Moderate Inhibition Research Articles

Investigating the optimistic in-vitro and in-vivo therapeutic effects of wild grape: Vitis jacqumantii R. Parker

Vitis jacquemontii R. Parker is a wild grape traditionally used by indigenous people as a substitute for cultivated grapes. However, its therapeutic effects have not been extensively studied. In this study, we investigated the antioxidant, anticholinesterase, analgesic, and antidepressant properties of V. jacquemontii. The antioxidant potential of this wild fruit plant was evaluated using two widely recognized assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-asino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). In-vitro anticholinesterase effects were determined by assessing butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibition. The analgesic activity was assessed through writhing and tail immersion test models, while the antidepressant effect was evaluated using forced swimming and tail suspension test models. Results revealed the exceptional potential of V. jacquemontii as a valuable natural resource. The fruit extract (VJF-Crd) demonstrated remarkable free radical scavenging abilities, with an impressive IC50 value of 34.96 μg/mL for DPPH and 56.48 μg/mL for ABTS. The leaf extract (VJL-Crd) also exhibited considerable antioxidant properties, with IC50 values of 73.68 μg/mL for DPPH and 86.72 μg/mL for ABTS. Furthermore, VJF-Crd and VJL-Crd extracts displayed potent inhibitory activity against cholinesterase enzymes, with VJF-Crd demonstrating strong inhibition and VJL-Crd showing moderate inhibition. In terms of analgesia, these extracts exhibited dose-dependent responses in various pain models, with significant protection against acetic acid-induced writhing and tail immersion, showcasing their potential as natural pain relievers. Moreover, both VJF-Crd and VJL-Crd extracts displayed a notable decrease in immobility in the forced swimming and tail suspension test models, indicating their potential as natural antidepressants. These findings underscore the untapped potential of V. jacquemontii as a source of valuable chemical constituents. The isolation and identification of phyto-constituents from this plant hold promise for new bioactive compounds, particularly in pain management. This study sheds light on the multifaceted medicinal attributes of V. jacquemontii and opens new avenues for developing natural remedies for different ailments, especially pain management.

Dizocilpine derivatives as neuroprotective NMDA receptor antagonists without psychomimetic side effects

We aimed to prepare novel dibenzo[a,d][7]annulen derivatives that act on N-methyl-D-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (∼90% for GluN1/GluN2A), while 3l showed moderate inhibition (∼50%). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound 3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo[a,d][7]annulen derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.

Clinical and Physiologically Based Pharmacokinetic Model Evaluations of Adagrasib Drug-Drug Interactions.

Adagrasib is a potent, highly selective, orally available, small molecule, covalent inhibitor of G12C mutated KRAS. As both a substrate and strong inhibitor of cytochrome P450 (CYP) 3A4, adagrasib inhibits its own CYP3A4-mediated metabolism following multiple dosing, resulting in time-dependent drug-drug interaction (DDI) liabilities. A physiologically-based pharmacokinetic (PBPK) model was developed and verified using a combination of physicochemical, in vitro and clinical pharmacokinetic (PK) data from healthy volunteers and cancer patients. The PBPK model well-described the single and multiple-dose adagrasib PK data as well as DDI data with itraconazole, rifampin, midazolam, warfarin, dextromethorphan, and digoxin, with model predictions within 1.5-fold of the observed clinical data. The PBPK model was used to predict untested scenarios including the clinical victim and perpetrator DDI liabilities at the approved dosing regimen of 600 mg twice daily (b.i.d.) in cancer patients. Strong, moderate, and weak inhibitors of CYP3A4 are predicted to have a negligible effect on the steady-state exposure of adagrasib 600 mg b.i.d. resulting from the significant inactivation of CYP3A4 by adagrasib. Additionally, strong and moderate inducers of CYP3A4 are predicted to decrease adagrasib exposure by 68% and 22%, respectively. As a perpetrator, adagrasib 600 mg b.i.d. is predicted to be a strong inhibitor of CYP3A4, a moderate inhibitor of CYP2C9 and CYP2D6, and an inhibitor of P-glycoprotein (P-gp). These results successfully supported regulatory interactions with the United States Food and Drug Administration regarding dosing recommendations for when adagrasib is used concomitantly with other medications, supporting a range of label claims in lieu of clinical trials.

Features of eyelid microcirculation in chronic mixed blepharitis and type 2 diabetes mellitus

BACKGROUND: Microcirculatory dysfunction in patients with diabetes mellitus leads to tissue trophic insufficiency, reduction of adaptation reserves. It is possible to perform lifetime assessment of structural and functional changes in the microcirculation system by laser Doppler flowmetry. The presence of microcirculatory disorders is established in eyelids in chronic blepharitis and meibomian gland dysfunction. The article presents the results of the study concerning the peculiarities of neoangiogenesis as a mechanism of development of chronic blepharitis and meibomian gland dysfunction in diabetes mellitus (DM).AIM: to reveal the peculiarities of microcirculatory disorders of the eyelid in chronic mixed blepharitis in patients with type 2 diabetes mellitus (T2DM).MATERIALS AND METHODS: The study was conducted in 57 patients: 37 patients with chronic mixed bilateral blepharitis and a verified diagnosis of T2DM (group 1, n=74 eyes, average age 69.5 ± 7.5 years; subgroup 1a, n=38 eyes — patients with T2DM and glycated hemoglobin average level (HbA1с) 6.7±1.2; subgroup 1b, n=36 eyes — patients with T2DM and HbA1с average level 8.2±1.3) and 20 patients with chronic mixed bilateral blepharitis without signs of DM (group 2, n=40 eyes, mean age 67.2±4.3 years). Laser Doppler flowmetry was performed on the device «LAZMA MC-1».RESULTS: In patients with chronic blepharitis against the background of T2DM the development of ischemia of the eyelid tissue with increasing tension of functioning of the regulatory systems of microcirculation blood flow and lymph flow was detected, and in persons without DM — venous stasis with moderate inhibition of vasomotor, respiratory and dominance of cardiac oscillations of blood flow, as well as insufficiency of neurogenic oscillations of lymph flow. In this case in 1a subgroup the dominance of neurogenic oscillations of blood flow was revealed, in 1b - myogenic. Microcirculatory changes of lymph flow in the 1b subgroup were more pronounced in comparison with the 1a subgroup.CONCLUSION: The results proves the negative influence of T2DM on the microcirculatory bed of patients with chronic mixed blepharitis. The disorders detected by laser Doppler flowmetry vary depending on the HbA1с.

A botanical nanoemulsion against phytopathogenic fungi Colletotrichum sp. and Fusarium oxysporum: Preparation, in vitro and in vivo bioassay

A botanical nanoemulsion (NE) comprised of cinnamaldehyde (from Cinnamomum cassia oil) and annonaceous acetogenin (AAs) (from Annona squamocin seeds extract) was fabricated using sonication. The nanoemulsion was tested for their in vitro and in vivo antifungal activity against Colletotrichum sp. and Fusarium oxysporum the disease-causal agents in fruit and vegetable crops. The best average of nanoemulsion hydrodynamic diameter was 245.3 nm, and the polydispersity index (PI) was 0.499 based on DLS measurement. Zeta potential of the nanoemulsion was determined to be −44.2 mV, indicating the stability of the droplets. In vitro antifungal bioassay of the nanoemulsion showed the best inhibition against Colletotrichum sp. by 53.9 % when tested at a dilution rate of 1:100 (v/v). For F. oxysporum, the nanomaterial also inhibited mycelial growth by 91.6 % at the same dilution rate. When tested at dilution rates of 1:200 and 1:400 (v/v), the nanoemulsions caused moderate and weak inhibitions from 30.9 % to 52.8 % for all fungi. In vivo experiment, the nano-emulsion at 1:200 (v/v) dilution demonstrated an antifungal efficacy of 57.1 % (after 4 days) and 49.6 % (after 7 days) of testing. Besides, the mechanism of action has also been elucidated through molecular interaction models between the main compounds with eburicol 14α-demethylase. Our research indicates that botanical nanoemulsion containing cinnamon oil and AAs have a remarkable potential to suppress phytopathogenic fungi and prevent the spread of fungal diseases in tropical fruits and vegetables such as tomato and other crops of Solanaceae family.

Pharmacological screening of anti-inflammatory potential of polyherbal extract

Inflammation is the immune response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation and acts by removing injurious stimuli and initiating the healing process. Inflammation is therefore a defense mechanism that is vital to health. Usually, during acute inflammatory responses, cellular and molecular events and interactions efficiently minimize impending injury or infection. Current herbal medicine has been found effective with minimal or no side effect.Polyherbal extract of plants which contains curcumin, withanolides, withanoferins, linoleic acid are the active constituents responsible for Anti-inflammatory effect. Extraction of the plant material was done to obtain extract and further proceed for physical characterization and phytochemical analysis. TLC was done to confirm the active constituents present in polyherbal with reference to standard. The polyherbal extract was compared with standard to evaluate the anti-inflammatory by in-vitro assessment of Bovine albumin fraction and Protein denaturation assay. The percentage yield of extracts were found to 66.7, 74.2, 63.7.The R value of polyherbal extract was found to be 0.82 which matches with the standard and hence presence of curcumin, withanolides, withanoferins, linoleic acid was confirmed. The dose dependent study and statistical comparison with the help of graph pad prism, version 9.03 by one way ANOVA followed by dunnett’s multiple comparison test has revealed that moderate inhibition (p≤0.05) is observed in albumin and protein denaturation treated with Polyherbal extract when compared with standard Diclofenac sodium and hence the Anti-inflammatory effect of Polyherbal extract is justified.

Nifedipine May Be an Inhibitor of Clozapine Metabolism, as Seen in 5 Patients: 2 from a US Double-Blind Study and 3 from a German TDM Study

Background: Clozapine is the only licensed antipsychotic for treatment-refractory schizophrenia. Therapeutic drug monitoring (TDM) refers to the measurement of clozapine concentration. Clozapine TDM can be used to optimize treatment, particularly by identifying pharmacokinetic interactions between clozapine and comedications. Methods: We identified 5 cases of patients with available clozapine concentrations who were concomitantly receiving nifedipine and clozapine. These cases were drawn from 2 independent datasets: 2 from a double-blind, randomized clinical trial in the United States and 3 from a German TDM naturalistic database. As an index of clozapine clearance, we used the trough-level concentration-to-dose (C/D) ratios to estimate the minimum therapeutic doses. To estimate dose-correction factors for nifedipine treatment, we included only clozapine concentrations at steady state. We divided the clozapine minimum therapeutic doses (MTD) from the on-condition by the off-nifedipine condition. Results: In 4 patients, the ratio of on/off nifedipine for MTD ranged between 0.58 and 0.82. Another patient had no data and had to be compared with published control data (female smoker of African ancestry), providing a correction factor of 0.52 after eliminating 5 concentrations contaminated by the development of obesity. Conclusions: In the absence of access to TDM, when prescribing nifedipine to clozapine-treated patients, we recommend reducing the daily dose of clozapine by one-third because of the weak inhibition of clozapine metabolism. With access to TDM, TDM should guide dosing as unusual patients may need larger dose reductions, as it is possible that in some patients, nifedipine may be a moderate inhibitor requiring halving clozapine dose. Further prospective studies are warranted.

Peroxydisulfate Activation by Biochar from Banana Peel Promoted with Copper Phosphide for Bisphenol S Degradation in Aqueous Media

In this work, the decomposition of bisphenol S (BPS) by biochar derived from banana peel (BPB) promoted by copper phosphide (Cu3P) was examined. Different materials with Cu3P loadings from 0.25 to 4.00 wt.% on biochar were synthesized, characterized using the Brunauer–Emmett–Teller (BET) method, X-ray diffraction (XRD) and a scanning electron microscope (SEM) equipped with an energy dispersive spectrometer (EDS), and evaluated. Nearly all of the synthesized materials exhibited low to moderate adsorption capacity, attributable to their limited surface area (<3.1 m2/g). However, in the presence of sodium persulfate (SPS), the 2%Cu3P/ΒPB/SPS system was capable of removing 90% of 500 μg/L BPS in less than 10 min. The system’s performance was enhanced under inherent pH, and the reaction rate followed pseudo-first-order kinetics with respect to BPS and persulfate concentrations. Interestingly, the presence of 250 mg/L of sodium chloride had a negligible effect, while low to moderate inhibition was observed in the presence of bicarbonates and humic acid. In contrast, significant retardation was observed in experiments performed in real matrices, such as secondary effluent (WW) and bottled water (BW). According to scavenging experiments, both radical and non-radical mechanisms participated in the BPS degradation. Four transformation products were identified using the UHPLC/TOF-MS system in negative ionization mode, with two of them having higher molecular weights than BPS, while the other two TBPs involved the ring-opening reaction, and a BPS decomposition pathway was proposed.

Inhibition of Human Salivary and Pancreatic α-Amylase by Resveratrol Oligomers.

A key strategy to mitigate postprandial hyperglycemia involves inhibiting α-amylases, which commence the starch digestion process in the gut. This study examined the inhibitory effects of resveratrol and stilbenoid tetramers, vaticanol B, (-)-hopeaphenol, and vatalbinoside A on human salivary and pancreatic α-amylases experimentally and through molecular docking studies. Vaticanol B demonstrated the most potent inhibition with IC50 values of 5.3 ± 0.3 μM for salivary and 6.1 ± 0.5 μM for pancreatic α-amylase (compared to acarbose with IC50 values of 1.2 ± 0.1 μM and 0.5 ± 0.0 μM, respectively). Kinetic analysis suggested a competitive inhibition mode for vaticanol B. Resveratrol and vatalbinoside A were poor inhibitors of human α-amylases, while (-)-hopeaphenol exhibited moderate inhibition. Molecular docking supported the inhibition data, and several aspects of the structural configurations explained the stronger inhibition exerted by vaticanol B. Overall, vaticanol B shows promise as a natural alternative to acarbose for inhibiting α-amylase.

Structurally Diverse Duclauxins from a Coral-Derived Talaromyces sp. and Insight into Determining the Configuration at C-1 of Heptacyclic Duclauxins by 1H NMR.

A chemical investigation of the coral-derived fungus Talaromyces sp. TJ403-AL05 led to the isolation of 18 duclauxin analogues (1-18), 14 of which, taladuxins A-N (1-14), are new and consist of the first example of duclauxin fused with one 1,6-dioxaspiro[4.5]decan-2-one moiety (1), as well as its biosynthetic product (2), and 12 6/6/6/5/6/6/6 heptacyclic derivatives (3-14). Comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, DP4+ probability analyses, single-crystal X-ray diffraction, and vibrational circular dichroism (VCD) calculations were employed to characterize their structures and revise the published structure of verruculosin B. An efficient 1H NMR method was established to discriminate 1R and 1S configurations at C-1 of 6/6/6/5/6/6/6 heptacyclic duclauxins according to chemical shift differences of diastereotopic methylene H2-11 or H2-12 (ΔδH-11 or ΔδH-12). Compounds 4, 7-8, 13-15, and 18 exhibited moderate inhibition of Arabidopsis thaliana 4-hydroxyphenylpyruvate dioxygenase (AtHPPD), with IC50 values ranging from 17.1 to 71.3 μM.

Hydroxydiorygmone A, a New Guaiane-Sesquiterpene from the Cultured Lichen Mycobiont of Diorygma sp

Objective: Cultured mycobiont of the Vietnamese crustose-lichen Diorygma sp. has been chemically investigated. Biological activities including cytotoxicity against HepG2 cell line, α-glucosidase inhibition, and nitric oxide inhibitory activity were evaluated. Methods: Extensive spectroscopic methods (NMR and ECD) and HRESI mass data were employed for structural elucidation. These isolates were evaluated for their cytotoxicity against HepG2 cell line, α-glucosidase inhibition, and inhibitory activity toward nitric oxide production in LPS-stimulated RAW 264.7 cells. Results: Four compounds (1–4), including a new guaiane-sesquiterpene, hydroxydiorygmone A (1), along with three known analogues, diorygmones A and B (2 and 3) and pruinosone (4), were isolated and characterized. Compound 1 showed moderate α-glucosidase inhibition with an IC50 value of 160 ± 2.2 µM and significant inhibitory activity toward nitric oxide production in LPS-stimulated RAW 264.7 cells with an IC50 value of 8.11 ± 0.21 µM. Others were inactive in α-glucosidase inhibitory and nitric oxide inhibitory tests. Conclusion: A new guaiane-sesquiterpene, hydroxydiorygmone A (1) was isolated and showed moderate α-glucosidase inhibition with an IC50 value of 160 ± 2.2 µM and significant inhibitory activity toward nitric oxide production in LPS-stimulated RAW 264.7 cells with an IC50 value of 8.11 ± 0.21 µM.

Drug-Drug Interaction Management with the Novel Anti-Cytomegalovirus Agents Letermovir and Maribavir: Guidance for Clinicians.

Letermovir and maribavir have demonstrated efficacy in the prevention and treatment, respectively, of immunosuppressed patients with cytomegalovirus (CMV) infection and disease. These patients often have polypharmacy making them at risk for drug-drug interactions. Both letermovir and maribavir can be perpetrators and victims of drug-drug interactions. Letermovir is a moderate inhibitor of CYP3A, CYP2C8 and OATP1B1/3, and a moderate inducer of CYP2C19. It is a substrate of UGT1A1/3, BCRP, P-gp and OATP1B1/3. Maribavir is a moderate CYP2C9 inhibitor and a substrate of CYP3A. Drug-drug interactions between these anti-CMV agents and a number of therapeutic classes, such as immunosuppressants, antifungal agents, and hemato-oncological agents, can have clinical consequences and deserve dose modification or close monitoring. In a number of examples, three-way drug interactions need to be assessed. The objective of this review is to provide clinicians with guidance for drug-drug interaction management, based on existing data from drug-drug interaction studies, and extrapolation to other relevant co-medications that have not (yet) been studied but that are frequently used in these patient populations.

Antifungal Activity of Citrus Essential Oil in Controlling Sour Rot in Tahiti Acid Lime Fruits.

Sour rot, caused by Geotrichum citri-aurantii, is a significant post-harvest disease in citrus, resulting in economic losses due to the lack of effective fungicides. This study investigates the antifungal activity of citrus essential oils in controlling sour rot in Tahiti acid lime fruits. Essential oils were extracted via hydrodistillation with chemical composition analyzed by CG-MS and tested in vitro and in vivo. In vitro assays evaluated mycelial growth inhibition at 2 to 32 µL mL-1 concentrations. In vivo trials involved preventive and curative treatments on artificially inoculated fruits stored at 25 °C ± 2, and the results showed that Pera IAC sweet orange oil, at 32 µL mL-1, reduced disease severity by 96% in curative treatments. In contrast, Late IAC 585 willowleaf mandarin oil demonstrated moderate inhibition (44%) at the highest concentration in vitro. The oils did not affect key fruit quality parameters such as juice yield and total soluble solids. These findings suggest that citrus essential oils could be natural alternatives to synthetic fungicides for post-harvest sour rot management, combining effectiveness with maintaining fruit quality.

Effect of Valproate Coprescription on Clozapine Pharmacokinetics in Clinical Practice

Abstract Background Sodium valproate has been coprescribed with clozapine for seizure prophylaxis and for augmentation in treatment-refractory schizophrenia. However, the effect of valproate on clozapine metabolism and on the incidence of clozapine-related side effects is unclear. Methods We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in smokers and nonsmokers of both sexes in samples submitted for clozapine therapeutic drug monitoring, 1996–2017 in relation to valproate coprescription. Results There were 1217 (665 patients) and 3823 (1600 patients) samples from nonsmokers and from smokers, respectively, who were coprescribed valproate and clozapine. Data from 9774 (5065 patients) and 15,465 (7298 patients) samples from nonsmokers and from smokers, respectively, for whom drugs other than valproate were coprescribed were used as controls. Valproate coprescription in nonsmokers was associated with an increase in average plasma clozapine of 22.5%, suggesting moderate inhibition of clozapine metabolism, but there was no marked effect of valproate coprescription on plasma clozapine in smokers. In all the valproate-treated groups (male and female smokers and nonsmokers), the median plasma norclozapine concentration and the median plasma clozapine-to-norclozapine ratio were significantly lower and higher, respectively, as compared with the controls. Mixed-effects models showed a significant dose-response effect of valproate on lowering the plasma norclozapine concentration and on increasing the plasma clozapine-to-norclozapine ratio. Implications Given the complexity of the effect of valproate coadministration on clozapine pharmacokinetics and the possibility that the toxicity of clozapine may be enhanced in the presence of valproate, the use of these drugs in combination must now be questioned in all patients and not only in women of childbearing age.

Anti-diabetic and anti-inflammatory activities of Marrubiin isolated from Marrubium vulgare: Indications of its interaction with PPAR γ

BackgroundThe aerial parts of Marrubium vulgare L. were used for many ailments like catarrh to diabetes in many parts of Latin America and Asia. PurposeIdentifying the active principle responsible for anti-diabetic activity of methanol extract of M. vulgare leaves and to predict the possible targets. Study designAll the activity investigations were conducted simultaneously for the extract, fraction, and isolated compounds to decipher the activity profile in comparison to each other which allowed the identification of an active principle followed by use of in silico methods to identify the possible target/s. MethodsThe aerial parts of M. vulgare were extracted using methanol. A chloroform fraction was prepared. Marrubiin and marrubinone B were isolated from this fraction. The anti-hyperglycemic, hypoglycemic, and postprandial blood glucose lowering activities were investigated using streptozotocin-induced diabetic and non-diabetic rat models. Pro-inflammatory cytokine inhibitory potential was investigated using LPS induced acute-inflammatory mouse model and RAW 264.7 cells. Further, antioxidant activity was investigated using a DPPH assay. The in silico analysis, using the Swiss-target prediction tool, was carried out to predict the probable targets of the isolated molecules. ResultsMarrubiin exhibited anti-hyperglycemic effect in diabetic rats followed by hypoglycemia, and postprandial blood glucose lowering in non-diabetic rats. Methanol extract (Mv extract) and chloroform fraction (Mv fraction) showed anti-hyperglycemic and hypoglycemic effects. Moderate inhibition of IL-1β, TNF-α, and IL-6 was observed for marrubiin, marrubinone B, Mv extract, and Mv fraction, in vitro and in vivo. Neither marrubiin nor marrubinone B could quench the DPPH free radicals while Mv extract and Mv fraction could show 80 % suppression. In silico analysis has predicted that marrubiin can interact with PPAR γ but not marrubinone B. ConclusionsMarrubiin and marrubinone B were responsible for the anti-inflammatory effect of Mv extract and Mv fraction while not contributing to the antioxidant effect. Marrubiin was found to be responsible for the anti-diabetic activity of Mv extract. The predicted interaction propensity of marrubiin with PPAR γ could explain its dual activity observed in the experimental setup.

Anti-dengue viral activity of Glycyrrhiza glabra roots in Vero cells

Despite being a global public health problem, there are no antiviral agents for dengue. Plants are the sources of most approved drugs and many phytochemicals have exhibited in vitro antiviral activity. We explored the antiviral potential of the aqueous extract of Glycyrrhiza glabra roots (GGaq) on dengue viruses. Plaque reduction antiviral assay for half maximal inhibitory concentrations (IC50) was done in Vero cells infected with dengue serotypes 1–4 and exposed to varying concentrations of GGaq. Half-maximal cytotoxic concentration (CC50) of the GGaq was 651.9 µg/mL. The IC50 of the four dengue serotypes (10–50 µg/mL) indicated moderate inhibition by GGaq. 98–100% inhibition of all dengue serotypes was seen with GGaq at the maximum nontoxic dose. Preparative thin layer chromatography of GGaq, isolated sub fractions E and F which had low to moderate antiviral activity (IC50 12.65–85.95 and IC50 13.14–69.27 respectively). They exhibited good therapeutic potential only for dengue serotype-4. Virus adsorption to cells was significantly inhibited by GG (50%) and sub fraction E (24.9%). Chloroquine diphosphate was used as the positive control in all assays. The aqueous extract of GG was non-toxic and had better antiviral activity than sub fractions E and F.

Control of fungal diseases of tomato (<i>Lycopersicum esculentum</i> Mill) fruits using various plant extracts

Plant harmful fungi induce symptoms of illnesses that significantly impair the quantity and quality of tomato (Lycopersicum esculentum) yields. The high-water composition of tomatoes renders it highly vulnerable to fungal decay. These fungi, responsible for the decay of tomatoes, generate mycotoxins that pose serious risks to human health. Thus, this research goal is to separate, characterize, and classify the fungi linked with the decline of tomato produce sold across four markets in Mkpat Enin and Ikot Abasi Local Government Areas of Akwa Ibom State, Nigeria. Among the fungal pathogens extracted from afflicted tomato fruits were Fusarium moniliformes, Rhizopus stolonifera, and Aspergillus alternata. Different concentrations of the extracts were individually introduced into Potato Dextrose Agar media. The fungal pathogens were at that point individually introduced into the media and left to incubate for 7 days. Findings revealed that P < 0.05 suppressed the mycelial evolution of the fungal pathogens at a greater concentration tested, with the extent of inhibition varying among different extracts. The results concerning the proportion inhibition of plant extracts on different fungus indicated that, at concentrations ranging from 40% to 80%, ethanolic extracts derived from Cola acuminata and Zingiber officinale significantly (p<0.05) restrained the growth of F. moniliformes, R. stolonifera, and A. alternata. Specifically, the ethanolic leaf extract of C. acuminata demonstrated moderate inhibition on A. alternata at 60%, while the ethanolic extract of Zingiber officinale exhibited low inhibition on F. moniliformes at 40%. At a concentration of 60% in ethanolic extracts, F. moniliformes experienced the greatest inhibition among the plant extracts, whereas A. alternata displayed the least inhibition. Pathogenicity testing indicated that Aspergillus alternata exhibited the largest decay of 25mm in diameter in a healthy tomato fruit, while Rhizopus stolonifera had the smallest decay diameter. Thus, to cover the ledge life of tomato fruits, therefore there’s adequate need to implement proper handling techniques and utilize adequate storage facilities.

Development of a Novel 99mTc-Labeled Folate Derivative Containing Phenyl Isonitrile to Target Folate Receptor with Reduced Renal Uptake.

The folate receptor has attracted much attention in the field of radiolabeled imaging agents due to the significant difference in its expression levels between tumor cells and most normal cells. However, the development of folate-based imaging agents has been limited by their high uptake in the kidney. In this study, to reduce the high renal uptake of radiolabeled folate-based tracers, a phenyl-isonitrile folate derivative (CNMBFA) was designed and labeled with technetium-99m. The complex obtained via the one-step kit labeling method had a high labeling yield (>95%) and high in vitro stability and hydrophilicity (log D7.4 = -1.72 ± 0.13). The results of the in vitro cell uptake and blocking studies and competitive binding experiments revealed that the [[99mTc]Tc-(CNMBFA)6]+ complex was specific for the folate receptor. Biodistribution and inhibition studies in KB tumor-bearing mice revealed moderate uptake and significant inhibition of the complex in tumors, whereas the renal uptake of [[99mTc]Tc-(CNMBFA)6]+ was significantly lower than that of previously reported tracers. Micro-SPECT/CT images further supported its ability to target the folate receptor for tumor imaging. Taken together, these results indicate that [[99mTc]Tc-(CNMBFA)6]+ is a potential tumor imaging agent that has good tumor-targeting properties with minimal radiation damage to the kidney.

Long-term reprogramming of primed microglia after moderate inhibition of CSF1R signaling.

In acute neuroinflammation, microglia activate transiently, and return to a resting state later on. However, they may retain immune memory of such event, namely priming. Primed microglia are more sensitive to new stimuli and develop exacerbated responses, representing a risk factor for neurological disorders with an inflammatory component. Strategies to control the hyperactivation of microglia are, hence, of great interest. The receptor for colony stimulating factor 1 (CSF1R), expressed in myeloid cells, is essential for microglia viability, so its blockade with specific inhibitors (e.g. PLX5622) results in significant depletion of microglial population. Interestingly, upon inhibitor withdrawal, new naïve microglia repopulate the brain. Depletion-repopulation has been proposed as a strategy to reprogram microglia. However, substantial elimination of microglia is inadvisable in human therapy. To overcome such drawback, we aimed to reprogram long-term primed microglia by CSF1R partial inhibition. Microglial priming was induced in mice by acute neuroinflammation, provoked by intracerebroventricular injection of neuraminidase. After 3-weeks recovery, low-dose PLX5622 treatment was administrated for 12 days, followed by a withdrawal period of 7 weeks. Twelve hours before euthanasia, mice received a peripheral lipopolysaccharide (LPS) immune challenge, and the subsequent microglial inflammatory response was evaluated. PLX5622 provoked a 40%-50% decrease in microglial population, but basal levels were restored 7 weeks later. In the brain regions studied, hippocampus and hypothalamus, LPS induced enhanced microgliosis and inflammatory activation in neuraminidase-injected mice, while PLX5622 treatment prevented these changes. Our results suggest that PLX5622 used at low doses reverts microglial priming and, remarkably, prevents broad microglial depletion.

Inhibitory Effects of Mangifera indica Secondary Metabolites and Their Synthetic Derivatives against SARS-CoV-2 Mpro and NS2B/NS3 (ZIKV and DENV-2).

Chemical studies of Mangifera indica twigs yielded two compounds, identified as taraxerol (1) and methyl gallate (2). The galloyl moiety was suggested as a potential scaffold that can interfere with proteases by previous biological investigations on SARS-CoV-2 main protease (Mpro) inhibitors in combination with docking studies. Therefore, a series of 13 gallate esters were prepared by treating gallic acid with natural and non-natural alcohols. Their inhibitory effects were evaluated against Mpro and NS2B/NS3 of Zika and Dengue viruses. Among the obtained compounds, 2e and 2i were the most potent against Mpro with IC50 values of 2.60 and 4.0 μM, respectively. Compounds 2f and 2g were more potent than others against ZIKV protease with IC50 values of 2.7 and 1.9 μM, respectively. The bioactivity profile against DENV NS2B/NS3 was different with 2e and 2f showing moderate inhibition with IC50 values of 66.0 and 59.29 μM, respectively. It was found that 2f and 2g inhibited ZIKV NS2B/NS3 via a noncompetitive mechanism. The study also showed that 2e and 2f could exert noncompetitive inhibition at the previously described allosteric pocket of flaviviral NS2B/NS3 proteases. Molecular docking revealed different types of interactions among the most prominent were hydrogen bonding with the galloyl moiety.