Background: Cannabis sativa L. is widely used in traditional medicine for its analgesic, anticonvulsant, hypnotic, tranquilizing, and anti-inflammatory properties.Objective: The current study aims to investigate the potential chemotherapeutic effects of Lebanese Cannabis sativa oil extract (COE) against squamous cell carcinoma (SCC) in vitro and in vivo.Methods: GCMS analysis of COE revealed the presence of two major cannabinoids, CBD (59.1%) and THC (20.2%). Cell proliferation assay (MTS) conducted on COE-treated tumorigenic human epidermal keratinocytes (HaCaT-ras II4) showed a significant dose- and time-dependent cytotoxicity. Flow cytometry analysis on COE-treated HaCaT-ras II4 cells demonstrated an induction of apoptosis. Western blot analysis confirmed the involvement of apoptosis via both the extrinsic and intrinsic pathways and implicated an additional alteration in autophagy. Topical COE treatment, using a DMBA/TPA skin carcinogenesis mouse model, was also evaluated.Results: COE-treated HaCaT-ras II4 cells exhibited IC₅₀ values of 20.96 and 11.49 μg/mL at 24 and 48 hours, respectively. COE (200 μl; 10% or 25% COE in acetone; twice per week) or cisplatin (2.5 mg/kg; IP; once per week) showed a significant decrease in tumor volume with respect to control, with no effect on animal body weight.Conclusions: COE displayed a promising anticancer activity against in vivo and in vitro models of SCC. These findings highlight the need for additional studies to investigate the role of COE in the treatment of squamous cell carcinoma.​

Background/Objectives: Cannabidiol (CBD) is known for its anti-cancer properties in preclinical models and is increasingly used alongside conventional chemotherapy in cancer treatment. This study aims to evaluate the anti-cancer activity of CBD from Lebanese Cannabis sativa as a monotherapy and in combination with cisplatin or paclitaxel on human ovarian adenocarcinoma cells. Methods: Cytotoxicity of CBD was tested on OVCAR-3 and SK-OV-3 cell lines using the MTS assay. The Chou-Talalay method and CompuSyn software were used to determine the combination indices (CIs) for predicting interactions between CBD and chemotherapeutic agents. CBD showed dose-dependent tumor growth inhibition at 72 h with comparable IC50 values for both cell lines. Results: The combination of CBD with cisplatin or paclitaxel showed significant antagonistic interaction in SK-OV-3 cells (CI > 1), but mild synergism (CI < 1) at high growth inhibition rates (95% and 97%) was observed in SK-OV-3 cells with CBD/cisplatin. Pure antagonism was found in OVCAR-3 cells with CBD/cisplatin. Priming SK-OV-3 cells with CBD reduced the IC50 values of both drugs significantly, with a similar effect seen when cells were primed with cisplatin or paclitaxel before CBD treatment. Conclusions: Integrating CBD with chemotherapy could improve cancer therapy and address drug resistance. Sequential administration of CBD and chemotherapeutic agents is more beneficial than simultaneous administration. Further in vivo studies are necessary to validate these findings and understand CBD's interactions with other drugs fully.

Abstract Background Cisplatin is an anti-cancer drug used to treat a plethora of solid tumors. However, it is associated with dose dependent nephrotoxicity limiting its use as anticancer agent. Objective The current study aimed to investigate the nephroprotective effect of native Lebanese Cannabis sativa in both in vitro and in vivo mice model of cisplatin-induced nephrotoxicity. Methods Podocytes cell viability was assessed using MTS assay with cisplatin (30µM) in presence or absence of Cannabis oil extract (COE) at 0.5, 1 and 2µg/ml for 24h. Acute renal injury was established in adult female C57BL/6 mice with 20mg/kg, i.p. single dose cisplatin. Mice were divided into control group (vehicle), COE group, cisplatin group and cisplatin plus COE (2.5, 5 and 20mg/kg, i.p.). Animal body weight, serum creatinine, blood urea nitrogen (BUN), and proteinuria were measured. Results Cell viability assay and western blot analysis revealed that COE prevented apoptosis induced by cisplatin in cultured immortalized rat podocytes. In addition, in vitro scratch assay demonstrated the ability of COE to promote and restore the migratory capacity of podocytes in cisplatin-treated cells. Interestingly, COE treatment improved urinary and serum parameters characterized by a significant decrease in serum creatinine, urea, and proteinuria at various COE doses. Western blot analysis showed that COE inhibited COX-2 protein induction as well as apoptosis marker production (Bax/Bcl2 ratio) in cisplatin-treated mice when compared to mice treated with cisplatin alone. Conclusion Collectively, the aforementioned findings indicate that COE could be a promising approach to protect against cisplatin-induced nephrotoxicity.

Sodium orthovanadate is a non-selective protein tyrosine phosphatase inhibitor that can cause several types of kidney injury, including glomerulosclerosis, inflammation, and tubular damage. Cannabis is widely known for its medicinal use, and several studies have demonstrated its anti-diabetic and anti-inflammatory properties. The current study investigated the therapeutic effect of Lebanese cannabis oil extract (COE) against sodium orthovanadate-induced nephrotoxicity both in vitro and in vivo. Sprague Dawley male rats were intraperitoneally injected with 10 mg/kg sodium orthovanadate for 10 days followed by 5 mg/kg; 10 mg/kg; or 20 mg/kg intraperitoneal injection of cannabis oil extract, starting on day 4 until day 10. The body weight of the rats was monitored during the study, and clinical parameters, including serum urea, creatinine, and electrolytes, as well as kidney and heart pathology, were measured. Conditionally immortalized cultured rat podocytes were exposed to either sodium orthovanadate or selective phosphatase inhibitors, including DUSPi (DUSP1/6 inhibitor) and SF1670 (PTEN inhibitor), in the presence or absence of cannabis oil extract. MTS and an in vitro scratch assay were used to assess podocyte cell viability and migration, respectively. Western blot analysis was used to evaluate the phosphorylation levels of AKT and p38 MAPK. Rats injected with sodium orthovanadate displayed a marked reduction in body weight and an increase in serum creatinine and urea in comparison to the control non-treated group. All doses of COE caused a significant decrease in serum urea, with a significant decrease in serum creatinine observed at a dose of 20 mg/kg. Moreover, the COE treatment of rats injected with orthovanadate (20 mg/kg) showed a marked reduction in renal vascular dilatation, scattered foci of acute tubular necrosis, and numerous mitoses in tubular cells compared to the sodium orthovanadate-treated group. The cell viability assay revealed that COE reversed cytotoxicity induced by sodium orthovanadate and specific phosphatase inhibitors (DUSPi and SF1670) in rat podocytes. The in vitro scratch assay showed that COE partially restored the migratory capacity of podocytes incubated with DUSPi and SF1670. Time-course and dose-dependent experiments showed that COE (1 μg/mL) induced a significant increase in phospho-(S473)-AKT, along with a decrease in phospho (T180 + Y182) P38 levels. The current results demonstrated that Lebanese cannabis oil possesses important kidney protective effects against sodium orthovanadate-induced renal injury.

Background: In 2020, the Lebanese parliament legalized cannabis for medical and industrial use, sparking diverse reactions among health care professionals (HCP). Few studies have been conducted to reflect the position of HCP on the topic, and no previous studies targeted all physicians with relevant specialties or had a large sample size. The current study aimed to assess the knowledge, attitude, and practice of the Lebanese medical community toward medicinal cannabis (MC).Methods: A cross-sectional study was conducted targeting HCP from different backgrounds and specialties. The survey questionnaire was disseminated through different scientific societies in the Lebanese Order of Physicians and other professional bodies. An online survey was shared with oncologists, rheumatologists, psychiatrists, neurologists, pharmacists, and psychotherapists across different geographic regions. It covered questions about sociodemographic details, knowledge, attitude, and practice related to MC. Descriptive and bivariate analyses were performed. A total of 202 HCP responded to the survey, yielding a response rate of 34%.Results: Eighteen percent of the participants described their level of knowledge about the indications of MC as good. Twenty-five percent of the respondents are willing to prescribe, and 30% "may consider" it. Among those willing to prescribe, the majority may consider MC to treat chronic pain, palliative care, post-traumatic stress disorder, epilepsy, and anxiety. Respondents' knowledge about the side effects of MC is as follows: driving difficulties (82%), addiction (69%), drug interactions (65%), and weight gain (43%). Willingness to prescribe varies by medical specialty, previous clinical experience with MC, and gender. The majority of the participants expressed concerns about the potential harm of using MC and indicated that legalization would negatively impact society. Sixty-nine percent of the respondents reported not receiving any formal education about MC and agreed on the need to expand knowledge about its indications and side effects. The majority agreed that MC should be dispensed based on a prescription from a physician with special training and recognized the importance of establishing a national registry for patients undergoing MC treatment, as well as the necessity of guidelines for approval.Conclusion: The current data indicate that attitudes toward prescribing MC vary by medical specialty, gender, and clinical experience. Implementation of effective educational strategies in Lebanon to enhance HCP knowledge about MC and promote its proper use is crucial.

The medicinal plant Cannabis sativa L. (C. sativa) is currently being extensively studied to determine the full extent of its therapeutic pharmacological potential. Delta 9-tetrahydocannabinol (THC) and cannabidiol (CBD) are the most thoroughly investigated compounds. We aimed to explore the anticancer activity of cannabinoids mixture isolated from the Lebanese C. sativa plant in ratios comparable to the local medicinal plant, to elucidate its mechanism of action in breast cancer cells in vitro. Cells were subjected to cytotoxicity assay, cell cycle analysis, Annexin V/PI dual staining, cell death ELISA, immunofluorescence, in addition to western blot analysis of apoptotic and autophagy markers. We further evaluated the anti-metastatic effect of cannabinoids on MDA-MB-231 using the scratch wound-healing, trans-well migration and invasion assays. Our results revealed the promising therapeutic benefits of CBD/THC on inhibiting the growth of breast cancer cells by promoting cellular fragmentation, phosphatidylserine translocation to the outer membrane leaflet and DNA fragmentation in both cell lines while inhibiting the motility of the triple negative breast cancer cells. In our study, CBD/THC mixture was found to exhibit a pro-apoptotic activity via the activation of the mitochondrial apoptotic pathway, independent from ROS production while also suggesting the activation of a caspase-dependent apoptotic pathway. Even though autophagy was altered upon exposure to the cannabinoid mixture, our data suggested that it is not the mechanism responsible of inducing cell death. In conclusion, our study demonstrates the promising therapeutic benefits of CBD and THC isolated from the Lebanese C. sativa plant on breast cancer cells in vitro.

The growing interest in the therapeutic potential of cannabidiol (CBD) has led to the need for effective and reliable delivery methods that overcome its low oral absorption. Zeolites, a class of porous nanoparticles, offer unique advantages as drug carriers due to their high surface area and adjustable pore size. In this study, a zeolite-based drug delivery system was developed for the encapsulation of CBD. The zeolite particles were characterized using various techniques such as Scanning Electron Microscopy (SEM), N2 adsorption analysis, Solid-state Fourier Transform Infrared (FTIR), Direct Light Scattering (DLS), X-ray diffraction (XRD) and thermogravimetric analysis (TGA) before and after the loading. The drug encapsulation efficiency, and the release profile of CBD from the zeolite matrix were evaluated in addition to in vitro dissolution experiments in the intestinal and gastric simulated fluids. The results showed that the loaded zeolite particles exhibited high encapsulation efficiency of 73.5 %. XRD analysis proved that the USY structure remained intact after loading with CBD. DLS and N2 adsorption analysis indicated that CBD was successfully loaded into the zeolite matrix. When compared to CBD containing particles in a commercialized capsule, the in-vitro dissolution rate of CBD loaded zeolite was significantly higher after 30 min in the simulated stomach (pH 1.8) and the intestinal (pH 6.8) fluids, 67.8 % versus 43.6 % and 62.6 % vs 38.4 % respectively. Our findings open new avenues for the use of zeolites as an efficient drug delivery system for drugs with low bioavailability like CBD.

Background Renal fibrosis is a major manifestation of chronic kidney disease. To date, there are no treatments to reverse kidney fibrosis. Cannabis is an aromatic herb that is widely known for its anti-diabetic and anti-inflammatory properties. The aim of this study is to evaluate the protective effect of Lebanese cannabis oil extract (COE) against folic acid (FA) induced renal injury both in vitro and in vivo. Materials and methods A single dose of 250 mg/kg of Folic acid was administered to induce renal fibrosis in rats. COE was injected at varying doses of 5, 10, and 20 mg/kg. Body weight of rats were monitored and clinical parameters including serum creatinine, urea, and electrolytes were measured. Moreover, pathological examination of the kidney and heart was performed. Conditionally immortalized cultured rat podocytes were exposed to high concentrations of folic acid in the presence or absence of COE. MTS and in vitro scratch assay were used to assess podocyte cells viability and migration respectively. Western blot analysis was used to evaluate the phosphorylation levels of AKT and p38 MAPK. Results Rats that received FA showed a marked increase in serum creatinine when compared to the non-treated control group. COE at doses of 5 and 10 mg/kg significantly decreased serum creatinine induced by FA. Serum sodium was significantly reduced in all the groups receiving COE. Furthermore, COE ameliorated renal and cardiac pathology abnormalities caused by FA in a dose-dependent manner. Cell viability assay revealed that COE reversed cytotoxicity induced by FA in rat podocytes. In vitro scratch assay showed that COE partially restored the migratory capacity of podocytes incubated with FA. Dose-dependent experiments showed that COE (1 and 2μg/ml) induced a significant increase of phospho-(S473)-AKT along with a decrease in phospho (T180 + Y182) P38 levels. Conclusion The current results revealed important protective effect of Lebanese cannabis oil extract against folic acid—induced renal fibrosis in rats.

Ethnopharmacological relevance The Cannabis sativa L. ssp. indica (Lam.) plant has been historically utilized as a natural herbal remedy for the treatment of several ailments. In Lebanon, cannabis extracts have long been traditionally used to treat arthritis, diabetes, and cancer. Aim of the study The current study aims to investigate the anti-cancer properties of Lebanese cannabis oil extract (COE) on acute myeloid leukemia using WEHI-3 cells, and a WEHI-3-induced leukemia mouse model. Materials and methods WEHI-3 cells were treated with increasing concentrations of COE to determine the IC50 after 24, 48 and 72-h post treatment. Flow cytometry was utilized to identify the mode of cell death. Western blot assay was performed to assess apoptotic marker proteins. In vivo model was established by inoculating WEHI-3 cells in BALB/c mice, and treatment commencing 10 days post-inoculation and continued for a duration of 3 weeks. Results COE exhibited significant cytotoxicity with IC50 of 7.76, 3.82, and 3.34 μg/mL at 24, 48, and 72 h respectively post-treatment. COE treatment caused an induction of apoptosis through an inhibition of the MAPK/ERK pathway and triggering a caspase-dependent apoptosis via the extrinsic and intrinsic modes independent of ROS production. Animals treated with COE exhibited a significantly higher survival rate, reduction in spleen weight as well as white blood cells count. Conclusion COE exhibited a potent anti-cancer activity against AML cells, both in vitro and in vivo. These findings emphasize the potential application of COE as a chemotherapeutic adjuvant in treatment of acute myeloid leukemia.

The majority of drugs are metabolized by cytochrome P450 (CYP) enzymes, primarily belonging to the CYP1, CYP2 and CYP3 families. Genetic variations are the main cause of inter-individual differences in drug response, which constitutes a major concern in pharmacotherapy. G-quadruplexes (G4s), are non-canonical DNA and RNA secondary structures formed by guanine-rich sequences. G4s have been implicated in cancer and gene regulation. In this study, we investigated putative G4-forming sequences (PQSs) in the CYP genes. Our findings reveal a high density of PQSs in the full genes of CYP family 2. Moreover, we observe an increased density of PQSs in the promoters of CYP family 1 genes compared to non-CYP450 genes. Importantly, stable PQSs were also identified in all studied CYP genes. Subsequently, we assessed the impact of the most frequently reported genetic mutations in the selected genes and the possible effect of these mutations on G4 formation as well as on the thermodynamic stability of predicted G4s. We found that 4 SNPs overlap G4 sequences and lead to mutated DNA and RNA G4 forming sequences in their context. Notably, the mutation in the CYP2C9 gene, which is associated with impaired (S)-warfarin metabolism in patients, alters a G4 sequence. We then demonstrated that at least 10 of the 13 chosen cytochrome P450 G4 candidates form G-quadruplex structures in vitro, using a combination of spectroscopic methods. In conclusion, our findings indicate the potential role of G-quadruplexes in the regulation of cytochrome genes, and emphasize the importance of G-quadruplexes in drug metabolism.

Daucus carota L., a member of the Apiaceae family, comprises 13 subspecies, with one being cultivated (D. carota L. ssp. sativus (Hoffm.) Arcang.) and the remaining being wild. Traditionally, the wild carrot has been recognized for its antilithic, diuretic, carminative, antiseptic, and anti-inflammatory properties and has been employed in the treatment of urinary calculus, cystitis, gout, prostatitis, and cancer. While extensive literature is available on the phytochemical, pharmacological, and therapeutic evaluations of the cultivated carrot, limited information has been published on the wild carrot. A thorough search was conducted on the phytochemical composition, folk-medicine uses, and pharmacological properties of wild carrot subspecies (Daucus carota L. ssp. carota). Various electronic databases were consulted, and the literature spanning from 1927 to early 2023 was reviewed. Thirteen wild Daucus carota subspecies were analyzed, revealing over 310 compounds, including terpenoids, phenylpropenoids, flavonoids, and phenolic acids, with 40 constituting more than 3% of the composition. This review also highlights the antioxidant, anticancer, antipyretic, analgesic, antibacterial, antifungal, hypolipidemic, and hepato- and gastroprotective properties of wild carrot subspecies. Existing in vitro and in vivo studies support their traditional uses in treating infections, inflammation, and cancer. However, further research on other subspecies is required to confirm additional applications. Well-designed preclinical and clinical trials are still necessary to establish the safety and efficacy of wild Daucus carota for human use.

The present study deals with the assessment of acrylamide levels, dietary intake and toxicity associated with food products which constitute the main components of a Lebanese breakfast including bread, crackers, toast and kaak. Quantification of acrylamide levels was performed on a UPLC-MS/MS spectrometer and upon correlation with the results of a community survey, the carcinogenic and neurotoxic risks associated with the dietary intake of acrylamide were calculated.The average exposure to acrylamide from the investigated dietary products was found to be 5 times higher than the intake of 0.08 μg/kg-bw/day, as estimated by the NFCA (Norwegian Food Control Authority) and 3 times higher than the intake of 0.14 μg/kg-bw/day as set by the WHO (World Health Organization). MOEN and MOEC (Margin of Exposure for neurotoxic and carcinogenic risks) values ranged between 290 and 556, and between 449 and 861 respectively.Kaak, Crackers, and Toast appear to pose no neurotoxic or carcinogenic risk of concern among the entire population as well as the individual age groups. French bread and Lebanese bread pose different levels of carcinogenic risk among the entire population as well as various age groups. The results also indicate that 24% of children, 4% of young adults and 8% of adults are at both neurotoxic and carcinogenic risks.

Daucus carota L. ssp. carota oil extract (DCOE) was shown to possess potent antitumor activity. This study investigates the chemopreventive and chemotherapeutic effects of DCOE against breast cancer induced by 7,12-Dimethylbenz(a)anthracene (DMBA) in rats. In the chemopreventive study, animals were pre-treated with DCOE (25 mg/kg; 1 week) followed by 14 weeks of treatment post-cancer induction with DMBA. In the chemotherapeutic study, animals were allocated into control, DCOE (25 mg/kg) and Cisplatin (2.5mg/kg) groups. When tumor size reached a diameter of 14-15 mm, the animals were divided into three groups each injected by either a vehicle (thrice a week), DCOE (thrice a week) or Cisplatin (twice a week), for 8 weeks to compare and assess the therapeutic value of DCOE with respect to Cisplatin and the vehicle. At 24 weeks, the experiment was terminated. DCOE pre-treatment protected against DMBA-induced toxicity and reduced tumor incidence. While 18% of control died few days post DMBA treatment, 100% survival in DCOE pre-treated group was observed just before week 8. In the chemotherapeutic experiment, treatment with either DCOE or Cisplatin caused significant inhibition of tumor growth. Unlike DCOE, Cisplatin caused drastic decrease in body weight with 75% and 100% death rates at week 6 and 8 respectively. DCOE produced a significant increase in Bax/Bcl2 ratio, Cytochrome c and cleaved caspase 3 proteins. DCOE may be considered a safe chemopreventive and/or chemotherapeutic agent, an effect that is partly due to the induction of the intrinsic apoptotic pathway.

Laurus nobilis, commonly known as bay, is used in folk medicine as a remedy for many ailments. The present study investigates the protective effect of L. nobilis leaves extract against high fat diet-induced type 2 diabetes in rats. Animals were divided into group 1 (control), groups 2, 3, and 4 (bay leaves aqueous (AQ) extracts; 50, 100, and 250 mg/kg of body weight, respectively), and groups 5, 6, and 7 (bay leaves methanol/acetone (MeAc) extract; 50, 100, and 250 mg/kg of body weight, respectively). Animals were fed an isocaloric high fat diet for four weeks. The intake of bay leaves extracts was associated with a significant decreases in serum levels of glucose (AQ, 100 and 250 mg/kg; MeAc, 50, 100, and 250 mg/kg) and serum triglyceride (AQ, 250 mg/kg; MeAc, 100, and 250 mg/kg) as well as lower abdominal fat (all AQ and MeAc groups) and body weight gain (MeAc groups only). In conclusion, L. nobilis leaves extract intake provides a protective remedy against high fat diet-induced type 2 diabetes. Key words: Laurus nobilis, type 2 diabetes, bay leaves, high fat diet.

Ethnopharmacological relevance: Cannabis sativa L. is an aromatic annual herb belonging to the family Cannabaceae and it is widely distributed worldwide. Cultivation, selling, and consumption of cannabis and cannabis related products, regardless of its use, was prohibited in Lebanon until April 22, 2020. Nevertheless, cannabis oil has been traditionally used unlawfully for many years in Lebanon to treat diseases such as arthritis, diabetes, cancer and few neurological disorders. Aim of the study: The present study aims to evaluate the phytochemical and anti-inflammatory properties of a cannabis oil preparation that is analogous to the illegally used cannabis oil in Lebanon. Materials and methods: Dried Cannabis flowers were extracted with ethanol without any purification procedures to simulate the extracts sold by underground dealers in Lebanon. GC/MS was performed to identify chemical components of the cannabis oil extract (COE). In vivo anti-inflammatory effect of COE was evaluated by using carageenan- and formalin-induced paw edema rat models. TNF-alpha production were determined by using LPS-activated rat monocytes. Anti-inflammatory markers were quantified using Western blot. Results: Chemical analysis of COE revealed that cannabidiol (CBD; 59.1%) and tetrahydrocannabinol (THC; 20.2%) were found to be the most abundant cannabinoids.Various monoterpenes (alpha-Pinene, Camphene, beta-Myrecene and D-Limonene) and sesquiterpenes (beta-Caryophyllene, alpha-Bergamotene, alpha-Humelene, Humulene epoxide II, and Caryophyllene oxide) were identified in the extract. Results showed that COE markedly suppressed the release of TNF-alpha in LPS-stimulated rat monocytes. Western blot analysis revealed that COE significantly inhibited LPS-induced COX-2 and i-NOS protein expressions and blocked the phosphorylation of MAPKs, specifically that of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 MAPK. COE displayed a significant inhibition of paw edema in both rat models. Histopathological examination revealed that COE reduced inflammation and edema in chronic paw edema model. Conclusion: The current findings demonstrate that COE possesses remarkable in vivo and in vitro anti-inflammatory activities which support the traditional use of the Lebanese cannabis oil extract in the treatment of various inflammatory diseases including arthritis.

The present study aims to determine the carcinogenic and neurotoxic risks associated with acrylamide intake from cereal products. Analysis on a UPLC–MS/MS spectrometer revealed that oat-based and mixed cereals contain the highest amount of acrylamide among cereal products with levels as high as 271 and 348 μg/kg, respectively. Children were shown to exhibit both carcinogenic and neurotoxic risks regardless of the type of cereal product consumed. For adults above 50 years of age, only consumers of oat-based cereal products seem to exhibit carcinogenic and neurotoxic risks. To avoid a carcinogenic and neurotoxic risk among the Lebanese population, we propose that food processors set the maximum tolerable concentration for acrylamide in cereal products at 94.8 μg/kg product, a value which is threefolds lower than the average acrylamide levels found in this study. Alternatively, and unreasonably, the average Lebanese population and children among the Lebanese population may choose to cut down on cereal consumption by 1.7- and 7.2-folds respectively, should they want to avoid a health hazard as a result of acrylamide intake. The industry should also respond by optimizing the production process in a way to reduce acrylamide levels in cereals.

New tetrahydro-1H-pyrazolo[3,4-b]quinoline derivatives were designed, synthesized and characterized as dual anticholinestrase and cyclooxygenase-2 inhibitors. The in vitro and in vivo anti-cholinesterase evaluation exhibited promising activities with lower hepatotoxicity for many candidates compared to tacrine as a reference. Furthermore, their anti-inflammatory activity using in vitro (COX-1/COX-2) inhibitory assay demonstrated superior activity to celecoxib with higher selectivity indices for some compounds. In addition, some candidates showed extended anti-inflammatory activity by inhibiting COX-2 protein induction. Besides, in silico docking experiments of the active compounds against hAChE rationalized the observed in vitro AChE inhibitory activity. In conclusion, this work provides an extension of the chemical space of tetrahydro-1H-pyrazolo[3,4-b]quinoline chemotype for the anticholinestrase and anti-inflammatory activity. This would aid to minimize the possible neuroinflammation linked to the pathogenesis of Alzheimer's disease.

The dinuclear complex Bis[(u-azido)-chloro-(1,10-phenanthroline)-copper(II)] (1) was synthesized, and characterized by X-ray. Complex (1) crystallizes in the monoclinic system, it consists of centrosymmetric [CuCl(phen)-mu-N-3](2) dimers bridged by azide groups. The phenanthroline ligand, chloride ion, and eta-N of equatorial bridging azide ligand are coplanar and the square pyramidal copper ion is displaced slightly out of this basal plane, toward the axial bridging azide. The presence of H-bonds, CH-pi and pi-pi interactions form layers of type ABAB within the supramolecular structure of (1). The magnetic susceptibility of (1) versus temperature data showed a weak antiferromagnetic coupling between Cu(II) ions. The best fitting parameters were for g = 2.01 +/- 0.01 and J = 0.55 +/- 0.01 cm(-1). Thermal analysis of (1) exhibited an exothermic peak due to decomposition of azide ligands. The calculated HOMO-LUMO gap from DFT is 0.03098 a.u. (0.08430 eV). Besides, complex (1) exhibited potent chemotherapeutic potential with strong activity after 48 h against MDA-MB-32 (breast adenocarcinoma), HT-29 (colon adenocarcinoma), A549 (lung adenocarcinoma), SF (astrocytoma) and B1 6F10 (melanoma) cell lines, with IC50 value 0.78 mu g/ml (1.21 uM) which is several folds higher than cisplatin 4.88 mu g/ml (16.3 mu M). (1) also has a better therapeutic index and toxicological profile compared to cisplatin, as evidenced by the median lethal dose (LD50).

Ethnopharmacological relevance: Cedrus libani A. Rich (C. libani) is majestic evergreen Mediterranean conifer growing in the mountains of Lebanon. The ethnobotanical and traditional uses of cedar wood oil traces back to ancient times for the treatment of various ailments including cancer. Previous work in our laboratories revealed that himachalol (7-HC), a major sesquiterpene isolated from C. libani, possesses potent cytotoxic activity against various human cancer cell lines as well as promising anti-inflammatory effect in isolated rat monocytes. Aim of the study: The present study aims to elucidate the mechanism of action behind the cytotoxic activity of 7-HC against murine melanoma cells (B16F-10) and evaluates its chemopreventive effect against chemically-induced skin carcinogenesis in mice. Materials and methods: 7-HC was extracted and purified from Cedrus libani wood. Cell viability was evaluated using WST-1 kit. Cell cycle analysis and apoptosis were assessed by Flow cytometry using propidium iodide (PI) and fluorescein Isothiocyanate (FITC)-conjugated Annexin V/PI staining respectively. Apoptosis related protein were quantified using western blot. The chemopreventive activity of 7-HC was evaluated for 20 weeks using a DMBA/TPA induced skin carcinogenesis model in Balb/c mice. Results: 7-HC displayed a potent anti-proliferative activity against the melanoma cells with an IC50 of 8.8 mu g/ml and 7.3 mu g/ml at 24 and 48 h, respectively. Co-treatment with Cisplatin did not show any synergistic or additive effect on cell viability. Flow cytometry analysis using PI revealed that 7-HC treatment (5 and 10 mu g/ml) induces the accumulation of cells in the sub-G1 phase and causes a decline in cell populations in the S and G2/M phases. Annexin/PI staining also reveals that 7-HC treatment significantly increases the percentage of cells undergoing early and late apoptosis. Western blot analysis shows that 7-HC treatment decreases the level of the antiapoptotic protein Bcl-2 and increases the level of the pro-apoptotic protein Bax. A reduction in the level of phosphorylated Erk and Akt was also observed. 7-HC via topical (2.5%), intraperitoneal (10, 25 and 50 mg/kg) or gavage (50 mg/kg) treatment revealed a significant decrease in papilloma volume with no adverse effect on liver and kidney function. Conclusions: The present study demonstrates that 7-HC treatment protects against chemically-induced skin carcinogenesis, promotes cell cycle arrest and induces apoptosis partially through an inhibition of both the MAPK/Erk and PI3K/Akt pathways.