A Ni(II)MOF-based hypersensitive dual-function luminescent sensor towards the 3-nitrotyrosine biomarker and 6-propyl-2-thiouracil antithyroid drug in urine.

Trace detection of bioactive small molecules (BSMs) in body fluids is of great importance for disease diagnosis, drug discovery, and health monitoring. Based on the chiral ligand of 4,4'-(1,2-dihydroxyethane-1,2-diyl)dibenzoic acid (H2L), an achiral 3D porous Ni(II)-MOF, with a trinuclear cluster based (3,9)-c {42·6}3{46·621·89}-xmz net, was constructed under solvothermal conditions. Benefiting from its robust framework and excellent luminescent performance, NiMOF was endowed with remarkable capabilities in efficiently, rapidly, and sensitively detecting the 3-nitrotyrosine (3-NT) biomarker and 6-propyl-2-thiouracil (6-PTU) thyroid drug based on the spectral overlap and photo-induced electron transfer (PET) caused luminescence quenching response. Notably, NiMOF exhibited exceptional performance in quantifying 3-NT and 6-PTU in urine samples, yielding highly satisfactory results. Additionally, an intelligent detection system was crafted to enhance the reliability and practicability of 3-NT/6-PTU detection in urine, based on tandem combinational logic gates. This work not only heralds a promising trajectory in the development of MOF-based luminescent sensors, but also paves the way for the intelligent monitoring of BSMs in real bodily fluids.

In silico exploration of deep-sea fungal metabolites as inhibitor of Ebola and Marburg VP35 and VP40.

VP30 and VP40 proteins of Ebola and Marburg viruses have been recognized as potential targets for antiviral drug development due to their essential roles in the viral lifecycle. Targeting these proteins could disrupt key stages of the viral replication process, inhibiting the viruses' ability to propagate and cause disease. The current study aims to perform molecular docking and virtual screening on deep-sea fungal metabolites targeting Marburg virus VP40 Dimer, matrix protein VP40 from Ebola virus Sudan, Ebola VP35 Interferon Inhibitory Domain, and VP35 from Marburg virus. The top ten compounds for each protein target were chosen using the glide score. All the compounds obtained indicate a positive binding interaction. Furthermore, AdmetSAR was utilized to investigate the pharmacokinetics of the inhibitors chosen. Gliotoxin was used as a ligand with Marburg virus VP40 Dimer, Austinol with matrix protein VP40 from Ebola virus Sudan, Ozazino-cyclo-(2,3-dihydroxyl-trp-tyr) with Ebola VP35 Interferon Inhibitory Domain, and Dehydroaustinol with VP35 from Marburg virus. MD modeling and MMPBSA studies were used to provide a better understanding of binding behaviors. Pre-clinical experiments can assist validate our in-silico studies and assess whether the molecule can be employed as an anti-viral drug.

Role of APOC3 3238C/G, APOB 12669G/A and SCARB1 1050C/T polymorphisms, their expression in patients of HIV-associated lipodystrophy.

Apolipoproteins and Scavenger Receptor Class B1 (SCARB1) proteins are involved in the etiology of HIV-associated lipodystrophy (HIVLD). APOC3 3238C/G, APOB 12669G/A and SCARB1 1050C/T polymorphisms were linked with increased level of APOB, TG, HDL-C and risk of cardiovascular diseases (CVDs). Hence, we evaluated the genetic variations of APOC3 3238C/G, APOB 12669G/A and SCARB1 1050C/T in 187 patients of HIV (64 with HIVLD, 123 without HIVLD) and 139 healthy controls using PCR-RFLP and expression by qPCR. The genotypes of SCARB1 1050 TT and APOB 12669AA showed a risk to severe HIVLD (P = 0.23, OR = 4.95; P = 0.16, OR = 2.02). The APOC3 3238 GG genotype was associated with a lesser risk of severe HIVLD (P = 0.07, OR = 0.22). The APOB 12669 GA genotype was associated with a greater risk of HIVLD severity in patients with impaired LDL, triglyceride (TG), and cholesterol levels (P = 0.34, OR = 4.13; P = 0.25, OR = 3.64; P = 0.26, OR = 5.47). Similarly, APOB 12669AA genotypes in the presence of impaired triglyceride levels displayed the susceptibility to severity of HIVLD (P = 0.77, OR = 2.91). APOB 12669 GA genotype along with impaired HDL and cholesterol levels indicated an increased risk for HIVLD acquisition among patients without HIVLD (P = 0.42, OR = 2.42; P = 0.26, OR = 2.27). In patients with and without HIVLD, APOC3 3238CG genotypes having impaired cholesterol and glucose levels had higher risk for severity and development of HIVLD (P = 0.13, OR = 2.84, P = 0.34, OR = 1.58; P = 0.71, OR = 1.86; P = 0.14, OR = 2.30). An increased expression of APOB and SCARB1 genes were observed in patients with HIVLD (+0.51 vs. -0.93; +4.78 vs. +3.29), and decreased expression of APOC3 gene was observed in patients with HIVLD (-0.35 vs. -1.65). In conclusion, the polymorphisms mentioned above were not associated with the modulation of HIVLD. However, in the presence of impaired triglyceride, HDL, cholesterol and glucose levels, APOB 12669AA and 12669 GA, APOC3 3238CG genotypes indicated a risk for the development and severity of HIVLD.

Identification of novel genetic variations in ABCB6 and GRN genes associated with HIV-associated lipodystrophy.

Protease inhibitors (PIs) are associated with an incidence of lipodystrophy among people living with HIV(PLHIV). Lipodystrophiesare characterised by the loss of adipose tissue. Evidence suggests that a patient's lipodystrophy phenotype is influenced by genetic mutation, age, gender, and environmental and genetic factors, such as single-nucleotide variants (SNVs). Pathogenic variants are considered to cause a more significant loss of adipose tissue compared to non-pathogenic. Lipid metabolising enzymes and transporter genes have a role in regulating lipoprotein metabolism and have been associated with lipodystrophy in HIV-infected patients (LDHIV). The long-term effect of the lipodystrophy syndrome is related to cardiovascular diseases (CVDs). Hence, we determined the SNVs of lipid metabolising enzymes and transporter genes in a total of 48 patient samples, of which 24 were with and 24 were without HIV-associated lipodystrophy (HIVLD) using next-generation sequencing. A panel of lipid metabolism, transport and elimination genes were sequenced. Three novel heterozygous non-synonymous variants at exon 8 (c.C1400A:p.S467Y, c.G1385A:p.G462E, and c.T1339C:p.S447P) in the ABCB6 gene were identified in patients with lipodystrophy. One homozygous non-synonymous SNV (exon5:c.T358C:p.S120P) in the GRN gene was identified in patients with lipodystrophy. One novelstop-gain SNV (exon5:c.C373T:p.Q125X) was found in the GRN gene among patients without lipodystrophy. Patients without lipodystrophy had one homozygous non-synonymous SNV (exon9:c.G1462T:p.G488C) in the ABCB6 gene. Our findings suggest that novel heterozygous non-synonymous variants in the ABCB6 gene may contribute to defective protein production, potentially intensifying the severity of lipodystrophy. Additionally, identifying a stop-gain SNV in the GRN gene among patients without lipodystrophy implies a potential role in the development of HIVLD.

Structure-based virtual identification of natural inhibitors of SARS-CoV-2 and its Delta and Omicron variant proteins.

Aim: Structure-based identification of natural compounds against SARS-CoV-2, Delta and Omicron target proteins. Materials & methods: Several known antiviral natural compounds were subjected to molecular docking and MD simulation against SARS-CoV-2 Mpro, Helicase and Spike, including Delta and Omicron Spikes. Results: Of the docked ligands, 20 selected for each complex exhibited overall good binding affinities (-7.79 to -5.06 kcal/mol) with acceptable physiochemistry following Lipinski's rule. Finally, two best ligands from each complex upon simulation showed structural stability and compactness. Conclusion: Quercetin-3-acetyl-glucoside, Rutin, Kaempferol, Catechin, Orientin, Obetrioside and Neridienone A were identified as potential inhibitors of SARS-CoV-2 Mpro, Helicase and Spike, while Orientin and Obetrioside also showed good binding affinities with Omicron Spike. Catechin and Neridienone A formed stable complexes with Delta Spike.

Mutant strains of SARS-CoV-2 called 'variants of concern' (VOCs) are linked to a good ability to infect, re-infect and spread among people. They are also linked to poor ability to fight the disease and reduced effectiveness of vaccines. Delta and Omicron are important VOCs because they are difficult to control and treat. Specific resistance to some drugs used to treat COVID-19 poses a further challenge. Therefore, discovering natural or plant-derived drugs with no known resistance would be valuable to the treatment of COVID-19. In this study, we screen and identify seven plant-derived compounds that may be useful to treating COVID-19 ­ we identify Quercetin-3-acetyl-glucoside, Rutin, Kaempferol, Catechin, Orientin, Obetrioside and Neridienone A as potential candidates. Orientin, Obetrioside, Catechin and Neridienone A are identified as candidates against Delta and Omicron for the first time.

In silico identification of deep-sea fungal alkaloids as potential inhibitors of SARS-CoV-2, Delta and Omicron spikes.

Aim: Virtual screening of deep-sea fungal metabolites against SARS-CoV-2 Delta and Omicron spikes as potential antivirals. Materials & methods: Deep-sea fungal alkaloids (n ≥ 150) were evaluated against SARS-CoV-2, Delta and Omicron spikes, using various in silico approaches, including Admet scores, physiochemical properties, molecular docking (MD) and MD simulation (150 ns). Results: The test alkaloids complied with Admet scores and physiochemical properties within acceptable ranges, and followed Lipinski's rule of five. Of these, Cladosporium sphaerospermum-derived cladosin K (tetramate alkaloid) for SARS-CoV-2, Cystobasidium laryngis-derived saphenol (phenazine alkaloid) for Delta and Chaetomium globosum-derived chaetoglobosin E (quinoline alkaloid) for Omicron were identified as potential spike-inhibitors. Conclusion: Our data therefore, strongly warrants further experimental validations of cladosin K, saphenol and chaetoglobosin E, especially against the Omicron and Delta spikes.

Deep-sea fungal metabolites as potential inhibitors of glucose-regulatory enzymes: In silico structure-activity analysis.

Chronic diabetes mellites related hyperglycemia is a major cause of mortality and morbidity due to further complications like retinopathy, hypertension and cardiovascular diseases. Though several synthetic anti-diabetes drugs specifically targeting glucose-metabolism enzymes are available, they have their own limitations, including adverse side-effects. Unlike other natural or marine-derived pharmacologically important molecules, deep-sea fungi metabolites still remain under-explored for their anti-diabetes potential. We performed structure-based virtual screening of deep-sea fungal compounds selected by their physiochemical properties, targeting crucial enzymes viz., α -amylase, α -glucosidase, pancreatic-lipoprotein lipase, hexokinase-II and protein tyrosine phosphatase-1B involved in glucose-metabolism pathway. Following molecular docking scores and MD simulation analyses, the selected top ten compounds for each enzyme, were subjected to pharmacokinetics prediction based on their AdmetSAR- and pharmacophore-based features. Of these, cladosporol C, tenellone F, ozazino-cyclo-(2,3-dihydroxyl-trp-tyr), penicillactam and circumdatin G were identified as potential inhibitors of α -amylase, α -glucosidase, pancreatic-lipoprotein lipase, hexokinase-II and protein tyrosine phosphatase-1B, respectively. Our in silico data therefore, warrants further experimental and pharmacological studies to validate their anti-diabetes therapeutic potential.

Green extraction of Milletia pinnata oil for the development, and characterization of pectin crosslinked carboxymethyl cellulose/guar gum herbal nano hydrogel.

Milletia pinnata oil and Nardostachys jatamansi are rich sources of bioactive compounds and have been utilized to formulate various herbal formulations, however, due to certain environmental conditions, pure extract form is prone to degradation. Therefore, in this, study, a green hydrodistillation technology was used to extract M. pinnata oil and N. jatamansi root for the further application in development of pectin crosslinked carboxymethyl cellulose/guar-gum nano hydrogel. Both oil and extract revealed the presence of spirojatamol and hexadecanoic acid methyl ester. Varied concentrations (w/w) of cross-linker and gelling agent were used to formulate oil emulsion extract gel (OEEG1, OEG1, OEEG2, OEG2, OEEG3, OEG3, OEEG4, OEG4, OEEG5, OEG5), in which OEEG2 and OEG2 were found to be stable. The hydrogel displayed an average droplet size of 186.7 nm and a zeta potential of -20.5 mV. Endo and exothermic peaks and the key functional groups including hydroxyl, amide II, and amide III groups confirmed thermal stability and molecular structure. The smooth surface confirmed structural uniformity. Bactericidal activity against both Gram-positive (25.41 ± 0.09 mm) and Gram-negative (27.25 ± 0.01 mm) bacteria and anti-inflammatory activity (49.25%-83.47%) makes nanohydrogel a potential option for treating various infections caused by pathogenic microorganisms. In conclusion, the use of green hydrodistillation technology can be used to extract the bioactive compounds that can be used in formulation of biocompatible and hydrophobic nanohydrogels. Their ability to absorb target-specific drugs makes them a potential option for treating various infections caused by pathogenic microorganisms.

Organosulfurs, S-allyl cysteine and N-acetyl cysteine sequester di-carbonyls and reduces carbonyl stress in HT22 cells.

Diabetes, characterized by high blood glucose level, is a progressive metabolic disease that leads to serious health complications. One of the major pathological consequences associated with diabetes is the accumulation of highly reactive carbonyl compounds called advanced glycation end products (AGEs). Most of the AGEs are dicarbonyls and have the potential to covalently modify proteins especially at the lysine residues in a non-enzymatic fashion (a process termed as glycation) resulting in the functional impairment and/or toxic gain in function. Therefore, non-toxic small molecules that can inhibit glycation are of interest for the therapeutic intervention of diabetes. In the present communication, we have investigated the effect of organosulfurs (S-allyl cysteine, SAC and N-acetyl cysteine, NAC) that are major principal components of Allium sativa against the glycation of different proteins. We discovered that both SAC and NAC are potent anti-glycating agents. We also found that both SAC and NAC reduce ROS level and inhibit apoptosis caused by protein glycation.

Novel anti­hepatitis B virus flavonoids sakuranetin and velutin from Rhus retinorrhoea.

Drug­resistance in hepatitis B virus (HBV), especially due to prolonged treatment with nucleoside analogs, such as lamivudine (LAM), remains a clinical challenge. Alternatively, several plant products and isolated phytochemicals have been used as promising anti­HBV therapeutics with no sign of resistance. Among all known Rhus species, R. coriaria, R. succedanea and R. tripartite have been widely studied for their anti­HBV efficacy, however, the effects of R. retinorrhoea have not been previously investigated. The current study reported the isolation of two flavonoids, namely sakuranetin (SEK) and velutin (VEL), from the dichloromethane fraction of R. retinorrhoea aerial parts using chromatography and spectral analyses. The two flavonoids (6.25­50 µg/ml) were pre­tested for non­hepatocytotoxicity using an MTT assay and their dose­ and time­dependent inhibitory activities against HBV [hepatitis B surface antigen (HBsAg) and hepatitis B 'e' antigen (HBeAg)] in cultured HepG2.2.15 cells were assessed by ELISA. SEK and VEL at the selected doses (12.5 µg/ml) significantly inhibited HBsAg by ~58.8 and ~56.4%, respectively, and HBeAg by ~55.5 and ~52.4%, respectively, on day 5. The reference drugs LAM and quercetin (anti­HBV flavonoids), suppressed the production of HBsAg/HBeAg by ~86.4/~64 and ~84.5/~62%, respectively. Furthermore, molecular docking of the flavonoids with HBV polymerase and capsid proteins revealed the formation of stable complexes with good docking energies, thus supporting their structure­based antiviral mechanism. In conclusion, the present study was the first to demonstrate the anti­HBV therapeutic activities of SEK and VEL isolated from R. retinorrhoea.

Inhibition of hepatitis B virus activities by Rhazya stricta­derived acacetin and acetyl­ß­carboline.

Hepatitis B virus (HBV) causes acute and chronic liver diseases, leading to cirrhosis and hepatocellular carcinoma. Although direct-acting nucleoside analogs, such as lamivudine (LAM), adefovir and famciclovir, are available, emergence of drug-resistance due to mutations in HBV polymerase (POL) restricts their further use. Alternatively, numerous plant products and compounds isolated from plants have been reported to confer anti-HBV efficacies without any sign of resistance in vitro or in vivo. As, flavonoids and alkaloids are the most widely reported antivirals, the anti-HBV activities of the flavonoid acacetin (ACT) and the alkaloid acetyl-ß-carboline (ABC) from the aerial parts of Rhazya stricta were assessed in the present study. Both compounds were isolated from the ethyl acetate fraction of the total methanol extract using column and thin-layer chromatography, and their structures were determined by nuclear magnetic resonance spectroscopy (NMR). Both compounds (at 6.25-50 µg/ml) showed a lack of hepatocytotoxicity in cultured HepG2.2.15 cells. Anti-HBV ELISA [hepatitis B surface antigen (HBsAg) and hepatitis B pre-core-antigen (HBeAg)] on HepG.2.2.15 cells following treatment with selected concentrations (12.5, 25 and 50 µg/ml) of both compounds showed dose- and time-dependent anti-HBV activities. Compared with those in the untreated control at day 5, ACT and ABC (25 µg/ml, each) maximally inhibited HBsAg synthesis by 43.4 and 48.7%, respectively, whilst also maximally inhibiting HBeAg synthesis by 41.2 and 44.2%, respectively, in HepG2.2.15 cells. Comparatively, quercetin and LAM (standards; POL inhibitors) suppressed HBsAg (63.9 and 60.2%, respectively) and HBeAg synthesis (87.1 and 84.3%, respectively) by larger magnitudes. Molecular docking of ACT and ABC structures performed in AutoDock revealed their hydrogen bonding with the drug-sensitive [wild-type (wt)-POL] 'Tyr-Met-Asp-Asp' motif, in addition to the drug-resistant [mutant (mut)-POL] 'Tyr-Ile-Asp-Asp' motif residues of the polymerase binding-pocket, along with other electrostatic interactions. In the wt-POL complex, both compounds showed good interactions with Asp205. In the mut-POL complex, ACT and ABC interacted with Tyr203-Asp205 and Tyr203-Ile204, respectively. In conclusion, to the best of our knowledge, the present study demonstrates anti-HBV efficacies of ACT and ABC in vitro for the first time, endorsed by in silico data. However, further molecular and pharmacological studies are required to validate their pre-clinical therapeutic potential.

Role of APOC3 3238C/G polymorphism in HIV-associated neurocognitive disorder.

Apolipoprotein not only have a role in cholesterol metabolism but also play a role in normal brain function. Apolipoprotein gene polymorphisms are known risk factors for a number of mental and neurological disorders. The expression of brain apolipoproteins is significantly altered in several brain disorders. Therefore, we assed ApoC33238 C/G polymorphism in a total of 248 patient infected with HIV (45 with HAND, 89 without HAND, 114 without ART) and 134 healthy controls using PCR-RFLP. ApoC3 3238CG, 3238 GG genotypes and 3238G allele showed a non-significant increased risk for severity of HAND (P = 0.16, OR = 1.83; P = 0.32, OR = 2.78; P = 0.10, OR = 1.65) while comparing individuals with and without HAND. ApoC3 3238 GG genotype and 3238G allele revealed an increased risk for disease progression when compared between HIV patients with and without ART (P = 0.55, OR = 1.76; P = 0.65, OR = 1.12) though risk could not reach statistical significance. ApoC3 3238 GG genotype and 3238G allele were associated with the reduced risk of acquiring HIV infection when comparing HIV patients who are not on ART with healthy controls (P = 0.05, OR = 0.29; P = 0.04, OR = 0.66). In HIV patients on ART,ApoC3 3238 GG genotype showed an increased susceptibility to development of HAND (P = 0.48, OR = 2.24) when comparing alcohol drinkers and non-drinkers however risk could not reach statistical significance. In conclusion, the genotype ApoC33238GG displayed an inclination of risk for the severity of HAND and HIV disease progression. The polymorphism of APOC3 3238C/G may have a role to reduce the risk for acquisition of HIV infection. ApoC33238GG genotype in presence of alcohol may increase susceptibility to development of HAND.

The anti­hepatitis B virus activity of sea buckthorn is attributed to quercetin, kaempferol and isorhamnetin.

The present study assessed the in vitro anti-hepatitis B virus (HBV) effects of cold-adapted sea buckthorn (Hippophae rhamnoides). Sea buckthorn leaf ethanol extracts subjected to chloroform (SB-Chl), ethyl acetate (SB-Eac), n-butanol (SB-But) and aqueous (SB-Aqu) fractionation were first examined (MTT assay) for their toxic effects on HepG2 cells. While SB-Chl (IC50, 32.58 µg/ml) exhibited high cytotoxicity, SB-Eac, SB-But SB-Aqu were non-toxic at up to 150 µg/ml. High performance liquid chromatography analysis led to the identification of the anti-HBV active flavonols, quercetin (93.09 µg/g), kaempferol (44.19 µg/g) and isorhamnetin (138.75 µg/g) in the extract. The analysis of the anti-HBV effects of SB-Eac, SB-But and SB-Aqu (50 µg/ml, each) on HepG2.2.15 cells revealed the marked inhibition of HBsAg and HBeAg expression levels. At the concentration of 10 µg/ml, quercetin and kaempferol exerted potent inhibitory effects on HBsAg (60.5 and 62.3%, respectively) and HBeAg synthesis (64.4 and 60.2%, respectively), as compared to isorhamnetin (30.5 and 28.4%, respectively). The HBV-polymerase inhibitor drug, lamivudine (2 µM), inhibited HBsAg and HBeAg expression by 87.4 and 83.5%, respectively. The data were in good agreement with a previous in vitro and in silico molecular docking analysis performed by the authors where quercetin, kaempferol and lamivudine had formed stable complexes with HBV-polymerase binding-pocket amino acids. On the whole, to the best of our knowledge, the present study provides the first report of the anti-HBV therapeutic potential of sea buckthorn, attributed to quercetin, kaempferol and isorhamnetin.

Novel anti-hepatitis B virus-active catechin and epicatechin from Rhus tripartita.

Bioactive natural or phytoproducts have emerged as a potential source of antiviral agents. Of the Rhus spp., R. coriaria and R. succedanea have been reported for their antiviral activities against hepatitis B virus (HBV), while the anti-HBV efficacy of R. tripartita has remained elusive. In the present study, the anti-HBV activities of R. tripartita-derived novel catechin [3,5,13,14-flavantetrol-catechin or rhuspartin (RPT)] and epicatechin-3-O-rhamnoside (ECR), were assessed using the HBV-reporter cell line HepG2.2.15. RPT and ECR proved to efficiently inhibit HBV surface antigen (HBsAg) synthesis by 68.8 and 71.3%, respectively, and HBV pre-core antigen (HBeAg) production by 62.3 and 71.2%, respectively, after 5 days of treatment. Of note, RPT had a lower anti-HBV activity than ECR. In comparison, the reference drug lamivudine (LAM) inhibited HBsAg and HBeAg expression by 83.6 and 85.4%, respectively. Further molecular docking analysis revealed formations of strong complexes of RPT, ECR and LAM with HBV polymerase through interactions with binding pocket residues. Taken together, the present results demonstrated promising therapeutic potential of the novel R. tripartita-derived catechin and epicatechin for HBV, warranting their further molecular and pharmacological evaluation.

The anti-hepatitis B virus and anti-hepatotoxic efficacies of solanopubamine, a rare alkaloid from Solanum schimperianum.

Chronic liver disease caused by hepatitis B virus (HBV) remains an important health issue. Though there are effective HBV-polymerase inhibitors (e.g., lamivudine), their prolonged use leads to emergence of drug-resistant (polymerase mutant) strains. Several herbal formulations and phytochemicals have been therefore, reported as potential anti-HBV agents with no sign of resistance in experimental and clinical settings. In this study, we assessed the anti-HBV as well as hepatoprotective salutations of solanopubamine, a rare alkaloid isolated from S. schimperianum. In cultured HepG2.2.15 cells, solanopubamine showed marked anti-HBV activity in a time and dose-dependent manner. Solanopubamine (30 µM) efficiently inhibited HBsAg and HBeAg expressions by 66.5%, 70.5%, respectively as compared to 82.5% and 86.5% respective inhibition by lamivudine (2 µM) at day 5. Molecular docking analyses of solanopubamine revealed formations of stable complexes with lamivudine-sensitive as well as lamivudine-resistant polymerase through interactions of catalytic 'YMDD/YIDD' motif residues. Moreover, solanopubamine attenuated DCFH-induced oxidative and apoptotic damage and restored HepG2 cell viability by 28.5%, and downregulated caspase-3/7 activations by 33%. Further docking analyses of solanopubamine showed formation of stable complexes with caspase-3/7. Taken together, our data demonstrates promising anti-HBV and anti-hepatotoxic therapeutic potential of solanopubamine, and warrants further molecular and pharmacological studies.

The anti-oxidative, anti-cell proliferative and anti-microbial efficacies of cold-adapted Crepis flexuosa: HPTLC and GC/MS analyses.

The genus Crepis constitutes cold-adapted plant spp., of these some are traditionally used in folk medicine against inflammation or fungal infections without scientific validations. Here, we report the biological activities of Crepis flexuosa total ethanol-extract (CF-EtOH) and its hexane (CF-Hex), ethyl acetate (CF-EtOA), butanol (CF-ButOH), and aqueous (CF-Aqua) fractions. Our in vitro DPPH and ABTS radical-scavenging assays showed CF-EtOH, CF-ButOH and CF-Aqua with maximal, CF-EtOA with moderate, and CF-Hex with mild anti-oxidant activities. When tested on human cancer cell lines, high cytotoxicity was demonstrated by CF-EtOH (IC50: 42.45 µg/ml) and CF-Aqua (IC50: 46.37 µg/ml) on HepG2, followed by CF-Hex (IC50: 63.24 µg/ml) and CF-ButOH (IC50: 65.32 µg/ml) on MCF7 cells. The human primary cell line (HUVEC) had comparatively lower cytotoxicity for the tested samples. Moreover, when assessed for anti-microbial efficacy, CF-ButOH and CF-Aqua exhibited the strongest activity (MIC: 156.25 µg/ml) against S. aureus, E. faecalis and C. albicans. Further, while the developed RP-HPTLC identified the bioactive flavonoid luteolin-7-O-glucoside (17.58 mg/g), GS/MS analysis revealed sixteen compounds in C. flexuosa extract. In conclusion, we for the first time show the promising anti-oxidative, anti-cell proliferative and anti-microbial efficacies of C. flexuosa. This warrants further phytochemical and bio-efficacy studies towards isolations and identifications of active principles.

Isolation and Characterization of Two Chalcone Derivatives with Anti-Hepatitis B Virus Activity from the Endemic Socotraen Dracaena cinnabari (Dragon's Blood Tree).

Hepatitis B virus (HBV) infection is prevalent and continues to be a global health concern. In this study, we determined the anti-hepatitis B virus (HBV) potential of the Socotra-endemic medicinal plant Dracaena cinnabari and isolated and characterized the responsible constituents. A bioassay-guided fractionation using different chromatographic techniques of the methanolic extract of D. cinnabari led to the isolation of two chalcone derivatives. Using a variety of spectroscopic techniques, including 1H-, 13C-, and 2D-NMR, these derivatives were identified as 2,4'-dihydroxy-4-methoxydihydrochalcone (compound 1) and 2,4'-dihydroxy-4-methoxyhydrochalcone (compound 2). Both compounds were isolated for the first time from the red resin (dragon's blood) of D. cinnabari. The compounds were first evaluated for cytotoxicity on HepG2.2.15 cells and 50% cytotoxicity concentration (CC50) values were determined. They were then evaluated for anti-HBV activity against HepG2.2.15 cells by assessing the suppression of HBsAg and HBeAg production in the culture supernatants and their half maximum inhibitory concentration (IC50) and therapeutic index (TI) values were determined. Compounds 1 and 2 indicated inhibition of HBsAg production in a dose- and time-dependent manner with IC50 values of 20.56 and 6.36 µg/mL, respectively.

Structure and ligand-based drug discovery of IL-4 inhibitors via interaction-energy-based learning approaches.

Interleukin-4 (IL-4), an anti-inflammatory cytokine plays significant in the development of various diseases especially asthmatic allergies. Previous structural and functional studies of IL-4 with its receptor bring forth different types of inhibitors to block their interaction but each of them failed in clinical trials. Since, no synthetic molecules have been identified against IL-4, so far. Therefore, 21 in-house tested IL-4 inhibitors were blindly docked over the entire surface of IL-4 to predict a suitable and druggable binding site as the crystal structure of IL-4 protein in complex with ligand has not been reported yet. After binding site prediction, both ligand-based and structure-based pharmacophore were generated to screen three ZINC libraries (24.5 M) i.e. purchasable, natural product and natural derivative. A total 5,800 top-scored compounds were further subjected towards score-based screening to find the potential leads. Following protein-ligand interaction fingerprints (PLIF) and molecular visualization of selected hits, six top-scored compounds (five from purchasable and one from natural product library) were further moved towards their stability dynamics, followed by their absolute binding free energy and residue-based energy decomposition calculation by MM-GBSA method. These efforts help us to reveal the key factors responsible for ligand binding that might help to improve the binding and stability of these newly discovered hits by structural modifications.Communicated by Freddie R. Salsbury.

Novel Anti-Hepatitis B Virus Activity of Euphorbia schimperi and Its Quercetin and Kaempferol Derivatives.

Natural or plant products, because of their structural diversity, are a potential source for identifying new anti-hepatitis B virus (HBV) agents. Here, we report the anti-HBV activity of Euphorbia schimperi and its quercetin (QRC) and kaempferol derivatives. The anti-HBV-active methanol fraction of E. schimperi was subjected to chromatographic techniques, leading to isolation of three flavonols, following their structure determination by 1H and 13C NMR spectroscopies. Their cytotoxicity and anti-HBV potential were assessed using HBV reporter HepG2.2.15 cells, and their modes of action were delineated by molecular docking. The isolated compounds identified as quercetin-3-O-glucuronide (Q3G), quercetin-3-O-rhamnoside (Q3R), and kaempferol-3-O-glucuronide (K3G) were non-cytotoxic to HepG2.2.15 cells. The viral HBsAg/HBeAg production on day 5 was significantly inhibited by K3G (∼70.2/∼73.4%), Q3G (∼67.8/∼72.1%), and Q3R (∼63.2%/∼68.2%) as compared to QRC (∼70.3/∼74.8%) and lamivudine (∼76.5/∼84.5%) used as standards. The observed in vitro anti-HBV potential was strongly supported by in silico analysis, which suggested their structure-based activity via interfering with viral Pol/RT and core proteins. In conclusion, this is the first report on the anti-HBV activity of E. schimperi-derived quercitrin-3-O-glucuronide, quercitrin-3-O-rhamnoside, and kaempferol-3-O-glucuronide, most likely through interfering with HBV proteins.

New terpenic and phenolic compounds from Suaeda monoica reverse oxidative and apoptotic damages in human endothelial cells.

Elevation in hyperglycemia-associated methylglyoxal level can trigger vascular endothelial cells oxidative stress and apoptosis. The present work assesses the cell proliferative, anti-oxidative and anti-apoptotic potential of Suaeda monoica derived four new terpenes: a norsesquaterpenol (normonisesquaterpenol), a monocyclic triterpenoid (suaedanortriterpene dione), an aromatic monoterpenic ester and a labdane-type norditerpenic xyloside as well as two new phenols: an alkylated ß-naphthol and a ß-methoxy naphthalene in cultured human umbilical vein endothelial cells (HUVEC). Of these, suaedanortriterpenedione (53.7%), normonisesquaterpenol (51.4%) and norditerpenic xyloside (48%) showed the most promising cell proliferative activities compared to others. Moreover, normonisesquaterpenol, norditerpenic xyloside and suaedanortriterpenedione efficiently reversed the oxidative and apoptotic cell damage via downregulation of capase-3/7 by 44.3%, 42.2% and 39.4%, respectively against dichlorofluorescin, whereas by 46.2%, 43.5% and 42.5%, respectively against methylglyoxal. Aminoguanidine, the reference drug inhibited caspase-3/7 activity by 56.2% and 54.7% through attenuation of dichlorofluorescin and methylglyoxal, respectively. Further in silico molecular docking analysis revealed formation of stable complexes between the tested compounds and caspase-3/7. Conclusively, we for the first time demonstrate the growth stimulatory, anti-oxidative and anti-apoptotic salutations of S. monoica derived novel compounds in human endothelial cells. This warrants their further assessment as vascular cell protective and rejuvenating therapeutics, especially in hyperglycemic conditions.