Sahar Majdi Jaffal

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Sahar Majdi Jaffal

ASUApplied Science Private University - Home PageDentistrySahar Majdi JaffalResearch

Research

Research Title :Jasmine sambac L. essential oil attenuates inflammation and pain via TRPV1. Accepted in Inflammopharmacology, August 2025

Authors :Jaffal SM, Aluck Thipayarat, Samer Alqaraleh, Jakrapop Wongwiwat, Pattarin Supanivatin.

Abstract :Pain and inflammation are complex physiological responses. The drugs that are available in the market have multiple side effects. Thus, the search for safer effective therapeutics became a significant area of research. In this study, Jasmine sambac L. essential oil, which is aromatic and therapeutic in nature, has been studied for its potential anti-inflammatory and anti-nociceptive activities as well as its mechanism of action. The findings from this research indicated that the intraplantar (ipl) administration of jasmine essential oil to the animals produced anti-inflammatory effects in the carrageenan-induced paw edema model. In addition, jasmine essential oil showed significant inhibition of pain responses compared to the control group in the acetic acid-induced writhing test and immersion tail-flick test. These findings suggest that jasmine oil exhibits anti-nociceptive and anti-inflammatory effects in animals. More data are needed to determine its therapeutic value in human clinical trials. The anti-inflammatory and anti-nociceptive effects were mediated by the transient receptor potential vanilloid 1 (TRPV1), a key pain receptor. The chemical composition of jasmine essential oil was analyzed by gas chromatography-mass spectrometry (GC-MS) to determine the bioactive constituents that can be responsible for these effects. The results showed that the oil consists of active constituents with various therapeutic activities as reported in earlier studies. Thus, jasmine essential oil can be utilized as a complementary therapy for pain and inflammation treatment.

Keywords :Essential oil; Inflammation; Jasmine; Mechanism; Pain; TRPV1.

Research Title :Neuroplasticity in chronic pain: insights into diagnosis and treatment.

Authors :Jaffal SM.

Abstract :Chronic pain is a universal problem that directly evolves the central nervous system, altering both its structure and function. This review discusses neuroplastic alterations in critical areas in the brain like the anterior cingulate cortex, insula, prefrontal cortex, primary (S1) and secondary (S2) somatosensory cortices, and thalamus. These regions exhibit gray matter decrease and changes in connectivity during chronic pain. Several cortical networks, mainly the central executive network, the default mode network, and the salience network exhibit neuroplasticity which reallocates cognitive and emotional resources to pain processing. Thus, it was reported that sensitivity to pain enhances emotional suffering, indicating that altered connectivity and functional reorganization of these networks support maladaptive pain processing and underpin chronic pain persistence. Neuroplasticity-focused treatments such as brain stimulation, neuro-feedback, and exercise-based therapies constitute potential interventions for preventing such negative changes. Further, innovative neuroimaging biomarkers are effective in demonstrating precise neural changes and in providing information about the diagnosis of chronic pain syndromes. This review highlights neuro-plastic changes in chronically painful patients and acknowledges the brain’s plasticity as a target for chronic pain treatment. It, also, points to the diagnostic strategies and practical interventions that address these alterations.

Keywords :Brain, Central Nervous System, Chronic Pain, Default Mode Network, Gyrus Cinguli, Neuronal Plasticity, Prefrontal Cortex, Somatosensory Cortex, Thalamus,

Research Title :Evaluation of interactions between transient receptor potential vanilloid 1 and active constituents using molecular docking.

Authors :Jaffal SM, Khan S, Khan M

Abstract :Pain, whether acute or chronic, imposes huge economic burdens in the societies due to complexities in the signaling pathways that lead to pain. There are many nociceptive receptors and channels that play key roles in the processing and maintenance of pain. Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that is considered a crucial target in pain. Drugs that are available in the market have side effects, highlighting the need to find new analgesics that have no side effects. Methods: In this study, we assessed the interactions between active constituents and TRPV1 receptor using molecular docking in comparison to capsazepine and the analgesic drug SB-3567791; 3-(4-chlorophenyl)-N-(3-methoxyphenyl)-2-propenamide. Molecular docking is a computational technique that provides calculation for the non-covalent binding of protein or receptor and ligand molecule(s) and aids in investigating the binding interaction between ligands and receptors. These selected active constituents belong to different classes of secondary metabolites including alkaloids, terpenoids, and flavonoids. Results: The results indicate promising binding affinities between and TRPV1 receptor and speciofoline, mitragynine, 7-hydroxymitragynine, salvinorin, mescaline, acacetin, ladanein, vulgarin, marrubiin, geranial, neral, epi-α-cadinol (t-cadinol), myrtenol, δ- cadinene, and α-terpineol. The compound α-calacorene showed no affinity toward TRPV1 receptor at all. Conclusion: Many active compounds are ligands for TRPV1 channel and can be assessed to determine their effects on inhibiting TRPV1 as analgesics. These results allow us to assess the effects of many of these compounds on TRPV1 channel in vivo and in vitro.

Keywords : TRPV1, active constituents, ligands, docking, receptor

Research Title :Targeting nerve growth factor for pain relief: Pros and cons. Korean Journal of pain.

Authors :Jaffal SM, Khalil, R

Abstract :Nerve growth factor (NGF) is a neurotrophic protein that has crucial roles in survival, growth and differentiation. It is expressed in neuronal and non-neuronal tissues. NGF exerts its effects via two types of receptors including the high affinity receptor, tropomyosin receptor kinase A and the low affinity receptor p75 neurotrophin receptor highlighting the complex signaling pathways that underlie the roles of NGF. In pain perception and transmission, multiple studies shed light on the effects of NGF on different types of pain including inflammatory, neuropathic, cancer and visceral pain. Also, the binding of NGF to its receptors increases the availability of many nociceptive receptors such as transient receptor potential vanilloid 1, transient receptor potential ankyrin 1, N-methyl-D-aspartic acid, and P2X purinoceptor 3 as well as nociceptive transmitters such as substance P and calcitonin gene-related peptide. The role of NGF in pain has been documented in pre-clinical and clinical studies. This review aims to shed light on the role of NGF and its signaling in different types of pain.

Keywords :Acute Disease; Chronic Disease; Inflammation; Low Back Pain; Musculoskeletal; Neoplasms; Nerve Growth Factor; Neuropathic Pain; Orofacial Pain; Osteoarthritis; Pain.

Research Title :The green synthesis of selenium nanoparticles: a comprehensive review on methodology, characterization.

Authors : Samer Alqaraleh, Wael Alzereni, Nesrin Mwafi, Sahar Jaffal, Aiman Al-Qtaitat.

Abstract :The synthesis of nanoparticles has garnered significant attention due to their wide range of applications and exceptional properties and due to the toxicity of chemicals used in conventional methods, a matter that imposes considerable risks to human health and the environment. As a response to this issue, eco-friendly alternatives known as green synthesis techniques have emerged such as selenium nanoparticles (SeNPs) that hold great promise in biomedical applications. Green synthesis which utilizes plants, microorganisms, and waste materials offers distinct advantages including precise control over the size and shape of the nanoparticles. By carefully optimizing various parameters, this approach enables the production of uniform and stable SeNPs. Importantly, green synthesis eliminates the need for hazardous chemicals, thereby reducing environmental pollution and potential harm to human health. The process typically involves heating a mixture of sodium selenite, plant extracts or culturing microorganisms with selenium precursors to facilitate the formation of SeNPs. Various techniques such as UV-visible (UV-Vis) spectrophotometry, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) are used to characterize these SeNPs. Of note, bacterial-mediated synthesis of SeNPs, achieved through intracellular or extracellular processes, effectively reduces selenium ions into SeNPs. To add, the type of the plant extract plays a crucial role andit was found that different extracts yield SeNPs with distinct properties. Moreover, a large body of evidence revealed that the plant extracts that are rich in reducing and stabilizing agents such as flavonoids and alkaloids can reduce selenium ions into SeNPsresulting in a biocompatible surface. Accordingly, green synthesis methods that employ plant extracts and bacteria hold great promise and sustainability, as they allow a control over the shapes of nanoparticles and the generation of unique properties tailored for biomedical applications. These approaches are not only cost-effective but also environmentallyfriendly, consistently producing nanoparticles with narrow size distributions. Despite certain limitations of this approach, the potential of green synthesis in nanoparticle synthesis is undeniable

Keywords : Green synthesis, selenium, nanoparticles, plant

Research Title :Effects of PGf2α On P-Erk1/2 Mapk Activation, Proliferation and Formation of Trans-Endothelial Tunnels in Swiss 3t3 Fibroblast Cells

Authors :Sahar Jaffal

Abstract :Fibroblast cells are key cells that play a pivotal role in maintaining hemostasis in the body. Keeping the balance between proliferation, differentiation and apoptosis of fibroblast cells is fundamental for the role of these cells. Many mediators can increase fibroblasts' proliferation including prostaglandin F2α [PGF2α]-induced phosphorylated extracellular signal regulated kinase [p-ERK1/2] mitogen activated protein kinase [MAPK]. Thus, the effects and mechanisms of PGF2α in p-ERK1/2 MAPK activation, proliferation and the cytoskeleton of fibroblast cells were explored in the current study. The results showed that sustained p-ERK1/2 MAPK activation was dependent on MAP kinase kinase [MEK-1], proto-oncogene non-receptor tyrosine kinase [c-Src], protein kinase C [PKC] and insulin like growth factor-1 receptor [IGF1R]. The transient p-ERK1/2 MAPK activation involved c-Src, phosphatidylinositol 3-kinase [PI3K]/AKT and PKC pathways. Further, Gαq but not Gαi was involved in the activity of PGF2α in inducing p-ERK1/2 MAPK activation at all time points. In contrast, p-ERK1/2 MAPK activation evoked by PGF2α did not involve Rho, Rho-associated protein kinase [ROCK], adenylyl cyclase [AC], the mammalian target of rapamycin [mTOR] or epidermal growth factor receptor [EGFR]. Notably, PGF2α increased fibroblasts' proliferation via PI3K, MEK1, c-Src, PKC and IGF1R but not EGFR, Gαi, AC or mTOR pathways suggesting a correlation between proliferation and pathways that are involved in the transient and sustained p-ERK1/2 MAPK activation or in the sustained phase alone. Additionally, PGF2α produced a noticeable change in the cytoskeleton of fibroblast cells and increased the number of trans-endothelial tunnels by 54.12% compared to control group. These findings provide further insights into the mechanisms of PGF2α in p-ERK1/2 MAPK activation, proliferation and the cytoskeleton of swiss 3t3 fibroblast cells and can open an avenue to conduct more researches on PGF2α signalling to tailor drugs that can prevent specific routes in PGF2α-FP signalling pathways and decrease fibroblasts' proliferation.

Keywords : Fibroblasts, PGF2 alpha, signaling, tunnel

Research Title :Role of TRPV1 in Health and Disease

Authors : Jaffal SM.

Abstract :Transient receptor potential vanilloid 1 (TRPV1) channel is a non-selective cation channel that plays a pivotal role in pain transduction. However, more than a pain sensor, it is involved in an array of vital processes in different body systems. The findings of several studies illustrated that many disorders are associated with alterations in the function and/or expression of the TRPV1 channel. Accordingly, the TRPV1 channel has become an important target in numerous therapeutic interventions. Several TRPV1 antagonists are already in the market, however, there is a need for new drugs with fewer or no side effects. This review highlights the involvement of the TRPV1 channel in a plethora of physiological and pathological conditions and points to its importance as a therapeutic target.

Keywords : TRPV1, Expression, Function, Health, Disease, Target

Research Title :: Interaction of the synthetic cannabinoid WIN55212 with tramadol on nociceptive thresholds and core body temperature in a chemotherapy-induced peripheral neuropathy pain model.

Authors :: Haddad, M., Alsalem, M., Saleh, T., Jaffal, S. M., Barakat, N. A., & El-Salem, K.

Abstract :Chemotherapy-induced peripheral neuropathy (CIPN) is a significant adverse effect of many anticancer drugs. Current strategies for the management of CIPN pain are still largely unmet. The aim of this study is to investigate the antinociceptive potential of combining tramadol with the synthetic cannabinoid WIN55212, and to evaluate their associated adverse effects, separately or in combination, in a CIPN rat model, and to investigate their ability to modulate the transient receptor potential vanilloid 1 (TRPV1) receptor activity. Von Frey filaments were used to determine the paw withdrawal threshold in adult male Sprague-Dawley rats (200-250 g) following intraperitoneal (i.p) injection of cisplatin. Single cell ratiometric calcium imaging was used to investigate WIN55212/tramadol combination ability to modulate the TRPV1 receptor activity. Both tramadol and WIN55212 produced dose-dependent antinociceptive effect when administered separately. The lower dose of tramadol (1 mg/kg) significantly enhanced the antinociceptive effects of WIN55212 without interfering with core body temperature. Mechanistically, capsaicin (100 nM) produced a robust increase in [Ca 2+ ] i in dorsal root ganglia (DRG) neurons ex vivo . Capsaicin-evoked calcium responses were significantly reduced upon pre-incubation of DRG neurons with only the highest concentration of tramadol (10 µM), but not with WIN55212 at any concentration (0.1, 1 and 10 µM). However, combining sub-effective doses of WIN55212 (1 µM) and tramadol (0.1 µM) produced a significant inhibition of capsaicin-evoked calcium responses. Combining WIN55212 with tramadol shows better antinociceptive effects with no increased risk of hypothermia, and provides a potential pain management strategy for CIPN.

Keywords :Neuropathy, antinociceptive, TRPV1, CALCIUM.

Research Title :Medicinal Plants of Jordan Possessing Anti-Nociceptive, Anti Inflammatory and Antipyretic Properties. Archives in traditional and complementary medicine

Authors :Jaffal SM

Abstract : Since ancient period, man depended on the surrounding environment for survival and used plants for the treatment of diseases. To date, there is increasing trend towards exploring the effects of medicinal plants as they are affordable, cheap, and available and have fewer side effects. Earlier reports showed that several plants are used in folk medicine for the treatment of different diseases and disorders. Medicinal plants are rich in flavonoids, alkaloids, tannins, triterpenes, polysaccharides, phenolic acids, organic acids, fatty acids, vitamins and carotenoids. The active ingredients from herbs are valued as raw materials in herbal preparations and modern medicines. Jordan is one of the countries that are rich in flora in general and in medicinal plants in particular due to its geographic and climatic diversity. There are 363 medicinal plants in Jordan. The effect of some of these plants was proved scientifically in variable experiments done in different countries. Literature search from PubMed and Google Scholar was conducted for articles in this context. The aim of this review was to highlight the researches that proved the anti-nociceptive, anti-inflammatory and antipyretic properties of medicinal plants in Jordan and list multiple uses of medicinal plants by Jordanian practitioners. Summarizing these studies is of vital importance to direct the attention of researchers towards medicinal plants that are used in traditional medicine while their effects were not determined scientifically. Discovering new effects for medicinal plants is an asset for pharmaceutical industry and the world trade.

Keywords : Jordan; medicinal plants; nociception; inflammation; pyrexia

Research Title :Effect of Arbutus andrachne L. Methanolic Leaf Extract on TRPV1 Function: Experimental and Molecular Docking Studies. Journal of Applied Pharmaceutical Science, 12(10): 69-77.

Authors : Jaffal SM, Oran SA, Alsalem M, Al-Najjar.

Abstract :: Currently used analgesics have several side effects urging the need for new natural sources of therapeutics. Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel and a key receptor in pain. In this study, we explored the effect of a methanolic leaf extract from Arbutus andrachne (a medicinal plant growing in Jordan) and its mechanism of action on TRPV1 function and expression. Our findings showed that the extract decreased capsaicin-induced cobalt (Co +2) influx in dorsal root ganglia (DRG) neurons, an effect that involved cannabinoid receptor 1 (CB1) and TRPV1 but not alpha (α)2-adre)2-adrenergic receptors. The extract had no effect on capsaicin-evoked TRPV1 expression in the skin, DRGs, spinal cord and brain. Importantly, the effect of A. andrachne was similar to the responses shown in the positive control group. Additionally, by conducting molecular docking between the ingredients identified in A. andrachne extract and TRPV1 receptor, it was found that α)2-adre-tocopherol, ursolic acid and β-sitosterol (similar to TRPV1 antagonist, capsazepine) fit in the same pocket of TRPV1 receptor indicating that these compounds are the active ingredients responsible for the effect of the extract in decreasing capsaicin-induced Co +2 influx. A. andrachne decreased capsaicin-induced Co +2 influx significantly and can be a good candidate as an analgesic.

Keywords :TRPV1, medicinal plants, molecular, docking

Research Title :Substance Abuse among University Students: Assessing Prevalence, Risk and Preventive Measures.

Authors :Abazid H, Abutayeh R, Abu Farha R, Jaffal SM, Alkaddah D, Al Jomaa EE.

Abstract :: Objectives: This research was undertaken to determine the prevalence and beliefs about drug abuse among university students in Jordan and to recommend certain preventive measures for the problem of drug addiction. Methods: A descriptive cross-sectional online survey was conducted in April 2021 and included 679 students from private and public universities in Jordan. Students were asked to fill out the study survey through social media (Facebook and WhatsApp). Results: The study included a survey conducted among 679 students from private and public universities whereby two third of them were females and more than half were studying in medical and health departments. It was found that 7.1% of university students used drugs in their life including illicit drugs, alcohol and cigarettes. Also, the addictive students started using drugs at a mean age of 18 years old ± 3.9. Importantly, around half of the addictive students succeeded to quit using drugs, 20.8% reported not trying to quit, while 33.3% of them tried but could not quit. In addition, the findings of this study revealed that peer pressure (n= 657, 96.8%), and the lack of religious commitment (n= 654, 96.3%), were the most motivational factors for drug abuse. Finally, regression analysis showed that female gender (OR= 0.094, p-value <0.001), and studying in public university (OR= 0.496, p-value= 0.042) were considered protective factors against substance abuse. Conclusion: Focusing on increasing the awareness of youths about the risks of using drugs is a major framework in the society. Our recommendations are to increase awareness among the students, parents and society about drug abuse.

Keywords :Students, substance use, knowledge, attitude.

Research Title The role of adenosine receptor ligands on inflammatory pain: Possible modulation of TRPV1 receptor function. :

Authors :Haddad, M., Alsalem, M., Aldossary, S. A., Kalbouneh, H., Jaffal, S. M., Alshawabkeh, Q., Al Hayek, S., Abdelhai, O., Barakat, N. A., & El-Salem, K.

Abstract :: Chronic pain has a debilitating consequences on health and lifestyle. The currently available analgesics are often ineffective and accompanied by undesirable adverse effects. Although adenosine receptors (AR) activation can affect nociceptive, inflammatory, and neuropathic pain states, the specific regulatory functions of its subtypes (A1, A2A, A2B and A3 ARs) are not fully understood. The aim of this study was to investigate the role of different AR ligands on inflammatory pain. The von Frey filament test was used to assess the anti-nociceptive effects of adenosine ligands on Complete Freund's Adjuvant (CFA)-induced mechanical allodynia in (180-220 g) adult male Sprague Dawley rats (expressed as paw withdrawal threshold, PWT). Neither the A2AAR selective agonist CGS 21680 hydrochloride (0.1, 0.32 and 1 mg/kg) nor the A2BAR selective agonist BAY 60-6583 (0.1, 0.32 and 1 mg/kg) produced any significant reversal of the PWT. However, the A1AR selective agonist ( ±)-5'-Chloro-5'-deoxy-ENBA, the A3AR selective agonist 2-Cl-IB-MECA, the A2AAR selective antagonist ZM 241385 and the A2BAR selective antagonist PSB 603 produced a significant reversal of the PWT at the highest dose of 1 mg/kg. Co-administration of the selective antagonists of A1AR and A3AR PSB36 (1 mg/ml) and MRS-3777 (1 mg/ml); respectively, significantly reversed the anti-nociceptive effects of their corresponding agonists. Furthermore, calcium imaging studies reveled that the effective AR ligands in the behavioral assay also significantly inhibit capsaicin-evoked calcium responses in cultured rat dorsal root ganglia (DRG) neurons. In conclusion, modulating the activity of the transient receptor potential vanilloid 1 (TRPV1) receptor by ARs ligands could explain their anti-nociceptive effects observed in vivo. Therefore, the cross talk between ARs and TRPV1 receptor may represent a promising targets for the treatment of inflammatory pain conditions.

Keywords :Adenosine receptors; Inflammation; Pain; TRPV1

Research Title :Imbalances of key parameters needed for energy-yielding processes in the serum of tramadol-treated male rats.

Authors : Abazid H, Jaffal SM, Abu-Samak M

Abstract :Addiction is one of the major health challenges in the world. Tramadol is an analgesic that has been widely abused, causing negative health consequences. This study sheds light on the effect of the administration of tramadol hydrochloride (HCl) on the serum levels of key parameters needed for energy production. Male Wistar rats received oral administration of tramadol HCl for 30 days and then were sacrificed to collect blood from the eyes and determine the levels of nutritional measures in the serum by kits. Our findings showed that the daily oral gavage of 50 or 100 mg/kg tramadol HCl for a month decreased the serum levels of ferrous iron and glucose significantly compared to the nontreated rats. Additionally, both doses increased the levels of total protein, triglycerides, and magnesium compared to the nontreated animals. Only the dose of 50 mg/kg tramadol HCl was effective in elevating the serum concentration of vitamin B12. Moreover, tramadol HCl treatment did not trigger any change in the levels of zinc in comparison to the control group. In conclusion, tramadol causes imbalances of key parameters needed for energy production.

Keywords : Tramadol-HCl, oral, biochemical, energy, fatigue

Research Title :Alleviation of capsaicin-induced mechanical allodynia by Arbutus andrachne L. methanolic leaf extract in male rats.

Authors : Jaffal SM, Oran SA, Alsalem M.

Abstract :Pain is one of the major health problems that impose huge social and economic burdens all over the world. Mechanical allodynia is a symptom of pain defined as a painful sensation resulting from innocuous stimuli such as touch. Currently available drugs have several side effects urging the need for new natural sources that alleviate mechanical allodynia. This study investigated the effect of Arbutus andrachne L. (a medicinal plant growing in Jordan) on capsaicin (Caps)-induced mechanical allodynia in male rats and the mechanism that underlie its effect. Caps injection decreased paw withdrawal threshold (PWT) significantly compared to control group. Mechanical allodynia was detected 30, 90 and 150 min after Caps injection to the plantar surface of the left hind paw of rats. The intraplantar (ipl) injection of 100 µg (but not 50 or 200 µg) of A. andrachne extract, ipsilaterally, prior to Caps injection increased PWT at all-time points similar to the anti-nociceptive effect in the positive group that was treated with 2.5% diclofenac sodium prior to Caps injection. The ipsilateral pre-treatment with the antagonists of transient receptor potential vanilloid-1 (TRPV1), cannabinoid receptor 1 (CB1) and peroxisome proliferator-activated receptor alpha (PPARα) reversed the activity of the leaf extract in contrast to the antagonists of PPARγ and α2-adrenergic receptors. In all groups, no effect was detected on the contralateral hind paw of animals at any time point. In conclusion, A. andrachne can be exploited as an anti-nociceptive agent.

Keywords : Arbutus andrachne, TRPV1, mechanical allodynia, PPAR, CB1, α2-adrenergic

Research Title :Evaluation of the antiproliferative effect of selected plant extracts on colon and skin cancer cell lines.

Authors : Oran SA, Yousef If, Jaffal SM.

Abstract :The aim of this study was to assess the antiproliferative effect of extracts obtained from medicinal plants that grow wild in Jordan against the human melanoma (WM136-1A) and colon cancer (Caco-2 cancer) cell lines using fibroblast cell lines as control cells. The selected plants are Varthemia iphionoides (Asteraceae), Micromeria myrtifolia (Lamiaceae), Micromeria nervosa (Lamiaceae), Origanum dayi (Lamiaceae), Ajuga chia (Lamiaceae), Salvia palaestina (Lamiaceae), and Bongardia chrysogonum (Berberidaceae). The results showed that M. nervosa and O. dayi exhibited antiproliferative activity against Caco-2 cancer cell line, with half-maximal inhibitory concentrations (IC50) that equal 98 ± 2.5 and 73.6 ± 3.4 μg/ml, respectively. Furthermore, A. chia, B. chrysogonum, and O. dayi exhibited antiproliferative activity against the WM136-1A cancer cell line, with IC50 that equals 400 ± 5.1, 98.1 ± 3.2, and 245 ± 3.6 μg/ml, respectively. None of the extracts had an effect on fibroblast cells at any used concentration. In conclusion, the extracts of M. nervosa, O. dayi, A. chia, and B. chrysogonum showed promising antiproliferative potential and can be good candidates for the development of novel anticancerous agents

Keywords : Ajuga chia, Micromeria myrtifolia, Micromeria nervosa, Origanum dayi, Salvia palaestina, Varthemia iphionoides, Bongardia chrysogonum, antiproliferation

Research Title :Effect of explant type and different plant growth regulators on callus induction and growth in citrus sinensis (l.) osbeck.

Authors : Jaffal SM, Tamini S.

Abstract :In this study, we analyzed the effect of using different explants (zygotic embryos, leaves, stems, and cotyledons) on callus induction and the effect of different PGRs on the growth response of the callus. The results showed that callogenesis was faster when all explants were incubated in the dark than in light incubation. Maximum callus induction was observed in zygotic embryos (compared to other explants) and in the group cultured in 3 mg/L 2,4 D and 1 mg/L 6- BAP combination. Similarly, 3 mg/L 2,4 D and 1 mg/L BAP PGRs were also the effective concentrations for callus induction from cotyledons and leaves. However, a 2 mg/L 2,4 D and 1 mg/L BAP combination was the most potent in inducing callus from stems. In addition, our results indicated that the best hormonal combination for callus multiplication of callus derived from zygotic embryos was 1 mg/L 2,4 D and 1 mg/L BAP. The inhibition of ethylene activity improved callus growth during the multiplication stage in two groups being treated with 1 mg/L 2,4 D alone or with 2 mg/L 2,4 D in combination with 1 mg/L BAP. In contrast, ethylene synthesis inhibitors had insignificant effects on callus multiplication in any of the groups cultured in different PGRs combinations. The calluses obtained in all treated groups were friable, loose, and had a white to yellow color.

Keywords :Citrus sinensis, 6-benzyl amino purine, 2,4 dichloro phenoxy acetic acid, callus, ethylene

Research Title :Anti-inflammatory and antipyretic potential of Arbutus andrachne L. methanolic leaf extract in rats. (Asian Pacific Journal of Tropical Biomedicine, 11(11): 491-499, 2021).

Authors : Jaffal SM; Oran SA; Alsalem M.

Abstract :Objective: To explore the anti-inflammatory and antipyretic effects of methanolic leaf extract from Arbutus andrachne and its mechanism of action. Methods: Paw edema was induced by intraplantar injection of λ-carrageenan (1% w/v, 100 µL/paw) while pyrexia was evoked by intraperitoneal injection of 20% baker’s yeast (20 mL/kg body wt) in male Wistar rats. The anti-inflammatory and antipyretic effects of A. andrachne methanolic leaf extract were explored by injecting rats with different doses of the plant extract (150, 300, and 600 mg/kg body wt, i.p.). Selective antagonists for TRPV1, CB1, and α₂-adrenergic receptor (a2-AR) were used to unravel the extracts’ mechanism of action. Blood samples were collected from the heart of rats to measure levels of IL-6 and PGE₂ by ELISA. Results: The extract exhibited potent anti-inflammatory activity by decreasing paw thickness and IL-6 levels. In addition, yeast-evoked pyrexia was attenuated by the extract treatment via TRPV1 and CB1 receptors and a reduction in PGE₂ levels. No significant effects were found for a2-AR. Moreover, the rats that received the plant extract demonstrated similar responses to the positive control group. Conclusions: Arbutus andrachne can be a good candidate for treating inflammation and pyrexia and should be further investigated.

Keywords :Arbutus andrachne; anti-inflammatory; antipyretic; PGE₂; IL-6; TRPV1; CB1; a2-ARs.

Research Title :TRP channels in COVID-19 disease: Potential targets for prevention and treatment. Chemico Biological Interactions, 345: 109567 (2021).

Authors : Jaffal SM; Abbas MA.

Abstract :Coronavirus disease 2019 (COVID-19) is a global health threat caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that requires two proteins for entry: angiotensin-converting enzyme 2 (ACE2) and membrane protease serine 2 (TMPRSS2). Many patients complain of pneumonia, cough, fever, and gastrointestinal problems. Notably, different TRP channels are expressed in various tissues infected by SARS-CoV-2. TRP channels are cation channels that show a common architecture with high permeability to Ca²⁺ in most sub-families. Literature review sheds light on the possible role of TRP channels in COVID-19 disease. TRP channels may take part in inflammation, pain, fever, anosmia, ageusia, respiratory, cardiovascular, gastrointestinal and neurological complications related to COVID-19. Also, TRP channels could be the targets for many active compounds that showed effectiveness against SARS-CoV-2. Desensitization or blocking TRP channels by antibodies, aptamers, small molecules or venoms can be an option for COVID-19 prevention and future treatment

Keywords : COVID-19; Prevention; SARS-CoV-2; Symptoms; TRP channels; Treatment

Research Title :Ononis spinosa alleviated capsaicin-induced mechanical allodynia in a rat model through transient receptor potential vanilloid 1 modulation. Korean Journal of Pain, 34(3): 262-270 (2021).

Authors :Jaffal SM; Al-Najjar BO; Abbas MA

Abstract :Background: Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel implicated in pain sensation in response to heat, protons, and capsaicin (CAPS). It is well established that TRPV1 is involved in mechanical allodynia. This study investigates the effect of Ononis spinosa (Fabaceae) in CAPS-induced mechanical allodynia and its mechanism of action. Methods: Mechanical allodynia was induced by intraplantar injection of 40 µg CAPS into the left hind paw of male Wistar rats. Animals received an ipl injection of 100 µg O. spinosa methanolic leaf extract or 2.5% diclofenac sodium 20 min before CAPS injection. Paw withdrawal threshold (PWT) was measured using von Frey filament at 30, 90, and 150 minutes after CAPS injection. A molecular docking tool (AutoDock 4.2) was used to study the binding energies and intermolecular interactions between O. spinosa constituents and TRPV1 receptor. Results: The ipsilateral intraplantar injection of O. spinosa before CAPS injection increased PWT in rats at all time points. O. spinosa decreased mechanical allodynia by 5.35-fold compared to a 3.59-fold decrease produced by diclofenac sodium. The ipsilateral pretreatment with TRPV1 antagonist (300 µg BCTC) as well as β2-adrenoreceptor antagonist (150 µg butoxamine) attenuated the action of O. spinosa. Molecular docking results suggest the activity of the extract could be attributed to bindings of campesterol, stigmasterol, and ononin compounds to TRPV1. Conclusions: O. spinosa alleviated CAPS-induced mechanical allodynia through two mechanisms: the direct modulation of TRPV1 and the involvement of β2-adrenoreceptor signalling.

Keywords :Butoxamine; Capsaicin; Fabaceae; Hyperalgesia; Molecular Docking Simulation; Neuralgia; Ononis; Pain; Stigmasterol; TRPV Cation Channels.

Research Title :Analgesic property of Loranthus acaciae studied by molecular docking and biological assays. Systematic Reviews in Pharmacy, 12(03): 712-719 (2021).

Authors :Abbas MA; Al-Najjar BO; Jaffal SM.

Abstract :Loranthus acaciae (Loranthaceae) is a perennial semiparasitic mistletoe. This study investigates the analgesic, antidepressant and anxiolytic effects of this plant. Different animal models were used. Also, chemical composition of the extract was analyzed using LC-MS. In the writhing test, 150 mg/kg and 300 mg/kg of L. acaciae inhibited abdominal cramps by 94.14% and 94.78%, respectively, compared to 57.95% inhibition produced by 70 mg/kg indomethacin. In the hot-plate but not tail-flick test, 300 mg/kg L. acaciae significantly increased latency time. In the formalin test, 300 mg/kg L. acaciae decreased paw-licking and flinching in the early and late phases by 68.5% and 83.3% respectively, compared to 39.2% and 56.1% inhibition by indomethacin (50 mg/kg). Naloxone and caffeine but not glibenclamide reversed the analgesic action of this plant in the late phase, while only caffeine reversed its action in the early phase. The LC-MS analysis of the methanolic leaf extract identified 17 compounds, with loranthin as the major constituent. Based on molecular docking results, activity of L. acaciae could be due to binding of lupeol, campesterol & rhoifolin to the µ-opioid receptor. The study indicates that the analgesic action of L. acaciae was mediated by interaction with opioid and adenosine receptors; no antidepressant or anxiolytic effects were found.

Keywords : Loranthus acaciae; analgesic; molecular docking; µ-opioid receptor; adenosine receptor; LC-MS; pain.

Research Title :The desensitization of the transient receptor potential vanilloid 1 by nonpungent agonists and its resensitization by bradykinin. Neuroreport, 31(11): 781-786 (2020

Authors :Alsalem M; Aldossary SA; Haddad M; Altarifi A; Kalbouneh H; Jaffal SM; Azab B; Mustafa AG; El-Salem K.

Abstract :Transient receptor potential vanilloid type-1 (TRPV1) channels have crucial roles in inflammatory hyperalgesia. Different inflammatory mediators can modulate TRPV1 sensitization. Bradykinin is an algogenic substance released at the site of inflammation. The aim of the present study is to investigate the desensitization of the TRPV1 receptor by non-pungent agonists and to determine how bradykinin and prostaglandin E₂ receptors (EP₃ and EP₄) modulate the resensitization of the TRPV1 receptor after being desensitized by non-pungent agonists. Tail-flick test was used to investigate capsaicin-induced thermal hyperalgesia and the desensitization of TRPV1 by the non-pungent agonists (olvanil and arvanil) in male BALB/c mice (22-25 g). Resensitization of TRPV1 by bradykinin and the role of prostaglandin receptors in mediating sensitization of TRPV1 were also investigated. Intraplantar injection of capsaicin (0.3 µg) produced a robust thermal hyperalgesia in mice, while olvanil (0.3 µg) or arvanil (0.3 µg) produced no hyperalgesia, emphasising their lack of pungency. Olvanil and arvanil significantly attenuated capsaicin-induced thermal hyperalgesia in mice. Bradykinin significantly reversed the desensitising effects of arvanil, but not olvanil. EP₄ but not EP₃ receptors mediate the sensitisation of TRPV1 by bradykinin in vivo. The present study provides evidence for a novel signalling pathway through which bradykinin can regulate TRPV1 ion-channel function via the EP₄ receptor.

Keywords :TRPV1; desensitisation; non-pungent agonists; olvanil; arvanil; bradykinin; prostaglandin E₂ receptors; EP₄ receptor; thermal hyperalgesia.

Research Title :Anti-nociceptive effect of Arbutus andrachne L. methanolic leaf extract mediated by CB1, TRPV1 and PPARs in mouse pain models. Inflammopharmacology, 37: 189-195 (2020).

Authors :Jaffal SM; Oran SA; Alsalem M.

Abstract :Arbutus andrachne L. is a medicinal plant that grows in Jordan and has many valuable effects. In the present study, the anti-nociceptive effect of A. andrachne methanolic leaf extract was determined in mice using thermal and chemical tests. Our findings show that different doses of A. andrachne extract reduced the number of writhings significantly compared to control group. The leaf extract also reduced the time of paw licking in the early and late phases of the formalin test. In all the conducted tests, 300 mg/kg body weight was the most effective dose. A peroxisome proliferator-activated receptor alpha (PPARα) antagonist reversed the action of the plant extract in the early phase of the formalin test while antagonists of PPARα, PPARγ and cannabinoid 1 (CB1) receptors were responsible for abolishing its effect in the late phase of this test. Also, the extract administration increased the latency time in hot plate and tail-flick tests, an effect that was reversed by the antagonists of PPARγ, CB1 and transient receptor potential vanilloid 1 (TRPV1). No effect was noticed for an α₂-adrenergic receptor antagonist in the action of A. andrachne in any of the conducted tests in this study. Furthermore, analysis of the constituents in the methanolic leaf extract using LC-MS showed that the extract is rich in compounds that have anti-nociceptive and/or anti-inflammatory effects such as arbutin, rutin, linalool, linoleic acid, gallic acid, lauric acid, myristic acid, hydroquinone, β-sitosterol, ursolic acid, isoquercetin, quercetin, (+)-gallocatechin, kaempferol, α-tocopherol, myricetin 3-O-rhamnoside and catechin gallate.

Keywords :Arbutus andrachne; anti-nociceptive; CB1; TRPV1; PPARα; PPARγ; mice pain models.

Research Title :Antinociceptive Action of Moringa peregrina is Mediated by an Interaction with α₂-Adrenergic Receptor. Balkan Medical Journal, 37: 189-195 (2020).

Authors :Jaffal SM; Al-Najjar BO; Abbas MA; Oran SA

Abstract :Background: M. peregrina is an edible, drought-resistant tree native to semi-arid countries and traditionally used as a pain-killer. Aims: To examine the antinociceptive effects of the methanolic leaf extract of M. peregrina in mice and identify its mechanism of action. Methods: Male BALB/c mice were tested with thermal (hot plate, tail-immersion) and chemical (writhing, formalin) pain models. The extract and antagonists (yohimbine for α₂-adrenergic receptor; methysergide for 5-HT₂ receptor) were used. LC-MS was performed to determine major constituents; molecular docking to assess binding to α₂-adrenergic receptor. Results: In writhing test, 200 mg/kg extract inhibited abdominal cramps by ~55.97% and 400 mg/kg by ~88% versus control. In formalin test, paw licking time was reduced in early (~56.8%) and late (~65.5%) phases compared to diclofenac. The effect was reversed by yohimbine but not by methysergide, indicating involvement of α₂-adrenergic receptor. In hot-plate test (but not tail-immersion) the high dose (400 mg/kg) increased latency; yohimbine blocked this effect. LC-MS revealed chrysoeriol 7-O-diglucoside, lupeol acetate, quercetin, rutin among major constituents. Docking suggested affinity of chrysoeriol 7-O-diglucoside, quercetin and rutin to α₂-adrenergic receptor. Conclusion: The antinociceptive action of M. peregrina is mediated by interaction with α₂-adrenergic receptor.

Keywords :Moringa peregrina; antinociceptive; α₂-adrenergic receptor; molecular docking; analgesic; chrysoeriol; quercetin; rutin.

Research Title :Antinociceptive action of Achillea biebersteinii methanolic flower extract is mediated by interaction with cholinergic receptor in mouse pain models. Inflammopharmacology, 27(5): 961-968 (2019).

Authors :Jaffal SM; Abbas MA

Abstract :Achillea biebersteinii is a perennial aromatic herb traditionally used for stomachache and abdominal pain. In this study the analgesic effect of its methanolic flower extract was tested in three pain models: writhing (acetic acid), tail-flick and paw-licking (formalin) tests. The extract inhibited abdominal cramps more effectively than 70 mg/kg indomethacin. It increased latency in the tail-flick test at 30 min comparably to 100 mg/kg diclofenac. In the formalin test it reduced paw-licking and flinching responses in both early and late phases. The effect (300 mg/kg) was blocked by atropine (5 mg/kg) in the late phase of the formalin test, and in writhing and tail-flick tests, indicating involvement of the cholinergic receptor. GC–MS analysis revealed ascaridole and iso-ascaridole as major constituents.

Keywords : Achillea biebersteinii; antinociceptive effect; cholinergic receptor; writhing test; tail-flick test; formalin test; GC–MS.

Research Title :Antinociceptive action of Ononis spinosa leaf extract in mouse pain models. Acta Poloniae Pharmaceutica Drug Research 76(2): 299-304 (2019).

Authors :Jaffal SM; Abbas MA

Abstract :Ononis spinosa (spiny restharrow) is a perennial herb of the Fabaceae family used in traditional medicine for toothache and inflammatory conditions. This study evaluated the analgesic effects of its methanolic leaf extract in mice using writhing (acetic acid), formalin (early & late phases), hot-plate and tail-flick tests. The extract at 300 mg/kg and 600 mg/kg produced 90.1 % and 94.5 % inhibition of writhing versus 23.6 % for diclofenac (30 mg/kg). In formalin tests, the extract reduced paw-licking by ~54.9–63.1 % at early phase and ~81.0–85.3 % at late phase, outperforming diclofenac (50.5 % in late phase). In the hot-plate and tail-flick tests, the extract increased latency time, and the effect was antagonised by naloxone (but not glibenclamide or atropine), suggesting involvement of opioid receptors for thermal antinociception. Phytochemical screening identified phenolics, saponins, flavonoids and terpenoids; HPLC confirmed kaempferol, apigenin and myricetin in the extract.

Keywords : Ononis spinosa; antinociceptive; methanolic leaf extract; writhing test; formalin test; hot-plate; tail-flick; opioid receptor.

Research Title :Evidence for the involvement of opioid receptor in Ajuga chamaepitys action in chemical and thermal models of pain in BALB/c mice. Medicinal Chemistry Research, 28(7): 992-999 (2019).

Authors :Jaffal SM; Abbas MA; Alsalem M; Al-Najjar BO

Abstract :The methanolic extract of Ajuga chamaepitys was evaluated for antinociceptive activity in BALB/c mice using acetic acid-induced writhing, the hot-plate test, and the formalin test. The extract produced significant reduction in writhing counts and increased latency in both early and late phases of the formalin test. Pretreatment with naloxone (an opioid receptor antagonist) reversed these effects, indicating involvement of opioid receptors in the extract’s mechanism of action. The data support the traditional use of A. chamaepitys for pain relief

Keywords : Ajuga chamaepitys; antinociceptive; opioid receptor; writhing test; hot-plate; formalin test.

Research Title :Gastroprotective activity of Loranthus acaciae flower extract in a rodent model of ethanol-induced ulcer. Applied Physiology Nutrition and Metabolism, 44(12): 1283-1288 (2019

Authors :Abbas MA; Kandil YI; Disi AM; Jaffal SM

Abstract :Loranthus acaciae (Loranthaceae) is a perennial green semi-parasitic plant used in ethnopharmacological medicine for healing wounds. The protective effect of the flower extract was investigated in a rat model of ethanol-induced gastric ulcer. Ulcer index and total glutathione level were measured; histological and immunohistochemical studies for cyclooxygenase-2 (COX-2) expression were also performed. Ulcer index was significantly reduced in extract-treated groups: protection ratios were 75.9 % (250 mg/kg) and 98.9 % (500 mg/kg) versus 70.7 % for esomeprazole (40 mg/kg). Histology revealed fewer hemorrhages and less edema in mucosa/submucosa. Immunostaining for COX-2 was negative in both control and extract groups. Total glutathione level was higher in the extract groups compared with control. LC-MS analysis identified loranthin and rutin as major constituents. Concluding: L. acaciae provided strong gastroprotective action against ethanol-induced ulcers in rats.

Keywords :Loranthus acaciae; gastroprotective; ethanol-induced ulcer; ulcer index; glutathione; COX-2; loranthin; rutin.

Research Title :Analgesic and Anxiolytic Activities of Achillea biebersteinii: Evidence for the Involvement of GABAergic Systems. Oriental Journal of Chemistry, 35(4): 1433-1442 (2019).

Authors : Abbas MA; Jaffal SM; Al-Najjar BO

Abstract :Achillea biebersteinii (Asteraceae) is used in traditional medicine for treating abdominal pain, menstrual pain and headache. The analgesic, antidepressant and anxiolytic activities of this plant were studied. Moreover, molecular docking technique was used for plant constituents to determine their energy of binding against GABAA and GABAB receptors. A. biebersteinii decreased flinching in early and late phases of formalin test and increased the latency time in hot-plate test. In forced-swimming test, no difference in immobility time was found. In open field test, high doses decreased the crossed-lines number and rearing behavior. A. biebersteinii increased the time that the animals spent in the open arm side of elevated plus-maze apparatus. Both bicuculline and SCH 50911 reversed A. biebersteinii action. Lavndulyl-2-methylbutanoate and sesquisabinene hydrate showed the lowest binding energies for both GABAA and GABAB receptors. In conclusion, A. biebersteinii exerted analgesic, anxiolytic but no antidepressant activity. Its effect involved interaction with GABAA and GABAB

Keywords :Achillea biebersteinii; Analgesic; Anxiolytic; GABA receptor; Molecular docking

Research Title :Role of Cannabinoid Receptor 1 and the Peroxisome Proliferator-Activated Receptor α in Mediating Anti-nociceptive Effects of Synthetic Cannabinoids and a Cannabinoid-like Compound. Inflammopharmacology, 27(6): 1131-1142 (2019). .

Authors :Alsalem M; Haddad M; Aldossary SA; Kalbouneh H; Altarifi A; Jaffal SM; Abbas MA; Aldaoud N; El-Salem K

Abstract :Osteoarthritis (OA) pain represents a major chronic pain state for which new treatments are needed. Synthetic cannabinoids (WIN-55,212 and HU210) and a cannabinoid-like compound (palmitoylethanolamide, PEA) were evaluated in a rat model of OA induced by intra-articular injection of monosodium iodoacetate (MIA). Anti-nociceptive effects were assessed by paw-withdrawal threshold (PWT) via von Frey filament and weight-bearing difference. Locomotor activity was also measured. HU210, WIN-55,212 and PEA each dose-dependently improved PWT and weight-bearing deficits. The CB1 receptor antagonist SR141716A reversed the anti-nociceptive effects of all compounds for PWT; for weight-bearing, only HU210’s effect was reversed by SR141716A. The PPARα antagonist GW6471 reversed the anti-nociceptive effect of PEA, but not that of HU210 or WIN-55,212. These results suggest that CB1 plays a major role in mediating the analgesic effects of these cannabinoids, while PPARα contributes specifically to PEA’s effect

Keywords : cannabinoid receptor 1; CB1; PPARα; synthetic cannabinoids; palmitoylethanolamide; osteoarthritis; anti-nociceptive; HU210; WIN-55,212.

Research Title :Cough reflex hypersensitivity: A role for neurotrophins. Experimental Lung Research, 43(2): 93-108 (2017).

Authors : El-Hashim AZ; Jaffal SM

Abstract :Cough is one of the most common complaints for which sufferers seek medical assistance. However, currently available drugs are not very effective in treating cough, particularly that which follows an upper respiratory tract infection. Nonetheless, there has been a significant increase in our understanding of the mechanisms and pathways of the defensive cough as well as the hypersensitive/pathophysiological cough, both at airway and central nervous system (CNS) levels. Numerous molecules and signalling pathways have been identified as potential targets for antitussive drugs, including neurotrophins (NTs). NTs belong to a family of trophic-factors and are critical for the development and maintenance of neurons in the central and peripheral nervous system including sympathetic efferents, sensory neuron afferents, and immune cells. Nerve growth factor (NGF) was the first member of the NT family to be discovered, with wide-ranging actions associated with synapse formation, survival, proliferation, apoptosis, axonal and dendritic outgrowth, expression and activity of functionally important proteins such as ion channels, receptors, and neurotransmitters. In addition, NGF has been implicated in several disease states particularly neuropathic pain and most recently in the sensitization of the cough reflex. This review will briefly address the peripheral and central sensitization mechanisms of airway neurons and will then focus on NGF signalling and its role in cough hypersensitivity.

Keywords :cough; hypersensitivity; neurotrophins; NGF; airway sensory neurons; central sensitisation

Research Title :Nerve growth factor enhances cough via a central mechanism of action. Pharmacological Research, 74: 68-77 (2013).

Authors : El-Hashim AZ; Jaffal SM; Al-Rashidi F; Luqmani YA; Akhtar S.

Abstract :The mechanisms involved in enhanced cough induced by centrally-administered (intracerebroventricular, i.c.v.) and inhaled Nerve Growth Factor (NGF) in guinea pigs were investigated. Cough and airway function were assessed by whole-body plethysmography after citric-acid challenge. The mRNA and protein expression of the high-affinity NGF receptor (TrkA) and the ion channel TRPV1 were measured in bronchi and brainstem. Central and inhaled NGF both enhanced citric-acid-induced cough and airway obstruction. Pretreatment via i.c.v. with a TrkA antagonist (K252a) or TRPV1 antagonist (IRTX) significantly reduced both NGF (i.c.v.)-enhanced cough and obstruction, while an NK1 antagonist inhibited only cough. Inhaled NGF increased TrkA receptor phosphorylation in bronchi but not brainstem at 0.5 h post-treatment; TrkA mRNA was elevated in bronchi at 0.5 h, in brainstem at 24 h; TRPV1 mRNA was elevated in brainstem from 0.5-24 h and in bronchi at 24 h. Pretreatment (i.c.v.) with IRTX, but not K252a, significantly inhibited the inhaled NGF-enhanced cough. These data show NGF has a significant central mechanism in enhancement of cough and airway obstruction, involving central activation of TrkA, TRPV1 and NK1 receptors

Keywords : NGF; cough reflex; central mechanism; TrkA; TRPV1; airway obstruction.

Research Title :Biasing the prostaglandin F₂α receptor responses toward EGFR-dependent transactivation of MAPK. Molecular Endocrinology, 26(7): 1189-1202 (2012

Authors : Goupil E; Wisehart V; Khoury E; Zimmerman B; Jaffal S; Hébert TE; Laporte SA

Abstract :The G protein-coupled prostanoid F (FP) receptor, which binds prostaglandin F₂α (PGF₂α), is involved in many physiological processes. Binding of PGF₂α to the FP receptor typically triggers inositol production and PKC-dependent ERK1/2 (MAPK) activation via Gα(q). In this study the authors show that AL-8810, previously considered an orthosteric antagonist of the FP receptor, instead activates ERK1/2 in a PKC-independent manner via epidermal growth factor receptor (EGFR) transactivation—demonstrating a biased signaling mode. They found that in HEK293 and MG-63 cells, activation did not recruit β-arrestins; the spatial and temporal patterns of ERK1/2 activation differed depending on the ligand (PGF₂α vs AL-8810). Their findings illustrate how a single receptor (FP) can adopt distinct signalling outcomes depending on the ligand, highlighting “biased agonism

Keywords :FP receptor; prostaglandin F₂α; EGFR transactivation; MAPK; biased signalling; ERK1/2; AL-8810.

Research Title :Anti-tussive and bronchodilator mechanisms of action for the enaminone E121. Life Sciences, 89(11-12): 378-387 (2011).

Authors :El-Hashim AZ; Edafiogho IO; Jaffal SM; Yousif MH; Ezeamuzie CI; Kombian SB

Abstract :In this study, the enaminone E121 was assessed for antitussive and bronchodilator effects in a guinea-pig model of cough and airway obstruction induced by aerosolised citric acid. Whole-body plethysmography measured cough and obstruction; intra-tracheal and intra-cerebroventricular administration were used to determine site of action. E121 significantly inhibited citric acid-induced cough and airway obstruction when administered intra-tracheally but not centrally (i.c.v.). In vitro, E121 inhibited carbachol-induced contractions of guinea-pig bronchioles; these effects were attenuated by glibenclamide (a K(ATP) channel antagonist) and propranolol (a β-adrenergic antagonist). The anti-tussive effect appears to be K(ATP) channel-dependent and the bronchodilator effect mediated via both K(ATP) channel activation and β₂-adrenergic receptor involvement

Keywords :E121; enaminone; antitussive; bronchodilator; K(ATP) channel; β₂-adrenergic receptor; airway obstruction; cough reflex.

Research Title :Effect of inhibition of the ubiquitin-proteasome-system and IκB kinase on airway inflammation and hyperresponsiveness in a murine model of asthma. International Journal of Immunopathology and Pharmacology, 24(1): 33-42 (2011).

Authors : El-Hashim AZ; Renno WM; Abduo HT; Jaffal SM; Akhtar S; Benter IF.

Abstract :The current treatment of asthma is far from optimal and there is a need for novel therapeutic approaches. NF-κB has recently been highlighted as an important pro-inflammatory transcriptional factor and its blockade is believed to represent a new therapeutic approach for asthma. The purpose of this study is to investigate the effects of blocking the actions of NF-κB, through inhibition of the ubiquitin-proteasome system (UPS) or IκB kinase (IKK), in a murine model of asthma. Treatment with the UPS inhibitor MG-132 (0.03 and 0.1 mg/kg) did not significantly affect the ovalbumin-induced increase in total and differential cell numbers, histological changes such as perivascular and peribronchial inflammatory cell infiltration, perivascular and peribronchial fibrosis or the increased Penh to methacholine. In contrast, treatment of mice with the IKK inhibitor BAY 11-7085 (3 and 10 mg/kg) dose-dependently inhibited the ovalbumin-induced increase in airway leukocyte influx and decreased the percentage of airway lymphocytes, neutrophils and eosinophils. Also, BAY 11-7085-treated (10 mg/kg) mice showed a significant decrease in the histologically assessed inflammatory indices as well as a significant reduction in the ovalbumin-induced increase in Penh to inhaled methacholine. Furthermore, BAY 11-7085 significantly inhibited the ovalbumin-induced increase in the level of phosphorylation of IκBα and extracellular-regulated kinases (ERK1/2), whilst MG-132 significantly increased the phosphorylation of ERK1/2. These findings confirm the critical role that NF-κB plays in airway inflammation, highlight the importance of IKK in regulating the pro-inflammatory activity of NF-κB and also suggest that UPS may not be a useful drug target for asthma treatment.

Keywords :ubiquitin-proteasome system; IκB kinase; NF-κB; airway inflammation; airway hyperresponsiveness; asthma model; ERK1/2 phosphorylation.

Research Title :Nerve growth factor enhances cough and airway obstruction via TrkA receptor- and TRPV1-dependent mechanisms. , 64(9): 791-797 (2009).

Authors :El-Hashim AZ; Jaffal SM.

Abstract :Background: Nerve growth factor (NGF) is an important mediator of airway hyper-responsiveness and hyperalgesia, but its role in cough is unknown. Objectives: To examine the effects of NGF on the cough reflex and airway calibre in guinea-pigs, and to investigate whether the tropomyosin-related kinase A (TrkA) receptor, the transient receptor potential vanilloid-1 (TRPV1) channel, and the p38 mitogen-activated protein kinase (MAPK) pathway are involved. Methods: Guinea-pigs were placed in a transparent whole-body plethysmograph box; cough was assessed visually, acoustically and by airflow signal. Airway obstruction was measured via enhanced pause (Penh). Animals were exposed to NGF before citric acid inhalation; the effects of a TrkA antagonist (K252a), TRPV1 antagonist (iodoresiniferatoxin), and p38 MAPK inhibitor (SB203580) were tested. Results: NGF exposure by itself did not significantly induce cough or airway obstruction, but when given immediately before citric acid inhalation, NGF significantly increased the citric acid-induced cough and airway obstruction compared to vehicle–treated controls. Pretreatment with the TrkA antagonist or the TRPV1 antagonist significantly inhibited the NGF-enhanced cough and airway obstruction. The p38 MAPK inhibitor prevented NGF-induced p38 phosphorylation but did not affect the NGF-enhanced cough or airway obstruction. Conclusions: NGF can enhance both cough and airway obstruction via a mechanism that involves activation of TrkA receptor and TRPV1 channel, but not p38 MAPK signalling.

Keywords : Nerve Growth Factor (NGF); TrkA receptor; TRPV1 channel; cough reflex; airway obstruction; guinea-pig; citric acid

Research Title :Effects of Meloxicam on Implantation and Parturition of Rat. Jordan Medical Journal, 40(2): 88-95 (2006).

Authors : Jaffal S.M.; Salhab A.S.; Disi A.M.; Al-Qaadan F.

Abstract :Meloxicam, a selective cyclooxygenase-2 preferential inhibitor, was studied for its effects on implantation and parturition in pregnant rats. For the implantation experiment, rats were dosed orally at 7.5 mg/kg/day or 10 mg/kg/day from gestation days 1–3 or 3–5 respectively. For the parturition study, the same doses were given on days 20–22 of gestation. The implantation treated groups showed a significant decrease in the number of implantation sites and a significant increase in resorption sites in a dose- and time-dependent fashion. In parturition experiments, meloxicam significantly prolonged the duration of delivery, and treated dams delivered significantly fewer viable pups than controls

Keywords : Meloxicam; implantation; parturition; COX-2 inhibitor; oxytocin; resorption. .

Research Title :Potent antiproliferative effects of resveratrol on human osteosarcoma SJSA1 cells: Novel cellular mechanisms involving the ERKs/p53 cascade. Free Radical Biology & Medicine, 41(2): 318-325 (2006).

Authors :Alkhalaf M; Jaffal S

Abstract :The chemopreventive activity of resveratrol (RSVL) has been demonstrated in several types of cancer. However, its effects and the underlying mechanisms remain poorly understood. In this study we investigated the involvement of the mitogen-activated protein kinase (MAPK)/p53 signalling mechanism in RSVL-induced growth inhibition using a human osteosarcoma cell line (SJSA1). We demonstrate that RSVL reduces cell viability and growth of SJSA1 osteosarcoma cells. Morphological profiles and DAPI nuclear staining of RSVL-treated cells indicated marked nuclear fragmentation. Cleavage of the 116-kDa poly(ADP-ribose) polymerase (PARP) protein into an 89-kDa fragment (a pro-apoptotic marker) was substantially augmented by RSVL treatment. RSVL dependent growth impairment was preceded by enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 (at Thr202/Tyr204). Likewise, RSVL increased the phosphorylation of p53 tumour suppressor protein (at Ser15). The effects of RSVL on ERKs and on p53 phosphorylation were abrogated by either the MAPK inhibitor PD98059 or the p53 inhibitor pifithrine-α. The present study indicates that RSVL antiproliferative effects on osteosarcoma cells are mediated by the activation of the ERKs/p53 signalling pathway and therefore identifies new targets for strategies to treat and/or prevent osteosarcoma

Keywords : resveratrol; antiproliferative; osteosarcoma; SJSA1; ERK1/2; p53; PARP cleavage.

Research Title :Nongenomic activation of the GC-A enzyme by resveratrol and estradiol downstream from membrane estrogen receptors in human coronary arterial cells. Nutrition, Metabolism & Cardiovascular Diseases, 17(7): 508-516 (2007).

Authors :El-Mowafy AM; Al-Khalaf M; Jaffal SM.

Abstract :Resveratrol (RSVL), a polyphenolic phytoestrogen found in grapes, has cardiovascular protective effects. In human coronary smooth muscle cells (HCSMCs), RSVL markedly (≈3.2-fold) increased cyclic GMP (cGMP) formation with a half-time of ~6.3 min and an EC₅₀ of ~1.8 µM. This effect was independent of nitric oxide synthase (L-NMMA) and soluble guanylyl cyclase (ODQ) inhibition; rather, RSVL activated a particulate guanylyl-cyclase (GC-A) enzyme, similar to the atrial natriuretic peptide (ANP) receptor-mediated pathway. Estradiol (E2) mimicked this response, albeit with ~46% lower maximal effect. The increase in cGMP formation by RSVL or E2 was significantly inhibited by the pure estrogen receptor antagonist ICI-182,780 (10 µM), indicating involvement of membrane estrogen receptors. The data suggest a novel, nongenomic pathway by which RSVL and E2 activate GC-A downstream of membrane estrogen receptors, contributing to coronary vasoprotection.

Keywords : Resveratrol; Estradiol; GC-A enzyme; cGMP; membrane estrogen receptors; human coronary smooth muscle cells; non-genomic signalling.

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