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.

Toxicity assessment of microplastic (MPs); a threat to the ecosystem.

Plastic is now considered part and parcel of daily life due to its extensive usage. Microplastic (MP) pollution is becoming a growing worry and has been ranked as the second most critical scientific problem in the realm of ecology and the environment. Microplastics are smaller in size than the plastic and are more harmful to biotic and as well as abiotic environments. The toxicity of microplastic depends upon its shape and size and increases with an increase in its adsorption capacity and their toxicity. The reason behind their harmful nature is their small size and their large surface area-to-volume ratio. Microplastic can get inside fruits, vegetables, seeds, roots, culms, and leaves. Hence microplastic enters into the food chain. There are different entry points for microplastic to enter into the food chain. Such sources can include polluted food, beverages, spices, plastic toys, and household (packing, cooking, etc.). The concentration of microplastic in terrestrial environments is increasing day by day. Microplastic causes the destruction of soil structure; destroys soil microbiota, cause depletion of nutrients in the soil, and their absorption by plants decreases plant growth. Apart from other environmental problems caused by microplastic, human health is also badly affected by microplastic pollution present in the terrestrial environment. The presence of microplastics in the human body has been confirmed. Microplastic enters into the body of humans in different possible ways. According to their way of entering the body, microplastics cause different diseases in humans. MPs also cause negative effects on the human endocrine system. At the ecosystem level, the impacts of microplastic are interconnected and can disrupt ecological processes. Although recently different papers have been published on several aspects of the microplastic present in the terrestrial environment but there is no complete overview that focus on the interrelationship of MPs in plants, and soil and their effect on higher animals like a human. This review provides a completely detailed overview of existing knowledge about sources, occurrences, transport, and effects of microplastic on the food chain and soil quality and their ecotoxicological effects on plants and humans.

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.

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.

Self-emulsifying micelles as a drug nanocarrier system for itraconazole oral bioavailability enhancement; in vitro and in vivo assessment.

Itraconazole (ITZ) is a renowned antifungal medication, however its therapeutic efficacy is limited by low solubility and oral bioavailability. The current research work attempted to augment the oral bioavailability of ITZ by incorporating into self-emulsifying micelles (SEMCs). To fabricate the SEMCs, various preparation techniques including physical mixture, melt-emulsification, solvent evaporation and kneading, were opted by using different weight ratio of drug and solubilizers i.e. Gelucire-50/13 or Gelucire-44/14 and characterized both in vitro and in vivo. The prepared SEMCs were found to be in the size range from 63.4 ± 5.2 to 284.2 ± 19.5 nm with surface charges ranging from -16 ± 1.2 to -27 ± 2.0 mV. The drug solubility was improved to a reasonable extent with all investigated formulations, however, SEMCs in group 6 prepared by kneading method (KMG6) using Gelucire-44/14: drug (10:1 presented 87.6 folds' increase (964.93 ± 2 µg/mL) compared to solubility of crystalline ITZ (11 ± 2 µg/mL) through kneading method. In addition, KMG6 SEMCs shows the fast drug release compared to other SEMCs. Further, KMG6 SEMCs also exhibited 5.12-fold higher relative intestinal serosal fluid absorption compared to crystalline ITZ. The pharmacokinetic parameters such Cmax, AUC and Tmax of KMG6 SEMCs significantly improved compared to crystalline ITZ. In conclusion, the manipulation of ITZ solubility, dissolution rate and absorption using SEMCs is a promising strategy for bioavailability enhancement.

Monoterpene Indole Alkaloids from the Aerial Parts of Rhazya stricta Induce Cytotoxicity and Apoptosis in Human Adenocarcinoma Cells.

Chromatographic investigation of the aerial parts of the Rhazya stricta (Apocynaceae) resulted in the isolation of two new monoterpene indole alkaloids, 6-nor-antirhine-N1-methyl (1) and razyamide (2), along with six known compounds, eburenine (3), epi-rhazyaminine (4), rhazizine (5), 20-epi-sitsirikine (6), antirhine (7), and 16-epi-stemmadenine-N-oxide (8). The chemical structures were established by various spectroscopic experiments. Compounds 1-8 exhibited cytotoxic effects against three cancer cells with IC50 values ranging between 5.1 ± 0.10 and 93.2 ± 9.73 µM against MCF-7; 5.1 ± 0.28 and 290.2 ± 7.50 µM against HepG2, and 3.1 ± 0.17 and 55.7 ± 4.29 µM against HeLa cells. Compound 2 showed the most potent cytotoxic effect against all cancer cell lines (MCF-7, HepG2 and HeLa with IC50 values = 5.1 ± 0.10, 5.1 ± 0.28, and 3.1 ± 0.17 µM, respectively). Furthermore, compound 2 revealed a significant increase in the apoptotic cell population of MCF-7, HepG2, and HeLa cells, with 31.4 ± 0.2%, 29.2 ± 0.5%, and 34.9 ± 0.6%, respectively. Compound 2 decreased the percentage of the phagocytic pathway on HepG2 cells by 15.0 ± 0.1%. These findings can explain the antiproliferative effect of compound 2.

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.

L-Glutaminase Synthesis by Marine Halomonas meridiana Isolated from the Red Sea and Its Efficiency against Colorectal Cancer Cell Lines.

L-glutaminase is an important anticancer agent that is used extensively worldwide by depriving cancer cells of L-glutamine. The marine bacterium, Halomonas meridian was isolated from the Red Sea and selected as the more active L-glutaminase-producing bacteria. L-glutaminase fermentation was optimized at 36 h, pH 8.0, 37 °C, and 3.0% NaCl, using glucose at 1.5% and soybean meal at 2%. The purified enzyme showed a specific activity of 36.08 U/mg, and the molecular weight was found to be 57 kDa by the SDS-PAGE analysis. The enzyme was highly active at pH 8.0 and 37 °C. The kinetics' parameters of Km and Vmax were 12.2 × 10-6 M and 121.95 µmol/mL/min, respectively, which reflects a higher affinity for its substrate. The anticancer efficiency of the enzyme showed significant toxic activity toward colorectal adenocarcinoma cells; LS 174 T (IC50 7.0 µg/mL) and HCT 116 (IC50 13.2 µg/mL). A higher incidence of cell death was observed with early apoptosis in HCT 116 than in LS 174 T, whereas late apoptosis was observed in LS 174 T more than in HCT 116. Also, the L-glutaminase induction nuclear fragmentation in HCT 116 was more than that in the LS 174T cells. This is the first report on Halomonas meridiana as an L-glutaminase producer that is used as an anti-colorectal cancer agent.

Evaluation of the Anticancer Potential of Crude, Irradiated Cerastes cerastes Snake Venom and Propolis Ethanolic Extract & Related Biological Alterations.

We aimed to evaluate the anticancer potential of crude venom (CV), γ irradiated Certastes cerastes venom (IRRV), and propolis ethanolic extract (PEE). IRRV showed a higher toxicity than CV, while CV-PEE showed higher toxicity than IRRV and CV against lung [A549] and prostate [PC3] cancer cells. Toxicity to [A549] and [PC3] cells was concentration and cell type dependent. In comparison to controls, apoptotic genes showed a significant upregulation of P53 and Casp-3 and a downregulation of Bcl-2. Also, induced elevated DNA accumulation in the [S] phase post PC3 cell treatment with IRRV and CV, as well as a significant DNA accumulation at G2/M phase after IRRV treatment of A549 cells. In contrast, PC3 cells showed a negligible cellular DNA accumulation after PEE treatment. Glutathione reductase [GR] was reduced in case of PC3 and A549 cell treated with IRRV, CV, and PEE compared with its values in untreated cell control. The Malondialdehyde [MDA] values in both cells recorded a significant elevation post IRRV treatment compared to the rest of the treatment regimen and untreated cell control. Similarly, IRRV and CV-PEE mix showed obviously higher reactive oxygen species [ROS] values than PC3 and A549 cell treatments with CV and PEE.

Antiproliferative Isoprenoid Derivatives from the Red Sea Alcyonacean Xenia umbellata.

From the soft coral Xenia umbellata, seven isoprenoid derivatives were isolated, including a new xenicane diterpene, xeniolide O (5) and a new gorgostane derivative gorgst-3ß,5α,6ß,11α,20(S)-pentol-3-monoacetate (7), along with three known sesquiterpenes (1-3), a known diterpene (4), and a known steroid (6). The extensive analyses of the NMR, IR, and MS spectral data led to determination of their chemical structures. Compounds 1-7 displayed a cytotoxic effect against breast adenocarcinoma (MCF-7), hepatocellular carcinoma (HepG2), and cervix adenocarcinoma (HeLa), with IC50 values ranging between 1.5 ± 0.1-23.2 ± 1.5; 1.8 ± 0.1-30.6 ± 1.1 and 0.9 ± 0.05-12.8 ± 0.5 µg/mL, respectively. Compound 3 showed potent cytotoxic effects against MCF-7, HepG2, and HeLa with IC50 values = 2.4 ± 0.20, 3.1 ± 0.10 and 0.9 ± 0.05 µg/mL, respectively. Compounds 2, 5, and 7 displayed cytotoxic effect against Hela cells with IC50 values = 12.8 ± 0.50, 6.7 ± 1.00 and 11.5 ± 2.20 µg/mL, respectively. Two DNA binding dyes, acridine orange (AO) and ethidium bromide (EtBr) were used for the detection of viable, apoptotic, and necrotic cells. The early apoptotic cell death was observed in all types of treated cells. The late apoptotic cells were highly present in HepG2 cells. Compounds 5 and 7 induced a high percentage of necrosis towards HepG2 and HeLa cells. The late apoptosis was recorded as a high rate after treatment with 7 on all cancer cells.

Production of Terretonin N and Butyrolactone I by Thermophilic Aspergillus terreus TM8 Promoted Apoptosis and Cell Death in Human Prostate and Ovarian Cancer Cells.

The anticancer activity of terretonin N (1) and butyrolactone I (2), obtained from the thermophilic fungus Aspergillus terreus TM8, was intensively studied against prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines. According to this study, both compounds showed potent cytotoxicity towards ovarian adenocarcinoma cells (SKOV3) with IC50 1.2 and 0.6 µg/mL, respectively. With respect to metastatic prostate cells (PC-3), the two compounds 1 and 2 showed a significantly promising cytotoxicity effect with IC50 of 7.4 and 4.5 µg/mL, respectively. The tested fungal metabolites showed higher rates of early and late apoptosis with little or no necrotic apoptotic pathway in all treated prostate adenocarcinoma (PC-3) and ovary adenocarcinoma (SKOV3) human cell lines, respectively. The results reported in this study confirmed the promising biological properties of terretonin N (1) and butyrolactone I (2) as anticancer agents via the induction of cellular apoptosis. However, further studies are needed to elucidate the molecular mechanism by which cellular apoptosis is induced in cancer cells.

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.

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.

Development of an optimized febuxostat self-nanoemulsified loaded transdermal film: in-vitro, ex-vivo and in-vivo evaluation.

Febuxostat (FBX) is used to treat gout and chronic hyperuricemia. However, its bioavailability is moderate (49%) as a result of low solubility and first-pass metabolism. Therefore, the aim of our study is to improve FBX bioavailability by enhancement its solubility using self-nanoemulsifying drug delivery system (SNEDDS) technique in the form of transdermal film to avoid hepatic metabolism. To accomplish this goal, Eight SNEDDS formulae were prepared according to a three-factor, two-level D-Optimal mixture design to evaluate the effect of different ratios of the Lemon oil (X1), the surfactant Tween-20 (X2), and the co-surfactant PEG-400 (X3) on the globule size in order to reach smallest globular size. Results revealed that SNEDDS globule size ranged from 177 to 454 nm. The optimized formula consisted of 20% oil, 40% surfactant and 40% co-surfactant. Diffusion study showed improved enhancement in skin permeation that was confirmed by imaging using fluorescence microscope. In vivo plasma data showed significant (p < 0.05) difference in FBX plasma levels and pharmacokinetic parameters when compared with raw FBX loaded film. In conclusion, FBX-SNEDDS loaded transdermal film could be a successful way to improve solubility and skin permeability that would lead to improvement in patient's compliance.

Trans-resveratrol Inhibits Tau Phosphorylation in the Brains of Control and Cadmium Chloride-Treated Rats by Activating PP2A and PI3K/Akt Induced-Inhibition of GSK3ß.

This study investigated if resveratrol (RES) can protect against cadmium chloride (CdCl2)-induced memory loss and Tau protein hyperphosphorylation in rats and explored its effect on AMPK/PI3K/Akt signaling pathway. Rats (n = 10/group) were divided into seven groups as: control; control + DMSO; control + LY294002, a selective PI3K inhibitor (0.25 µg/100 g, i.p); control + RES (300 mg/kg, orally); CdCl2 (5 mg/kg, orally); CdCl2 + RES and CdCl2 + RES + LY294002. All treatments were carried out for 30 consecutive days on a daily basis. RES improved both short and long-term memory as analyzed by novel object recognition task and significantly increased brain levels of glutathione in both control and CdCl2-treated rats. It also inhibited ROS levels of malondialdehyde in the brains of CdCl2-treated rats. In both groups, RES decreased the phosphorylation rate of Tau at Ser199 and Ser296. Concomitantly, it significantly increased protein levels of p-GSK3ß (Ser9) and p-PP2A and decreased p-GSK3ß (Tyr216). Also, RES activated PI3K/Akt signaling pathway in both control and CdCl2 treated rats by increasing levels of p-PI3K (Tyr607) and p-Akt (Ser473). This was concomitant with significant increase in the levels of AMPK and p-AMPK, known upstream regulators of PI3K/Akt signaling pathway. Interestingly, all the above listed beneficial effects of RES, except their effect on AMPK/p-AMPK, were completely abolished in CdCl2 + RES + LY294002-treated rats. In conclusion, in addition to its antioxidant potential, RES inhibits Tau phosphorylation in rat's brain by activating PP2A protein and AMPK/PI3K/Akt-induced inhibition of GSK3ß.