N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.

Patterns and drivers of vector-borne microparasites in a classic metapopulation.

Many organisms live in fragmented populations, which has profound consequences on the dynamics of associated parasites. Metapopulation theory offers a canonical framework for predicting the effects of fragmentation on spatiotemporal host­parasite dynamics. However, empirical studies of parasites in classical metapopulations remain rare, particularly for vector-borne parasites. Here, we quantify spatiotemporal patterns and possible drivers of infection probability for several ectoparasites (fleas, Ixodes trianguliceps and Ixodes ricinus) and vector-borne microparasites (Babesia microti, Bartonella spp., Hepatozoon spp.) in a classically functioning metapopulation of water vole hosts. Results suggest that the relative importance of vector or host dynamics on microparasite infection probabilities is related to parasite life-histories. Bartonella, a microparasite with a fast life-history, was positively associated with both host and vector abundances at several spatial and temporal scales. In contrast, B. microti, a tick-borne parasite with a slow life-history, was only associated with vector dynamics. Further, we provide evidence that life-history shaped parasite dynamics, including occupancy and colonization rates, in the metapopulation. Lastly, our findings were consistent with the hypothesis that landscape connectivity was determined by distance-based dispersal of the focal hosts. We provide essential empirical evidence that contributes to the development of a comprehensive theory of metapopulation processes of vector-borne parasites.

Structural breakdown and phytotoxic assessments of PE degradation through acid hydrolysis, starch addition and Pseudomonas aeruginosa bioremediation.

Vast amounts of plastic waste are causing serious environmental issues and urge to develop of new remediation methods. The aim of the study is to determine the role of inorganic (nitric acid), organic (starch addition), and biological (Pseudomonas aeruginosa) soil amendments on the degradation of Polyethylene (PE) and phytotoxic assessment for the growth of lettuce plant. The PE-degrading bacteria were isolated from the plastic-contaminated soil. The strain was identified as Pseudomonas aeruginosa (OP007126) and showed the highest degradation percentage for PE. PE was pre-treated with nitric acid as well as starch and incubated in the soil, whereas P. aeruginosa was also inoculated in PE-contaminated soils. Different combinations were also tested. FTIR analysis and weight reduction showed that though nitric acid was efficient in degradation, the combined application of starch and bacteria also showed effective degradation of PE. Phytotoxicity was assessed using morphological, physiological, and biochemical parameters of plant. Untreated PE significantly affected plants' physiology, resulting in a 45% reduction in leaf chlorophyll and a 40% reduction in relative water content. It also had adverse effects on the biochemical parameters of lettuce. Bacterial inoculation and starch treatment mitigated the harmful impact of stress and improved plants' growth as well as physiological and biochemical parameters; however, the nitric treatment proved phytotoxic. The observed results revealed that bacteria and starch could be effectively used for the degradation of pre-treated PE.

Anti-ovarian cancer potential, in silico studies, and anti-Alzheimer's disease effects of some natural compounds as cholinesterase inhibitors.

Ovarian cancer ranks seventh in the most common malignant tumors in females and seriously threatens women's reproductive health. Natural sources may lead to basic research on potential bioactive components as lead compounds in drug discovery and, ultimately, therapeutic treatments for ovarian cancer and other diseases. Alzheimer's disease (AD) and ovarian cancer are complex diseases of aging that impose an enormous public health burden worldwide. Additionally, people with AD have low levels of acetylcholine in their brains. Enzymes called cholinesterases break down acetylcholine in the brain. If their action is inhibited, more acetylcholine is available for communication among brain cells. In this study, pregnanolone, diethylstilbestrol (DES), flavokawain C, and methyl 3,4,5-trihydroxybenzoate molecules obtained excellent-to-good inhibitory against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes with IC50 values ranging between 77.18 ± 8.62 to 461.35 ± 28.54 µM for AChE and 23.86 ± 4.07 to 306.62 ± 32.46 µM for BuChE. The calculations revealed the probable interactions and their characteristics at an atomic level. Indeed, the docking scores of DES, flavokawain C, pregnanolone, and methyl 3,4,5-trihydroxybenzoate for AChE are -6.685, -6.247, -6.672, and -5.183 (kcal/mol), respectively. This value for the compounds against BuChE is -6.042, -8.851, -5.655, and -5.898 (kcal/mol), respectively. Additionally, these compounds significantly decreased ovarian cancer cell viability. Additionally, 100 µM dose of all molecules caused good reductions in ovarian cancer cell viability.

Hepatic ultrastructural alterations induced by copper oxide nanoparticles: In vivo electron microscopy study.

Copper oxide nanomaterials (CuO NPs) have been widely utilized in many fields, including antibacterial materials, anti-tumor, osteoporosis treatments, imaging, drug delivery, cosmetics, lubricants for metallic coating, the food industry, and electronics. Little is known about the potential risk to human health and ecosystems. The present work was conducted to investigate the ultrastructural changes induced by 20 ± 5 nm CuO NPs in hepatic tissues. Adult healthy male Wister albino rats were exposed to 36 intraperitoneal (ip) injections of 25 nm CuO NPs (2 mg/kg bw). Liver biopsies from all rats under study were processed for transmission electron microscopy (TEM) processing and examination for hepatic ultrastructural alterations. The hepatic tissue of rats exposed to repeated administrations of CuO NPs exhibited the following ultrastructural alterations: extensive mitochondrial damage in the form of swelling, crystolysis and matrix lysis, formation of phagocytized bodies and myelin multilayer figures, lysosomal hyperplasia, cytoplasmic degeneration and vacuolation, fat globules precipitation, chromatin clumping, and nuclear envelope irregularity. The findings indicated that CuO NPs interact with the hepatic tissue components and could induce alterations in the hepatocytes with the mitochondria as the main target organelles of copper nanomaterials. More work is recommended for better understanding the pathogenesis of CuO NPs.

In Silico Computational Studies of Bioactive Secondary Metabolites from Wedelia trilobata against Anti-Apoptotic B-Cell Lymphoma-2 (Bcl-2) Protein Associated with Cancer Cell Survival and Resistance.

In the present study, the binding affinity of 52 bioactive secondary metabolites from Wedelia trilobata towards the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein (PDB: 2W3L) structure was identified by using in silico molecular docking and molecular dynamics simulation. The molecular docking results demonstrated that the binding energies of docked compounds with Bcl-2 protein ranged from -5.3 kcal/mol to -10.1 kcal/mol. However, the lowest binding energy (-10.1 kcal/mol) was offered by Friedelin against Bcl-2 protein when compared to other metabolites and the standard drug Obatoclax (-8.4 kcal/mol). The molecular dynamics simulations revealed that the Friedelin-Bcl-2 protein complex was found to be stable throughout the simulation period of 100 ns. Overall, the predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of Friedelin are relatively better than Obatoclax, with the most noticeable differences in many parameters where Friedelin has no AMES toxicity, hepatotoxicity, and skin sensitization. The ADMET profiling of selected compounds supported their in silico drug-likeness properties. Based on the computational analyses, the present study concluded that Friedelin of W. trilobata was found to be the potential inhibitor of the Bcl-2 protein, which merits attention for further in vitro and in vivo studies before clinical trials.

Evaluating the Antimicrobial and Anti-Hemolytic Activity of Synthesized Pseudopeptide against Leptospiral Species: In Silico and In Vitro Approach.

Bacterial infections are one of the leading causes of morbidity, mortality, and healthcare complications in patients. Leptospirosis is found to be the most prevalent, re-emergent, and neglected tropical zoonotic disease worldwide. The adaptation to various environmental conditions has made Leptospira acquire a large genome (~4.6 Mb) and a complex outer membrane, making it unique among bacteria that mimic the symptoms of jaundice and hemorrhage. Sph2 is another important virulence factor that enhances hemolytic sphingomyelinase-capable of moving inside mitochondria-which increases the ROS level and decreases the mitochondrial membrane potential, thereby leading to cell apoptosis. In the present study, 25 suspected bovine serum samples were subjected to the Microscopic Agglutination Test (MAT) across the Mysuru region. Different samples, such as urine, serum, and aborted materials from the confirmed MAT-positive animals, were used for isolation and genomic detection by conventional PCR targeting virulence gene, Lipl32, using specific primers. Further, in vitro and in silico studies were performed on isolated cultures to assess the anti-leptospiral, anti-hemolytic, and sphingomyelinase enzyme inhibition using novel pseudopeptides. The microdilution technique (MDT) and dark field microscope (DFM) assays revealed that at a concentration of 62.5 µg/mL, the pseudopeptide inhibited 100% of the growth of Leptospira spp., suggesting its efficiency in the treatment of leptospirosis. The flow cytometry analyses show the potency of the pseudopeptide against sphingomyelinase enzymes using human umbilical vein endothelial cells (HUVECs). Thus, the present study demonstrated the efficacy of the pseudopeptide in the inhibition of the growth of Leptospira, and therefore, this can be used as an alternative drug for the treatment of leptospirosis.

Resolvin D1 prevents cadmium chloride-induced memory loss and hippocampal damage in rats by activation/upregulation of PTEN-induced suppression of PI3K/Akt/mTOR signaling pathway.

This study evaluated the protective effect of resolvin D1 (RVD1) against cadmium chloride (CdCl2 )-induced hippocampal damage and memory loss in rats and investigated if such protection is mediated by modulating the PTEN/PI3K/Akt/mTOR pathway. Adult male Wistar rats (n = 18/group) were divided as control, control + RVD1, CdCl2 , CdCl2  + RVD1 and CdCl2  + RVD1 + bpV(pic), a PTEN inhibitor. All treatments were conducted for 4 weeks. Resolvin D1 improved the memory function as measured by Morris water maze (MWM), preserved the structure of CA1 area of the hippocampus, and increased hippocampal levels of RVD1 in the CdCl2 -treated rats. Resolvin D1 also suppressed the generation of reactive oxygen species (ROS), tumour necrosis factor-α and interleukine-6 (IL-6), inhibited nuclear factor κB (NF-κB) p65, stimulated levels of glutathione (GSH), manganese superoxide dismutase (MnSOD), and Bcl2 but reduced the expression of Bax and cleaved caspase 3 in hippocampi of CdCl2 -treated rats. Concomitantly, it stimulated levels and activity of PTEN and reduced the phosphorylation (activation) of PI3K, Akt and mTOR in hippocampi of CdCl2 -treated rats. In conclusion, RVD1 attenuates CdCl2 -induced memory loss and hippocampal damage in rats mainly by activating PTEN-induced suppression of PI3K/Akt/mTOR, an effect that seems secondary to its' anti-oxidant and anti-inflammatory potential.

Synthesis and Biological Activity Screening of Newly Synthesized Trimethoxyphenyl-Based Analogues as Potential Anticancer Agents.

A group of novel trimethoxyphenyl (TMP)-based analogues were synthesized by varying the azalactone ring of 2-(3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxybenzylidene)oxazolone 1 and characterized using NMR spectral data as well as elemental microanalyses. All synthesized compounds were screened for their cytotoxic activity utilizing the hepatocellular carcinoma (HepG2) cell line. Compounds 9, 10 and 11 exhibited good cytotoxic potency with IC50 values ranging from 1.38 to 3.21 µM compared to podophyllotoxin (podo) as a reference compound. In addition, compounds 9, 10 and 11 exhibited potent inhibition of ß-tubulin polymerization. DNA flow cytometry analysis of compound 9 shows cell cycle disturbance at the G2/M phase and a significant increase in Annexin-V-positive cells compared with the untreated control. Compound 9 was further studied regarding its apoptotic potential in HepG2 cells; it decreased the level of MMP and Bcl-2 as well as boosted the level of p53 and Bax compared with the control HepG2 cells.

Cell Cycle Arrest and Apoptosis-Inducing Ability of Benzimidazole Derivatives: Design, Synthesis, Docking, and Biological Evaluation.

In the current study, new benzimidazole-based 1,3,4-oxadiazole derivatives have been synthesized and characterized by NMR, IR, MS, and elemental analysis. The final compounds were screened for cytotoxicity against MDA-MB-231, SKOV3, and A549 cell lines and EGFR for inhibitory activities. Compounds 10 and 13 were found to be the most active against all the tested cell lines, comparable to doxorubicin, and exhibited significant inhibition on EGFR kinase, with IC50 0.33 and 0.38 µM, respectively, comparable to erlotinib (IC50 0.39 µM). Furthermore, these two compounds effectively suppressed cell cycle progression and induced cell apoptosis in MDA-MB-231, SKOV3, and A549 cell lines. The docking studies revealed that these compounds showed interactions similar to erlotinib at the EGFR site. It can be concluded that the synthesized molecules effectively inhibit EGFR, can arrest the cell cycle, and may trigger apoptosis and therefore, could be used as lead molecules in the development of new anticancer agents targeting EGFR kinase.

Cold-Active Enzymes and Their Potential Industrial Applications-A Review.

More than 70% of our planet is covered by extremely cold environments, nourishing a broad diversity of microbial life. Temperature is the most significant parameter that plays a key role in the distribution of microorganisms on our planet. Psychrophilic microorganisms are the most prominent inhabitants of the cold ecosystems, and they possess potential cold-active enzymes with diverse uses in the research and commercial sectors. Psychrophiles are modified to nurture, replicate, and retain their active metabolic activities in low temperatures. Their enzymes possess characteristics of maximal activity at low to adequate temperatures; this feature makes them more appealing and attractive in biotechnology. The high enzymatic activity of psychrozymes at low temperatures implies an important feature for energy saving. These enzymes have proven more advantageous than their mesophilic and thermophilic counterparts. Therefore, it is very important to explore the efficiency and utility of different psychrozymes in food processing, pharmaceuticals, brewing, bioremediation, and molecular biology. In this review, we focused on the properties of cold-active enzymes and their diverse uses in different industries and research areas. This review will provide insight into the areas and characteristics to be improved in cold-active enzymes so that potential and desired enzymes can be made available for commercial purposes.

In Vitro Anticancer Screening, Molecular Docking and Antimicrobial Studies of Triazole-Based Nickel(II) Metal Complexes.

Herein we describe the synthesis of a series of nickel(II) complexes (C1-C3) with Schiff bases (HL1-HL3) derived from 4-amino-5-mercapto-3-methyl-1,2,4-triazole and ortho/meta/para-nitrobenzaldehyde having composition [Ni(L)2(H2O)2]. The obtained ligands and their complexes were characterized using physico-chemical techniques viz., elemental analysis, magnetic moment study, spectral (electronic, FT-IR, 1H-NMR) and thermal analysis. The elemental analysis and spectral analysis revealed that Schiff bases behave as monoanionic bidentate ligands towards the Ni(II) ion. Whereas, the magnetic moment study suggested the octahedral geometry of all the Ni(II) complexes. The thermal behavior of the complexes has been studied by thermogravimetric analysis and agrees well with the composition of complexes. Further, the biological activities such as antimicrobial and antifungal studies of the Schiff bases and Ni(II) complexes have been screened against bacterial species (Staphylococcus aureus and Pseudomonas aeruginosa) and fungal species (Aspergillus niger and Candida albicans) activity by MIC method, the results of which revealed that metal complexes exhibited significant antimicrobial activities than their respective ligands against the tested microbial species. Furthermore, the molecular docking technique was employed to investigate the active sites of the selected protein, which indeed helped us to screen the potential anticancer agents among the synthesized ligand and complexes. Further, these compounds have been screened for their in vitro anticancer activity using OVCAR-3 cell line. The results revealed that the complexes are more active than the ligands.

Preparation, Characterization and In Vitro Biological Activities of New Diphenylsulphone Derived Schiff Base Ligands and Their Co(II) Complexes.

The present work describes the chemical preparation of Schiff bases derived from 4,4'-diaminodiphenyl sulfone (L1-L5) and their Co(II) metal complexes. The evaluation of antimicrobial and anticancer activities against MCF-7 cell line and human lung cancer cell line A-549 was performed. The aforementioned synthesized compounds are characterized by spectroscopic techniques and elemental analysis confirms successful synthesis. The results from the above analytical techniques revealed that the complexes are in an octahedral geometry. The antimicrobial activity of the synthesized Schiff base ligands and their metal complexes under study was carried out by using the agar well diffusion method. The ligand and complex interactions for biological targets were predicted using molecular docking and high binding affinities. Further, the anticancer properties of the synthesized compounds are performed against the MCF-7 cell line and human lung cancer cell line A-549 using adriamycin as the standard drug.

Exploration of Anti-HIV Phytocompounds against SARS-CoV-2 Main Protease: Structure-Based Screening, Molecular Simulation, ADME Analysis and Conceptual DFT Studies.

The ever-expanding pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has gained attention as COVID-19 and caused an emergency in public health to an unmatched level to date. However, the treatments used are the only options; currently, no effective and licensed medications are available to combat disease transmission, necessitating further research. In the present study, an in silico-based virtual screening of anti-HIV bioactive compounds from medicinal plants was carried out through molecular docking against the main protease (Mpro) (PDB: 6LU7) of SARS-CoV-2, which is a key enzyme responsible for virus replication. A total of 16 anti-HIV compounds were found to have a binding affinity greater than -8.9 kcal/mol out of 150 compounds screened. Pseudohypericin had a high affinity with the energy of -10.2 kcal/mol, demonstrating amino acid residual interactions with LEU141, GLU166, ARG188, and GLN192, followed by Hypericin (-10.1 kcal/mol). Moreover, the ADME (Absorption, Distribution, Metabolism and Excretion) analysis of Pseudohypericin and Hypericin recorded a low bioavailability (BA) score of 0.17 and violated Lipinski's rule of drug-likeness. The docking and molecular simulations indicated that the quinone compound, Pseudohypericin, could be tested in vitro and in vivo as potent molecules against COVID-19 disease prior to clinical trials.This was also supported by the theoretical and computational studies conducted. The global and local descriptors, which are the underpinnings of Conceptual Density FunctionalTheory (CDFT) have beenpredicted through successful model chemistry, hoping that they could be of help in the comprehension of the chemical reactivity properties of the molecular systems considered in this study.

Molecular epidemiology of virulent E. coli among rural small scale dairy herds and shops: Efficacy of selected marine algal extracts and disinfectants.

Virulent pathotypes of E. coli seriously affect the livestock regarding the misuse of antibiotics. All 180 samples collected from cow's environment and dairy shops in Qena, Egypt were serologically and molecularly positive for coliforms. Enteropathogenic E. coli (EPEC), Shiga toxin-producing E. coli (STEC), Enteroinvasive E. coli (EIEC) and Enterotoxigenic E. coli (ETEC) pathotypes were isolated from water and milk-related samples. STEC serogroups O26, O55, O111, O113, O145 were also recovered. The non-O157 STEC serotypes were recovered from human diarrheagenic patients contacting cattle or consuming contaminated water/milk products. BlaCTX-M and blaTEM genes were detected in 25.5% and 100%, respectively. Disinfectants and algal extracts, identified by GC-MS, were evaluated in vitro for antibacterial activities. TH4+® disinfectant and methanol extract of Turbinaria decurrens reduced E. coli at 13 log10 at 1.5% and 3 mg/ml concentrations, respectively. Ag-NPs/T. decurrens showed 8-9 log10 reduction at concentration of 1.6 × 105 NPs/ml. Examined water sources, milk and milk products were potential reservoirs for virulent antibiotic-resistant E.coli which may impose animal and public health threats.Abbreviations: APEC: Avian pathogenic E. coli; blaCTX-M: ß-lactamase inhibitors-Cefotaximase gene; blaTEM: ß-lactamase inhibitors-Temoneira gene; CFU: Colony-forming unit; DAEC: Diffusely adherent E. coli; DEC: Diarrheagenic Escherichia coli; DEMSO: Dimethyl sulfoxide; eaeA: Intimin or E. coli attaching gene; EAEC: Enteroaggregative E. coli; EHEC: Enterohemorrhagic E. coli; EIEC: Enteroinvasive E. coli; EOSQC: Egyptian Organization for Standardization and Quality Control; EPEC: Enteropathogenic E. coli; ETEC: Enterotoxigenic E. coli; ExPEC: Extra-intestinal pathogenic E. coli; GC-MS: Gas chromatography-mass spectrometry technique; hly: Hemolysin gene; STEC: Shiga like producing E. coli; stx1: Shiga-toxin 1 gene; ESBLs: Extended-spectrum beta-lactamases.

Biosynthesized silver nanoparticles and their genotoxicity.

The human-pathogenic bacteria have become highly resistant to conventional antibiotics; for this reason, a new biosynthesized nanomaterial might be a solution. The culture filtrate of two isolates of Fusarium oxysporum (14, 17) was used in the biosynthesis of nanosilver (AgNPs). The size of the nanoparticles produced by isolate F14 ranged from 19 to 30 nm, whereas the size of those formed via isolate F17 ranged between 16 and 25 nm. Moreover, the produced bio-nanosilver was tested against the human-pathogenic bacteria Proteus vulgaris, Escherichia coli, Staphylococcus aureus, and Klebsiella pneumonia and the outcome results displayed great antibacterial efficacy in a different manner compared with the three different biogenic antibiotics. Collectively, the results depicted that the silver nanoparticles (AgNPs) showed a three and a half times greater activity than the used antibiotics. Differential display reverse transcription-polymerase chain reaction was used to study gene regulation in the treated E. coli (F14) compared with the nontreated ones. Different upregulated and downregulated genes were observed. The cytotoxicity of the produced AgNPs was examined on rats with an average body weight of 200 g each; these animals were grouped into three different groups. The obtained AgNPs showed very low toxicity on the treated rats in comparison to the control group. The physiological parameters, for example, alanine aminotransferase, aspartate transaminase, albumin, creatinine, and urea in the treated animals were changed within to a lower degree compared with those in the nontreated animals. The current study exhibited that AgNPs might be favorable antibacterial agents, especially against multidrug-resistant bacteria.

Doxorubicin-induces NFAT/Fas/FasL cardiac apoptosis in rats through activation of calcineurin and P38 MAPK and inhibition of mTOR signalling pathways.

This study investigated the role of NFAT/Fas/FasL axis in cardiomyocyte apoptosis following doxorubicin (DOX) treatment in rats and evaluated the involvement and regulation of all NFAT members in cardiac apoptosis. Forty adult male Wistar rats were divided equally into control or DOX-treated groups (15 mg/kg over 2 weeks). Cardiomyocytes were cultured and pre-incubated with various inhibitors and activators (10 µmol/L) prior to DOX exposure (1 µmol/L). In the left ventricles and cultured cells, DOX increased cytoplasmic protein levels of cytochrome C, Bax and increased the activities of caspase-8, caspase3, ERK1/2, JNK, and P38 mitogen-activated protein kinases (MAPKs), reducing levels of Bcl-2 and the activity of mTOR, and inducing cell death. In addition, DOX enhanced mRNA and protein levels of Fas and FasL. Furthermore, the nuclear and cytoplasmic levels of NFAT1 and nuclear accumulation of NFAT2-4were increased with DOX treatment. The inhibition of calcineurin with FK506 significantly inhibited the nuclear levels of NFAT2 and NFAT4 and the inhibition of P38 MAPK with SB203580 inhibited the nuclear and cytoplasmic accumulation of NFAT1. However, the activation of mTOR by IGF-1 significantly lowered NFAT3. In conclusion, NFAT/Fas/FasL-induced cell death in cardiac myocytes of DOX-treated rats is regulated, at least, by the activation of calcineurin and P38 MAPK and inhibition of mTOR.

Salidroside protects against diabetes mellitus-induced kidney injury and renal fibrosis by attenuating TGF-ß1 and Wnt1/3a/ß-catenin signalling.

This study evaluated if the nephroprotective effect of Salidroside in type 1 diabetes mellitus (T1DM) involves modulation of Wnt/ß-catenin signalling pathways. Control or Streptozotocin (STZ, 50 mg/kg, iv)-induced T1DM adult male Wister rats were treated with the vehicle and Salidroside (100 mg/kg, orally) for 8 weeks daily. As compared to T1DM-induced rats, Salidroside improved kidney structure, reduced urinary protein and albumin level, increased creatinine clearance, and suppressed renal fibrosis. It also decreased mRNA and protein levels of Wnt1, Wnt3, and TGF-ß1, phosphorylation of Smad-3, total and nuclear levels of ß-catenin, and levels and activities of cleaved caspase-3. Concomitantly, Salidroside significantly increased the levels of p-ß-catenin (Ser33/37 /Thr41 ) and suppressed protein levels of Axin-2, fibronectin, and, mRNA and protein levels of collagen IIIa, the main targets of ß-catenin. In both control and T1DM rats, Salidroside significantly lowered fasting glucose levels and reduced renal levels of reactive oxygen species (ROS) p-and GS3Kß (Ser9) but significantly increased levels of SOD and GSH. In conclusion, Salidroside protected the kidney of rats against T1DM-induced injury and fibrosis by activating GS3Kß-induced inhibition of Wnt1/Wnt3a ß-catenin. This was associated with hypoglycaemic and antioxidant effects.

The anti-tumourigenic effect of ellagic acid in SKOV-3 ovarian cancer cells entails activation of autophagy mediated by inhibiting Akt and activating AMPK.

This study investigated the effect of ellagic acid (EA) on SKOV-3 cell growth and invasiveness and tested if the underlying mechanism involves modulating autophagy. Cells were treated with EA in the presence or absence of chloroquine (CQ), an autophagy inhibitor, compound C (CC), an AMPK inhibitor, or an insulin-like growth factor-1 (IGF-1), a PI3K/Akt activator. EA, at an IC50 of 36.6 µmol/L, inhibited cell proliferation, migration, and invasion and induced cell apoptosis in SKOV-3 cells. These events were prevented by CQ. Also, EA increased levels of Beclin-1, ATG-5, LC3I/II, Bax, cleaved caspase-3/8 and reduced those of p62 and Bcl-2 in these cancer cells. Mechanistically, EA decreased levels of p-S6K1 (Thr389 ) and 4EBP-1 (Thr37/46 ), two downstream targets of mTORC1, and p-Akt (Thr308 ) but increased levels of AMPK (Thr172 ) and p-raptor (Ser792 ), a natural inhibitor of mTORC1. CC or IGF-1 alone partially prevented the effect of EA on cell survival, cell invasions, and levels of LDH, Beclin-1, and cleaved caspase-3. In conclusion, EA can inhibit SKOV-3 growth, migration, and invasion by activating cytotoxic autophagy mediated by inhibition of mTORC1 and Akt and activation of AMPK.

Flavonol Glycosides: In Vitro Inhibition of DPPIV, Aldose Reductase and Combating Oxidative Stress are Potential Mechanisms for Mediating the Antidiabetic Activity of Cleome droserifolia.

Diabetes is a major health problem that is associated with high risk of various complications. Medicinal plants hold great promise against diabetes. The traditional use of Cleome droserifolia as an antidiabetic agent was correlated to its flavonol glycosides content. In the current study, five major flavonol glycosides appeared on the RP-HPLC chromatogram of the aqueous extract namely; quercetin-3-O-ß-d-glucosyl-7-O-α-rhamnoside (1), isorhamnetin-7-O-ß-neohesperidoside (2), isorhamnetin-3-O-ß-d-glucoside (3) kaempferol-4'-methoxy-3,7-O-α-dirhamnoside (4), and isorhamnetin-3-O-α-(4″-acetylrhamnoside)-7-O-α-rhamnoside (5). The inhibitory activities of these compounds were tested in vitro against several enzymes involved in diabetes management. Only the relatively less polar methoxylated flavonol glycosides (4, 5) showed mild to moderate α-amylase and α-glucosidase inhibitory activities. Compounds 1-4 displayed remarkable inhibition of dipeptidyl peptidase IV (DPPIV) enzyme (IC50 0.194 ± 0.06, 0.573 ± 0.03, 0.345 ± 0.02 and 0.281 ± 0.05 µg/mL, respectively) comparable to vildagliptin (IC50 0.154 ± 0.02 µg/mL). Moreover, these compounds showed high potential in preventing diabetes complications through inhibiting aldose reductase enzyme and combating oxidative stress. Both isorhamnetin glycoside derivatives (2, 3) exhibited the highest activities in aldose reductase inhibition and compound 2 (IC50 5.45 ± 0.26 µg/mL) was even more potent than standard quercetin (IC50 7.77 ± 0.43 µg/mL). Additionally, these flavonols exerted excellent antioxidant capacities through 2, 2-diphenyl-1-picrylhydrazil (DPPH) and ferric reducing antioxidant (FRAP) assays.