Targeting sterol alpha-14 demethylase of Leishmania donovani to fight against leishmaniasis.

Leishmaniasis is a neglected tropical disease caused by the protozoan parasite Leishmania. It is endemic in more than 89 different countries worldwide. Sterol alpha-14 demethylase (LdSDM), a sterol biosynthetic pathway enzyme in Leishmania donovani, plays an essential role in parasite survival and proliferation. Here, we used a drug repurposing approach to virtually screen the library of the Food and Drug Administration (FDA)-approved drugs against LdSDM to identify the potential lead-drug against leishmaniasis. Zafirlukast and avodart showed the best binding with LdSDM. Zafirlukast was tested for in vitro antileishmanial assay, but no significant effect on L. donovani promastigotes was observed even at higher concentrations. On the other hand, avodart profoundly inhibited parasite growth at relatively lower concentrations. Further, avodart showed a significant decrease in the number of intra-macrophagic amastigotes. Avodart-induced reactive oxygen species (ROS) in the parasites in a dose-dependent manner. ROS induced by avodart led to the induction of apoptosis-like cell death in the parasites as observed through annexin V/PI staining. Here, for the first time, we reported the antileishmanial activity and its possible mechanism of action of FDA-approved drug, avodart, establishing a nice example of the drug-repurposing approach. Our study suggested the possible use of avodart as an effective antileishmanial agent after further detailed validations.

Virtual screening of natural compounds for potential inhibitors of Sterol C-24 methyltransferase of Leishmania donovani to overcome leishmaniasis.

Leishmaniasis is a neglected tropical disease caused by trypanosomatid parasite belonging to the genera Leishmania. Leishmaniasis is transmitted from one human to other through the bite of sandflies. It is endemic in around 98 countries including tropical and subtropical regions of Asia, Africa, Southern America, and the Mediterranean region. Sterol C-24 methyltransferase (LdSMT) of Leishmania donovani (L. donovani) mediates the transfer of CH3-group from S-adenosyl methionine to C-24 position of sterol side chain which makes the ergosterol different from cholesterol. Absence of ortholog in human made it potential druggable target. Here, we performed virtual screening of library of natural compounds against LdSMT to identify the potential inhibitor for it and to fight leishmaniasis. Gigantol, flavan-3-ol, and parthenolide showed the best binding affinity towards LdSMT. Further, based on absorption, distribution, metabolism, and excretion properties and biological activity prediction, gigantol showed the best lead-likeness and drug-likeness properties. Therefore, we further elucidated its antileishmanial properties. We found that gigantol inhibited the growth and proliferation of promastigotes as well as intra-macrophagic amastigotes. Gigantol exerted its antileishmanial action through the induction of reactive oxygen species in dose-dependent manner. Our study, suggested the possible use of gigantol as antileishmanial drug after further validations to overcome leishmaniasis.

Repurposing of FDA-approved drugs as inhibitors of sterol C-24 methyltransferase of Leishmania donovani to fight against leishmaniasis.

Leishmaniasis is a vector-borne disease caused by around 20 species of Leishmania. The main clinical forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). VL is caused by Leishmania infantum in Central and South America, Mediterranean Basin, Middle East, and by L. donovani in Asia and Africa. Sterol C-24 methyltransferase (LdSMT) of L. donovani is a transferase enzyme of the sterol biosynthesis pathway. This pathway is one of the major targets for drug developments in Leishmania. Due to insufficient evidence about the exact function of SMT inside the cell and the uniqueness of the SMT enzyme in the Leishmania parasites made it a significant target for an effective drug development approach. We performed virtual screening of the Food and Drug Administration (FDA)-approved drug library against LdSMT and found simeprevir, an antiviral drug on top in the binding score. It showed a significant binding affinity with LdSMT. The binding was supported by hydrogen bonds and several other interactions. Simeprevir inhibited L. donovani growth of promastigotes with 50% inhibitory concentration (IC50 ) of 51.49 ± 5.87 µM. Further studies showed that simeprevir induced ROS generation in 44.7% of parasites at 125-µM concentration. Here, we for the first time reported simeprevir as an antileishmanial lead molecule using a drug repurposing approach.

Prevalence of Hemoglobinopathies (ß-Thalassemia and Sickle Cell Trait) in the Adult Population of Al Majma'ah, Saudi Arabia.

Despite the high prevalence of hemoglobinopathies in Saudi Arabia, the prevalence data in some regions are lacking. Updating the epidemiological survey of hemoglobinopathies at regular intervals is necessary to develop effective prevention and control strategies. Therefore, the primary aim of this study was to determine the prevalence of selected hemoglobinopathies in Saudi adults attending premarital screening at the King Khaled General Hospital (KKGH), Al Majma'ah, Saudi Arabia. The current retrospective study was approved by the Central Institutional Review Board (IRB) of the Ministry of Health (with central IRB log #2019-0039E) and was carried out at the above hospital. The data of the premarital couples, who attended the premarital screening center at KKGH from 1 October 2016 to 30 September 2019, was included in this study. A cation exchange high performance liquid chromatography (HPLC) system was used for screening of the selected hemoglobinopathies. In total, 3755 cases including 1953 (52.01%) males and 1802 (47.99%) females, were screened for hemoglobinopathies. Abnormal hemoglobin (Hb) fractions were observed in 38 (1.01%) cases. The prevalence of ß-thalassemia (ß-thal) trait was 0.69% (26/3755) and that of sickle cell trait 0.32% (12/3755). Our results showed that the prevalence of ß-thal trait is higher than that of sickle cell trait in the adult population of Al Majma'ah. Further comprehensive programs should be carried out to determine the prevalence of hemoglobinopathies in various provinces and cities of Saudi Arabia and other countries. This will help to maintain the updated records of the disease incidence for improving the control measures.

Multidrug-Resistant Bacteria Associated with Cell Phones of Healthcare Professionals in Selected Hospitals in Saudi Arabia.

Cell phones may be an ideal habitat for colonization by bacterial pathogens, especially in hot climates, and may be a reservoir or vehicle in transmitting nosocomial infections. We investigated bacterial contamination on cell phones of healthcare workers in three hospitals in Saudi Arabia and determined antibacterial resistance of selected bacteria. A questionnaire was submitted to 285 healthcare workers in three hospitals, and information was collected on cell phone usage at the work area and in the toilet, cell phone cleaning and sharing, and awareness of cell phones being a source of infection. Screening on the Vitek 2 Compact system (bioMérieux Inc., USA) was done to characterize bacterial isolates. Of the 60 samples collected from three hospitals, 38 (63.3%) were positive with 38 bacterial isolates (4 Gram-negative and 34 Gram-positive bacteria). We found 38.3% of cell phones were contaminated with coagulase-negative staphylococci, particularly Staphylococcus epidermidis (10 isolates). Other bacterial agents identified were S. aureus, S. hominis, Alloiococcus otitis, Vibrio fluvialis, and Pseudomonas stutzeri. Antimicrobial susceptibility testing showed that most coagulase-negative staphylococci were resistant to benzylpenicillin, erythromycin, and rifampicin. Eight isolates were resistant to oxacillin, specifically S. epidermidis (3), S. hominis (2), and S. warneri (2). A. otitis, a cause of acute otitis media showed multidrug resistance. One isolate, a confirmed hetero-vancomycin intermediate-resistant S. aureus, was resistant to antibiotics, commonly used to treat skin infection. There was a significant correlation between the level of contamination and usage of cell phone at toilet and sharing. Our findings emphasize the importance of hygiene practices in cell phone usage among healthcare workers in preventing the transmission of multidrug-resistant microbes.

Implication of sphingosine-1-phosphate signaling in diseases: molecular mechanism and therapeutic strategies.

Sphingosine-1-phosphate signaling is emerging as a critical regulator of cellular processes that is initiated by the intracellular production of bioactive lipid molecule, sphingosine-1-phosphate. Binding of sphingosine-1-phosphate to its extracellular receptors activates diverse downstream signaling that play a critical role in governing physiological processes. Increasing evidence suggests that this signaling pathway often gets impaired during pathophysiological and diseased conditions and hence manipulation of this signaling pathway may be beneficial in providing treatment. In this review, we summarized the recent findings of S1P signaling pathway and the versatile role of the participating candidates in context with several disease conditions. Finally, we discussed its possible role as a novel drug target in different diseases.

Mechanism of bacterial interference with TLR4 signaling by Brucella Toll/interleukin-1 receptor domain-containing protein TcpB.

Upon activation of Toll-like receptors (TLRs), cytoplasmic Toll/interleukin-1 receptor (TIR) domains of the receptors undergo homo- or heterodimerization. This in turn leads to the recruitment of adaptor proteins, activation of transcription factors, and the secretion of pro-inflammatory cytokines. Recent studies have described the TIR domain-containing protein from Brucella melitensis, TcpB (BtpA/Btp1), to be involved in virulence and suppression of host innate immune responses. TcpB interferes with TLR4 and TLR2 signaling pathways by a mechanism that remains controversial. In this study, we show using co-immunoprecipitation analyses that TcpB interacts with MAL, MyD88, and TLR4 but interferes only with the MAL-TLR4 interaction. We present the crystal structure of the TcpB TIR domain, which reveals significant structural differences in the loop regions compared with other TIR domain structures. We demonstrate that TcpB forms a dimer in solution, and the crystal structure reveals the dimerization interface, which we validate by mutagenesis and biophysical studies. Our study advances the understanding of the molecular mechanisms of host immunosuppression by bacterial pathogens.

The TLR signalling adaptor TRIF/TICAM-1 has an N-terminal helical domain with structural similarity to IFIT proteins.

TRIF/TICAM-1 (TIR domain-containing adaptor inducing interferon-ß/TIR domain-containing adaptor molecule 1) is the adaptor protein in the Toll-like receptor (TLR) 3 and 4 signalling pathway that leads to the production of type 1 interferons and cytokines. The signalling involves TIR (Toll/interleukin-1 receptor) domain-dependent TRIF oligomerization. A protease-resistant N-terminal region is believed to be involved in self-regulation of TRIF by interacting with its TIR domain. Here, the structural and functional characterization of the N-terminal domain of TRIF (TRIF-NTD) comprising residues 1-153 is reported. The 2.22 Šresolution crystal structure was solved by single-wavelength anomalous diffraction (SAD) using selenomethionine-labelled crystals of TRIF-NTD containing two additional introduced Met residues (TRIF-NTDA66M/L113M). The structure consists of eight antiparallel helices that can be divided into two subdomains, and the overall fold shares similarity to the interferon-induced protein with tetratricopeptide repeats (IFIT) family of proteins, which are involved in both the recognition of viral RNA and modulation of innate immune signalling. Analysis of TRIF-NTD surface features and the mapping of sequence conservation onto the structure suggest several possible binding sites involved in either TRIF auto-regulation or interaction with other signalling molecules or ligands. TRIF-NTD suppresses TRIF-mediated activation of the interferon-ß promoter, as well as NF-κB-dependent reporter-gene activity. These findings thus identify opportunities for the selective targeting of TLR3- and TLR4-mediated inflammation.

Crystallization and X-ray diffraction analysis of the N-terminal domain of the Toll-like receptor signalling adaptor protein TRIF/TICAM-1.

As part of the mammalian innate immune response, Toll-like receptors 3 and 4 can signal via the adaptor protein TRIF/TICAM-1 to elicit the production of type-I interferons and cytokines. Recent studies have suggested an auto-inhibitory role for the N-terminal domain (NTD) of TRIF. This domain has no significant sequence similarity to proteins of known structure. In this paper, the crystallization and X-ray diffraction analysis of TRIF-NTD and its selenomethionine-labelled mutant TRIF-NTD(A66M/L113M) are reported. Thin plate-like crystals of native TRIF-NTD obtained using polyethylene glycol 3350 as precipitant diffracted X-rays to 1.9 Å resolution. To facilitate phase determination, two additional methionines were incorporated into the protein at positions chosen based on the occurrence of methionines in TRIF homologues in different species. Crystals of the selenomethionine-labelled protein were obtained under conditions similar to the wild-type protein; these crystals diffracted X-rays to 2.5 Å resolution. The TRIF-NTD and TRIF-NTD(A66M/L113M) crystals have the symmetry of space groups P212121 and P1, and most likely contain two and four molecules in the asymmetric unit, respectively. These results provide a sound foundation for the future structure determination of this novel domain.

Cloning, expression, purification, crystallization and preliminary X-ray crystallographic analysis of the TIR domain from the Brucella melitensis TIR-domain-containing protein TcpB.

In mammals, Toll-like receptors (TLRs) recognize conserved microbial molecular signatures and induce an early innate immune response in the host. TLR signalling is mediated by interactions between the cytosolic TIR (Toll/interleukin-1 receptor) domains of the receptor and the adaptor proteins. Increasingly, it is apparent that pathogens target this interaction via pathogen-expressed TIR-domain-containing proteins to modulate immune responses. A TIR-domain-containing protein TcpB has been reported in the pathogenic bacterium Brucella melitensis. Studies have shown that TcpB interferes with the TLR2 and TLR4 signalling pathways to inhibit TLR-mediated inflammatory responses. Such interference may involve TIR-TIR-domain interactions between bacterial and mammalian proteins, but there is a lack of information about these interactions at the molecular level. In this study, the cloning, expression, purification, crystallization and preliminary X-ray crystallographic analysis of the protein construct corresponding to the TIR domain of TcpB (residues 120-250) are reported. The crystals diffracted to 2.6 Šresolution, have the symmetry of the monoclinic space group P21 and are most likely to contain four molecules in the asymmetric unit. The structure should help in understanding the molecular basis of how TcpB affects the innate immunity of the host.

Immunoinformatics-Based Identification of B and T Cell Epitopes in RNA-Dependent RNA Polymerase of SARS-CoV-2.

INTRODUCTION: The ongoing coronavirus disease 2019 (COVID-19), which emerged in December 2019, is a serious health concern throughout the world. Despite massive COVID-19 vaccination on a global scale, there is a rising need to develop more effective vaccines and drugs to curb the spread of coronavirus. METHODOLOGY: In this study, we screened the amino acid sequence of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 (the causative agent of COVID-19) for the identification of B and T cell epitopes using various immunoinformatic tools. These identified potent B and T cell epitopes with high antigenicity scores were linked together to design the multi-epitope vaccine construct. The physicochemical properties, overall quality, and stability of the designed vaccine construct were confirmed by suitable bioinformatic tools. RESULTS: After proper in silico prediction and screening, we identified 3 B cell, 18 CTL, and 10 HTL epitopes from the RdRp protein sequence. The screened epitopes were non-toxic, non-allergenic, and highly antigenic in nature as revealed by appropriate servers. Molecular docking revealed stable interactions of the designed multi-epitope vaccine with human TLR3. Moreover, in silico immune simulations showed a substantial immunogenic response of the designed vaccine. CONCLUSIONS: These findings suggest that our designed multi-epitope vaccine possessing intrinsic T cell and B cell epitopes with high antigenicity scores could be considered for the ongoing development of peptide-based novel vaccines against COVID-19. However, further in vitro and in vivo studies need to be performed to confirm our in silico observations.

Phytoconstituents from Moringa oleifera fruits target ACE2 and open spike glycoprotein to combat SARS-CoV-2: An integrative phytochemical and computational approach.

Therapeutic drugs based on natural products for the treatment of SARS-CoV-2 are currently unavailable. This study was conducted to develop an anti-SARS-CoV-2 herbal medicine to face the urgent need for COVID-19 treatment. The bioactive components from ethanolic extract of Moringa oleifera fruits (MOFs) were determined by gas chromatography-mass spectroscopy (GC-MS). Molecular-docking analyses elucidated the binding effects of identified phytocomponents against SARS-CoV-2 spike glycoprotein (PDB ID: 6VYB) and human ACE2 receptor (PDB ID: 1R42) through the Glide module of Maestro software. GC-MS analysis unveiled the presence of 33 phytocomponents. Eighteen phytocomponents exhibited good binding affinity toward ACE2 receptor, and thirteen phytocomponents had a high affinity with spike glycoprotein. This finding suggests that the top 11 hits (Docking score ≥ -3.0 kcal/mol) could inhibit SARS-CoV-2 propagation. Intriguingly, most of the phytoconstituents displayed drug-likeness with no predicted toxicity. However, further studies are needed to validate their effects and mechanisms of action. PRACTICAL APPLICATIONS: Moringa oleifera (MO) also called "drumstick tree" has been used as an alternative food source to combat malnutrition and may act as an immune booster. GC-MS analysis unveiled that ethanolic extract of Moringa oleifera fruits (MOFs) possessed 33 active components of pyridine, aromatic fatty acid, oleic acid, tocopherol, methyl ester, diterpene alcohol, triterpene and fatty acid ester and their derivatives, which have various pharmacological and medicinal values. Virtual screening study of phytocomponents of MOF with human ACE2 receptor and SARS-CoV-2 spike glycoprotein exhibited good binding affinity. Based on molecular docking, the top 11 hits (Docking score ≥-3.0 kcal/mol) might serve as potential lead molecules in antiviral drug development. Intriguingly, most of the phytoconstituents displayed drug-likeness with no predicted toxicity. Thus, MOF might be used as a valuable source for antiviral drug development to combat COVID-19, an ongoing pandemic.

Prevalence of rheumatoid arthritis and diagnostic validity of a prediction score, in patients visiting orthropedic clinics in the Madinah region of Saudi Arabia: a retrospective cross-sectional study.

Introduction: In Saudi Arabia, the epidemiology of rheumatoid arthritis (RA) is not well studied and is marked by inconsistencies in clinical diagnosis. Therefore, in this study, we explored the prevalence, clinical characteristics, and diagnostic validity of a prediction score based upon disease markers in orthropedic clinics' patients in the Madinah region of Saudi Arabia. Method: The clinical data for this retrospective cross-sectional study were retrieved from the database registry of orthopedic clinics in selected hospitals of the Medinah province of Saudi Arabia. Sociodemographic features, disease markers and the clinical characteristics were collected for a period of 6 months, from December 1, 2020, to May 31, 2021. The prediction score was generated from the sum of disease markers, coded as dichotomous variables. Results: The total sample size of our study was 401. The prevalence of RA in the study subjects (n = 401) was 14.46% (n = 58). Among RA patients, the majority were females (60.3%). Painful joints (69%) and swollen joints (51.7%) were the most common clinical complaints among RA patients. RA patients suffered from arthritis (51.7%) and experienced fatigue (46.6%), weight loss (44.8%), and loss of appetite (41.4%). Diabetes (55.2%) was the most common comorbidity in the RA patients. The sensitivity and specificity of the prediction score at the criterion score of 2.5 were 67.3% and 63.0%, respectively. The area under the curve was 0.69 (95% CI [0.62-0.76]). Conclusion: There was a moderately high prevalence of RA in patients visiting the orthropedic clinics of the selected hospitals of Madinah region of Saudi Arabia. The diagnostic validity of the prediction score, though promising, was slightly lower than the acceptable range.

Pioneer Role of Extracellular Vesicles as Modulators of Cancer Initiation in Progression, Drug Therapy, and Vaccine Prospects.

Cancer is one of the leading diseases, causing deaths worldwide. Nearly 10 million deaths were reported in 2020 due to cancer alone. Several factors are involved in cancer progressions, such as lifestyle and genetic characteristics. According to a recent report, extracellular vesicles (EVs) are involved in cancer initiation, progression, and therapy failure. EVs can play a major role in intracellular communication, the maintenance of tissue homeostasis, and pathogenesis in several types of diseases. In a healthy person, EVs carry different cargoes, such as miRNA, lncRNA etc., to help other body functions. On the other hand, the same EV in a tumor microenvironment carries cargoes such as miRNA, lncRNA, etc., to initiate or help cancer progression at various stages. These stages may include the proliferation of cells and escape from apoptosis, angiogenesis, cell invasion, and metastasis, reprogramming energy metabolism, evasion of the immune response, and transfer of mutations. Tumor-derived EVs manipulate by altering normal functions of the body and affect the epigenetics of normal cells by limiting the genetic makeup through transferring mutations, histone modifications, etc. Tumor-derived EVs also pose therapy resistance through transferring drug efflux pumps and posing multiple drug resistances. Such EVs can also help as biomarkers for different cancer types and stages, which ultimately help with cancer diagnosis at early stages. In this review, we will shed light on EVs' role in performing normal functions of the body and their position in different hallmarks of cancer, in altering the genetics of a normal cell in a tumor microenvironment, and their role in therapy resistance, as well as the importance of EVs as diagnostic tools.

Therapeutic potential of nitric oxide synthase inhibitor from natural sources for the treatment of ischemic stroke.

Nitric oxide (NO) is one of the major signalling molecules in the mammalian body playing critical role in regulation of blood pressure, cardiovascular disease including stroke, immune activation, neuronal and cell communication. Moreover, hyper production of NO by the activity of nitric oxide synthase (NOS) involved in neuropathic pain, neurodegenerative disorders and stroke. Hence, the search on small molecules from the natural sources for the inhibition of NOS is desirable in therapeutic point of view. The elevated level of NO caused by NOS enzyme become a novel target in finding new inhibitors from natural sources as antistroke agents. The present study focuses on the molecular docking of quercetin and its analogues against NOS. The active site of the enzyme was docked with the ligand and pharmacological properties were analysed. From this result, we suggest the therapeutic property of quercetin and its analogues against NOS.

Identification of SARS-CoV-2 RNA-dependent RNA polymerase inhibitors from the major phytochemicals of Nigella sativa: An in silico approach.

The coronavirus disease 2019 (COVID-19), which emerged in December 2019, continues to be a serious health concern worldwide. There is an urgent need to develop effective drugs and vaccines to control the spread of this disease. In the current study, the main phytochemical compounds of Nigella sativa were screened for their binding affinity for the active site of the RNA-dependent RNA polymerase (RdRp) enzyme of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The binding affinity was investigated using molecular docking methods, and the interaction of phytochemicals with the RdRp active site was analyzed and visualized using suitable software. Out of the nine phytochemicals of N. sativa screened in this study, a significant docking score was observed for four compounds, namely α-hederin, dithymoquinone, nigellicine, and nigellidine. Based on the findings of our study, we report that α-hederin, which was found to possess the lowest binding energy (-8.6 kcal/mol) and hence the best binding affinity, is the best inhibitor of RdRp of SARS-CoV-2, among all the compounds screened here. Our results prove that the top four potential phytochemical molecules of N. sativa, especially α-hederin, could be considered for ongoing drug development strategies against SARS-CoV-2. However, further in vitro and in vivo testing are required to confirm the findings of this study.

Repurposing of phytomedicine-derived bioactive compounds with promising anti-SARS-CoV-2 potential: Molecular docking, MD simulation and drug-likeness/ADMET studies.

In view of the potential of traditional plant-based remedies (or phytomedicines) in the management of COVID-19, the present investigation was aimed at finding novel anti-SARS-CoV-2 molecules by in silico screening of bioactive phytochemicals (database) using computational methods and drug repurposing approach. A total of 160 compounds belonging to various phytochemical classes (flavonoids, limonoids, saponins, triterpenoids, steroids etc.) were selected (as initial hits) and screened against three specific therapeutic targets (Mpro/3CLpro, PLpro and RdRp) of SARS-CoV-2 by docking, molecular dynamics simulation and drug-likeness/ADMET studies. From our studies, six phytochemicals were identified as notable ant-SARS-CoV-2 agents (best hit molecules) with promising inhibitory effects effective against protease (Mpro and PLpro) and polymerase (RdRp) enzymes. These compounds are namely, ginsenoside Rg2, saikosaponin A, somniferine, betulinic acid, soyasapogenol C and azadirachtin A. On the basis of binding modes and dynamics studies of protein-ligand intercations, ginsenoside Rg2, saikosaponin A, somniferine were found to be the most potent (in silico) inhibitors potentially active against Mpro, PLpro and RdRp, respectively. The present investigation can be directed towards further experimental studies in order to confirm the anti-SARS-CoV-2 efficacy along with toxicities of identified phytomolecules.

Nobiletin as a Neuroprotectant against NMDA Receptors: An In Silico Approach.

Excitotoxicity is a type of neurodegenerative disorder. It caused by excessive glutamate receptor activation, which leads to neuronal malfunction and fatality. The N-methyl-D-aspartate (NMDA) receptors are found in glutamatergic neurons, and their excessive activation is primarily responsible for excitotoxicity. They are activated by both glutamate binding and postsynaptic depolarization, facilitating Ca2+ entry upon activation. Therefore, they are now widely acknowledged as being essential targets for excitotoxicity issues. Molecular docking and molecular dynamics (MD) simulation analyses have demonstrated that nobiletin efficiently targets the binding pocket of the NMDA receptor protein and exhibits stable dynamic behavior at the binding site. In this study, five potential neuroprotectants, nobiletin, silibinin, ononin, ginkgolide B, and epigallocatechin gallate (EGCG), were screened against the glutamate NMDA receptors in humans via computational methods. An in silico ADMET study was also performed, to predict the pharmacokinetics and toxicity profile for the expression of good drug-like behavior and a non-toxic nature. It was revealed that nobiletin fulfills the criteria for all of the drug-likeness rules (Veber, Lipinski, Ghose, Muegge, and Egan) and has neither PAINS nor structural alerts (Brenks). In conclusion, nobiletin demonstrated a possible promising neuroprotectant activities compared to other selected phytochemicals. Further, it can be evaluated in the laboratory for promising therapeutic approaches for in vitro and in vivo studies.

Assessment of IL-1ß, IL-6, TNF-α, IL-8, and CCL 5 levels in newly diagnosed Saudi patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder which mainly affects small joints, occurs most commonly in middle-aged adults, and can be fatal in severe cases. The exact etiology of RA remains unknown. However, uncontrolled expression of pro-inflammatory cytokines and chemokines can contribute to the pathogenesis of RA. AIM: In the current study, we assessed the potential of serum concentrations of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, IL-8, and C-C motif chemokine ligand (CCL)5 as early predictive markers for RA. METHODS: In addition to clinical examination, blood samples were collected from 100 Saudi patients recently diagnosed with early RA for basic and serological tests, including rheumatoid factor (RF), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Sera of 32 healthy individuals were used as controls. Specific enzyme-linked immunosorbent assay was used to quantify the serum IL-1ß, IL-6, TNF-α, IL-8, and CCL5 levels in the samples. RESULTS: Our results indicated that RF, CRP, and ESR levels were higher in RA patients compared to controls. Furthermore, serum levels of IL-1ß, IL-6, IL-8, and CCL5, but not TNF-α, significantly increased in RA patients compared to controls. CONCLUSION: Overall, the findings suggested that IL-1ß, IL-6, IL-8, and CCL5 can be used as biomarkers in the early diagnosis of RA.

Predictive Modeling and Validation on Growth, Production of Asexual Spores and Ochratoxin A of Aspergillus Ochraceus Group under Abiotic Climatic Variables.

This study aimed to generate predictive models for growth, sporulation, and ochratoxin A (OTA) production under abiotic climatic variables, including temperatures (15-35 °C) and water activity levels (0.99-0.90 aw) by Aspergillus ochraceus group. The data were divided into three sets: one for training, one for testing, and the third one for model validation. Optimum growth occurred at 0.95 aw and 25 °C and 0.95 aw and 30 °C for A. westerdijkiae and A. steynii, respectively. Significantly improved A. westerdijkiae and A. steynii spore production occurred at 0.95 aw and 20 °C and 0.90 aw and 35 °C, respectively. A. steynii and A. westerdijkiae produced the majority of OTA at 35 °C and 0.95 aw and 25-30 °C at 0.95-0.99 aw, respectively. The accuracy of the third-order polynomial regression model reached 96% in growth cases, 94.7% in sporulation cases, and 90.9% in OTA production cases; the regression coefficients (R2) ranged from 0.8819 to 0.9978 for the Aspergillus ochraceus group. A reliable agreement was reached between the predicted and observed growth, sporulation, and OTA production. The effects of abiotic climatic variables on growth, sporulation, and OTA production of A. ochraceus group have been effectively defined, and the models generated were responsible for adequately predicted and validated models against data from other strains within A. ochraceus group that had been published in the literature under the current treatments. These models could be successfully implemented to predict fungal growth and OTA contamination on food matrices for these strains under these conditions.