Chemistry and Pharmacology of Delta-8-Tetrahydrocannabinol.

Cannabis sativa is one of the oldest plants utilized by humans for both economic and medical purposes. Although the use of cannabis started millennia ago in the Eastern hemisphere, its use has moved and flourished in the Western nations in more recent centuries. C. sativa is the source of psychoactive cannabinoids that are consumed as recreational drugs worldwide. The C21 aromatic hydrocarbons are restricted in their natural occurrence to cannabis (with a few exceptions). Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component in cannabis, with many pharmacological effects and various approved medical applications. However, a wide range of side effects are associated with the use of Δ9-THC, limiting its medical use. In 1966, another psychoactive cannabinoid, Delta-8-tetrahydrocannabinol (Δ8-THC) was isolated from marijuana grown in Maryland but in very low yield. Δ8-THC is gaining increased popularity due to its better stability and easier synthetic manufacturing procedures compared to Δ9-THC. The passing of the U.S. Farm Bill in 2018 led to an increase in the sale of Δ8-THC in the United States. The marketed products contain Δ8-THC from synthetic sources. In this review, methods of extraction, purification, and structure elucidation of Δ8-THC will be presented. The issue of whether Δ8-THC is a natural compound or an artifact will be discussed, and the different strategies for its chemical synthesis will be presented. Δ8-THC of synthetic origin is expected to contain some impurities due to residual amounts of starting materials and reagents, as well as side products of the reactions. The various methods of analysis and detection of impurities present in the marketed products will be discussed. The pharmacological effects of Δ8-THC, including its interaction with CB1 and CB2 cannabinoid receptors in comparison with Δ9-THC, will be reviewed.

New flavonoids with multiple bronchodilator activity pathways from Tephrosia purpurea L. (Pers.) growing in Saudi Arabia.

Total extract of Tephrosia purpurea (T. purpurea) expressed potent ex-vivo bronchodilator effect in isolated Guinea pigs' tracheal muscles. Fractionation of T. purpurea total extract (TPTE) using liquid-liquid technique followed by ex-vivo bronchodilator testing indicated that the activity was trapped to the chloroform (CHCl3) soluble fraction. Phytochemical study of the CHCl3 fraction guided by ex-vivo bronchodilator activity led to the isolation of 7 active flavones of which compounds 1 (epi-Tephroapollin G), 3 (Acetyltephroapollin C), 4 (4''-Dehydroxytephroapollin E), and 5 (epi-Tephroapollin F) were new. Structures were identified using relevant spectroscopic tools including optical rotations and CD data. Compounds 1, 3, 4 and lanceolatin A (6) behaved like papaverine by inhibiting carbachol (CCh) as well as high potassium (K+)-mediated contractions at equivalent concentrations with varied potencies whereas (-)-Tephroapollin G (2) selectively inhibited CCh-mediated contractions but was not found active against high K+. epi-Tephroapollin F (5) and (-)-Pseudosemiglabrin (7) in contrast were significantly more potent to abolish CCh induced contraction when compared with high K+ similar to dicyclomine. Papaverine like dual phosphodiesterase enzyme Ca++ ion inhibitory activities of 1, 3, 4 and 6 were confirmed indirectly by the bolster of the isoprenaline curves against CCh to the left whereas Ca++ inhibitory effect of 1 and 3-7 was confirmed by the rightward deflection of Ca++ concentration-response curves (CRCs) towards right with quashing of the maximum response in same fashion like verapamil. Moreover, compounds 2, 5 and 7 at lower concentrations showed selective blockade of muscarinic receptor similar to atropine. Oral administration of the TPTE, CHCl3 and 7 to guinea pigs significantly protected against bronchospasm induced by 0.2 % histamine aerosol in vivo.

Targeting inflammation and oxidative stress for protection against ischemic brain injury in rats using cupressuflavone.

Inflammatory responses and oxidative stress contribute to the pathogenesis of brain ischemia/reperfusion (IR) injury. Naturally occurring bioflavonoids possess antioxidant and anti-inflammatory properties. The phytochemicals of Juniperus sabina L., known as "Abhal" in Saudi Arabia, have been studied and cupressuflavone (CUP) has been isolated as the major bioflavonoid. This study aimed to investigate the neuroprotective potential of CUP in reducing brain IR damage in rats and to understand probable mechanisms. After 60 min of inducing cerebral ischemia by closing the left common carotid artery (CCA), blood flow was restored to allow reperfusion. The same surgical procedure was performed on sham-operated control rats, excluding cerebral IR. CUP or vehicle was given orally to rats for 3 days prior to ischemia induction and for a further 3 days following reperfusion. Based on the findings of this study, compared to the IR control group, CUP-administered group demonstrated reduced neurological deficits, improved motor coordination, balance, and locomotor activity. Additionally, brain homogenates of IR rats showed a decrease in malondialdehyde (MDA) level, an increase in reduced glutathione (GSH) content, and an increase in catalase (CAT) enzyme activity following CUP treatment. CUP suppressed neuro-inflammation via reducing serum inflammatory cytokine levels, particularly those of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß) and enhancing the inflammatory cytokine levels, such as Nuclear factor kappa- B (NF-κB), TANK-binding kinase-1 (TBK1), and interferon beta (IFN-ß) in brain tissues. Furthermore, CUP ameliorated the histological alterations in the brain tissues of IR rats. CUP significantly suppressed caspase-3 expression and downregulated the Toll-like receptor 4 (TLR4)/NF-κB signaling pathway as a result of suppressing High mobility group box 1 (HMGB1). To our knowledge, this is the first study to document the neuroprotective properties of CUP. Thus, the study findings revealed that CUP ameliorates IR-induced cerebral injury possibly by enhancing brain antioxidant contents, reducing serum inflammatory cytokine levels, potentiating the brain contents of TBK1 and IFN-ß and suppressing the HMGB1/TLR-4 signaling pathway. Hence, CUP may serve as a potential preventive and therapeutic alternative for cerebral stroke.

Amentoflavone attenuates oxidative stress and neuroinflammation induced by cerebral ischemia/reperfusion in rats by targeting HMGB1-mediated TLR4/NF-κB signaling pathway.

Surveys indicated that stroke classified among the leading cause of death as well as combined death and disability worldwide resulting in a great loss for the global economy. The present study aims to evaluate the neuroprotective potential of the biflavonoid amentoflavone (AMNT) in alleviating cerebral ischemia/reperfusion (IR) injury in rats, and to elucidate the possible underlying mechanism of an experimental condition with similar circumstances to stroke. Cerebral ischemia was achieved through left common carotid artery occlusion for 60 min, followed by blood flow restoration. Sham-operated control rats subjected to the same surgical process except for brain IR. Rats were orally administered AMNT/ or vehicle for three days' prior surgical operation, and for another three days after left brain IR. Rats of all groups were assessed for neurological deficits 24 h following brain IR. Each group was divided into two subgroups one for the rotarod testing and biochemical assessment while the other subgroup to perform the activity cage testing, histopathological study, immunohistochemistry, and gene expression analysis. AMNT enhanced brain levels of GSH and CAT activities, suppressed neuroinflammation via reducing the inflammatory cytokines in the serum, and enhanced brain contents of TBK1 and IFNß. AMNT downregulated TLR4-/NF-κB signaling pathway as a result of the HMGB1 suppression. Moreover, AMNT blocked apoptotic cell death by suppressing the NF-κB signaling pathway and reducing the activation of caspase-3. These findings revealed that AMNT attenuates I/R-induced cerebral injury possibly by regulating the HMGB1-mediated TLR4/NF-kB pathway. Thus, AMNT could provide potential preventive and therapeutic option for cerebral stroke.

Chemistry and Biological Activities of Cannflavins of the Cannabis Plant.

Background: Throughout history, Cannabis has had a significant influence on human life as one of the earliest plants cultivated by humans. The plant was a source of fibers used by the oldest known civilizations. Cannabis was also used medicinally in China, India, and ancient Egypt. Delta-9-tetrahydrocannabinol (Δ9-THC), the main psychoactive compound in the plant was identified in 1964 followed by more than 125 cannabinoids. More than 30 flavonoids were isolated from the plant including the characteristic flavonoids called cannflavins, which are prenylated or geranylated flavones. Material and Methods: In this review, the methods of extraction, isolation, identification, biosynthesis, chemical synthesis, analysis and pharmacological activity of these flavonoids are described. Results: The biosynthetic routes of the cannflavins from phenylalanine and malonyl CoA as well as the microbial biotransformation are also discussed. Details of the chemical synthesis are illustrated as an alternative to the isolation from the plant materials along with other possible sources of obtaining cannflavins. Detailed methods discussing the analysis of flavonoids in cannabis are presented, including the techniques used for separation and detection. Finally, the various biological activities of cannflavins are reviewed along with the available molecular docking studies. Conclusion: Despite the low level of cannflavins in cannabis hamper their development as naturally derived products, efforts need to be put in place to develop high yield synthetic or biosynthetic protocols for their production in order for their development as pharmaceutical products.

A New Saponin (Zygo-albuside D) from Zygophyllum album Roots Triggers Apoptosis in Non-Small Cell Lung Carcinoma (A549 Cells) through CDK-2 Inhibition.

Phytochemical study of the ethyl acetate root extract of Zygophyllum album has resulted in the isolation of a new saponin, Zygo-albuside D (1), along with two known compounds; (3-O-[ß-D-quinovopyranosyl]-quinovic acid) (2), which is first reported in the root, and catechin (3), first reported in the genus. Their chemical structures were established by NMR and high-resolution mass spectrometry (HRMS). The new saponin (1) exhibited promising cytotoxicity with IC50 values of 3.5 and 5.52 µM on A549 and PC-3 cancer cell lines, respectively, compared to doxorubicin with IC50 values of 9.44 and 11.39 µM on A549 and PC-3 cancer cell lines, respectively. While it had an IC50 value of 46.8 µM against WISH cells. Investigating apoptosis-induction, compound 1 induced total apoptotic cell death in A549 lung cancer cells by 32-fold; 21.53% compared to 0.67% in the untreated control cells. Finally, it upregulated the pro-apoptotic genes and downregulated the antiapoptotic gene using gene expression levels. Compound 1 exhibited remarkable CDK-2 target inhibition by 96.2% with an IC50 value of 117.6 nM compared to Roscovitine. The molecular docking study further confirmed the binding affinity of compound 1 as CDK2 and Bcl2 inhibitors that led to apoptosis induction in A549 cancer cells. Hence, this study highlights the importance of compound 1 in the design of a new anticancer agent with specific mechanisms.

Phytochemical profiling of Salsola tetragona Delile by LC-HR/MS and investigation of the antioxidant, anti-inflammatory, cytotoxic, antibacterial and anti-SARS-CoV-2 activities.

This study aimed to investigate the phytochemical composition and biological activity of Salsola tetragona Delile. (Amaranthaceae), a medicinal plant. The study evaluated the antioxidant potential of the crude extract and five fractions of S. tetragona using DPPH•, ABTS•+, CUPRAC, and metal chelating assays. The anti-inflammatory activity was determined using a protein denaturation assay, and the antibacterial activity was determined by the Minimum inhibitory concentrations (MICs) for the growth of Escherichia coli and Staphylococcus aureus strains. The MTT test and an in vitro scratch assay evaluated the effects on cell viability and cell migration. The potential anti-SARS-CoV-2 activity was assessed by analyzing the effects on the interaction between ACE2 and Spike protein. The bioactive compounds present in the plant were identified using LC-HR/MS analysis. The crude hydromethanolic extract (STM) and five fractions of S. tetragona, n-hexane (STH), dichloromethane (STD), ethyl acetate (STE), n-butanol (STB), and aqueous (STW) showed significant antioxidant activity in four different tests. In the anti-inflammatory assay, the ethyl acetate fraction exhibited significantly higher activity than Aspirin® (IC50 = 13 ± 5 µg/mL). The crude extract and its fractions showed positive antibacterial activity with similar MICs. In the cytotoxicity assay against the breast cancer cell line MCF7, the dichloromethane fractions (STD) were very effective and demonstrated superiority over the other fractions (IC50 = 98 µg/mL). Moreover, the potential of the extract and fractions as anti-SARS-CoV-2, the ethyl acetate, and dichloromethane fractions demonstrated important activity in this test. LC-HR/MS analysis identified 16 different phenolic compounds, Eleven of which had not been previously reported in the genus Salsola. The results suggest that the extracts of S. tetragona have the potential to become new sources for developing plant-based therapies for managing a range of diseases.

Ameliorative Potential of (-) Pseudosemiglabrin in Mice with Pilocarpine-Induced Epilepsy: Antioxidant, Anti-Inflammatory, Anti-Apoptotic, and Neurotransmission Modulation.

One prevalent neurological disorder is epilepsy. Modulating GABAergic/glutamatergic neurotransmission, Nrf2/HO-1, PI3K/Akt, and TLR-4/NF-B pathways might be a therapeutic strategy for epilepsy. Eight-week-old BALB/c mice were administered 12.5, 25, or 50 mg/kg (-) pseudosemiglabrin orally one hour before inducing epilepsy with an i.p. injection of 360 mg/kg pilocarpine. (-) Pseudosemiglabrin dose-dependently alleviated pilocarpine-induced epilepsy, as revealed by the complete repression of pilocarpine-induced convulsions and 100% survival rate in mice. Furthermore, (-) pseudosemiglabrin significantly enhanced mice's locomotor activities, brain GABA, SLC1A2, GABARα1 levels, glutamate decarboxylase activity, and SLC1A2 and GABARα1mRNA expression while decreasing brain glutamate, SLC6A1, GRIN1 levels, GABA transaminase activity, and SLC6A1 and GRIN1 mRNA expression. These potentials can be due to the suppression of the TLR-4/NF-κB and the enhancement of the Nrf2/HO-1 and PI3K/Akt pathways, as demonstrated by the reduction in TLR-4, NF-κB, IL-1ß, TNF-α mRNA expression, MDA, NO, caspase-3, Bax levels, and Bax/Bcl-2 ratio, and the enhancement of Nrf2, HO-1, PI3K, Akt mRNA expression, GSH, Bcl-2 levels, and SOD activity. Additionally, (-) pseudosemiglabrin abrogated the pilocarpine-induced histopathological changes. Interestingly, the (-) pseudosemiglabrin intervention showed a comparable effect to the standard medication, diazepam. Therefore, (-) pseudosemiglabrin can be a promising medication for the management of epilepsy.

Samarcandin protects against testicular ischemia/reperfusion injury in rats via activation of Nrf2/HO-1-mediated antioxidant responses.

The purpose of this study was to evaluate the effectiveness of samarcandin (SMR) in preventing testicular injury caused by ischemia/reperfusion (I/R) in rats. Rats were divided into 4 groups at random: the sham group, the T/D control group (CONT), the T/D group receiving SMR treatment at 10 mg/kg (SMR-10), and the T/D group receiving SMR treatment at 20 mg/kg (SMR-20). When compared to the CONT group, SMR improved the oxidant/antioxidant balance by reducing malondialdehyde (MDA), nitric oxide (NOx), and increasing reduced glutathione (GSH), gluta-thione peroxide (GSH-Px), and superoxide dismutase (SOD). Moreover, SMR increased the levels of the steroid hormones' testosterone (TST), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in the blood as well as controlled the inflammatory mediators; interleukin-6 (IL6), tumor necrosis factor alpha (TNF-α), and nuclear factor κB (NF-κB). Nevertheless, SMR-treated animals showed a considerable downregulation of the apoptotic marker caspase-3. The T/D-induced histopathological changes were reduced and Proliferating Cell Nuclear Antigen (PCNA) protein expression was enhanced by SMR. These effects are associated with upregulation of testicular (Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme oxygenase-1 (HO-1), and downregulation of NF-κB mRNA expression levels. These findings suggest that SMR may be able to prevent T/D-induced testis damage by mainly regulating the expression of Nrf2 and NF-B, which seems to mediate its promising antioxidant, anti-inflammatory and antiapoptotic effects seen in this study.

In Vitro and In Silico Anti-Picornavirus Triterpene Alkanoic Acid Ester from Saudi Collection of Rhazya stricta Decne.

The total alcohol extract obtained from the aerial parts of R. stricta and fractions of the liquid-liquid fractionation process were tested against picornavirus-causing foot-and-mouth disease (FMD) based on the traditional use of the plant in Saudi Arabia. The most active petroleum ether soluble fraction was subjected to chromatographic purification, and nine compounds were isolated, identified using various chemical and spectroscopic methods, and tested for their anti-viral potential. The new ester identified as α-Amyrin 3-(3'R-hydroxy)-hexadecanoate (1) was the most active compound with 51% inhibition of the viral growth and was given the name Rhazyin A. Compounds with ursane skeleton were more active than those with lupane skeleton except in the case of the acid derivatives where betulenic acid showed 26.1% inhibition against the viral growth, while ursolic acid showed only 16.6% inhibition. Moreover, molecular docking analysis using a glide extra-precision module was utilized for investigating the possible molecular interactions accounting for anti-viral activity against picornavirus of the nine isolated compounds. Molecular docking studies revealed a strong binding of the discovered hits within the active site of FMDV 3Cpro. Compound 1 showed the lowest docking score within the nine isolated compounds comparable to the two known anti-viral drugs; glycyrrhizic acid and ribavirin. The results of this research will provide lead candidates from natural origin with potential safety and efficacy compared to the synthetic ones with lower production costs for managing FMVD.

Microbial Transformation of the Sesquiterpene Lactone, Vulgarin, by Aspergillus niger.

The biotransformation of vulgarin (1), an eudesmanolides-type sesquiterpene lactone obtained from Artemisia judaica, by the microorganism, Aspergillus niger, was carried out to give three more polar metabolites; 1-epi-tetrahydrovulgarin (1α,4α-dihydroxy-5αH,6,11ßH-eudesman-6,12-olide (2), 20% yield, 1α,4α-dihydroxyeudesm-2-en-5αH,6,11ßH-6,12-olide (3a), 10% yield, and C-1 epimeric mixture (3a, b), 4% yield, in a ratio of 4:1, 3a/3b. The structures of vulgarin and its metabolites were elucidated by 1 and 2D NMR spectroscopy in conjunction with HRESIMS. Metabolites (3a) and (3b) are epimers, and they are reported here for the first time as new metabolites obtained by biotransformation by selective reduction at C-1. Vulgarin and its metabolites were evaluated as anti-inflammatory agents using the human cyclooxygenase (COX) inhibitory assay. The obtained data showed that (1) exhibited a good preferential inhibitory activity towards COX-2 (IC50 = 07.21 ± 0.10) and had a moderate effect on COX-1 (IC50 = 11.32 ± 0.24). Meanwhile, its metabolite (3a) retained a selective inhibitory activity against COX-1 (IC50 = 15.70 ± 0.51). In conclusion, the results of this study revealed the necessity of the presence α, ß unsaturated carbonyl group in (1) for better COX-2 inhibitory activity. On the other hand, the selectivity of (1) as COX-1 inhibitor may be enhanced via the reduction of C-1 carbonyl group.

Synthesis, Antimicrobial, and Antibiofilm Activities of Some Novel 7-Methoxyquinoline Derivatives Bearing Sulfonamide Moiety against Urinary Tract Infection-Causing Pathogenic Microbes.

A new series of 4-((7-methoxyquinolin-4-yl) amino)-N-(substituted) benzenesulfonamide 3(a-s) was synthesized via the reaction of 4-chloro-7-methoxyquinoline 1 with various sulfa drugs. The structural elucidation was verified based on spectroscopic data analysis. All the target compounds were screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and unicellular fungi. The results revealed that compound 3l has the highest effect on most tested bacterial and unicellular fungal strains. The highest effect of compound 3l was observed against E. coli and C. albicans with MIC = 7.812 and 31.125 µg/mL, respectively. Compounds 3c and 3d showed broad-spectrum antimicrobial activity, but the activity was lower than that of 3l. The antibiofilm activity of compound 3l was measured against different pathogenic microbes isolated from the urinary tract. Compound 3l could achieve biofilm extension at its adhesion strength. After adding 10.0 µg/mL of compound 3l, the highest percentage was 94.60% for E. coli, 91.74% for P. aeruginosa, and 98.03% for C. neoformans. Moreover, in the protein leakage assay, the quantity of cellular protein discharged from E. coli was 180.25 µg/mL after treatment with 1.0 mg/mL of compound 3l, which explains the creation of holes in the cell membrane of E. coli and proves compound 3l's antibacterial and antibiofilm properties. Additionally, in silico ADME prediction analyses of compounds 3c, 3d, and 3l revealed promising results, indicating the presence of drug-like properties.

Anti-ulcerative colitis effect of Calligonum comosum L'Hér. using rat model: Chemical, pharmacological and histopathological evidences.

Calligonum comosum is a perennial shrub growing and widely used in traditional medicinal system in Saudi Arabia. The total phenolic content and in vitro antioxidant activity were compared between the water extract (WE) and methanol extract (ME). The protective potential against acetic acid (AA) induced ulcerative colitis (UC) was also evaluated in rats. The obtained results showed that the total phenolic content of the WE and ME were 8.378 ± 0.738 and 33.819 ± 0.488 µg/mL. The antioxidant properties of the two extracts were directly influenced by their total phenolic contents. The ME with higher phenolic contents and stronger antioxidant power was more effective than the WE in protection against AA-induced colitis. Phytochemical study of the ME led to the identification of three flavonoid derivatives: (-)-epi-catechin, quercetin-3-O-α-l-arabinofuranoside (Avicularin) and quercetin-3-O-ß-d-glucuronide-6″-methyl ester by various spectroscopic methods. (-)-Epi-catechin was the major component while the other two compounds were obtained in minute quantities. The anti-ulcerative colitis effect of the ME can be explained by the presence of the antioxidant flavonoids since AA-induced colitis featured by imbalance between oxidant and antioxidant substances. Further support of such explanation was provided by HPLC quantification of (-)-epi-catechin in the ME and WE. The percentage in ME was higher than the WE but the difference was higher in term of Total Phenolic Content (TPC). These results support the traditional use of C. comosum as anti-ulcerative colitis.

Biochemical Profile and In Vitro Therapeutic Properties of Two Euhalophytes, Halocnemum strobilaceum Pall. and Suaeda fruticosa (L.) Forske., Grown in the Sabkha Ecosystem in the Algerian Sahara.

This study reports the biochemical profile and in vitro biological activities of the aerial part of two shrubs: Halocnemum strobilaceum and Suaeda fruticosa, a halophytes species native to saline habitats. The biomass was evaluated by determining its physiological properties and approximate composition. Hydro-methanolic extracts from Halocnemum strobilaceum and Suaeda fruticosa have been investigated for the inhibition of bacterial growth, the protection of proteins (albumin) from denaturation, and cytotoxicity to hepatocellular carcinomas (Huh-7 and HepG2). Their antioxidant activity was evaluated by five tests, including one that examined their ability to inhibit hydrogen peroxide (H2O2)-induced hemolysis. The profile of their phenolic compounds was also determined. These two euhalophytes had a high moisture content, high levels of photosynthetic pigments, elevated levels of ash and protein, low oxidative damage indices, MDA (Malondialdehyde) and proline, and low lipids levels. Their content was also characterized by a moderate acidity with good electrical conductivity. They contained abundant levels of phytochemicals and varied phenolic contents. Reverse phase high performance liquid chromatography (RP-HPLC) analysis revealed the presence of caffeic acid, p-coumaric acid, rutin, and quercetin in both plant extracts. On the pharmaceutical level, the two euhalophytes had anti-inflammatory, antibacterial, antioxidant, and cytotoxic properties, and therefore it was recommended to isolate and identify biologically active compounds from these plants and evaluate them in vivo.

Biomarker Quantification, Spectroscopic, and Molecular Docking Studies of the Active Compounds Isolated from the Edible Plant Sisymbrium irio L.

Phytochemical investigation of the ethanolic extract of the aerial parts of Sisymbrium irio L. led to the isolation of four unsaturated fatty acids (1-4), including a new one (4), and four indole alkaloids (5-8). The structures of the isolated compounds were characterized with the help of spectroscopic techniques such as 1D, 2D NMR, and mass spectroscopy, and by correlation with the known compounds. In terms of their notable structural diversity, a molecular docking approach with the AutoDock 4.2 program was used to analyze the interactions of the identified fatty acids with PPAR-γ and the indole alkaloids with 5-HT1A and 5-HT2A, subtypes of serotonin receptors, respectively. Compared to the antidiabetic drug rivoglitazone, compound 3 acted as a potential PPAR-γ agonist with a binding energy of -7.4 kcal mol-1. Moreover, compound 8 displayed the strongest affinity, with binding energies of -6.9 kcal/mol to 5HT1A and -8.1 kcal/mol to 5HT2A, using serotonin and the antipsychotic drug risperidone as positive controls, respectively. The results of docked conformations represent an interesting target for developing novel antidiabetic and antipsychotic drugs and warrant further evaluation of these ligands in vitro and in vivo. On the other hand, an HPTLC method was developed to quantify α-linolenic acid in the hexane fraction of the ethanol extract of S. irio. The regression equation/correlation coefficient (r2) for linolenic acid was Y = 6.49X + 2310.8/0.9971 in the linearity range of 100-1200 ng/band. The content of α-linolenic acid in S. irio aerial parts was found to be 28.67 µg/mg of dried extract.

Brain Targeting by Intranasal Drug Delivery: Effect of Different Formulations of the Biflavone "Cupressuflavone" from Juniperus sabina L. on the Motor Activity of Rats.

The polar fractions of the Juniperus species are rich in bioflavonoid contents. Phytochemical study of the polar fraction of Juniperus sabina aerial parts resulted in the isolation of cupressuflavone (CPF) as the major component in addition to another two bioflavonoids, amentoflavone and robustaflavone. Biflavonoids have various biological activities, such as antioxidant, anti-inflammatory, antibacterial, antiviral, hypoglycemic, neuroprotective, and antipsychotic effects. Previous studies have shown that the metabolism and elimination of biflavonoids in rats are fast, and their oral bioavailability is very low. One of the methods to improve the bioavailability of drugs is to alter the route of administration. Recently, nose-to-brain drug delivery has emerged as a reliable method to bypass the blood-brain barrier and treat neurological disorders. To find the most effective CPF formulation for reaching the brain, three different CPF formulations (A, B and C) were prepared as self-emulsifying drug delivery systems (SEDDS). The formulations were administered via the intranasal (IN) route and their effect on the spontaneous motor activity in addition to motor coordination and balance of rats was observed using the activity cage and rotarod, respectively. Moreover, pharmacokinetic investigation was used to determine the blood concentrations of the best formulation after 12 h. of the IN dose. The results showed that formulations B and C, but not A, decreased the locomotor activity and balance of rats. Formula C at IN dose of 5 mg/kg expressed the strongest effect on the tested animals.

Chemical constituents from Centaurothamnus maximus and their antimicrobial activity.

A new sesquiterpene lactone, 3ß,10α-dihydroxy-10ß-(hydroxymethyl)-8α-(4-hydroxymethacrylate)-1αH,5αH,6ßH,7αH-guai-4(15), 11(13)-dien-6,12-olide (1), along with twenty-one known compounds, were identified from the aerial parts of Centaurothamnus maximus. The structures of the isolated compounds were elucidated on the basis of spectroscopic evidences and correlated with known compounds. Compounds (2, 3, 5‒13 and 15‒22) were identified from C. maximus for the first time. Antibacterial and antifungal activities of the isolated compounds were tested using the agar disc diffusion method. Compounds that demonstrated promising antimicrobial activity were evaluated for their minimum inhibitory concentration (MIC). The results showed that compounds 3 and 7 were the most effective antibacterial compounds against B. subtilis ATCC 6633, S. aureus ATCC 25923 and S. pyogenes ATCC 27736, with MIC estimates between 8 and 32 mg/mL. In addition, compound 2 exhibited the strongest antifungal activity against C. albicans ATCC 14243 and C. krusei ATCC 14243 with MIC 8 mg/mL.

Twenty-two compounds were first isolated from Centaurothamnus maximusThe structure of the new sesquiterpene lactone, thamnolide (1), was established.Antibacterial and antifungal activities were tested for the isolated compounds.Compounds 3 and 7 were the strongest antibacterial compounds whilst 2 exhibited the strongest antifungal activity.

Protective Effect of Beta-Carotene against Myeloperoxidase- Mediated Oxidative Stress and Inflammation in Rat Ischemic Brain Injury.

Oxidative stress and inflammatory reaction play critical roles in ischemia/reperfusion (I/R) injury in the brain. ß-carotene (ßCAR) is a naturally occurring pigment present in fruits and vegetables that expresses antioxidant and anti-inflammatory activities. This study was conducted to investigate the involvement of Bcl2/Bax and NF-κB signaling pathways in the potential protective role of ßCAR against brain injury in a middle cerebral artery occlusion (MCAO) rat model. A focal brain ischemia model was created for 2 h, followed by reperfusion. Rats were given 10 and 20 mg/kg of ßCAR for 7 days orally before induction of ischemia, at the start of reperfusion, and 3 days after ischemia. Scores of neurological deficit were rated 24 h after induction of ischemia. Motor coordination and spontaneous coordinate activities were assessed using rotarod and activity cage, respectively. After 2 h of the last dose, the animals were killed and their brains were extracted for further examinations. The results of the study show that ßCAR diminished the score of neurological deficits and ameliorated motor coordination, balance, and locomotor activity in the I/R control group. Further, ßCAR resulted in diminution of malondialdehyde (MDA) and augmentation of reduced glutathione (GSH) contents, as well as the elevation of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzyme activities in the brain homogenates of I/R rats. ßCAR treatment significantly reduced nuclear factor kappa B (NF-κB) brain content and myeloperoxidase (MPO) activity and ameliorated the histological alterations in the brain tissues. ßCAR significantly suppressed Bcl-2-associated X protein (Bax) and caspase-3 expression, as well as upregulated B-cell lymphoma-2 (Bcl-2) expression, suggesting a neuroprotective potential via downregulating NF-kB and protecting the rat brain against the I/R-associated apoptotic injury.

Vulgarin, a Sesquiterpene Lactone from Artemisia judaica, Improves the Antidiabetic Effectiveness of Glibenclamide in Streptozotocin-Induced Diabetic Rats via Modulation of PEPCK and G6Pase Genes Expression.

The current investigation assessed the effect of the eudesmanolid, Vulgarin (VGN), obtained from Artemisia judaica (A. judaica), on the antidiabetic potential of glibenclamide (GLB) using streptozotocin (STZ) to induce diabetes. Seven groups of rats were used in the study; the first group received the vehicle and served as normal control. The diabetic rats of the second to the fifth groups were treated with the vehicle (negative control), GLB at 5 mg/kg (positive control), VGN at 10 mg/kg (VGN-10) and VGN at 20 mg/kg (VGN-20), respectively. The diabetic rats of the sixth and seventh groups were administered combinations of GLB plus VGN-10 and GLB plus VGN-20, respectively. The diabetic rats treated with GLB plus VGN-20 combination showed marked improvement in the fasting blood glucose (FBG), insulin and glycated hemoglobin (HbA1c), as well as the lipid profile, compared with those treated with GLB alone. Further, the pancreatic tissues of the diabetic rats that received the GLB+VGN-20 combination showed superior improvements in lipid peroxidation and antioxidant parameters than those of GLB monotherapy. The insulin content of the ß-cells was restored in all treatments, while the levels of glucagon and somatostatin of the α- and δ-endocrine cells were reduced in the pancreatic islets. In addition, the concurrent administration of GLB+VGN-20 was the most effective in restoring PEPCK and G6Pase mRNA expression in the liver. In conclusion, the results demonstrated that the GLB+VGN-20 combination led to greater glycemic improvement in diabetic rats compared with GLB monotherapy through its antioxidant effect and capability to modulate PEPCK and G6Pase gene expression in their livers.

Comparative Cytotoxic Evaluation of Zygophyllum album Root and Aerial Parts of Different Extracts and Their Biosynthesized Silver Nanoparticles on Lung A549 and Prostate PC-3 Cancer Cell Lines.

The current work demonstrates a comparative study between aerial and root parts of Zygophyllum album L. The total phenolic (TPC) and flavonoid content (TFC), in addition to the antioxidant activity, of the crude extracts were investigated, where the aerial parts revealed a higher value overall. By means of UV-VIS and HPLC, rutin and caffeic acid were detected and then quantified as 5.91 and 0.97 mg/g of the plant extract, respectively. Moreover, the biosynthesis of AgNPs utilizing the crude extract of the arial parts and root of Z. album L. and the phenolic extracts was achieved in an attempt to enhance the cytotoxicity of the different plant extracts. The prepared AgNPs formulations were characterized by TEM and zeta potential measurements, which revealed that all of the formulated AgNPs were of a small particle diameter and were highly stable. The mean hydrodynamic particle size ranged from 67.11 to 80.04 nm, while the zeta potential ranged from 29.1 to 38.6 mV. Upon biosynthesis of the AgNPs using the extracts, the cytotoxicity of the tested samples was improved, so the polyphenolics AgNPs of the aerial parts exhibited a potent cytotoxicity against lung A549 and prostate PC-3 cancer cells with IC50 values of 6.1 and 4.36 µg/mL, respectively, compared with Doxorubicin (IC50 values of 6.19 and 5.13 µg/mL, respectively). Regarding the apoptotic activity, polyphenolics AgNPs of the aerial parts induced apoptotic cell death by 4.2-fold in PC-3 and 4.7-fold in A549 cells compared with the untreated control. The mechanism of apoptosis in both cancerous cells appeared to be via the upregulation proapoptotic genes; p53, Bax, caspase 3, 8, and 9, and the downregulation of antiapoptotic gene, Bcl-2. Hence, this formula may serve as a good source for anticancer agents against PC-3 and A549 cells.