Beetroot supplemented diet exhibit anti-amnesic effect via modulation of cholinesterases, purinergic enzymes, monoamine oxidase and attenuation of redox imbalance in the brain of scopolamine treated male rats.

OBJECTIVES: Beta vulgaris, commonly known as beetroot, is a vegetable that contains red pigment and rich in betalains, phenolic acids, and flavonoids. This study was designed to assess the effect of beetroot supplemented diet (BRSD) on cognitive function and altered neurochemicals associated with Alzheimer's disease (AD) in the brain of rats treated with scopolamine (SCOP). METHODS: Rats were fed with BRSD (2 and 4%) for 14 days and administered with 2 mg/kg of SCOP intraperitoneally on the last day. Morris water Maze and Y-maze tests were performed to assess cognitive function. Purinergic enzymes [ectonucleotidase (NTPdase) and adenosine deaminase (ADA)], monoamine oxidase (MAO), and angiotensin-I converting enzyme (ACE) activities were determined in rat brain tissues. Furthermore, catalase activity, total thiol (T-SH) and non-protein thiol (NP-SH) levels were also assessed. Beetroot was characterized using liquid chromatography-mass spectrometry, and the structure-activity relationship between the constituents and target enzymes was assessed. RESULTS: BRSD improved cognitive function by increasing memory index in SCOP treated rats. An increase in NTPdase, ADA, MAO, and ACE activities were observed in the brain of rats treated with SCOP. However, the activities of these enzymes were significantly lower after treatment with BRSD. Treatment with BRSD triggered a significant increase in catalase activity, T-SH and NP-SH levels in SCOP-treated rats. Catechin, 6,7-benzocoumarin, gentisin, 5,7-dimethoxyflavone, and vulgaxanthin I was identified in beetroots. DISCUSSION: The result suggests that beetroot could prevent cognitive dysfunction in SCOP-treated rats, and enhance memory function, via modulation of purinergic enzymes, MAO and ACE activities, and neuronal antioxidant status.

Neuroprotective effect of Bryophyllum pinnatum flavonoids against aluminum chloride-induced neurotoxicity in rats.

Toxic metals such as aluminum accumulation in the brain have been associated with the pathophysiology of several neurodegenerative disorders. Bryophyllum pinnatum leaves contain a vast array of polyphenols, particularly flavonoids, that may play a role in the prevention of toxic and degenerative effects in the brain. This study assessed the neuro-restorative potential of leaves of B. pinnatum enriched flavonoid fraction (BPFRF) in aluminum-induced neurotoxicity in rats. Neurotoxicity was induced in male Wistar rats by oral administration of 150 mg/kg body weight of aluminum chloride (AlCl3) for 21 days. Rats were grouped into five (n = 6); Control (untreated), Rivastigmine group, AlCl3 group and BPFRF group (50 and 100 mg/kg b.wt.) for 21 days. Neuronal changes in the hippocampus and cortex were biochemically and histologically evaluated. Expression patterns of acetylcholinesterase (AChE) mRNA were assessed using semi-quantitative reverse-transcription-polymerase chain reaction protocols. Molecular interactions of BPFRF compounds were investigated in silico. The results revealed that oral administration of BPFRF ameliorated oxidative imbalance by augmenting antioxidant systems and decreasing lipid peroxidation caused by AlCl3. BPFRF administration also contributed to the down-regulation of AChE mRNA transcripts and improved histological features in the hippocampus and cortex. Molecular docking studies revealed strong molecular interactions between BPFRF compounds, catalase, superoxide dismutase and glutathione peroxidase Overall, these findings suggest the neuroprotective effect of Bryophyllum pinnatum against aluminum-induced neurotoxicity.

UPLC-PDA-ESI-QTOF-MS/MS fingerprint of purified flavonoid enriched fraction of Bryophyllum pinnatum; antioxidant properties, anticholinesterase activity and in silico studies.

CONTEXT: Bryophyllum pinnatum (Lam.) Oken (Crassulaceae) is used traditionally to treat many ailments. OBJECTIVES: This study characterizes the constituents of B. pinnatum flavonoid-rich fraction (BPFRF) and investigates their antioxidant and anticholinesterase activity using in vitro and in silico approaches. MATERIALS AND METHODS: Methanol extract of B. pinnatum leaves was partitioned to yield the ethyl acetate fraction. BPFRF was isolated from the ethyl acetate fraction and purified. The constituent flavonoids were structurally characterized using UPLC-PDA-MS2. Antioxidant activity (DPPH), Fe2+-induced lipid peroxidation (LP) and anticholinesterase activity (Ellman's method) of the BPFRF and standards (ascorbic acid and rivastigmine) across a concentration range of 3.125-100 µg/mL were evaluated in vitro for 4 months. Molecular docking was performed to give insight into the binding potentials of BPFRF constituents against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). RESULTS: UPLC-PDA-MS2 analysis of BPFRF identified carlinoside, quercetin (most dominant), luteolin, isorhamnetin, luteolin-7-glucoside. Carlinoside was first reported in this plant. BPFRF significantly inhibited DPPH radical (IC50 = 7.382 ± 0.79 µg/mL) and LP (IC50 = 7.182 ± 0.60 µg/mL) better than quercetin and ascorbic acid. Also, BPFRF exhibited potent inhibition against AChE and BuChE with IC50 values of 22.283 ± 0.27 µg/mL and 33.437 ± 1.46 µg/mL, respectively compared to quercetin and rivastigmine. Docking studies revealed that luteolin-7-glucoside, carlinoside and quercetin interact effectively with crucial amino acid residues of AChE and BuChE through hydrogen bonds. DISCUSSION AND CONCLUSIONS: BPFRF possesses an excellent natural source of cholinesterase inhibitor and antioxidant. The material could be further explored for the potential treatment of oxidative damage and cholinergic dysfunction in Alzheimer's disease.

Vanillin and vanillic acid modulate antioxidant defense system via amelioration of metabolic complications linked to Fe2+-induced brain tissues damage.

The therapeutic effect of phenolics on neurodegenerative diseases has been attributed to their potent antioxidant properties. In the present study, the neuroprotective activities of vanillin and vanillic acid were investigated in Fe2+- induced oxidative toxicity in brain tissues by investigating their therapeutic effects on oxidative imbalance, cholinergic and nucleotide-hydrolyzing enzymes activities, dysregulated metabolic pathways. Their cytotoxicity was investigated in hippocampal neuronal cell lines (HT22). The reduced glutathione level, SOD and catalase activities were ameliorated in tissues treated with the phenolics, with concomitant depletion of malondialdehyde and nitric oxide levels. They inhibited acetylcholinesterase and butyrylcholinesterase activities, while concomitantly elevated ATPase activity. Treatment with vanillin led to restoration of oxidative-depleted metabolites and reactivation of the pentose phosphate and purine metabolism pathways, with concomitant activation of pathways for histidine and selenoamino metabolisms. While vanillic acid restored and reactivated oxidative-depleted metabolites and pathways but did not activate any additional pathway. Both phenolics portrayed good binding affinity for catalase, with vanillic acid having the higher binding energy of -7.0 kcal/mol. Both phenolics were not cytotoxic on HT22 cells, and their toxicity class were predicted to be 4. Only vanillin was predicted to be permeable across the blood brain barrier (BBB). These results insinuate that vanillin and vanillic acid confer a neuroprotective effect on oxidative brain damage, when vanillin being the most potent.

The Driving Force for the Acylation of ß-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study.

ß-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the ß-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C-N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of ß-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a-2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C-N), which is why the six-membered ring lactams C-N bond are more rigid than those with five-membered ring lactams. The calculated ΔG# values from the acylation reaction of the lactams (involving the S-H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C-N cleavage in the five-membered ring lactams especially in the 1-2 derivatives (17.58 kcal mol-1 ). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the ß-lactam ring, than ring strain.

Vernonia Amygdalina Del. stimulated glucose uptake in brain tissues enhances antioxidative activities; and modulates functional chemistry and dysregulated metabolic pathways.

Brain glucose uptake is usually reduced in type 2 diabetes owing to downregulation of brain glucose transporters. The ability of Vernonia amygdalina to stimulate glucose uptake as well as ameliorate glucose-induced oxidative stress and proinflammation were investigated in rat brain. Hot infusion of V. amygdalina leaves was incubated with rat brain tissues for 2 h in the presence of glucose. Another incubation with glucose only, served as negative control while metformin served as positive control. Incubation of brain tissues with V. amygdalina led to significant (p < 0.05) increase in glucose uptake, reduced glutathione, nitric oxide and non-thiol proteins levels, superoxide dismutase, catalase and ATPase activities, while concomitantly decrease in myeloperoxidase activity and malondialdehyde level compared to the negative control. Incubation with glucose only, led to the development of nitrate, amide II and amide I functional groups which were removed on incubation with the infusion. LC-MS analysis revealed depletion of oxidative stress-induced 2-keto-glutaramic acid and cysteinyl-tyrosine metabolites in brain tissues, with concomitant generation of S-formylglutathione and adenosine tetraphosphate by the infusion. Pathway analysis of the metabolites revealed an activation of pyruvate metabolism pathway in the negative control, with the infusion reducing the intensity fold. LC-MS analysis of the infusion revealed the presence of l-serine, l-cysteine, l-proline, nicotinic acid, cumidine, salicylic acid, isoquinoline, 3-methyl-, and γ-octalactone. Except for l-serine, l-cysteine and l-proline, the other compounds were predicted to be permeable across the blood brain barrier. These results indicate the brain glucose uptake stimulatory and neuroprotective effect of V. amygdalina.

Molecular insight on the non-covalent interactions between carbapenems and L,D-transpeptidase 2 from Mycobacterium tuberculosis: ONIOM study.

Tuberculosis remains a dreadful disease that has claimed many human lives worldwide and elimination of the causative agent Mycobacterium tuberculosis also remains elusive. Multidrug-resistant TB is rapidly increasing worldwide; therefore, there is an urgent need for improving the current antibiotics and novel drug targets to successfully curb the TB burden. L,D-Transpeptidase 2 is an essential protein in Mtb that is responsible for virulence and growth during the chronic stage of the disease. Both D,D- and L,D-transpeptidases are inhibited concurrently to eradicate the bacterium. It was recently discovered that classic penicillins only inhibit D,D-transpeptidases, while L,D-transpeptidases are blocked by carbapenems. This has contributed to drug resistance and persistence of tuberculosis. Herein, a hybrid two-layered ONIOM (B3LYP/6-31G+(d): AMBER) model was used to extensively investigate the binding interactions of LdtMt2 complexed with four carbapenems (biapenem, imipenem, meropenem, and tebipenem) to ascertain molecular insight of the drug-enzyme complexation event. In the studied complexes, the carbapenems together with catalytic triad active site residues of LdtMt2 (His187, Ser188 and Cys205) were treated at with QM [B3LYP/6-31+G(d)], while the remaining part of the complexes were treated at MM level (AMBER force field). The resulting Gibbs free energy (ΔG), enthalpy (ΔH) and entropy (ΔS) for all complexes showed that the carbapenems exhibit reasonable binding interactions towards LdtMt2. Increasing the number of amino acid residues that form hydrogen bond interactions in the QM layer showed significant impact in binding interaction energy differences and the stabilities of the carbapenems inside the active pocket of LdtMt2. The theoretical binding free energies obtained in this study reflect the same trend of the experimental  observations. The electrostatic, hydrogen bonding and Van der Waals interactions between the carbapenems and LdtMt2 were also assessed. To further examine the nature of intermolecular interactions for carbapenem-LdtMt2 complexes, AIM and NBO analysis were performed for the QM region (carbapenems and the active residues of LdtMt2) of the complexes. These analyses revealed that the hydrogen bond interactions and charge transfer from the bonding to anti-bonding orbitals between catalytic residues of the enzyme and selected ligands enhances the binding and stability of carbapenem-LdtMt2 complexes. The two-layered ONIOM (B3LYP/6-31+G(d): Amber) model was used to evaluate the efficacy of FDA approved carbapenems antibiotics towards LdtMt2.

Singlet-triplet gaps in polyacenes: a delicate balance between dynamic and static correlations investigated by spin-flip methods.

Over the last few years people have been interested in the process of singlet fission, owing to its relevance to solar cell technology. The energetics of singlet fission is intimately related to singlet-triplet (ST) gaps and energies of singlet excited states. However, accurate calculations of ST gaps in polyacenes are complicated due to near degeneracies in the π orbitals, and therefore, have been quite challenging. The spin-flip equation-of-motion coupled-cluster (SF-EOM-CC) and its perturbative approximation have been shown to correctly treat situations involving electronic degeneracies and near degeneracies. In this work, we use various spin-flip methods to benchmark the ST gaps of small polyacenes and show that the error in the ST gaps with respect to the experiment is small and does not increase appreciably with the system size. The diradical and polyradical character of the polyacene ground states increase with the system size. However, for the small polyacenes the open-shell character of the ground state is still small enough to be treated using single reference methods.

Synthesis, experimental and computational studies on the anti-corrosion performance of substituted Schiff bases of 2-methoxybenzaldehyde for mild steel in HCl medium.

Corrosion inhibition performance of two synthesized Schiff base ligands; (E)-2-((2-methoxybenzylidene)amino)phenol L1 and (E)-2-((4-methoxybenzylidene)amino)phenol L2 were carried out by weight loss measurement in 0.1 M hydrochloric acid (HCl) solution. Density Functional Theory (DFT) and Molecular dynamics (MD) simulation were applied to theoretically explain the inhibitors' intrinsic properties and adsorption mechanism in the corrosion study. The result of the inhibition performances carried out at varying concentrations and temperatures were compared. The corrosion inhibition efficiencies of L1 and L2 at an optimal concentration of 10 × 10-4 M were 75% and 76%. Langmuir isotherm model fits the data obtained from the experiment with a correlation coefficient (R2) value closer to unity. The adsorption mechanism of inhibitor on the surface of the Fe metal occurred via chemisorption inferred from the Gibbs free energy (ΔGads). Scanning electron microscopy showed a mild degradation on the surface of the mild steel immersed in the L1, and L2 inhibited acid solution, which could be due to surface coverage. The energy dispersive X-ray spectroscopy showed the metal surface's elemental composition and the existence of the chlorine peak, which emanates from the HCl medium. DFT calculations revealed that the hybrid B3LYP functional performed better than the M06-2X meta-functional in estimating the energies of the synthesized Schiff bases for corrosion inhibition as seen in the lower ΔE values of 3.86 eV and 3.81 eV for L1 and L2. The MD simulation revealed that the orientation of inhibitors on the surface of the metal resulted in the coordination bond formation and that the interaction energy of L2 was -746.84 kJ/mol compared to -743.74 kJ/mol of L1. The DFT and MD results agreed with the observed trend of the experimental findings.

In vitro and computational studies of the antioxidant and anti-diabetic properties of Bridelia ferruginea.

The leaves, stem and root bark of Bridelia ferruginea were sequentially extracted with solvents of increasing polarity to yield the hexane, ethyl acetate, ethanol and aqueous extracts. In vitro analysis revealed the ability of the extracts to scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH), nitric oxide (NO) and hydroxyl radical. They also inhibited the activities of α-glucosidase, α-amylase and lipase enzymes. Gas chromatography-mass spectroscopic (GC-MS) analysis of the extracts revealed the presence of sterols, aromatics, aliphatic acids and esters. The identified compounds were molecularly docked with α-glucosidase, α-amylase and lipase enzymes. All compounds showed good binding affinities with the enzymes studied. The strongest binding affinities were observed for ß-amyrin, 4-phenylbenzophenone and lupenone for α-glucosidase, α-amylase and lipase enzymes, respectively. The data suggest antioxidant and antidiabetic potential of the different parts of B. ferruginea, with the leaves having the highest potential. These properties can be explored for development of novel anti-diabetic drugs.Communicated by Ramaswamy H. Sarma.

Natural phyto, compounds as possible noncovalent inhibitors against SARS-CoV2 protease: computational approach.

At present, there is no cure or vaccine for the devastating new highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has affected people globally. Herein, we identified potent phytocompounds from two antiviral plants Momordica charantia L. and Azadirachta indica used locally for the treatment of viral and parasitic infections. Structure-based virtual screening and molecular dynamics (MD) simulation have been employed to study their inhibitory potential against the main protease (Mpro) SARS-CoV-2. A total of 86 compounds from M. charantia L. and A. indica were identified. The top six phytocompounds; momordicine, deacetylnimninene, margolonone, momordiciode F2, nimbandiol, 17-hydroxyazadiradione were examined and when compared with three FDA reference drugs (remdesivir, hydroxychloroquine and ribavirin). The top six ranked compounds and FDA drugs were then subjected to MD simulation and pharmacokinetic studies. These phytocompounds showed strong and stable interactions with the active site amino acid residues of SARS-CoV-2 Mpro similar to the reference compound. Results obtained from this study showed that momordicine and momordiciode F2 exhibited good inhibition potential (best MMGBA-binding energies; -41.1 and -43.4 kcal/mol) against the Mpro of SARS-CoV-2 when compared with FDA reference anti-viral drugs (Ribavirin, remdesivir and hydroxychloroquine). Per-residue analysis, root mean square deviation and solvent-accessible surface area revealed that compounds interacted with key amino acid residues at the active site of the enzyme and showed good system stability. The results obtained in this study show that these phytocompounds could emerge as promising therapeutic inhibitors for the Mpro of SARS-CoV-2. However, urgent trials should be conducted to validate this outcome.Communicated by Ramaswamy H. Sarma.

In vitro study on efficacy of PHELA, an African traditional drug against SARS-CoV-2.

In 2019, coronavirus has made the third apparition in the form of SARS-CoV-2, a novel strain of coronavirus that is extremely pathogenic and it uses the same receptor as SARS-CoV, the angiotensin-converting enzyme 2 (ACE2). However, more than 182 vaccine candidates have been announced; and 12 vaccines have been approved for use, although, even vaccinated individuals are still vulnerable to infection. In this study, we investigated PHELA, recognized as an herbal combination of four exotic African medicinal plants namely; Clerodendrum glabrum E. Mey. Lamiaceae, Gladiolus dalenii van Geel, Rotheca myricoides (Hochst.) Steane & Mabb, and Senna occidentalis (L.) Link; as a candidate therapy for COVID-19. In vitro testing found that PHELA inhibited > 90% of SARS-CoV-2 and SARS-CoV infection at concentration levels of 0.005 mg/ml to 0.03 mg/ml and close to 100% of MERS-CoV infection at 0.1 mg/ml to 0.6 mg/ml. The in vitro average IC50 of PHELA on SARS-COV-2, SARS-CoV and MERS-COV were ~ 0.01 mg/ml. Secondly in silico docking studies of compounds identified in PHELA showed very strong binding energy interactions with the SARS-COV-2 proteins. Compound 5 showed the highest affinity for SARS-COV-2 protein compared to other compounds with the binding energy of - 6.8 kcal mol-1. Our data showed that PHELA has potential and could be developed as a COVID-19 therapeutic.

In vitro and computational studies on the antiglycation activity of compounds isolated from antidiabetic Tetracera alnifolia stem bark.

The continuous search for new compounds in natural-based plants is a promising strategy for the prevention of diseases. This work examined antiglycation activity compounds isolated from the antidiabetic extract of T. alnifolia stem bark via in vitro and computational [molecular dynamics (MD)] approach. Phytochemical investigation of ethyl acetate fraction and the application of spectroscopic methods led to the isolation and elucidation of 3 compounds: quercetin (1), kaempferol (2), and gallic acid (3). Compounds 1, 2 and 3 were then screened for antioxidant and antiglycation activities. Results show that the ethanol extract of T. alnifolia demonstrated good antioxidant activity compared to the standard gallic acid. There was a significant reduction in fasting blood glucose level progressively in diabetic rats, for 21 days compared to diabetic control. Consequently, the antiglycation activity of ethyl acetate fraction had the highest antiglycation activities, followed by dichloromethane (DCM) fraction. Compounds isolated from ethyl acetate fraction, exhibited the highest antiglycation effect for kaempferol followed by quercetin, while gallic acid had the least antiglycation effect. The root mean square of deviation (RMSD) and MM/GBSA energies obtained from molecular dynamics agree with the in vitro antiglycation activity with the sequence of structural stability in the order; kaempferol > quercetin > gallic acid. Therefore, findings from these results suggest that compounds isolated from T. alnifolia possess antiglycation activity.Communicated by Ramaswamy H. Sarma.

Targeting the initiation and termination codons of SARS-CoV-2 spike protein as possible therapy against COVID-19: the role of novel harpagide 5-O-ß-D-glucopyranoside from Clerodendrum volubile P Beauv. (Labiatae).

The global spread of the coronavirus infections disease - 2019 (COVID-19) and the search for new drugs from natural products particularly from plants are receiving much attention recently. In this study, the therapeutic potential of a new iridoid glycoside isolated from the leaves of Clerodendrum volubile against COVID-19 was investigated. Harpagide 5-O-ß-D-glucopyranoside (HG) was isolated, characterised and investigated for its druglikeness, optimized geometry, and pharmacokinetics properties. Its immunomodulatory was determined by chemiluminescence assay using polymorphonuclear neutrophils (PMNs) in addition to T-cell proliferation assay. In silico analysis was used in determining its molecular interaction with severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). HG displayed potent druglikeness properties, with no inhibitory effect on cytochrome P450 (1A2, 2C19, 2C9, 2D6 and 3A4) and a predicted LD50 of 2000 mg/kg. Its 1H-NMR chemical shifts showed a little deviation of 0.01 and 0.11 ppm for H-4 and H-9, respectively. HG significantly suppressed oxidative bursts in PMNs, while concomitantly inhibiting T-cell proliferation. It also displayed a very strong binding affinity with the translation initiation and termination sequence sites of spike (S) protein mRNA of SARS-COV-2, its gene product, and host ACE2 receptor. These results suggest the immunomodulatory properties and anti-SARS-COV-2 potentials of HG which can be explored in the treatment and management of COVID-19.Communicated by Ramaswamy H. Sarma.

Mechanistic insight on the inhibition of D, D-carboxypeptidase from Mycobacterium tuberculosis by ß-lactam antibiotics: an ONIOM acylation study.

Mycobacterium tuberculosis cell wall is intricate and impermeable to many agents. A D, D-carboxypeptidase (DacB1) is one of the enzymes involved in the biosynthesis of cell wall peptidoglycan and catalyzes the terminal D-alanine cleavage from pentapeptide precursors. Catalytic activity and mechanism by which DacB1 functions is poorly understood. Herein, we investigated the acylation mechanism of DacB1 by ß-lactams using a 6-membered ring transition state model that involves a catalytic water molecule in the reaction pathway. The full transition states (TS) optimization plus frequency were achieved using the ONIOM (B3LYP/6-31 + G(d): AMBER) method. Subsequently, the activation free energies were computed via single-point calculations on fully optimized structures using B3LYP/6-311++(d,p): AMBER and M06-2X/6-311++(d,p): AMBER with an electronic embedding scheme. The 6-membered ring transition state is an effective model to examine the inactivation of DacB1 via acylation by ß-lactams antibiotics (imipenem, meropenem, and faropenem) in the presence of the catalytic water. The ΔG# values obtained suggest that the nucleophilic attack on the carbonyl carbon is the rate-limiting step with 13.62, 19.60 and 30.29 kcal mol-1 for Imi-DacB1, Mero-DacB1 and Faro-DacB1, respectively. The electrostatic potential (ESP) and natural bond orbital (NBO) analysis provided significant electronic details of the electron-rich region and charge delocalization, respectively, based on the concerted 6-membered ring transition state. The stabilization energies of charge transfer within the catalytic reaction pathway concurred with the obtained activation free energies. The outcomes of this study provide important molecular insight into the inactivation of D, D-carboxypeptidase by ß-lactams.Communicated by Ramaswamy H. Sarma.

Modulatory effect of ursolic acid on neurodegenerative activities in oxidative brain injury: An ex vivo study.

Natural products-based antioxidants have been well reported for their therapeutic benefits in the treatment and management of neurodegenerative diseases. The neuroprotective effect of ursolic acid (UA) against oxidative injury was investigated in isolated rat brain. Induction of oxidative injury in isolated rat brains with 0.1 mM FeSO4 led to depleted levels of glutathione, superoxide dismutase, catalase, and ENTPDase activities, with concomitant exacerbation of malondialdehyde and nitric oxide levels, α-chymotrypsin, ATPase, and acetylcholinesterase activities. These levels and activities were significantly reversed following treatment of the brain tissues with UA. Molecular docking studies revealed strong molecular interactions between UA, catalase, and ATPase. Overall, these results indicate the neuroprotective effect of UA against oxidative injury in isolated rat brains as depicted by their ability to mitigate oxidative stress, purinergic, and cholinergic dysfunctions, with concomitant suppression of proteolytic activity. PRACTICAL APPLICATIONS: Neurodegenerative diseases are among the common diseases associated with aging and has been implicated as oxidative mediated. Natural products have received increasing recognition in their use as treatment remedy for various oxidative-mediated diseases including neurodegeneration. These natural products include plant secondary metabolites commonly known as phytochemicals. Ursolic acid is a phytochemical usually present in leafy vegetables and fruits. The present study describes the possible therapeutic mechanism of ursolic acid in the amelioration of complications linked to neurodegeneration in oxidative-mediated brain injury. These findings thus give insights into the use of natural products of plant origin in treating and managing neurodegenerative diseases, which may have little or no side effects.

Isolation, characterization, and hepatoprotective properties of betulinic acid and ricinine from Tetracarpidium conophorum seeds (Euphorbiaceae).

The present study is to isolate and characterize betulinic acid and ricinine from T. conophorum seeds. Phytochemical investigation on hexane fraction of T. conophorum seeds led to the isolation of two compounds, Betulinic acid (1), and Ricinine (2). Betulinic acid and ricinine were screened against HepG2 cells and tested in vivo in CCl4 -induced experimental rats model. Results from this study showed that the compounds had hepatoprotective and cytotoxic activities. It was observed that betulinic acid inhibited HepG2 cell with percentage inhibition of 54% compared with standard doxorubicin (64%), while ricinine was inactive against HepG2 cell lines. Furthermore, molecular docking was carried out on betulinic acids and ricinine, with binding energies of -11.2 kcal/mol and -5.4 kcal/mol, respectively, indicating strong binding sites and interactions with Hepatitis B Virus DNA polymerase. Therefore, findings from this study suggest that betulinic acid possess cytotoxic and hepatoprotective properties, while ricinine exhibited hepatoprotection in CCl4 -induced liver damage. PRACTICAL APPLICATIONS: Medicinal plants contain unrestricted ability to make compounds that intrigue researchers in the quest for novel phyto-therapeutic drugs. The continuous exploration of new compounds in the medicinal plant is an auspicious strategy for the prevention of diseases. Therefore, the purpose of this research is to evaluate the cytotoxic and hepatoprotective compounds (betulinic acid and ricinine) isolated from T. conophorum seeds.

Functionalized MWCNTs-quartzite nanocomposite coated with Dacryodes edulis stem bark extract for the attenuation of hexavalent chromium.

Multiwalled carbon nanotubes/quartzite nanocomposite modified with the extract of Dacryodes edulis leaves was synthesized and designated as Q, which was applied for the removal of Cr(VI) from water. The adsorbents (PQ and Q) were characterized using the SEM, EDX, FTIR, TGA, XRD, and BET analyses. The XRD revealed the crystalline composition of the nanocomposite while the TGA indicated the incorporated extract as the primary component that degraded with an increase in temperature. The implication of the modifier was noticed to enhance the adsorption capacity of Q for Cr(VI) by the introduction of chemical functional groups. Optimum Cr(VI) removal was noticed at a pH of 2.0, adsorbent dose (50 mg), initial concentration (100 mg dm-3), and contact time (180 min). The kinetic adsorption data for both adsorbents was noticed to fit well to the pseudo-second-order model. The adsorption equilibrium data were best described by the Langmuir model. The uptake of Cr(VI) onto PQ and Q was feasible, endothermic (ΔH: PQ = 1.194 kJ mol-1 and Q = 34.64 kJ mol-1) and entropy-driven (ΔS : PQ = 64.89 J K-1 mol-1 and q = 189.7 J K-1 mol-1). Hence, the nanocomposite demonstrated potential for robust capacity to trap Cr(VI) from aqueous solution.

A Sensitization-Free Dimethyl Fumarate Prodrug, Isosorbide Di-(Methyl Fumarate), Provides a Topical Treatment Candidate for Psoriasis.

Dimethyl fumarate (DMF) is an effective oral treatment for psoriasis administered in Europe for nearly 60 years. However, its potential has been limited by contact dermatitis that prohibits topical application. This paper characterizes a DMF derivative, isosorbide DMF (IDMF), which was designed to have antipsoriatic effects without skin-sensitizing properties. We show that IDMF exhibits neither genotoxicity nor radiation sensitivity in skin fibroblasts and is nonirritating and nonsensitizing in animal models (rat, rabbit, guinea pig). Microarray analysis of cytokine-stimulated keratinocytes showed that IDMF represses the expression of genes specifically upregulated in psoriatic skin lesions but not those of other skin diseases. IDMF also downregulated genes induced by IL-17A and TNF in keratinocytes as well as predicted targets of NF-κB and the antidifferentiation noncoding RNA (i.e., ANCR). IDMF further stimulated the transcription of oxidative stress response genes (NQO1, GPX2, GSR) with stronger NRF2/ARE activation compared to DMF. Finally, IDMF reduced erythema and scaling while repressing the expression of immune response genes in psoriasiform lesions elicited by topical application of imiquimod in mice. These data show that IDMF exhibits antipsoriatic activity that is similar or improved compared with that exhibited by DMF, without the harsh skin-sensitizing effects that have prevented topical delivery of the parent molecule.

Copper(II)-N-hydroxy-N,N'-diarylformamidine complexes: Synthesis, crystal structures, antibacterial and molecular docking studies.

A series of Cu(II) complexes were synthesized by using N-hydroxy-N,N'-diarylformamidine ligands: N-hydroxy-N,N'-(phenyl)formamidine (L1), N-hydroxy-N'-(4-methylphenyl)formamidine (L2), N-hydroxy-N,N'-(2,6-dimethylphenyl)formamidine (L3), N-hydroxy-N,N'-(2,6-diisopropylphenyl)formamidine (L4). Reaction of ligands L1-L4 with hydrated copper acetate furnished mononuclear Cu(II) complexes 1-4 with general formula [Cu-(L)2]. The molecular structures of complexes 3 and 4, as determined by single crystal X-ray diffraction, showed both to have square planar geometry with a near C2 symmetry. The antimicrobial potency of all four complexes was evaluated against three gram-(-) bacteria (S. typhimurium, P. aeruginosa, and E. coli) and two gram-(+) bacteria (Methicillin-resistant S. aureus (MRSA) and S. aureus), with ciprofloxacin as the reference drug. All tested complexes were inactive against gram-(+) bacteria strains except for complex 1, which displayed excellent activity when compared to the reference. Molecular docking studies showed that hydrogen bonding, pi-sigma and van der Waals interactions are prominent complex-protein connections, with complex 2 displaying good binding affinities with the studied biological targets.