various thermal parameters including apparent activation energy (Ea), pre-exponential factor (A) were worked out, and the fitness of data to different models describing the degradation kinetics of polysaccharides was studied. The polysaccharides from Mimosa pudica (MP), Plantago ovata (PO), Argyreia speciosa (AS), Acacia nilotica (AN), P. ovata husk (HK) and Acacia modesta (AM) exhibited multistep degradation while those from Astragalus gummifer (AG), Salvia aegyptiaca (SA) and Ocimum basicilicum (OB) degraded mainly in single step. Generally, the degradation was exothermal. The average Ea values as determined by Flynn-Wall-Ozawa method were found to be in the range 132-187 kJ mol(-1). The mean comprehensive index of thermal stability (ITS) fell in the range 0.33-0.43. All the materials under investigation except those from SA and AS appear to be as stable as some of the important commercial materials used as pharmaceutical ingredients. Model-fitting analysis revealed that the major degradation step follows first-order kinetics.

Arabinoxylan-mediated synthesis of gold and silver nanoparticles having exceptional high stability.

A green synthesis of highly stable gold and silver nanoparticles (NPs) using arabinoxylan (AX) from ispaghula (Plantago ovata) seed husk is being reported. The NPs were synthesized by stirring a mixture of AX and HAuCl(4)·H(2)O or AgNO(3), separately, below 100 °C for less than an hour, where AX worked as the reducing and the stabilizing agent. The synthesized NPs were characterized by surface plasmon resonance (SPR) spectroscopy, transmission electron microscopy (TEM), atomic force microscopy (AFM), and X-ray diffraction (XRD). The particle size was (silver: 5-20 nm and gold: 8-30 nm) found to be dependent on pH, temperature, reaction time and concentrations of AX and the metal salts used. The NPs were poly-dispersed with a narrow range. They were stable for more than two years time.

Kinetics and mechanism of thermal degradation of pentose- and hexose-based carbohydrate polymers.

This work aims at study of thermal degradation kinetics and mechanism of pentose- and hexose-based carbohydrate polymers isolated from Plantago ovata (PO), Salvia aegyptiaca (SA) and Ocimum basilicum (OB). The analysis was performed by isoconversional method. The materials exhibited mainly two-stage degradation. The weight loss at ambient-115°C characterized by low activation energy corresponds to loss of moisture. The kinetic triplets consisting of E, A and g(α) model of the materials were determined. The major degradation stage represents a loss of high boiling volatile components. This stage is exothermic in nature. Above 340°C complete degradation takes place leaving a residue of 10-15%. The master plots of g(α) function clearly differentiated the degradation mechanism of hexose-based OB and SA polymers and pentose-based PO polymer. The pentose-based carbohydrate polymer showed D(4) type and the hexose-based polymers showed A(4) type degradation mechanism.

2-[(E)-({4-[(4,6-Dimethyl-pyrimidin-2-yl)sulfamo-yl]phen-yl}iminio)meth-yl]-6-hy-droxy-phenolate.

The title compound, C(19)H(18)N(4)O(4)S, exists as a zwitterion in the solid state, with nominal proton transfer from a phenol group to the imine N atom. The 2,3-dihy-droxy-benzaldehyde fragment is oriented at a dihedral angle of 35.51 (11)° to the adajacent aniline group and makes a dihedral angle of 76.99 (6)° with the 4,6-dimethyl-pyrimidin-2-amine group. Intra-molecular O-H⋯O and N-H⋯O hydrogen bonds close S(5) and S(6) rings, respectively; the same O atom accepts both bonds. In the crystal, polymeric chains along [001] are formed from mol-ecules joined end-to-end by N-H⋯O and O-H⋯N hydrogen bonds; these feature R(2) (3)(6) loops. The polymeric chains are linked by C-H⋯O inter-actions and there are π-π inter-actions between the pyrimidine rings with a centroid-centroid distance of 3.446 (2) Å.

(2Z)-N-(2-Chloro-benz-yl)-2-(2-oxo-2,3-dihydro-1H-indol-3-yl-idene)hydrazinecarbothio-amide.

In the title compound, C(16)H(13)ClN(4)OS, the isatin ring system is oriented at dihedral angles of 10.60 (7) and 72.60 (3)° with respect to the thio-semicarbazide and 2-chloro-benzyl groups, respectively. The near planarity of the isatin and thio-semicarbazide groups [r.m.s. deviations of 0.0420 and 0.0163 Å, respectively] is reinforced by intra-molecular N-H⋯O and N-H⋯N hydrogen bonds, which generate S(6) and S(5) rings, respectively. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R(2) (2)(8) loops. Aromatic π-π stacking inter-actions between the centroids of heterocyclic five-membered and benzene rings [distance = 3.6866 (11) Å] are also observed.

4-{[(E)-2,3-Dihy-droxy-benzyl-idene]amino}-N-(5-methyl-1,2-oxazol-3-yl)benzene-sulfonamide.

In the title compound, C(17)H(15)N(3)O(5)S, the 2,3-dihy-droxy-benzaldehyde unit is oriented at a dihedral angles of 16.83 (10) and 78.87 (6)° with the anilinic and 5-methyl-1,2-oxazol-3-amine groups, respectively. An S(6) loop exists due to intramolecular O-H⋯N hydrogen bonding. In the crystal, inversion dimers with R(2) (2)(8) rings are formed due to N-H⋯N hydrogen bonding between the 5-methyl-1,2-oxazol-3-amine groups. These dimers are inter-linked by O-H⋯O hydrogen bonds, forming chains along [101] and resulting in R(2) (2)(26) rings. π-π inter-actions occur between the central benzene rings with a centroid-centroid distance of 3.7928 (16) Å.

Antibacterial dimeric copper(II) complexes with chromone-derived compounds.

A new series of six chromone-derived compounds and their Cu(II) complexes have been synthesized and characterized by their physical, spectral and analytical data. The ligands and their Cu(II) complexes were screened for their in vitro antibacterial activity against four Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, Shigella flexneri) and two Gram-positive (Bacillus subtilis, Staphylococcus aureus) bacterial strains by agar-well diffusion method. The ligands were found to exhibit either no or low-to-moderate activities against one or more bacterial species whereas, the Cu(II) complexes exhibited moderate-to-high activity. The ligands which were inactive before complexation became active upon complexation with the Cu(II) metal ion and less active became more active.

4-(2-Fluoro-phen-yl)-1-(2-oxoindolin-3-yl-idene)thio-semicarbazide.

The title compound, C(15)H(11)FN(4)OS, is almost planar, the dihedral angle between the aromatic ring systems being 5.00 (13)°. The conformation is stabilized by intra-molecular N-H⋯N and N-H⋯O hydrogen bonds, which generate S(5) and S(6) rings, respectively. N-H⋯F and C-H⋯S inter-actions also occur. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds occur, generating R(2) (2)(8) loops.