Evaluating the Therapeutic Potential of Curcumin and Synthetic Derivatives: A Computational Approach to Anti-Obesity Treatments.

Natural compounds such as curcumin, a polyphenolic compound derived from the rhizome of turmeric, have gathered remarkable scientific interest due to their diverse metabolic benefits including anti-obesity potential. However, curcumin faces challenges stemming from its unfavorable pharmacokinetic profile. To address this issue, synthetic curcumin derivatives aimed at enhancing the biological efficacy of curcumin have previously been developed. In silico modelling techniques have gained significant recognition in screening synthetic compounds as drug candidates. Therefore, the primary objective of this study was to assess the pharmacokinetic and pharmacodynamic characteristics of three synthetic derivatives of curcumin. This evaluation was conducted in comparison to curcumin, with a specific emphasis on examining their impact on adipogenesis, inflammation, and lipid metabolism as potential therapeutic targets of obesity mechanisms. In this study, predictive toxicity screening confirmed the safety of curcumin, with the curcumin derivatives demonstrating a safe profile based on their LD50 values. The synthetic curcumin derivative 1A8 exhibited inactivity across all selected toxicity endpoints. Furthermore, these compounds were deemed viable candidate drugs as they adhered to Lipinski's rules and exhibited favorable metabolic profiles. Molecular docking studies revealed that both curcumin and its synthetic derivatives exhibited favorable binding scores, whilst molecular dynamic simulations showed stable binding with peroxisome proliferator-activated receptor gamma (PPARγ), csyclooxygenase-2 (COX2), and fatty acid synthase (FAS) proteins. The binding free energy calculations indicated that curcumin displayed potential as a strong regulator of PPARγ (-60.2 ± 0.4 kcal/mol) and FAS (-37.9 ± 0.3 kcal/mol), whereas 1A8 demonstrated robust binding affinity with COX2 (-64.9 ± 0.2 kcal/mol). In conclusion, the results from this study suggest that the three synthetic curcumin derivatives have similar molecular interactions to curcumin with selected biological targets. However, in vitro and in vivo experimental studies are recommended to validate these findings.

Therapeutic Effects of Curcumin Derivatives against Obesity and Associated Metabolic Complications: A Review of In Vitro and In Vivo Studies.

Obesity is a major cause of morbidity and mortality globally, increasing the risk for chronic diseases. Thus, the need to identify more effective anti-obesity agents has spurred significant interest in the health-promoting properties of natural compounds. Of these, curcumin, the most abundant and bioactive constituent of turmeric, possesses a variety of health benefits including anti-obesity effects. However, despite its anti-obesity potential, curcumin has demonstrated poor bioavailability, which limits its clinical applicability. Synthesizing curcumin derivatives, which are structurally modified analogs of curcumin, has been postulated to improve bioavailability while maintaining therapeutic efficacy. This review summarizes in vitro and in vivo studies that assessed the effects of curcumin derivatives against obesity and its associated metabolic complications. We identified eight synthetic curcumin derivatives that were shown to ameliorate obesity and metabolic dysfunction in diet-induced obese animal models, while five of these derivatives also attenuated obesity and associated metabolic complications in cell culture models. These curcumin derivatives modulated adipogenesis, lipid metabolism, insulin resistance, steatosis, lipotoxicity, inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis, autophagy, fibrosis, and dyslipidemia to a greater extent than curcumin. In conclusion, the findings from this review show that compared to curcumin, synthetic curcumin derivatives present potential candidates for further development as therapeutic agents to modulate obesity and obesity-associated metabolic complications.

Substituent and solvent effects on UV-visible absorption spectra of chalcones derivatives: Experimental and computational studies.

The electronic spectra of the title compounds were measured in ethanol and cyclohexane. Three band systems are distinguished in the spectra of which the first and second band systems are attributed to local excitation of PhCH and PhCO rings. The third absorption band is assigned to a charge transfer (CT) band and is associated with the CO-CH=CH moiety. The solvent plays an important role in the absorption spectra and causes the CT band to consist of two electronic transitions. The effect of substituents on the phenyl rings on the charge transfer band of chalcone derivatives was also established in the two solvents. The converged gas-phase geometries of the studied chalcones was optimized using the DFT PBE0 functional with the basis set 6-311++G**. DFT calculations has been performed for an ethanol solution (using TD-PBE0/6-311++G**) level to understand electronic transitions on terms of energies and oscillator strengths to study the substituent effect on the electronic transitions of the chalcone derivatives. To consider the solvation effect of ethanol on the absorptions, the integral equation formalism variant of the polarizable continuum model (IEFPCM) was used. The calculated energies were in good agreement with experiment results. The molecular modelling technique was followed to monitor the effect of substitutions on the HOMO/LUMO energy and total dipole moment. Transitions between natural transition orbitals are also described as part of this study.

Utilization of additive from waste products with gasoline fuel to operate spark ignition engine.

Impacts of blending fusel oil with gasoline on fuel combustion have been investigated experimentally in the current research to evaluate engine performance improvement and exhaust emission. Tested fuel include F10, F20 (10% and 20% of fusel oil by volume) and pure gasoline as baseline fuel have been used to operate 4-cylinder SI engine at increasing engine speed and constant throttle valve of 45%. The present results reveal a shorter combustion duration and better engine performance with F10 over engine speeds with maximum value of 33.9% for the engine brake thermal efficiency. The lowest BSFC of 251 g/kW h was recorded at 3500 rpm engine speed also with F10. All blended fuel have almost similar COVIMEP. Less NOx emission was measured with F10 at 4500 engine speed compared to gasoline. However, CO emissions reduced while higher CO2 was observed with introducing fusel oil in the blend. Moreover, HC emission increased an average by 11% over speed range and the highest value was achieved with 10% fusel oil addition compared to 20% and pure gasoline. Accordingly, higher oxygen content of fusel oil and octane number contribute to improve combustion of fuel mixture.

In Silico and In Vitro Screening of 50 Curcumin Compounds as EGFR and NF-κB Inhibitors.

The improvement of cancer chemotherapy remains a major challenge, and thus new drugs are urgently required to develop new treatment regimes. Curcumin, a polyphenolic antioxidant derived from the rhizome of turmeric (Curcuma longa L.), has undergone extensive preclinical investigations and, thereby, displayed remarkable efficacy in vitro and in vivo against cancer and other disorders. However, pharmacological limitations of curcumin stimulated the synthesis of numerous novel curcumin analogs, which need to be evaluated for their therapeutic potential. In the present study, we calculated the binding affinities of 50 curcumin derivatives to known cancer-related target proteins of curcumin, i.e., epidermal growth factor receptor (EGFR) and nuclear factor κB (NF-κB) by using a molecular docking approach. The binding energies for EGFR were in a range of −12.12 (±0.21) to −7.34 (±0.07) kcal/mol and those for NF-κB ranged from −12.97 (±0.47) to −6.24 (±0.06) kcal/mol, indicating similar binding affinities of the curcumin compounds for both target proteins. The predicted receptor-ligand binding constants for EGFR and curcumin derivatives were in a range of 0.00013 (±0.00006) to 3.45 (±0.10) µM and for NF-κB in a range of 0.0004 (±0.0003) to 10.05 (±4.03) µM, indicating that the receptor-ligand binding was more stable for EGFR than for NF-κB. Twenty out of 50 curcumin compounds showed binding energies to NF-κB smaller than −10 kcal/mol, while curcumin as a lead compound revealed free binding energies of >−10 kcal/mol. Comparable data were obtained for EGFR: 15 out of 50 curcumin compounds were bound to EGFR with free binding energies of <−10 kcal/mol, while the binding affinity of curcumin itself was >−10 kcal/mol. This indicates that the derivatization of curcumin may indeed be a promising strategy to improve targe specificity and to obtain more effective anticancer drug candidates. The in silico results have been exemplarily validated using microscale thermophoresis. The bioactivity has been further investigated by using resazurin cell viability assay, lactate dehydrogenase assay, flow cytometric measurement of reactive oxygen species, and annexin V/propidium iodide assay. In conclusion, molecular docking represents a valuable approach to facilitate and speed up the identification of novel targeted curcumin-based drugs to treat cancer.

Comparative study with practical validation of photovoltaic monocrystalline module for single and double diode models.

A photovoltaic (PV) module is an equipment that converts solar energy to electrical energy. A mathematical model should be presented to show the behavior of this device. The well-known single-diode and double-diode models are utilized to demonstrate the electrical behavior of the PV module. "Matlab/Simulink" is used to model and simulate the PV models because it is considered a major software for modeling, analyzing, and solving dynamic system real problems. In this work, a new modeling method based on the "Multiplexer and Functions blocks" in the "Matlab/Simulink Library" is presented. The mathematical analysis of single and double diodes is conducted on the basis of their equivalent circuits with simple modification. The corresponding equations are built in Matlab by using the proposed method. The unknown internal parameters of the PV panel circuit are extracted by using the PV array tool in Simulink, which is a simple method to obtain the PV parameters at certain weather conditions. Double-diode model results are compared with the single-diode model under various irradiances and temperatures to verify the performance and accuracy of the proposed method. The proposed method shows good agreement in terms of the I-V and P-V characteristics. A monocrystalline NST-120 W PV module is used to validate the proposed method. This module is connected to a variable load and tested for one summer day. The experimental voltage, current, and power are obtained under various irradiances and temperatures, and the I-V and P-V characteristics are obtained.

In silico molecular docking and in vitro antioxidant activity studies of novel α-aminophosphonates bearing 6-amino-1,3-dimethyl uracil.

In the present study, a new series of α-Aminophosphonates bearing 6-amino-1,3-dimethyluracil was synthesized in good to excellent yields (78-95%) by one-pot, three-component reaction of 6-amino-1,3-dimethyluracil, aromatic aldehydes and diethylphosphite via Kabachnik-Fields reaction by using an eco-friendly Eaton's reagent. All the compounds were screened for in vitro antioxidant studies by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) methods. Among the synthesized bioactive molecules, 4a, 4d, 4g, and 4h exhibited promising antioxidant activity compared with the standard drug Ascorbic acid. Furthermore, in order to support the biological results of the compounds, molecular docking studies were performed against Aromatase enzyme for four compounds which revealed that the compounds 4a, 4d, 4g, and 4h have significant binding modes, with docking scores of -8.6, -8.4, -8.1 and -8.1 respectively and the compound 4b specifically has equal dock score of -8.0 when compared with the standard drug Exemestane.

Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines.

BACKGROUND: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF-CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. MATERIAL AND METHODS: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC50 values and binding energies. RESULTS: The compounds displayed IC50 values between 0.7±0.03 and 20.2±0.25µM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from -9.00±0.10 to -6.20±0.02kcal/mol and pKi values from 0.24±0.04 to 29.17±0.88µM. At the ATP-binding site of P-gp, lowest binding energies ranged from -9.78±0.17 to -6.79±0.01kcal/mol and pKi values from 0.07±0.02 to 0.03±0.03µM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF-CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R=0.797 and R=0.794 for training and test sets). CONCLUSION: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR.

Biopiracy of natural products and good bioprospecting practice.

BACKGROUND: Biopiracy mainly focuses on the use of biological resources and/or knowledge of indigenous tribes or communities without allowing them to share the revenues generated out of economic exploitation or other non-monetary incentives associated with the resource/knowledge. METHODS: Based on collaborations of scientists from five continents, we have created a communication platform to discuss not only scientific topics, but also more general issues with social relevance. This platform was termed 'PhytCancer -Phytotherapy to Fight Cancer' (www.phyt-cancer.uni-mainz.de). As a starting point, we have chosen the topic "biopiracy", since we feel this is of pragmatic significance for scientists working with medicinal plants. RESULTS: It was argued that the patenting of herbs or natural products by pharmaceutical corporations disregarded the ownership of the knowledge possessed by the indigenous communities on how these substances worked. Despite numerous court decisions in U.S.A. and Europe, several international treaties, (e.g. from United Nations, World Health Organization, World Trade Organization, the African Unity and others), sharing of a rational set of benefits amongst producers (mainly pharmaceutical companies) and indigenous communities is yet a distant reality. In this paper, we present an overview of the legal frameworks, discuss some exemplary cases of biopiracy and bioprospecting as excellent forms of utilization of natural resources. CONCLUSIONS: We suggest certain perspectives, by which we as scientists, may contribute towards prevention of biopiracy and also to foster the fair utilization of natural resources. We discuss ways, in which the interests of indigenous people especially from developing countries can be secured.

A new vanadium (III) complex of 2,6-bis(3,5-diphenylpyrazol-1-ylmethyl)pyridine as a catalyst for ethylene polymerization.

The tridentate ligand 2,6-bis(3,5-diphenylpyrazol-1-ylmethyl)pyridine, abbreviated as 2,6-[(3,5-ph2pz-CH2)2-py], a new pyridine-pyrazole derivative, was prepared from 2,6-bis(bromomethyl)pyridine and 3,5-diphenylpyrazole. The ligand was characterized by means of elemental analyses, ATR-IR, ¹H- and ¹³C-NMR spectroscopy and single crystal X-ray crystallography. Using this ligand, a new mononuclear vanadium (III) complex, {2,6-[(3,5-ph2pz)CH2]2py}VCl3 was prepared and characterized by elemental analysis, ATR-IR and HR-MS. The complex was investigated as a catalyst for ethylene polymerization and compared with 2,6-[(3,5-Me2pz)CH2]2py}VCl3 to explore the effect of the substituent on the pyrazolyl rings on ethylene polymerization. High catalytic activity was observed at ambient temperature. After treatment with AlEtCl2, these complexes showed high activity for ethylene polymerization converting ethylene to highly linear polyethylene and affording high molecular weight polymers (up to 1.0 × 106 g/mol) with unimodal molecular weight distributions.

Do personal beliefs and peers affect the practice of alcohol consumption in university students in Lebanon?

Alcohol consumption is frequent among university students in Lebanon as elsewhere in the world. A cross- sectional study was conducted in Lebanon's public and private universities between October 2009 and September 2010 using a standardized questionnaire to assess personal beliefs about alcohol consumption, peers' behaviours and opinions and history of and current drinking practices. Of 1235 students, 199 [16.1%] had an AUDIT score >/=. Older age, male sex, Christian religion, attending a private university, studying a non-health specialty and residing in Beirut or Mount Lebanon were associated with a higher risk of harmful drinking. Beliefs concerning alcohol consumption and peers' opinions and behaviours were factors significantly associated with harmful drinking, especially: ignoring the dangers of alcohol consumption; higher frequency of consumption with friends; and a higher proportion of friends who drank regularly. University students'alcohol drinking behaviour was mostly influenced by peers' behaviour, and a peer education programme is recommended to decrease the risk of harmful drinking

Description and surface topography of the cercaria of Austrobilharzia sp. (Digenea: Schistosomatidae).

The cercaria of Austrobilharzia sp. from the marine prosobranch gastropod Planaxis sulcatus in Kuwait Bay is described. The surface microtopography and pattern of the tegumentary sensory receptors are examined using scanning electron microscopy. The general microtopography of the surface of the cercaria is similar to that previously observed in cercariae of mammalian schistosomes, although differences are recorded in the types, numbers and distribution of the sensory receptors. The study identified more than 13 types of receptors comprising aciliated, uniciliated and for the first time a multiciliated receptor in a strigeid cercaria. The ciliated receptor types differ in the cilium length and structure of the surrounding collar and tegumentary base. The receptor types are site specific: (1) the aciliated and pitlike on the anterior organ-neck region and ventral sucker; (2) the uniciliated with a long flexible cilium with or without collar or a tegumentary base on the body and tail; and (3) the uniciliated with a short rigid cilium and a robust collar and tegumentary base, and the multiciliated with 6 flexible cilia and a high cylindrical collar on the anterior organ tip. The reported SEM information on the sensory receptors may contribute to elucidating their functional role and to establishing morphological characters for the phylogeny of the family Schistosomatidae.

Temporal variations in the infection of a population of Cerithidea cingulata by larval trematodes in Kuwait Bay.

The prosobranch gastropod Cerithidea cingulata (Gastropoda: Potamididae) in Kuwait Bay was examined for larval trematode infections over a 17-month period. A total of 2537 snails were examined and 1265 (49.9%) found to be infected with one or more species of trematodes. The component community in the snail comprised 12 species representing the families Cyathocotylidae (2), Echinostomatidae (2), Haplosplanchnidae (1), Heterophyidae (2), Microphallidae (1), Philophthalmidae (2), Plagiorchiidae (1) and Schistosomatidae (1). Cyathocotylid II (41.6%) was by far the most prevalent species followed by the microphallid (3.9%), the two species comprised 90% of the total trematode fauna. The prevalence of infection increased with shell size and was significantly higher in male (47%) than female (33%) snails. Multiple infections were observed in only 15 (1.2%) of the infected snails; cyathocotylid I and cyathocotylid II combination occurred 14 times and heterophyid I and the microphallid occurred once. Trematode species were more diverse and prevalent in winter, and cercarial shedding peaked in summer. Behaviour of the definitive host and snail population dynamics were probably the major contributors to the detected temporal pattern in the infections.

Surface morphology of Probolocoryphe uca (Sarkisian, 1957) (Digenea: Microphallidae) from Kuwait bay.

The surface ultrastructure of Probolocoryphe uca (Digenea: Microphallidae), recovered from a rat experimentally fed on crabs, Nanosesarma minutum (Brachyura: Grapsidae), naturally infected with the metacercariae, was studied by scanning electron microscopy. The flukes were leaf-like, ventrally concave and pyriform or ovoid in outline. The anterior end was modified into a sucker-like organ, comprising a protrusible disc-shaped structure surrounded by single-pointed spines. This organ is probably involved in the attachment and feeding process in a manner similar to the action of the oral suckers. Apart from the sucker-like organ, the entire tegumental surface was covered with triangular spines with multi-pointed tips. Ciliated, dome-shaped papillae were observed, singly or in groups, arranged symmetrically on the sucker-like organ and around the oral and ventral suckers. Kuwait Bay constitutes a new geographical record and the crab N. minutum is a new second intermediate host record for P. uca.

Surface ultrastructure of Stictodora tridactyla (Trematoda: Heterophyidae) from Kuwait Bay.

The surface morphology of Stictodora tridactyla recovered from a kitten that was fed the killifish, Aphanius dispar, naturally infected with the metacercariae was studied using scanning electron microscopy. The body comprised a rounded head, elongate neck, and widely pyriform hind-body. The head bore a circular oral sucker on the ventral side, and concentric rows of peg-like cephalic spines on the dorsal side. The oral sucker was armed with pre-oral spines similar in shape and size to the cephalic spines. The neck and hind-body were densely covered with scale-like multipointed spines, the size and density of which decreased from anterior to posterior parts of the body. Ciliated dome-shaped papillae were found solitarily or as conjugated groups on the head apex and lips of the oral sucker. Non-ciliated dome-shaped papillae were restricted to the lower lip of the oral sucker. The body was devoid of a ventral sucker. The genital opening appeared as a round depression of the tegument at about the anterior third of the body. This is the first record of the occurrence of S. tridactyla in the Arabian Gulf region and A. dispar is a new second intermediate host.

Studies on Cercariae from Kuwait Bay. XI. Description and surface topography of Cercaria kuwaitae XI sp.n. (Digenea: Echinostomatidae).

A new echinostome cercaria, Cercaria kuwaitae XI sp.n., from the prosobranch gastropod Cerithidea cingulata (Gmelin) from Kuwait Bay is described. The new cercaria is characterized by 23 collar spines and primary excretory tubules with distinct diverticula. The cercaria encysts in the snail host and is similar to those of Acanthoparyphium sp. The surface topography of the redia, cercaria and metacercarial cyst wall is studied by scanning electron microscopy. This is the first echinostome cercaria to be recorded in a gastropod from the Arabian Gulf region.

Temporal variations in the infection of a population of Clypeomorus bifasciata (Gastropoda: Prosobranchia) by a digenean microphallid larva in Kuwait Bay.

The prosobranch snail Clypeomorus bifasciata in Kuwait Bay was examined for digenean infections over a one year period during 1994/1995. A total of 1500 snails was examined and 567 (37.8%) were found to harbour nine digenean species. The prevalence of a microphallid species was 33.9% while each of the others occurred in less than 1.2% of the snails. The prevalence of infection increased with shell size. Multiple infections were observed in only five of the infected snails and the microphallid was involved in all of them. Snails were infected with the microphallid throughout the year and there appeared to be two peaks in the proportion of infected snails shedding cercariae, a winter peak from November to January and a summer peak from June to August. The crab Xantho exaratus collected from snail sampling sites was heavily parasitized by microphallid metacercariae of the genera Longiductotrema and Microphallus. This is the first report on microphallid metacercariae in crabs in the Arabian Gulf region.

Studies on Cercariae from Kuwait Bay. X. Description and surface topography of Cercaria kuwaitae X sp. n. (Digenea: Renicolidae).

A new renicolid cercaria, Cercaria kuwaitae X sp. n., from the prosobranch gastropod Cerithium scabridum from Kuwait Bay is described. The new cercaria is nonstyleted gymnocephalous with voluminous Y-shaped excretory vesicle, flame cell formula 2[(3 + 3 + 3) + (3 + 3 + 3)] = 36, and without caudal fins. Surface topography of the new cercaria is studied by scanning electron microscopy. Domed papillae are abundant on the anterior and lateral aspects of the body, ciliated papillae are sparse dorsally. The ventral sucker bears nine domed papillae. Domed papillae form two circles around the oral sucker with three circles of spines in between. This is the first renicolid cercaria to be recorded in a gastropod from the Arabian Gulf region.

Studies on cercariae from the Kuwait Bay. VI. Description and surface topography of Cercaria kuwaitae VI sp. n. (Trematoda: Haplosplanchnidae).

A new haplosphlanchnid cercaria, Cercaria kuwaitae VI sp. n., was found in the prosobranch snail Cerithidea cingulata in the Kuwait Bay. Details are presented on the morphology and behavior of the cercaria and the encystment process. The new cercaria is a biocellate, distome, with a prominent single sac-like intestinal cecum extending well posterior to the ventral sucker and develops in simple sporocysts. It differ from known haplosplanchnid cercariae in the absence of finger-like processes on the tail, and the presence of V-shaped excretory vesicle extending beyond ventral sucker and the presence of cervical glands. The surface topography of the cercaria and its sporocyst is examined by scanning electron microscopy. This is the first haplosplanchnid cercaria to be described from a Cerithidea species.