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Herein, a green synthesis methodology for making copper oxide (CuO) nanoparticle clusters in a cost-effective and simple way is reported. While cuprous sulfate pentahydrate is used as a source of copper, the outer layer of green peas (Pisum Sativum) is used as a source of phenol. Extracting the phenol from pea peels is a simple process that uses water as a solvent. Copper salt is reduced by the phenolic content that is so produced. Both physicochemical and microscopic characterization Scanning Electron Microscope (SEM), and Energy-dispersive X-ray (EDX) analysis were performed on the particles. A variety of pea-peeling samples were used during the procedure's several executions to ensure reproducibility. The preparation process was appropriate, as the outcomes were identical. Analyses were also conducted on the produced particles' electrochemical activity as an application. A well-defined and organized redox reaction was seen at E' = +0.25 V against Ag/AgCl which were also shown to be highly electro-active. With the benchmarked redox mediator (5 mM ferricyanide), the particles also produced an outstanding redox peak at E1/2 = -0.01 V vs. Ag/AgCl. In a common reducing organic reaction, such as the reduction of p-nitro phenol to p-amino phenol, they were also found to be effective catalysts. Additionally, tests were conducted on the produced particles for their anti-bacterial and antifungal properties. Overall, a simple method for the formation of commercially viable CuO nanoparticle clusters is developed with the potential for diverse applications. [ABSTRACT FROM AUTHOR]

Despite advances in treatment, a significant proportion of patients with chronic lymphocytic leukemia (CLL) will relapse with drug-resistant disease. The imipridones, ONC-201 and ONC-212, are effective against a range of different cancers, including acute myeloid leukemia (AML) and tumors of the brain, breast, and prostate. These drugs induce cell death through activation of the mitochondrial protease, caseinolytic protease (CIpP), and the unfolded protein response (UPR). Here we demonstrate that the novel imipridone analog, TR-57, has efficacy as a single agent and synergises with venetoclax against CLL cells under in vitro conditions that mimic the tumor microenvironment. Changes in protein expression suggest TR-57 activates the UPR, inhibits the AKT and ERK1/2 pathways and induces pro-apoptotic changes in the expression of proteins of the BCL-2 family. The study suggests that TR-57, as a single agent and in combination with venetoclax, may represent an effective treatment option for CLL. [ABSTRACT FROM AUTHOR]

In humans, AMPylation of cellular proteins is carried out by Huntingtin yeast-interacting protein E (HYPE), activated under conditions of endoplasmic reticulum stress, such as in cancer cells. Extracts of the human chronic lymphocytic leukemia cell line, OSU-CLL, were fractionated using immuno-precipitation with antibodies against adenosine-phosphate and then AMP-Tyr. The proteins isolated were modified with AMP, the 'AMPylome.' AMP-labelled peptides isolated from HYPE wild-type (WT) and HYPE knock-out (KO) cells were identified using tandem mass spectrometry. A total of 213 proteins were identified from WT cell extracts, while only 23 of these were pulled down from KO cells, consistent with the presence of another AMPylator, besides HYPE. The KO cells were more sensitive to fludarabine nucleoside (2-FaraA) than WT cells. Ingenuity Pathway Analysis of the AMPylated proteins identified in WT cells clustered actin binding proteins of the cytoskeleton, and proteins of the RHO GTPase pathway that would jointly stimulate cell proliferation. [ABSTRACT FROM AUTHOR]

In mammals, AMPylation of cellular proteins is carried out by Huntingtin yeast-interacting protein E, and pseudokinase SelO. Lysates from mouse B16-F10 melanoma cells have been fractionated by immuno-precipitation using magnetic Dynabeads coated with antibodies against both adenosine 5′-monophosphate in phosphate ester linkage to tyrosine, and adenosine-phosphate. Proteins pulled down with both these antibodies were subject to post-translational modification, most likely AMPylation. Using tandem mass spectrometry, analysis of these protein fractions identified 333 proteins that could be pulled down by both antibodies. Many of these proteins clustered in 13 functional Ingenuity Pathway Analysis categories of 4 or more adenylated proteins including some from the cytoskeleton, and some involved with initiating the unfolded protein response. Supplemental data for this article is available online at https://doi.org/10.1080/15257770.2021.1995608. [ABSTRACT FROM AUTHOR]

Circadian rhythms are generated by the circadian clock, a self-sustained internal timing system that exhibits 24-h rhythms in the body. In mammals, circadian rhythms are driven by a central clock located in suprachiasmatic nucleus and various peripheral clocks located in different tissues and organs of the body. Many cellular, behavioral, and physiological processes are regulated by the circadian clock in coordination with environmental cues. The process of metabolism is also under circadian regulation. Loss of synchronization between the internal clock and environmental zeitgebers results in disruption of the circadian rhythms that seriously impacts metabolic homeostasis leading to changed eating behavior, altered glucose and lipid metabolism, and weight gain. This in turn augments the risk of having various cardio-metabolic disorders such as obesity, diabetes, metabolic syndrome, and cardiovascular disease. This review sheds light on circadian rhythms and their role in metabolism with the identification of gaps in the current knowledge that remain to be explored in these fields. In this review, the molecular mechanisms underlying circadian rhythms have been elaborated first. Then, the focus has been kept on explaining the physiological significance of circadian rhythms in regulating metabolism. Finally, the implications for metabolism when these rhythms are disrupted due to genetic mutations or social and occupational needs enforced by modern lifestyle have been discussed. [ABSTRACT FROM AUTHOR]

Obesity, a major health concern, is influenced by an individual's genetic makeup and lifestyle factors (eating, sedentary lifestyle, and sleep disruptions) that affect circadian clock and metabolism. This study investigates the impact of Clock gene variants rs6843722 and rs4864548 on obesity measures in the Pakistani population. Genetic-behavior interaction studies have focused on Western populations, overlooking South Asians. We included 306 overweight/obese and 306 normal-weight controls, matched for age and gender. Anthropometric measures (BMI, waist circumference, waist-to-height ratio, and body fat percentage) were taken using standard procedures while behavioral data (dietary and sleep-related behaviors, shiftwork, and physical activity) was collected by questionnaire. Genotyping was performed by Taqman assays. Data was analyzed using SPSS 19.0. Rank-based inverse normal transformation was executed for quantitative non-normal variables. The linear regression revealed that both Clock gene variants interacted significantly with dietary and sleep-related behaviors and low physical activity, impacting adiposity measures regardless of age and gender. Shiftwork interacted specifically with rs6843722, increasing body fat percentage. This study indicates that Clock gene variants, when interacting with lifestyle factors, play a substantial role in increasing obesity risk highlighting the link between lifestyle choices and disturbances in circadian rhythms controlled by Clock gene variations, ultimately leading to obesity. [ABSTRACT FROM AUTHOR]

We have developed a facile and efficient synthetic route to substituted isochromans for the first time by reacting 2-(2-bromoethyl)benzaldehyde with a variety of aryl, heteroaryl amines in AcOH. The reaction is catalyst/additive free and takes place at reflux conditions with short reaction time to furnish products in good to excellent yields. All the compounds have been characterized by spectral techniques such as IR, 1 H NMR and Mass etc. Synthesized compounds were evaluated for antimicrobial activity against specific bacterial like 1) Staphylococcus strains aureus 2) Bacillus subtilis 3) Escherichia coli 4) Pseudomonas aeruginosa . Compounds 3e, 3n, 3 m, 3 l, 3 k, 3j and 3b showed most potent in vitro activity against bacterial strains. [ABSTRACT FROM AUTHOR]

A diastereoselective synthesis of tetrahydro- and dihydro-pyrido[2,3- c ]coumarin derivatives has been achieved via a one-pot three-component aza-Diels–Alder reaction of aromatic aldehydes, 3-aminocoumarin and dienophiles catalyzed by BiCl 3 . NOE studies proved that exo -isomers were obtained in all cases with high selectivity. The reaction proceeded at room temperature providing good yields of products as well as applicability on a wide range of substrates. Among all the synthesized derivatives, compounds 4i and 4k showed promising DPPH radical scavenging activity as compared to other tested derivatives. [ABSTRACT FROM AUTHOR]

Abstract: Prins and olefin cross-metathesis reactions were used as the key steps for the stereoselective total synthesis of (+)-strictifolione and (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one. Removal of MOM protecting groups under neutral conditions using CeCl3·7H2O is an attractive addition to the present strategy. [Copyright &y& Elsevier]

Abstract: The total syntheses of (6R)-6-[(2R)-2-hydroxyhexyl]tetrahydro-2H-2-pyranone and 7-hydroxy-5-dodecanolide are described utilizing a Prins reaction and ring closing metathesis reaction sequence. [Copyright &y& Elsevier]

Natural flora is the richest source of novel therapeutic agents due to their immense chemical diversity and novel biological properties. In this regard, eighteen natural products belonging to different chemical classes were evaluated for their thymidine phosphorylase (TP) inhibitory activity. TP shares identity with an angiogenic protein platelet derived endothelial cell growth factor (PD-ECGF). It assists tumor angiogenesis and is a key player in cancer progression, thus an ideal target to develop anti-angiogenic drugs. Eleven compounds 1–2, 5–10, 11, 15, and 18 showed a good to weak TP inhibitory activity (IC50 values between 44.0 to 420.3 μM), as compared to standards i.e. tipiracil (IC50 = 0.014 ± 0.002 μM) and 7-deazaxanthine (IC50 = 41.0 ± 1.63 μM). Kinetic studies were also performed on active compounds, in order to deduce the mechanism of ligand binding to enzyme. To get further insight into receptor protein (enzyme) and ligand interaction at atomic level, in- sillico studies were also performed. Active compounds were finally evaluated for cytotoxicity test against mouse fibroblast (3T3) cell line. Compound 18 (Masoprocol) showed a significant TP inhibitory activity (IC50 = 44.0 ± 0.5 μM). Kinetic studies showed that it inhibits the enzyme in a competitive manner (Ki = 25.6 ± 0.008 μM), while it adopts a binding pose different than the substrate thymidine. It is further found to be non-toxic in MTT cytotoxicity assay. This is the first report on TP inhibitory activity of several natural compounds, some of which may serve as leads for further research towards drug the development. [ABSTRACT FROM AUTHOR]

Several key pathways mediate signaling via the B-cell receptor, including the mitogen-activated protein kinase-ERK1/2 pathway. However, inhibition of MEK1/2, a key component of the MAPK-ERK1/2 signaling cascade, results in paradoxical activation of AKT in chronic lymphocytic leukemia (CLL) cells. In the current study we demonstrate synergy between the MEK1/2 inhibitor binimetinib and the AKT inhibitor MK2206, which combined induce apoptosis of primary CLL cells and restrict the cell cycle progression and proliferation of the OSU-CLL cell line. The mechanisms of action of the drug combination involve dual inhibition of MAPK-ERK1/2 and AKT signaling and down-regulation of Mcl-1 expression. Collectively, these data suggest that dual inhibition of MEK1/2 and AKT may represent a therapeutic option for CLL, capable of overcoming the pro-survival effects of the lymph node and bone marrow microenvironments. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Synthesis of urea and thiourea derivatives of tryptamine. • Urease inhibitory activity of synthesized derivatives have been evaluated. • Kinetic study of the compounds (1 – 25) has been performed. • The in silico study of the active compounds was also done. Abstract Urease is an enzyme of amidohydrolase family and is responsible for the different pathological conditions in the human body including peptic ulcers, catheter encrustation, kidney stone formation, hepatic coma, encephalopathy, and many others. Therefore, the search for potent urease inhibitors has attracted major scientific attention in recent years. Urea and thiourea derivatives of tryptamine (1 – 25) were synthesized via reaction of tryptamine with different substituted phenyl isocyanates/isothiocyanates. The synthetic compounds were evaluated for their urease enzyme inhibitory activity and they exhibited good inhibitory potential against urease enzyme in the range of (IC 50 = 11.4 ± 0.4–24.2 ± 1.5 μM) as compared to the standard thiourea (IC 50 = 21.2 ± 1.3 μM). Out of twenty-five compounds, fourteen were found to be more active than the standard. Limited structure-activity relationship suggested that the compounds with CH 3 , and OCH 3 substituents at aryl part were the most potent derivatives. Compound 14 (IC 50 = 11.4 ± 0.4 μM) with a methyl substituent at ortho position was found to be the most active member of the series. Whereas, among halogen substituted derivatives, para substituted chloro compound 16 (IC 50 = 13.7 ± 0.9 μM) showed good urease inhibitory activity. These synthetic derivatives were found to be non-cytotoxic in cellular assay. Kinetic studies revealed that the compounds 11 , 12 , 14 , 17 , 21 , 22 , and 24 showed a non-competitive type of inhibition. In silico study identified the possible bindings interactions of potential inhibitors with the active site of enzyme. These newly identified inhibitors of urease enzyme can serve as leads for further research and development. [ABSTRACT FROM AUTHOR]

Seven metabolites were obtained from the microbial transformation of anabolic-androgenic steroid mibolerone (1) with Cunninghamella blakesleeana, C. echinulata, and Macrophomina phaseolina. Their structures were determined as 10β,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (2), 6β,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (3), 6β,10β,17β-trihydroxy-7α,17α-dimethylestr-4-en-3-one (4), 11β,17β-dihydroxy-(20-hydroxymethyl)-7α,17α-dimethylestr-4-en-3-one (5), 1α,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (6), 1α,11β,17β-trihydroxy-7α,17α-dimethylestr-4-en-3-one (7), and 11β,17β-dihydroxy-7α,17α-dimethylestr-4-en-3-one (8), on the basis of spectroscopic studies. All metabolites, except 8, were identified as new compounds. This study indicates that C. blakesleeana, and C. echinulata are able to catalyze hydroxylation at allylic positions, while M. phaseolina can catalyze hydroxylation of CH2 and CH3 groups of substrate 1. Mibolerone (1) was found to be a moderate inhibitor of β-glucuronidase enzyme (IC50 = 42.98 ± 1.24 μM) during random biological screening, while its metabolites 2–4, and 8 were found to be inactive. Mibolerone (1) was also found to be significantly active against Leishmania major promastigotes (IC50 = 29.64 ± 0.88 μM). Its transformed products 3 (IC50 = 79.09 ± 0.06 μM), and 8 (IC50 = 70.09 ± 0.05 μM) showed a weak leishmanicidal activity, while 2 and 4 were found to be inactive. In addition, substrate 1 (IC50 = 35.7 ± 4.46 μM), and its metabolite 8 (IC50 = 34.16 ± 5.3 μM) exhibited potent cytotoxicity against HeLa cancer cell line (human cervical carcinoma). Metabolite 2 (IC50 = 46.5 ± 5.4 μM) also showed a significant cytotoxicity, while 3 (IC50 = 107.8 ± 4.0 μM) and 4 (IC50 = 152.5 ± 2.15 μM) showed weak cytotoxicity against HeLa cancer cell line. Compound 1 (IC50 = 46.3 ± 11.7 μM), and its transformed products 2 (IC50 = 43.3 ± 7.7 μM), 3 (IC50 = 65.6 ± 2.5 μM), and 4 (IC50 = 89.4 ± 2.7 μM) were also found to be moderately toxic to 3T3 cell line (mouse fibroblast). Interestingly, metabolite 8 showed no cytotoxicity against 3T3 cell line. Compounds 1–4, and 8 were also evaluated for inhibition of tyrosinase, carbonic anhydrase, and α-glucosidase enzymes, and all were found to be inactive. [ABSTRACT FROM AUTHOR]

The edible plant Opuntia dillenii (Ker Gawl.) Haw. commonly known as Nagphana, belongs to the Cactaceae family. It is traditionally used to treat various ailments including inflammation, gastric ulcers, diabetes, hepatitis, asthma, whooping cough and intestinal spasm. Despite its traditional use in various countries, detailed toxicological studies of O. dillenii cladode are few. Thus in the current study, toxicity of O. dillenii cladode derived methanol extract, fractions and its α-pyrones: opuntiol and opuntioside have been addressed. The test agents were assessed using both in vitro and in vivo toxicity assays. MTT on human embryonic kidney cell line (HEK - 293), tryphan blue exclusion in rat neutrophils, Cytokinesis-B block micronucleus (CBMN) in human lymphocytes and genomic DNA fragmentation using agarose gel electrophoresis were performed. In acute toxicity test, mice orally received extract (5 g/kg) for 7 days followed by measurements of relative organ weight, biochemical (blood profile, liver and kidney function test) and histological studies (liver and kidney) were carried out. Rat bone marrow micronucleus genotoxicity assay was also conducted. O. dillenii derived test agents were non-cytotoxic and had no effect on the integrity of DNA. Methanol extract (5 g/kg) orally administered in mice did not cause any significant change in relative organ weights, biochemical parameters and liver and kidney histology as compared to vehicle control. In parallel, extract did not stimulate micronuclei formation in rat bone marrow polychromatic erythrocytes. These results led to conclude that edible O. dillenii extract is non-toxic via the oral route and appears to be non-cyto-, hepato-, nephro- or genotoxic, thereby supporting its safe traditional use against various ailments. Therefore, opuntiol and opuntioside may serve as lead compounds in designing new drug(s) derived from edible plants. [Display omitted] • Edible Opuntia dillenii cladode derived test agents were found to be non-cytotoxic and had no effect on DNA fragmentation. • O. dillenii methanol extract (5 g/kg) did not produce mortality in animals. • The O. dillenii cladode extract (5 g/kg) did not cause any significant changes in biochemical and histological profiles. • Extract up to 5 g/kg did not induce micronuclei formation. • Therefore, it is concluded that edible O. dillenii test agents are non-cyto-, hepato-, nephro- or genotoxic. [ABSTRACT FROM AUTHOR]