Evaluation of Major Constituents of Medicinally Important Plants for Anti-Inflammatory, Antidiabetic and AGEs Inhibiting Properties: In Vitro and Simulatory Evidence.

Diabetes mellitus (DM) is a global health concern that is associated with several micro- and macrovascular complications. We evaluated several important medicinal plant constituents, including polyphenols and flavonoids, for α-glucosidase inhibition, AGEs' inhibitory activities using oxidative and no-oxidative assays, the inhibition of protein cross link formation, 15-lipoxydenase inhibition and molecular docking. The molecular docking studies showed high binding energies of flavonoids for transcriptional regulars 1IK3, 3TOP and 4F5S. In the α-glucosidase inhibition assay, a significant inhibition was noted for quercitrin (IC50 7.6 µg/mL) and gallic acid (IC50 8.2 µg/mL). In the AGEs inhibition assays, quercetin showed significant results in both non-oxidative and (IC50 0.04 mg/mL) and oxidative assays (IC50 0.051 mg/mL). Furthermore, quercitrin showed inhibitory activity in the non-oxidative (IC50 0.05 mg/mL) and oxidative assays (IC50 0.34 mg/mL). A significant inhibition of protein cross link formation was observed by SDS-PAGE analysis. Quercitrin (65%) and quercetin (62%) showed significant inhibition of 15-lipoxygenase. It was thus concluded that flavonoids and other polyphenols present in plant extracts can be effective in management of diabetes and allied co-morbidities.

Antimicrobial and antioxidant chlorinated azaphilones from mangrove Diaporthe perseae sp. isolated from the stem of Chinese mangrove Pongamia pinnata.

Many plants remain unexplored for their endophytic fungi that may possess potentially important phytochemicals. Consequently, we have focused to discover new natural products from endophytic fungus Diaporthe perseae sp. isolated from the stem of the Chinese mangrove Pongamia pinnata (L.) Pierre plant that led to the isolation of one new chlorinated isochromophilone G (1) along with six known azaphilones (2-7). The structures of the isolated compounds were elucidated by UV, NMR and Mass spectroscopic analysis. All the isolated compounds were screened for their antimicrobial and anti-oxidant activities.

Penicamide A, A Unique N,N'-Ketal Quinazolinone Alkaloid from Ascidian-Derived Fungus Penicillium sp. 4829.

Previously unreported N,N'-ketal quinazolinone enantiomers [(-)-1 and (+)-1] and a new biogenetically related compound (2), along with six known compounds, 2-pyrovoylaminobenzamide (3), N-(2-hydroxypropanoyl)-2 amino benzoic acid amide (4), pseurotin A (5), niacinamide (6), citreohybridonol (7), citreohybridone C (8) were isolated from the ascidian-derived fungus Penicillium sp. 4829 in wheat solid-substrate medium culture. Their structures were elucidated by a combination of spectroscopic analyses (1D and 2D NMR and Electron Circular Dichroism data) and X-ray crystallography. The enantiomeric pair of 1 is the first example of naturally occurring N,N'-ketal quinazolinone possessing a unique tetracyclic system having 4-quinazolinone fused with tetrahydroisoquinoline moiety. The enantiomeric mixtures of 1 displayed an inhibitory effect on NO production in lipopolysaccharide-activated RAW264.7 cells, while the optically pure (-)-1 showed better inhibitory effect than (+)-1.

Induction of Diverse Bioactive Secondary Metabolites from the Mangrove Endophytic Fungus Trichoderma sp. (Strain 307) by Co-Cultivation with Acinetobacter johnsonii (Strain B2).

Two new sesquiterpenes, microsphaeropsisin B (1) and C (2), and two new de-O-methyllasiodiplodins, (3R, 7R)-7-hydroxy-de-O-methyllasiodiplodin (4) and (3R)-5-oxo-de-O-methyllasiodiplodin (5), together with one new natural product (6) and twelve known compounds (3, 7-17), were isolated from the co-cultivation of mangrove endophytic fungus Trichoderma sp. 307 and aquatic pathogenic bacterium Acinetobacter johnsonii B2. Their structures, including absolute configurations, were elucidated by extensive analysis of spectroscopic data, electronic circular dichroism, Mo2(AcO)4-induced circular dichroism, and comparison with reported data. All of the isolated compounds were tested for their α-glucosidase inhibitory activity and cytotoxicity. New compounds 4 and 5 exhibited potent α-glucosidase inhibitory activity with IC50 values of 25.8 and 54.6 µM, respectively, which were more potent than the positive control (acarbose, IC50 = 703.8 µM). The good results of the tested bioactivity allowed us to explore α-glucosidase inhibitors in lasiodiplodins.

Secondary Metabolites from the Marine-Derived Fungus Dichotomomyces sp. L-8 and Their Cytotoxic Activity.

Bioassay-guided isolation of the secondary metabolites from the fungus Dichotomomyces sp. L-8 associated with the soft coral Lobophytum crassum led to the discovery of two new compounds, dichotones A and B (1 and 2), together with four known compounds including dichotocejpin C (3), bis-N-norgliovictin (4), bassiatin (5) and (3R,6R)-bassiatin (6). The structures of these compounds were determined by 1D, 2D NMR and mass spectrometry. (3R,6R)-bassiatin (6) displayed significant cytotoxic activities against the human breast cancer cell line MDA-MB-435 and the human lung cancer cell line Calu3 with IC50 values of 7.34 ± 0.20 and 14.54 ± 0.01 µM, respectively, while bassiatin (5), the diastereomer of compound 6, was not cytotoxic.

Integrated computational and experimental evaluation of phenolic constituents of Apricot fruit L. for antiqourum sensing, antibiofilm, antioxidant, and 15-lox inhibitory properties.

The present study investigated the antioxidant profile together with the antibacterial potential of Apricot L. with the aim to find a functional food based anti-infective lead. Additionally the study evaluated the biofilm and QS inhibitory potential of the plant using Pseudomonas aeruginosa (ATCC 15442) and Chromo bacterium Violaceum (DSM 30191) respectively. Several fractions of the peel of Apricot were subjected to initial antimicrobial and antibiofilm screening. Among all the fractions, methanol and ethyl acetate fractions displayed significant antimicrobial activity against the strains selected with MIC values 1.25 mg/dL and 1.68 mg/dL respectively. Similarly, while evaluating antiqourum-sensing potential, methanol extract showed remarkable zone of inhibition (14mm) with Violaceum inhibition (58%) while aqueous part presented moderately good inhibition (32%) with zone of inhibition of (4mm). N-hexane fraction was least active in this regard. In case of free radicals scavenging aptitudes, Ethanolic fraction displayed the highest free radicals scavenging potential (IC50µg/mL 13.76 ± 23.61) while Aqueous and ethyl acetate part exhibited moderate to good antioxidant behaviors with IC50µg/mL of 26.74 ± 22.00 and 19.49 ± 2.91 respectively. Then the selected compounds were screened for putative binding sites and molecular docking studies followed by enzyme inhibition assays. The negative binding energies and close proximity to residues in the binding pocket of selected targets including human α- soybean lox (PDB ID 1IK3), quorum sensing regulators LasR (2UV0) were observed which indicated high affinity and tight binding capacity of compounds 1 and 5 towards the active sites of LasR 2UV0 and 15-lipoxygenase. The physicochemical characteristics and toxicity expectation were computationally accomplished. Bioactivity prediction study revealed that all of the selected Phytoconstituents displayed incredible Bioactivity score. None of the selected chemical compound was found to be toxic as discovered by toxicity studies. Compound 4 exhibited the highest inhibition of 15-lipoxygenase in vitro (69%, at 0.037 mM final concentration) and that is accompanied by compound 5 (60%) whereas in the biofilm inhibition assay, compound 1 was most active (IC50 0.05 mM), followed by compound 3 (IC50 0.07 mM). It was therefore determined that compounds 1 and 3 had the highest biofilm inhibitory activity, whereas compounds 4 and 5 were potent 15-lipoxygenase inhibitors with potentially anti-inflammatory properties. Future investigations are suggested for the characterization and formulation development.

DFT, GC-MS analysis and biological evaluation of Limbarda crithmoides L. Dumort essential oil; an important edible halophyte grown in Pakistan.

Antimicrobial resistance is a major health burden in Pakistan, and therefore new herbal medicine-based therapeutic regimens are being largely investigated. Limbarda crithmoides essential oil was extracted by using hydrodistillation method. Chemical profiling of essential was evaluated by using FTIR and GC-MS analysis. A total of 20 components were identified including, p-xylene, o-xylene, ß-linalool, acetophenole and 3-isopropylphenyl methylcarbamate. The HOMO and LUMO analysis in DFT investigations presented that 3-isopropylphenyl methylcarbamate, p-xylene and o-xylene posess a substantial capacity to transfer charge through molecules. The antimicrobial potential of essential oil showed moderate inhibition against E. coli (MIC = 6.25 mg/mL), whereras a significant inhibition Staphylococos aureus was recorded (MIC = 3.12 mg/mL). Further, significant antioxidant activities were recorded in DPPH radical scavenging (IC50 = 80.5 µg/mL), H2O2 (64 ± 1.2%) and FRAP (60.3 µg ferrous equivalents) assays. It was therefore concluded that Limbarda crithmoides essential oil has potential antioxidant and anti-antimicrobial properties and can be used for further investigations.

Multiple integrated computational approach to analyse wound healing potential of Symplocos racemosa bark as Matrix metalloproteinase inhibitors.

The healing of wounds is the flagging concern in chronic wound cases especially when accompanied by pathogenic, diabetic comorbidities. Matrix metalloproteinases are associated with widespread pathological ailments, and the selective inhibitors for metalloproteinases can be of great interest in wound healing strategies. In the present research study, six constituents of Symplocos racemosa Roxb were evaluated for the docking aptitudes on human matrix metalloproteinase MMP 2 (PDB ID: 1QIB) and MMP 9 (PDB ID: 4H1Q) utilising Autodock Vina followed by the visualisation using Discovery studio (DS). The Pymol was used to generate the poses and the best binding pose was chosen for the docking aptitudes. 2D interactions and the 3D poses of the docked complex were accomplished using DS and LigPlot + software respectively. Working on SWISS ADME and OSIRIS software accomplished the physicochemical characteristics, absorption, distribution, metabolism, excretion, molecular properties, bioactivity score, and toxicity predictions. The molecule's physiochemical investigations discovered that all of the ligands comply with Lipinski's rule of five except compound 6, which deviated with two violations. Docking studies against 4H1Q revealed that compounds 1, 3, 5 and 6 exhibited maximum interactions with the target protein, with the free binding energies of -8.3 kJ Mol-1, -9.3 kJ Mol-1, -7.2 kJ Mol-1 and -11.0 kJ Mol-1 respectively. In case of the 1QIB target, compounds 1, 3 and 6 displayed remarkable binding energies of -8.7 kJ mol-1, -9.0 kJ mol-1 and -8.8 kJ mol-1. Bioactivity prediction study revealed that all of the selected Phytoconstituents displayed incredible Bioactivity scores. None of the selected chemical compounds was found to be irritant to the skin as discovered by toxicity studies. The contacts of the ligand-protein complex during the simulation studies revealed that the H-bond interactions of the ligands with LEU188, ALA189, GLN402, ARG420, MET422, PRO421, and ARG424 of 4H1Q were stable for more than 30% of the simulation time. It was thus concluded that the tested compounds predominantly compounds 1, 5 and 6 might rank among the vital supplementary lead drugs in chronic wounds and healing complexities. It is also worth noting the potential aptitude of the compound 3, however, its toxicity concern must be considered.

Transition Metal-Decorated Mg12O12 Nanoclusters as Biosensors and Efficient Drug Carriers for the Metformin Anticancer Drug.

Drug carriers have been designed and investigated remarkably due to their effective use in the modern medication process. In this study, the decoration of the Mg12O12 nanocluster has been done with transition metals (Ni and Zn) for effective adsorption of metformin (anticancer drug). Decoration of Ni and Zn on a nanocluster allows two geometries, and similarly, the adsorption of metformin also provides two geometries. Density functional theory and time-dependent density functional theory have been employed at the B3LYP with 6-311G(d,p) level. The decoration of Ni and Zn offers good attachment and detachment of the drug, which is observed from their good adsorption energy values. Further, the reduction in the energy band gap is noted in the metformin-adsorbed nanocluster, which allows high charge transfer from a lower energy level to a high energy level. The drug carrier systems show an efficient working mechanism in a water solvent with the visible-light absorption range. Natural bonding orbital and dipole moment values suggested that the adsorption of the metformin causes charge separation in these systems. Moreover, low values of chemical softness with a high electrophilic index recommended that these systems are naturally stable with the least reactivity. Thus, we offer novel kinds of Ni- and Zn-decorated Mg12O12 nanoclusters as efficient carriers for metformin and also recommend them to experimentalists for the future development of drug carriers.

Characterisation of the essential oil from Iphiona grantioides and investigation of its antibacterial and antioxidant properties.

Iphiona grantioides (Boiss) Anderb. is a medicinal plant featuring several traditional uses. Nevertheless, this plant has not been widely investigated by modern medicinal chemistry yet, as also the properties of its extracts.In this study, we report the extraction of the essential oil by hydrodistillation from the leaves of I. grantioides. This was characterised by GC-MS analysis and ten chemical constituents were identified.Our findings demonstrate that the essential oil is effective in inhibiting the growth of bacterial strains, and of Klebsiela pneumonia and Staphylococcus aureus in particular. Additionally, its antioxidant properties were evaluated, and it showed radical scavenging activity in vitro.

Synthesis of Isatin Derivatives Exhibiting Antibacterial, Antifungal and Cytotoxic Activities.

OBJECTIVE: The current objective was to synthesize biologically active Isatin derivatives. For this purpose, six (06) chemical entities of Isatin derivatives such as 3a-3c and 4a-4c were synthesized from Isatin substrate. METHODS: The pure compounds were characterized with the help of 1H-NMR, FT-IR, EIMS spectroscopic techniques. The synthesized amines 3a-3c and hydrazones 4a-4c were evaluated for their toxicity potential with the help of brine shrimp bioassay. RESULTS: The obtained results revealed that 3c exhibited promising toxicity (LD50 = 1.03 × 10-5 M) against Artemia salina. The pure chemical entities such as compounds 3a-3c and 4a-4c were evaluated against four Gram-negative (E. coli, P. aeruginosa, S. typhi, S. flexneri) and two Gram-positive (B. subtilis, S. aureus) bacteriae. The compound 3a displayed significant activity against two bacterial strains; i.e. P. aeruginosa, S. typhi, compound 3c demonstrated significant activity against P. aeruginosa. Compound 4b was the most active against S. typhi, displaying a greater diameter of the growth of inhibition zone (GIZ) than the standard drug. Compound 4c exhibited significant activity against P. aeruginosa and S. typhi. Compounds 3a-3c and 4a-4c exhibited moderate to significant antibacterial activity against three out of five strains. Only Compound 3c revealed promising toxicity (LD50 = 1.03 × 10-5 M) against Artemia salina. Antifungal studies of the compounds 3a-3c and 4a-4c against six fungal cultures; T. longifusus, C. albicans, A. flavus, M. canis, F. solani, and C. glabrata. All the compounds were active against one or more pathogens having inhibition (10- 90 %). Compound 3a exhibited significant inhibition i.e. 90 % against M. canis, 70 % against T. longifusus, compound 4b further displayed significant inhibition (90 %) against A. flavus and thus proved to be the most active member of the series. CONCLUSION: All compounds showed better antibacterial, antifungal and cytotoxic activities, which may provide a ground to prepare enhanced molecules with much higher antibacterial activities.

Interventions for adults with a history of complex traumatic events: the INCiTE mixed-methods systematic review.

BACKGROUND: People with a history of complex traumatic events typically experience trauma and stressor disorders and additional mental comorbidities. It is not known if existing evidence-based treatments are effective and acceptable for this group of people. OBJECTIVE: To identify candidate psychological and non-pharmacological treatments for future research. DESIGN: Mixed-methods systematic review. PARTICIPANTS: Adults aged ≥ 18 years with a history of complex traumatic events. INTERVENTIONS: Psychological interventions versus control or active control; pharmacological interventions versus placebo. MAIN OUTCOME MEASURES: Post-traumatic stress disorder symptoms, common mental health problems and attrition. DATA SOURCES: Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1937 onwards); Cochrane Central Register of Controlled Trials (CENTRAL) (from inception); EMBASE (1974 to 2017 week 16); International Pharmaceutical Abstracts (1970 onwards); MEDLINE and MEDLINE Epub Ahead of Print and In-Process & Other Non-Indexed Citations (1946 to present); Published International Literature on Traumatic Stress (PILOTS) (1987 onwards); PsycINFO (1806 to April week 2 2017); and Science Citation Index (1900 onwards). Searches were conducted between April and August 2017. REVIEW METHODS: Eligible studies were singly screened and disagreements were resolved at consensus meetings. The risk of bias was assessed using the Cochrane risk-of-bias tool and a bespoke version of a quality appraisal checklist used by the National Institute for Health and Care Excellence. A meta-analysis was conducted across all populations for each intervention category and for population subgroups. Moderators of effectiveness were assessed using metaregression and a component network meta-analysis. A qualitative synthesis was undertaken to summarise the acceptability of interventions with the relevance of findings assessed by the GRADE-CERQual checklist. RESULTS: One hundred and four randomised controlled trials and nine non-randomised controlled trials were included. For the qualitative acceptability review, 4324 records were identified and nine studies were included. The population subgroups were veterans, childhood sexual abuse victims, war affected, refugees and domestic violence victims. Psychological interventions were superior to the control post treatment for reducing post-traumatic stress disorder symptoms (standardised mean difference -0.90, 95% confidence interval -1.14 to -0.66; number of trials = 39) and also for associated symptoms of depression, but not anxiety. Trauma-focused therapies were the most effective interventions across all populations for post-traumatic stress disorder and depression. Multicomponent and trauma-focused interventions were effective for negative self-concept. Phase-based approaches were also superior to the control for post-traumatic stress disorder and depression and showed the most benefit for managing emotional dysregulation and interpersonal problems. Only antipsychotic medication was effective for reducing post-traumatic stress disorder symptoms; medications were not effective for mental comorbidities. Eight qualitative studies were included. Interventions were more acceptable if service users could identify benefits and if they were delivered in ways that accommodated their personal and social needs. LIMITATIONS: Assessments about long-term effectiveness of interventions were not possible. Studies that included outcomes related to comorbid psychiatric states, such as borderline personality disorder, and populations from prisons and humanitarian crises were under-represented. CONCLUSIONS: Evidence-based psychological interventions are effective and acceptable post treatment for reducing post-traumatic stress disorder symptoms and depression and anxiety in people with complex trauma. These interventions were less effective in veterans and had less of an impact on symptoms associated with complex post-traumatic stress disorder. FUTURE WORK: Definitive trials of phase-based versus non-phase-based interventions with long-term follow-up for post-traumatic stress disorder and associated mental comorbidities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017055523. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 43. See the NIHR Journals Library website for further project information.

Traumatic events that happen often and that are difficult to escape from, such as childhood abuse, are sometimes known as complex traumatic events. People who have a history of complex traumatic events can develop post-traumatic stress disorder and can also suffer from other mental health problems. It is not known if people who experience complex traumatic events can benefit from existing psychological treatments or medications, or if these treatments are acceptable. This review aimed to find out which treatments are most effective and acceptable for mental health problems in people with complex trauma histories, and to identify the frontrunners for future research. We searched electronic databases for evidence about treatment effectiveness and acceptability in adults with a history of complex traumatic events. We found 104 randomised controlled trials and nine non-randomised controlled trials that tested the effectiveness of psychological and/or medications, as well as nine studies that used interviews and focus groups to describe the acceptability of psychological treatments. The studies were split across different populations that included veterans, refugees, people who had experienced childhood sexual abuse and domestic violence, and civilians affected by war. We found that psychological treatments that focused on improving symptoms associated with trauma were effective for reducing post-traumatic stress disorder symptoms and depression across all populations and fewer people dropped out of these treatments, suggesting that they are acceptable. However, trauma-focused treatments were less effective among veterans than among other groups and less effective for reducing other psychological symptoms commonly experienced by people with complex trauma histories. Phased treatments that first start with helping people to feel safe before focusing on trauma symptoms might be beneficial for both post-traumatic stress disorder and additional psychological symptoms. There was little evidence that medications, other than antipsychotics, were effective for post-traumatic stress disorder symptoms. Future work should test if phased treatments are more effective than non-phased treatments over the long term.

Two new isochromane derivatives penisochromanes A and B from ascidian-derived fungus Penicillium sp. 4829.

Seven polyketides, including two new isochromanes, penisochromanes A and B (1 and 2), as well as five known compounds were obtained from an ascidian-derived fungus Penicillium sp. 4829. Their structures were identified by extensive spectroscopic analyses. The structures of compounds 1 and 3 were further determined by the X-ray crystallography. Compounds 1 and 2 were the first example of isochromane with three adjacent oxy substituents in natural source. Compound 4 exhibited selective activities against two Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis, with MIC values 6.25 and 12.5 µM, respectively.

Two new sesquiterpenes derivatives from marine fungus Leptosphaerulina Chartarum sp. 3608.

Two new sesquiterpenes, leptoterpenes A (1) and B (2) were isolated from the fungus Leptosphaerulina Chartarum sp. 3608, derived from a crinoid. It was the first chemical study on this species. The structures of these compounds were elucidated by spectroscopic methods including NMR and MS spectrometry. The absolute configurations of the new compounds were determined on the basis of the single-crystal X-ray diffraction and electronic circular dichroism data analysis. All compounds were tested for their anti-inflammatory activity and the inhibitory effects on Tyrosyl DNA phosphodiesterase II (TDP2).

α-Glucosidase inhibitory and cytotoxic botryorhodines from mangrove endophytic fungus Trichoderma sp. 307.

One new depsidone, botryorhodine H (1), together with three known analogues, botryorhodines C, D and G (2-4), were obtained from the mangrove endophytic fungus Trichoderma sp. 307 by co-culturing with Acinetobacter johnsonii B2. Structures were determined by 1D and 2D NMR analyses and high-resolution mass spectrum. Compounds 1-3 showed α-glucosidase inhibitory activity with IC50 ranging from 8.1 to 11.2 µM, and compound 1 exhibited potent cytotoxicity against rat prolactinoma MMQ and rat pituitary adenoma GH3 cell lines (IC50 = 3.09 and 3.64 µM).

Effect of culture conditions on metabolites produced by the crinoid-derived fungus Aspergillus ruber 1017.

Two different culture media were used to cultivate fungus Aspergillus ruber 1017 and resulted in the isolation of one new compound (1) and 23 known compounds (2-24). Alkaloids were the major metabolite in soybean medium instead of anthraquinone from rice medium. The structures of these compounds were elucidated according to spectroscopic analysis and comparison with reported data. Antibacterial activities of compounds 1-12 against 12 aquatic bacteria were evaluated.

New lasiodiplodins from mangrove endophytic fungus Lasiodiplodia sp. 318.

Two new lasiodiplodins (1-2) together with three known analogues, were isolated from a mangrove endophytic fungus, Lasiodiplodia sp. 318#. Their structures were established by spectroscopic techniques (1D- and 2D-NMR, HR-ESI-MS, etc.), and electronic circular dichroism. Cytotoxic activities of compounds 1-5 were evaluated in vitro. Compound 4 was the most potent, with IC50 values of 5.29 µM against MMQ, 13.05 µM against GH3. Preliminary structural-activity analysis indicated that the functional group (resorcinol-3-OH) contributed greatly to the binding of Lasiodiplodins to the cytotoxic activities.