Diverse structural reactivity patterns of a POCOP ligand with coinage metals.

We have utilised the 4,6-di-tert-butyl resorcinol bis(diphenylphosphinite) (POCOP) ligand for exploring its coordination ability towards group 11 metal centres. The treatment of the bidentate ligand 1 with various coinage metal precursors afforded a wide range of structurally diverse complexes 2-12, depending upon the metal precursors used. This furnishes several multinuclear Cu(I) complexes with dimeric (2) and tetrameric cores (3, 4, and 5). The tetrameric stairstep complex 4 shows thermochromic behaviour, whereas the dimeric complex 2 and tetrameric complex 3 show luminescence properties at cryogenic temperatures. Interestingly, the halide substitution reaction of the dimeric complex 2 with KPPh2 produces a unique mixed phosphine-based tetrameric Cu(I) complex, 5. Treatment of the POCOP ligand with [CuBF4(CH3CN)4] in the presence of 2,2'-bipyridine afforded heteroleptic complex 6, consisting of tri- and tetra-coordinated cationic Cu(I) centres. Furthermore, we could also isolate cubane (8) and stairstep (9) complexes of Ag(I). The cationic Au(I) complex (12) was obtained from the dinuclear Au(I) complex of POCOP, 11. Complex 12 revealed the presence of a strong intramolecular aurophilic interaction with an Au⋯Au bond distance of 3.1143(9) Å. Subsequently, the photophysical properties of these complexes have been studied. All the complexes were characterised by single-crystal X-ray diffraction studies, routine NMR techniques, and mass spectroscopy.

Machine learning and traditional QSAR modeling methods: a case study of known PXR activators.

Pregnane X receptor (PXR), extensively expressed in human tissues related to digestion and metabolism, is responsible for recognizing and detoxifying diverse xenobiotics encountered by humans. To comprehend the promiscuous nature of PXR and its ability to bind a variety of ligands, computational approaches, viz., quantitative structure-activity relationship (QSAR) models, aid in the rapid dereplication of potential toxicological agents and mitigate the number of animals used to establish a meaningful regulatory decision. Recent advancements in machine learning techniques accommodating larger datasets are expected to aid in developing effective predictive models for complex mixtures (viz., dietary supplements) before undertaking in-depth experiments. Five hundred structurally diverse PXR ligands were used to develop traditional two-dimensional (2D) QSAR, machine-learning-based 2D-QSAR, field-based three-dimensional (3D) QSAR, and machine-learning-based 3D-QSAR models to establish the utility of predictive machine learning methods. Additionally, the applicability domain of the agonists was established to ensure the generation of robust QSAR models. A prediction set of dietary PXR agonists was used to externally-validate generated QSAR models. QSAR data analysis revealed that machine-learning 3D-QSAR techniques were more accurate in predicting the activity of external terpenes with an external validation squared correlation coefficient (R2) of 0.70 versus an R2 of 0.52 in machine-learning 2D-QSAR. Additionally, a visual summary of the binding pocket of PXR was assembled from the field 3D-QSAR models. By developing multiple QSAR models in this study, a robust groundwork for assessing PXR agonism from various chemical backbones has been established in anticipation of the identification of potential causative agents in complex mixtures.

Resource Document on Best Practices in Synchronous Videoconferencing-Based Telemental Health.

Background: This document represents an updated collaboration between the American Psychiatric Association (APA) and the American Telemedicine Association (ATA) to create a consolidated update of the previous APA and ATA official documents and resources in telemental health, to provide a single guide on clinical best practices for providing mental health services through synchronous videoconference. Methods: A joint writing committee drawn from the APA Committee on Telepsychiatry and the ATA TMH Special Interest Group (TMH SIG). was convened to draft and finalize the guidelines. This document draws directly from the 2018 APA/ATA guide and the ATA s previous guidelines, selecting from key statements/guidelines, consolidating them across documents, and then updating them where indicated. Guideline approval was provided following internal review by the APA, the ATA, the Board of Directors of the ATA, and the Joint Reference Committee of the APA. Results: The guidelines contain requirements, recommendations, and actions that are identified by text containing the keywords "shall," "should," or "may." Conclusions: Compliance with these recommendations will not guarantee accurate diagnoses or successful outcomes. The purpose of this guide is to assist providers in providing effective and safe medical care founded on expert consensus, research evidence, available resources, and patient needs.

Capsiate-Rich Fraction of Capsicum annuum Induces Muscular Glucose Uptake, Ameliorates Rosiglitazone-Induced Adipogenesis, and Exhibits Activation of NRs Regulating Multiple Signaling Pathways.

Capsiate is a key ingredient in the fruits of a nonpungent cultivar of Capsicum annuum. We investigated the effects of a C. annuum extract (CE) and a capsiate-rich fraction of CE (CR) on nuclear receptors involved in multiple signaling pathways, glucose uptake, and adipogenesis in comparison to pure capsiate (Ca). Similar to the effect of Ca (100 µM), CE (500 µg/mL) and CR (100 µg/mL) caused the activation of PPARα and PPARγ (>3-fold), while CR also activated LXR and NRF2 (>2 fold). CR (200 µg/mL) and Ca (100 µM) decreased lipid accumulation (22.6 ± 14.1 and 49.7 ± 7.3%, respectively) in adipocytes and increased glucose uptake (44.7 ± 6.2 and 30.1 ± 12.2%, respectively) in muscle cells and inhibited the adipogenic effect induced by rosiglitazone by 41.2 ± 5.6 and 13.9 ± 4.3%, respectively. This is the first report to reveal the agonistic action of CR and Ca on multiple nuclear receptors along with their enhanced glucose uptake and antiadipogenic effects. The results indicate the potential utility of the capsiate-rich fraction of C. annuum in alleviating the symptoms of metabolic syndrome and in preventing the undesired adipogenic effects of full PPARγ agonists such as rosiglitazone.

Prevalence and pattern of refractive errors among school-going children in district Baramulla, Kashmir: A cross sectional study.

PURPOSE: Uncorrected refractive error is one of the most important causes of visual impairment worldwide. Addressing childhood vision impairment (VI) is one of the main goals of the World Health Organization (WHO) to combat blindness strategies. OBJECTIVE: To ascertain the prevalence and pattern of refractive errors among children aged 10 to 16 years in Baramulla district, Kashmir. METHODS: A cross-sectional study was carried out among 680 school children during an eye camp under the school health program of the national program for control of blindness. The screening was conducted in four schools in Baramulla district, Kashmir. The schools were selected using the non-probability convenient sampling technique. RESULTS: A total of 680 school children from classes sixth to tenth aged 10-16 years participated in the study. Out of 680 students, 545 (80%) had normal vision, 97 (14%) had impaired visual acuity ranging between 6/9 and 6/24, and 38 (6%) had severe VI ranging from 6/36 to 6/60. Among the various types of refractive errors, myopia was the most prevalent affecting 54 children. Age distribution of refractive errors showed myopia to be more prevalent in the age group 13-14 years (16, 14 cases), hypermetropia was more prevalent in the age group 14-15 years (10, 8 cases), and astigmatism 5 cases in the age group 14-15 years. CONCLUSION: The study provides useful and baseline data about the refractive error amongst the school children of the Baramulla district. A larger study needs to be conducted in all schools of the state to get a clear picture of RE and other eye-related problems to detect vision problems earlier.

Chemical Profiles and Cytotoxic Activities of Essential Oils from Six Species of Baccharis Subgenus Coridifoliae (Asteraceae).

Several Baccharis species are popularly known in traditional medicine as "carquejas", "vassouras", "ervas-santas" and "mio-mios", and are used as anti-inflammatories, digestives, and diuretics. This study aimed to investigate the chemical compositions and cytotoxic activities of essential oils (EOs) of six Baccharis species belonging to subgenus Coridifoliae, namely B. albilanosa, B. coridifolia, B. erigeroides, B. napaea, B. ochracea, and B. pluricapitulata. GC/MS analyses of the EOs showed that the oxygenated sesquiterpenes spathulenol (7.32-38.22 %) and caryophyllene oxide (10.83-16.75 %) were the major components for all the species. The EOs of almost all species were cytotoxic against cancer (BT-549, KB, SK-MEL and SK-OV-3) and normal kidney (VERO and LLC-PK1) cell lines, whereas B. erigeroides EO showed cytotoxicity only against LLC-PK1. This article augments the current knowledge about the chemical-biological properties of Baccharis subgenus Coridifoliae and discusses the therapeutic potentials of these economically unexploited plants.

Juniper Berries Regulate Diabetes and Obesity Markers Through Modulating PPARα, PPARγ, and LXR: In Vitro and In Vivo Effects.

The berries of Juniperus communis have been traditionally used for therapeutic purposes. They have been reported to possess various pharmacological effects such as anti-inflammatory, hypoglycemic and hypolipidemic activities. In this study, a methanolic extract of J. communis berries (JB) was evaluated for its effects on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake and lipid accumulation using various cellular systems. At a concentration of 25 µg/mL, JB caused 3.77-fold activation of PPARα, 10.90-fold activation of PPARγ, and 4.43-fold activation of LXR in hepatic cells. JB inhibited (11%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (90%) in muscle cells. In high-fat diet (HFD) fed mice, JB at a dose of 25 mg/kg body weight exhibited a 21% decrease in body weight. Fasting glucose levels in mice treated with 12.5 mg/kg of JB were significantly decreased (39%) indicating its efficacy in regulating hyperglycemia and obesity induced by HFD thus ameliorating the symptoms of type 2 diabetes. A series of energy metabolic genes, including Sirt1 (2.00-fold) and RAF1 (2.04-fold), were upregulated by JB, while rosiglitazone regulated the hepatic PPARγ only. Phytochemical analysis of JB indicated presence of a number of flavonoids and biflavonoids which seem to be responsible for the observed activity. It was concluded that JB acted as a multiple agonist of PPARα, PPARγ and LXR without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. The regulation of PPARα, PPARγ and LXR seems to be through Sirt1 and RAF1. In vivo results confirmed the antidiabetic and antiobesity potential of JB and indicated its utility in metabolic disorder and type 2 diabetes.

Is Baikiain in Tara Flour a Causative Agent for the Adverse Events Associated with the Recalled Frozen French Lentil & Leek Crumbles Food Product? - A Working Hypothesis.

The French Lentil & Leek Crumbles frozen food product was recently recalled due to reports of gastrointestinal issues. So far, 393 adverse illness complaints and 133 hospitalizations have been reported from consumption of this food, and the tara (Tara spinosa) protein flour ingredient is hypothesized to be responsible. A multipronged approach resulted in identification of (S)-(-)-baikiain in tara as a compound of interest due to its abundance, possible metabolic fate, and close resemblance to irreversible inhibitors of L-pipecolate oxidase. Oral administration of baikiain in ND4 mice showed a statistically significant increase in blood ALT levels and a reduction in liver GSH.

Cannabinoid and Opioid Receptor Affinity and Modulation of Cancer-Related Signaling Pathways of Machaeriols and Machaeridiols from Machaerium Pers.

Machaeriols and machaeridiols are unique hexahydrodibenzopyran-type aralkyl phytocannabinoids isolated from Machaerium Pers. Earlier studies of machaeriol A (1) and B (2) did not show any affinity for cannabinoid receptor 1 (CB1 or CNR1), although they are structural analogs of psychoactive hexahydrocannabinol. This study comprehensively reports on the affinities of isolated Machaerium Pers. compounds, namely machaeriol A-D (1-4) and machaeridiol A-C (5-7), against cannabinoid (CB1 and CB2) and opioid (κ, δ and µ) receptors. Among the isolated compounds, machaeriol D (4) and machaeridiol A-C (5-7) showed some selective binding affinity for the CB2 receptor, using a radioligand binding assay, with Ki values of >1.3, >1.77, >2.18 and >1.1 µM, respectively. On the other hand, none of the compounds showed any binding to the CB1 receptor. Due to recent reports on the anticancer potential of the endocannabinoid system, compounds 1-7 were tested against a battery of luciferase reporter gene vectors that assess the activity of many cancer-related signaling pathways, including Stat3, Smad2/3, AP-1, NF-κB, E2F, Myc, Ets, Notch, FoxO, Wnt, Hedgehog and pTK in HeLa and T98G glioblastoma cells. Complete dose-response curves have been determined for each compound in both of these cell lines, which revealed that machaeridiol 6 displayed activities (IC50 in µM in HeLa and T98G cells) towards Stat3 (4.7, 1.4), Smad2/3 (1.2, 3.0), AP-1 (5.9, 4.2), NF-κB (0.5, 4.0), E2F (5.7, 0.7), Myc (5.3, 2.0), ETS (inactive, 5.9), Notch (5.3, 4.6), Wnt (4.2, inactive) and Hedgehog (inactive, 5.0). Furthermore, a combination study between machaeriol C (3) and machaeridiol B (6) displayed additive effects for E2F, ETS, Wnt and Hedgehog pathways, where these compounds individually were either minimally active or inactive. None of the compounds inhibited luciferase expression driven by the minimal thymidine kinase promoter (pTK), indicating the lack of general cytotoxicity for luciferase enzyme inhibition at the 50 µM concentration in both of these cell lines. The significance of the inhibition of these signaling pathways via machaeridiol 5-7 and their cross-talk potential has been discussed.

Evaluation of the Herb-Drug Interaction (HDI) Potential of Zingiber officinale and Its Major Phytoconstituents.

Ginger is currently one of the most popular herbs commonly added to diverse foods, beverages, and dietary supplements. We evaluated the ability of a well-characterized ginger extract, and several of its phytoconstituents, to activate select nuclear receptors as well as modulate the activity of various cytochrome P450s and ATP-binding cassette (ABC) transporters because phytochemical-mediated modulation of these proteins underlies many clinically relevant herb-drug interactions (HDI). Our results revealed ginger extract activated the aryl hydrocarbon receptor (AhR) in AhR-reporter cells and pregnane X receptor (PXR) in intestinal and hepatic cells. Among the phytochemicals investigated, (S)-6-gingerol, dehydro-6-gingerdione, and (6S,8S)-6-gingerdiol activated AhR, while 6-shogaol, 6-paradol, and dehydro-6-gingerdione activated PXR. Enzyme assays showed that ginger extract and its phytochemicals dramatically inhibited the catalytic activity of CYP3A4, 2C9, 1A2, and 2B6, and efflux transport capabilities of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dissolution studies with ginger extract conducted in biorelevant simulated intestinal fluid yielded (S)-6-gingerol and 6-shogaol concentrations that could conceivably exceed cytochrome P450 (CYP) IC50 values when consumed in recommended doses. In summary, overconsumption of ginger may disturb the normal homeostasis of CYPs and ABC transporters, which in turn, may elevate the risk for HDIs when consumed concomitantly with conventional medications.

Chemistry of Isoeugenol and Its Oxidation Products: Mechanism and Kinetics of Isoeugenol as a Skin Sensitizer.

Structurally similar phytochemical compounds may elicit markedly different skin sensitization responses. Eugenol and isoeugenol are natural phenylpropanoids found in various essential oils are frequently used as fragrance ingredients in consumer products due to their pleasing aromatic properties. Both compounds are also skin sensitizers with isoeugenol being a stronger sensitizer than eugenol. The most commonly accepted mechanisms for haptenation by eugenol involve formation of a quinone methide or an ortho-quinone intermediate. The mechanism for the increased skin response to isoeugenol remains elusive, although quinone methide intermediates have been proposed. The recent identification of diastereomeric 7,4'-oxyneolignans as electrophilic, thiol-depleting isoeugenol derivatives has revived interest in the possible role of elusive reactive intermediates associated with the isoeugenol's haptenation process. In the present work, integrated non-animal skin sensitization methods were performed to determine the ability of syn-7,4'-oxyneolignan to promote haptenation and activation of further molecular pathways in keratinocytes and dendritic cells, confirming it as a candidate skin sensitizer. Kinetic NMR spectroscopic studies using dansyl cysteamine (DCYA) confirmed the first ordered nature of the nucleophilic addition for the syn-7,4'-oxyneolignan. Computational studies reaffirmed the "syn" stereochemistry of the isolated 7,4'-oxyneolignans along with that of their corresponding DCYA adducts and provided evidence for the preferential stereoselectivity. A plausible rationale for isoeugenol's strong skin sensitization is proposed based on the formation of a hydroxy quinone methide as a reactive intermediate rather than the previously assumed quinone methide.

Patient and Clinician Satisfaction with the Early Implementation of Telemental Health Services in an Urban Behavioral Health Clinic During the COVID-19 Pandemic.

Objective: The COVID-19 pandemic served as an impetus for the rapid expansion of telehealth. In this study, we examined the experience of rapid transition to telemental health (TMH) within The Family Health Centers at NYU Langone, a large, urban, Federally Qualified Health Center, in the 3 months after the onset of the COVID-19 pandemic. Methods: We administered surveys to clinicians and patients who utilized TMH between March 16, 2020 and July 16, 2020. Patients were sent a web-based survey via email or received a phone survey (for those without email) with four languages choices: English, Spanish, Traditional Chinese, or Simplified Chinese. Results: The majority (79%) of clinicians (n = 83) rated the experience of TMH as "excellent" or "good," and felt that they could establish and maintain the patient relationship through TMH. Four thousand seven hundred seventy-two survey invitations were sent out to patients, and 654 (13.7%) responded. Ninety percent reported that they were satisfied with the service they received and rated TMH as better or the same as in-person care (81.6%) with a high mean satisfaction score (4.5 out of 5). Patients were more likely to rate TMH as better or the same as in-person care relative to the clinicians. Conclusions: These results are consistent with several recent studies that have explored patient satisfaction with TMH during the COVID-19 pandemic and demonstrate that both clinicians and patients experienced a high degree of satisfaction with mental health care delivered virtually compared with face-to-face encounters.

Expanding the scope of novel 1,2,3-triazole derivatives as new antiparasitic drug candidates.

We have previously shown that prenyl and aliphatic triazoles are interesting motifs to prepare new chemical entities for antiparasitic and antituberculosis drug development. In this opportunity a new series of prenyl-1,2,3-triazoles were prepared from isoprenyl azides and different alkynes looking for new antimalarial drug candidates. The compounds were prepared by copper(i) catalyzed dipolar cycloaddition of the isoprenyl azide equilibrium mixture providing exclusively 1,4-disubstituted 1,2,3-triazoles in a regiospecific fashion. The complete collection of 64 compounds was tested on chloroquine-sensitive (CQ sensitive), Sierra Leone (D6), and the chloroquine-resistant, Indochina (W2), strains of Plasmodium falciparum and those compounds which were not previously reported were also tested against Leishmania donovani, the causative agent for visceral leishmaniasis. Thirteen analogs displayed antimalarial activity with IC50 below 10 µM, while the antileishmanial activity of the newly reported analogs could not improve upon those previously reported. Compounds 1o and 1r were identified as the most promising antimalarial drug leads with IC50 below 3.0 µM for both CQ-sensitive and resistant P. falciparum strains with high selectivity index. Finally, a chemoinformatic in silico analysis was performed to evaluate physicochemical parameters, cytotoxicity risk and drug score. The validation of a bifunctional farnesyl/geranylgeranyl diphosphate synthase PfFPPS/GGPPS as the potential target of the antimalarial activity of selected analogs should be further investigated.

In Vitro Metabolism and CYP-Modulating Activity of Lavender Oil and Its Major Constituents.

The application of essential oils has historically been limited to topical (massage therapy) and inhalational (aromatherapy) routes of administration. More recently, however, evaluation of the therapeutic effects of essential oils has expanded to include the oral route of administration, which increases the herb-drug interaction potential. The purpose of this study was to evaluate the herb-drug interaction potential of lavender essential oil and two of its primary phytoactive constituents, namely linalool and linalyl acetate. The metabolic stability of linalool and linalyl acetate was determined in human liver microsomes (HLM) and S9 fractions by quantitative analysis using UPLC-MS/MS system. Linalool was metabolically unstable in HLM and S9 fractions with an intrinsic clearance of 31.28 mL·min-1·kg-1, and 7.64 mL·min-1·kg-1, respectively. Interestingly, it was observed that linalyl acetate converted to linalool both in HLM and S9 fractions. Lavender oil showed weak inhibitory effect on the catalytic activity of CYP3A4 and CYP1A2 enzymes (IC50 12.0 and 21.5 µg/mL). Linalyl acetate inhibited CYP3A4 (IC50 4.75 µg/mL) while linalool did not show any inhibitory effect on any of the enzymes. The lavender oil and its constituents did not activate PXR to a considerable extent, and no activation of AhR was observed, suggesting a lack of potential to modify the pharmacokinetic and pharmacodynamic properties of conventional medications if used concurrently.

Screening of medicinal plants for possible herb-drug interactions through modulating nuclear receptors, drug-metabolizing enzymes and transporters.

ETHNOPHARMACOLOGICAL RELEVANCE: The last three decades have witnessed a surge in popularity and consumption of herbal products. An unintended consequence of such popularity is that chronic consumption of these products can often modulate the functions of various proteins involved in drug disposition and may, in turn, impose risks for herb-drug interactions (HDIs), leading to serious adverse health outcomes. Identifying plants that may give rise to clinically relevant HDIs is essential, and proactive dissemination of such research outcomes is necessary for researchers, clinicians, and average consumers. AIM OF THE STUDY: The main objective of this study was to evaluate the HDI potential of plants commonly used as ingredients in many herbal products, including BDS. MATERIALS AND METHODS: The dried material of 123 plants selected from the NCNPR repository was extracted with 95% ethanol. The extracts were screened for agonistic effects on nuclear receptors (PXR and AhR) by reporter gene assays in PXR-transfected HepG2 and AhR-reporter cells. For cytochrome P450 enzyme (CYP) inhibition studies, CYP450 baculosomes were incubated with enzyme-specific probe substrates by varying concentrations of extracts. The inhibitory effect on the efflux transporter P-glycoprotein (P-gp) was investigated via rhodamine (Rh-123) uptake assay in P-gp overexpressing MDR1-MDCK cells. RESULTS: Out of 123 plants, 16 increased transcriptional activity of human PXR up to 4 to 7-fold at 60 µg/mL, while 18 plants were able to increase AhR activity up to 10 to 40-fold at 30 µg/mL. Thirteen plants inhibited the activity of CYP3A4, while 10 plants inhibited CYP1A2 activity with IC50 values in the range of 1.3-10 µg/mL. Eighteen plants (at 50 µg/mL) increased intracellular accumulation of Rh-123 (>150%) in MDR1-MDCK cells. Additionally, other plants tested in this study were able to activate PXR, AhR, or both to lesser extents, and several inhibited the catalytic activity of CYPs at higher concentrations (IC50 >10 µg/mL). CONCLUSIONS: The results indicate that prolonged or excessive consumption of herbal preparations rich in such plants (presented in Figs. 1a, 2a, 3a, 4a, and 5a) may pose a risk for CYP- and P-gp-mediated HDIs, leading to unwanted side effects due to the altered pharmacokinetics of concomitantly ingested medications.

Antiplasmodial and antimicrobial activities of ent-abietane diterpenoids from the roots of Suregada zanzibariensis.

The root extract of Suregada zanzibariensis Baill. afforded six previously described ent-abietane diterpenoids, namely 7-oxo-ent-abieta-5(6),8(14),13(15)-trien-16,12-olide (1), mangiolide (2), 8,14ß:11,12α-diepoxy-13(15)-abietane-16,12-olide (3), 7ß,11ß,12ß-trihydroxy-ent-abieta-8(14),13(15)-diene-16,12-olide (4), 8α,14-dihydro-7-oxo-jolkinolide E (5), jolkinolide A (6), together with 3ß-sitosterol (7), scopoletin (8) and vanillin (9). Their structures were deduced through 1D and 2D NMR spectroscopic techniques, and HRESIMS, as well as by comparison of the NMR data with those reported in the literature. The crude extract and compounds 1-9 were evaluated for their antiplasmodial, antifungal and antibacterial activities. Mangiolide (2) showed strong in vitro antiplasmodial activity against chloroquine sensitive (D6) and resistant (W2) strains of Plasmodium falciparum with IC50 values of 0.79 and 0.87 µg/mL, respectively, while 3 (IC50 1.24 and 1.17 µg/mL) was less active than 2. Compound 2 also displayed antimicrobial activity against Cryptococcus neoformans, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) with IC50 values of 1.20, 3.90 and 7.20 µg/mL, respectively.

Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents.

The dried roots and rhizomes of Glycyrrhiza species (G. glabra, G. uralensis and G. inflata), commonly known as licorice, have long been used in traditional medicine. In addition, two other species, G. echinata and G. lepidota are also considered "licorice" in select markets. Currently, licorice is an integral part of several botanical drugs and dietary supplements. To probe the botanicals' safety, herb-drug interaction potential of the hydroethanolic extracts of five Glycyrrhiza species and their key constituents was investigated by determining their effects on pregnane X receptor, aryl hydrocarbon receptor, two major cytochrome P450 isoforms (CYP3A4 and CYP1A2), and the metabolic clearance of antiviral drugs. All extracts enhanced transcriptional activity of PXR and AhR (>2-fold) and increased the enzyme activity of CYP3A4 and CYP1A2. The highest increase in CYP3A4 was seen with G. echinata (4-fold), and the highest increase in CYP1A2 was seen with G. uralensis (18-fold) and G. inflata (16-fold). Among the constituents, glabridin, licoisoflavone A, glyasperin C, and glycycoumarin activated PXR and AhR, glabridin being the most effective (6- and 27-fold increase, respectively). Licoisoflavone A, glyasperin C, and glycycoumarin increased CYP3A4 activity while glabridin, glyasperin C, glycycoumarin, and formononetin increased CYP1A2 activity (>2-fold). The metabolism of antiretroviral drugs (rilpivirine and dolutegravir) was increased by G. uralensis (2.0 and 2.5-fold) and its marker compound glycycoumarin (2.3 and 1.6-fold). The metabolism of dolutegravir was also increased by G. glabra (2.8-fold) but not by its marker compound, glabridin. These results suggest that licorice and its phytochemicals could affect the metabolism and clearance of certain drugs that are substrates of CYP3A4 and CYP1A2.Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2050875 .

Litoarbolide A: an undescribed sesquiterpenoid from the Red Sea soft coral Litophyton arboreum with an in vitro anti-malarial activity evaluation.

Soft corals distributed across the Red Sea coasts are a rich source of diverse and bioactive natural products. Chemical probing of the Red Sea soft coral Litophyton arboreum led to isolation and structural characterization of an undescribed sesquiterpenoid, litoarbolide A (1), along with 14 previously reported metabolites (2-15). The chemical structures of the isolates were assigned based on NMR as well as high resolution electrospray ionization mass spectrometry (HR-ESI-MS) data. Litoarbolide A is supposed to be the biosynthetic precursor to other sesquiterpenoids, which formed via further post-translational modifications. Furthermore, these metabolites were evaluated for anti-malarial activity, where only the acyclic sesquiterpenoid of a sec-germacrane nucleus (7) showed an activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 at 3.7 and 2.2 mg/mL, respectively. Moreover, the isolated metabolites were all non-toxic to the Vero cell line. These findings support the consideration of L. arboreum in further natural anti-malarial studies.

Evaluation of the Herb-Drug Interaction Potential of Commonly Used Botanicals on the US Market with Regard to PXR- and AhR-Mediated Influences on CYP3A4 and CYP1A2.

In this study, hydroethanolic extracts of 30 top-selling botanicals (herbs) commonly used as ingredients of herbal dietary supplements in the US were screened for their potential to activate the human pregnane X receptor (hPXR) and human aryl hydrocarbon receptor (hAhR) and to increase the activities of hPXR- and hAhR-regulated drug metabolizing cytochrome P450 enzymes (i.e., CYP3A4 and CYP1A2, respectively). Of the 30 botanicals tested, 21 induced PXR and 29 induced AhR transcriptional activities. Out of the 21 botanicals that induced hPXR transcriptional activity, 14 yielded >50% induction in CYP3A4 activity at concentrations ranging from 6 to 60 µg/mL and 16 out of the 29 botanicals that activated hAhR yielded >50% induction in CYP1A2 activity at concentrations ranging from 3 to 30 µg/mL. Moreover, eight botanicals (G. gummi-gutta [garcinia], Hemp [low and high CBD content], H. perforatum [St. John's wort], M. vulgare [horehound], M. oleifera [moringa], O. vulgare [oregano], P. johimbe [yohimbe] and W. somnifera [ashwagandha]) yielded >50% induction in both CYP3A4 and CYP1A2 activity. Herbal products are mixtures of phytoconstituents, any of which could modulate drug metabolism. Our data reveals that several top-selling botanicals may pose herb-drug interaction (HDI) risks via CYP450 induction. While in vitro experiments can provide useful guidance in assessing a botanical's HDI potential, their clinical relevance needs to be investigated in vivo. Botanicals whose effects on hPXR/CYP3A4, and hAhR/CYP1A2 activity were most pronounced will be slated for further clinical investigation.

A Recent Appraisal of Small-Organic Molecules as Anti-Alzheimer's Agents.

BACKGROUND: Alzheimer's disease (AD) is an irreversible, progressive and very complex brain disorder. There is still uncertainty about the etiology of AD; however, a few hallmarks like an aggregation of tau proteins, amyloid-ß plaques, oxidative stress, low level of choline in the brain etc., play significant roles. OBJECTIVE: In the present work, we aim to evaluate the recent progress in the development of small organic molecules containing heterocycles like thiazole, pyridines, dihydropyridines, piperidines, pyrrolidines, pyrazoles, quinolines etc. as anti-Alzheimer's agents. METHODS: Several databases, including SciFinder, ScienceDirect, Bentham Science, and PubMed, were searched for relevant articles and reviewed for the present work. RESULTS: Several research groups are actively working on these heterocycle-based compounds as potent single-target inhibitors. Most of the analogues have been evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition potential. Several studies have also reported the inhibitory potential of the analogues against MAO-A, MAO-B, and BACE-1 enzymes. However, instead of targeting one enzyme or protein, more than one heterocycle ring is being joined to develop MTDLs (multi-target-directed ligands). Donepezil has become the focal point of anti-AD drug discovery projects. Several research groups have reported various donepezil-based analogues by replacing/ modifying its various ring systems like indanone, piperidine or the methylene linker. CONCLUSION: Small molecules with nitrogen-containing heterocycles have become the core of drug discovery efforts for AD. With the increasing prominence of the MTDL approach, several new ligands are being discovered as potent anti-AD agents.