Development and Characterization of Selective CB2R Inverse Agonists as a Novel Anti-Inflammatory Therapy for Neuroinflammation – Mechanisms of Action in Murine and Human Microglia Models Provide Valuable Insights into Their Therapeutic Potential

Introduction: Recently, research has revealed the presence of cannabinoid receptor 2 (CB2R) in the central nervous system (CNS); since then, the receptor has emerged as a promising therapeutic target for treating multiple neurodegenerative diseases (NDD) such as Alzheimer’s (AD), Parkinson’s (PD), Human Immunodeficiency Virus (HIV) and Multiple Sclerosis (MS). The restricted and upregulated expression of CB2R in activated microglia and lack of psychotropic activity make this receptor an attractive target for discovering novel therapy to treat neuroinflammatory diseases for which there is currently no curative treatment. Methodology: A library of compounds were synthesized and evaluated in ACTOne and TANGO-bla functional assays for CB1 and CB2 activity in combination with affinity measurements for the CB1/2 receptors. Moreover, the compounds that demonstrated no activity at functional assays with high binding affinities to CB2R were further assessed in antagonist (competition) studies against the non-selective cannabinoid agonist CP 55,940. Compound 45 demonstrated CB2R inverse agonism at G-protein signaling with high potency, efficacy, and affinity in the binding and functional assays and was selected for further evaluation in murine and human microglia inflammatory models. On cell polarization assays were done to measure microglia M1 and M2 surface markers expression. Scratch assay and ROS measurements were performed to assess the effects of drug treatment on microglia migration and ROS production. Extensive signaling pathway studies were conducted to identify the downstream signaling mechanism for compound 45 and cytoskeleton staining was performed to evaluate the microglia morphological changes upon 45 treatment. A molecular docking study was utilized to explore ligand protein molecular interaction between 45 and CB2R. Additionally, the similarities and differences in the activity of compound 45, relative to standard CB2R agonist and inverse agonist, were examined in the aforementioned assays. Results: Compound 45 demonstrated the highest affinity and selectivity towards CB2R that translated to higher potency in CB2R ACTOne functional assay, whereas no functional activity was detected at CB1R. Moreover, testing compound 45 in the TANGO-bla assay revealed neutral antagonism at β-arrestins signaling, confirming the G-protein functional selectivity of this class of compounds. Treatment with compound 45 triggered a shift in murine and human microglia polarization from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype after 24 hours of treatment. The M1 markers were significantly decreased and M2 markers significantly increased relative to LPS stimulus. These results were further confirmed using microscopic examination wherein compound 45 induced a remarkable transformation of microglia into ramified morphology with a small cell body and several elongated cell projections, indicating microglia adopted an anti-inflammatory M2 phenotype. Moreover, compound 45 significantly reduced cell migration, suppressed the M1 associated ROS production which causes neurotoxicity and cell damage. Additionally, the application of compound 45 significantly increased JNK, c-JUN, CREB, and p38 phosphorylation levels and decreased ERK1/2 and NF-κB representing a unique anti-inflammatory mechanism of CB2R inverse agonists in activated microglia. The molecular docking study of compound 45 revealed that the thiophene C ring constrained the toggle switch residue Trp 258 via multiple π-π stacking interactions that stabilized CB2R in the inactive state and led to 45 inverse agonism activity at CB2R. These results were distinctly different when compared to standard CB2R agonists and inverse agonists, suggesting further research is needed to explore more precisely the utility of CB2R based therapeutics in human CNS disorders. Conclusion: The results of these studies provided valuable information that aids in the development of new analogs of the biaryl-aryl scaffold for treating neuroinflammation in human neurodegenerative diseases

Pola Interaksi Sosial Masyarakat Muslim dan Non Muslim di Kelurahan Tengan Kecamatan Mangkendek Kabupaten Tana Toraja

Penelitian ini dilatarbelakangi oleh ketertarikan peneliti dalam melihat harmonisasi antara masyarakat Muslim dan masyarakat Non-Muslim di Kelurahan Tengan Kecamatan Mengkendek Kabupaten Tana Toraja.   Harmonisasi dan kerukunan yang tercipta antar kedua masyarakat mengacu pada suatu interaksi yang yang damai, rukun dan tentram dalam lingkup masyarakat itu sendiri dan tidak menjadikan masyarakat yang berbeda keyakinan hidup berdampingan dan terlibat konflik. Penelitian ini dilakukan dengan menggunakan metode kualitatif, data-data yang diperoleh melalui hasil  observasi, wawancara dan dokumentasi. Pendekatan yang digunakan yaitu pendekatan Sosiologis. Data dari peneltian ini bersumber dari data primer dan sekunder, sedangkan teknik pengumpulan data yang digunakan yaitu reduksi data, penyajian data dan penarikan kesimpulan. Hasil penelitian menunjukkan bahwa pola interaksi sosial yang terjadi di antara masyarakat Muslim dan Non-Muslim terjalin dengan baik, hal ini terlihat dari interaksi yang terjadi di kelurahan Tengan sangat bersifat asosiatif, artinya bahwa terjadi kerja sama, asimilasi, akomodasi dan akulturasi, sehingga integrasi yang terjadi antar masyarakat Muslim dan Non-Muslim sangat berlangsung dengan baik. Tetapi tidak dapat dipungkiri bahwa proses sosial diasosiatif seperti persaingan tetap terjadi, namun persaingan yang dimakasud disini adalah persaingan ekonomi yang sehat dan sportif untuk memenuhi kebutuhan hidup masyarakat dengan cara berdagan. Selain proses sosial asosiatif dan diasosiatif terdapat juga faktor imitasi dan empati atau simpati yang mempengaruhi interaksi sosial, serta pandangan Islam tentang interaksi sosial sangat toleran, cinta damai dan rasa persudaraan

Comparison Between Hyaluronic Acid and Chlorhexidine in the Treatment of Orthodontically Induced Gingival Enlargement.

Abstract Aim: The study aimed to assess and compare the effectiveness of chlorhexidine and hyaluronic acid when used as an adjuvant to professional mechanical plaque removal (PMPR) in the treatment of orthodontically induced gingival enlargement. Methods: The study conducted was a randomized controlled clinical trial involving 45 patients. The patients will be categorized into 3 groups; control group receiving conventional PMPR, study 1 group receiving PMPR and chlorhexidine (CHX), and study 2 group receiving PMPR and hyaluronic acid (HA). Probing depth (PD), Gingival overgrowth index (GOI), gingival bleeding index (GBI), and plaque index (PI), will be recorded at baseline, 1 month, 2 months, and 4 months’ post therapy. A bivariate analysis was conducted to evaluate the parameters in function of the three study groups, and to evaluate the changes in PD and GBI between baseline, month 1, month 2 and month 4 in the three study groups. Results: A significant reduction in probing depth and gingival bleeding was observed in the three groups (p 0.05). The change in PD, PI, GBI and GOI was more in Group 1 and Group 2 than in the control group. Hyaluronic acid demonstrated the same effect of chlorhexidine. Conclusion: HA is just as effective as CHX in treating gingival enlargement. Based on the acceptance of HA by patients generally and the negative effects of CHX, HA may be a potential alternative to CHX

Optimal Trajectory Tracking Control for a Wheeled Mobile Robot Using Fractional Order PID Controller

يقدم هذا البحث, المتحكم التناسبي التكاملي التفاضلي الكسري الامثل اعتمادا على خوارزمية اسراب الطيور للسيطرة على تتبع المسار للانسان الالي ذو العجلات. حيث يتم تقليل مشكلة تتبع المسار مع إعطاء السرعة المرجعية المطلوبة للحصول على المسافة وانحراف زاوية يساوي الصفر، لتحقيق الهدف من تتبع المسار يتم استخدام اثنين من وحدات المتحكم التناسبي التكاملي التفاضلي الكسري للتحكم في السرعة والزاوية لتنفيذ سيطرة تتبع المسار.  تستخدم أساليب تخطيط وتتبع المسارات لإعطاء مسارات تتبع مختلفة. تم استخدام خوارزمية اسراب الطيور لإيجاد المعلمات المثلى لوحدات المتحكم التناسبي التكاملي التفاضلي الكسري. وتم محاكاة النماذج الحركية والحيوية للانسان الالي ذو العجلات لتتبع المسار المطلوب مع خوارزمية أسراب الطيور في برنامج المحاكاة  ماتلاب. وتبين نتائج المحاكاة أن  وحدات المتحكم التناسبي التكاملي التفاضلي الكسري الأمثل هي أكثر فعالية ولها أداء ديناميكي أفضل من الطرق التقليدية.This paper present an optimal Fractional Order PID (FOPID) controller based on Particle Swarm Optimization (PSO) for controlling the trajectory tracking of Wheeled Mobile Robot(WMR).The issue of trajectory tracking with given a desired reference velocity is minimized to get the distance and deviation angle equal to zero, to realize the objective of trajectory tracking a two FOPID controllers are used for velocity control and azimuth control to implement the trajectory tracking control. A path planning and path tracking methodologies are used to give different desired tracking trajectories.  PSO algorithm is using to find the optimal parameters of FOPID controllers. The kinematic and dynamic models of wheeled mobile robot for desired trajectory tracking with PSO algorithm are simulated in Simulink-Matlab. Simulation results show that the optimal FOPID controllers are more effective and has better dynamic performance than the conventional methods

Pengaruh Pengawasan dan Komunikasi Interaktif Terhadap Upaya Meningkatkan Disiplin Taruna

This study aims to analyze the influence of supervision, communication, and both on cadets' discipline at the Marine Science Training and Education Center (BP2IP) Tangerang. This study used a descriptive-analytical method, the population in this study were all cadet students at BP2IP Tangerang, Banten. This research data use three variables, namely: supervision (X1), communication (X2), and discipline development (Y). The results of this study indicate that the supervision variable carried out by the Tangerang Shipping Science Education and Training Center has an achievement level of 75.10%, the communication variable has an achievement level of 71.93%, and the discipline coaching variable has an achievement level of 75.56%. In conclusion, the supervision, communication, and discipline development for cadets at the Shipping Science Education and Training Center (BP2IP), Tangerang, has a significant effect. It has been carried out well by the Tangerang Shipping Science Training and Education Center.. Keywords: Discipline, Communication, Supervision, Youth

5G Hairpin and Interdigital Bandpass Filters

At two low 5G frequency bands: 3.7 GHz - 4.2 GHz and 5.975 GHz -7.125 GHz, Hairpin Bandpass Filter (HPBF) and Interdigital Bandpass Filter (IBF) are designed and simulated in this paper. Both filters show good results in terms of matching and transmission responses with a wide bandwidth through the two frequency bands. HPBF with simple design resulted in good return and insertion losses, < - 10.43 dB and – 0.63 dB, and < - 14.48 dB and –0.46 dB through frequency bands: 3.51 GHz - 4.27 GHz and 5.58 GHz – 7.24 GHz, respectively. In addition to good filter response that IBF provides, it supports high order second harmonics suppression. The simulated S11 and S12 of this filter are < -11.15 dB and –0.63 dB with out of band rejection up to 11.12 GHz through the frequency band 3.56  GHz – 4.25 GHz. Furthermore, at the second frequency band IBF is designed with two different grounding via hole radii (rVia), case 1: rVia = 0.4 mm and case 2: rVia = 0.7 mm. For both cases, the designed filter shows good results with high order second harmonics suppression up to 18.33 GHz and 18.96 GHz. In this paper, High Frequency Structure Simulator (HFSS) software is used to carry out the simulation

Biological Evaluation and Theoretical Study of Bi-dentate Ligand for Amoxicillin Derivative with Some Metal Ions

       في هذا البحث  تم تحضير معقدات قواعد شف للمركب ميثيل 6- (2- (ثنائي فينيل ميثيلين) أمينو) -2- (4-هيدروكسي فينيل) أسيتاميدو) -2،2-ثنائي ميثيل -5-أوكسو -1-ثيا-4-أزاباي سايكلو(3،2،0)هبتانس -3-كاربوكسيلت مع ايونات كوبلت ،نيكل ،نحاس والزنك ثنائية التكافؤ.تم تشخيص المعقدات المحضرة بطرق مختلفة منها طيف الاشعة تحت الحمراء   (FT-IR)وطيف الاشعة فوق البنفسجية-المرئية (Uv-vis) ،الحساسية المغناطيسية ،التحليل الذري للعناصر (C.H.N.S) ،الامتصاص الذري والتوصيلية المولارية. الواضح من الدراسة الطيفية ان المعقدات تمتلك تركيب احادي النوية وان الليكاند المحضر متناسق مع الايونات الفلزية بشكل ثنائي السن مع شكل ثماني السطوح باستثناء معقد الكوبلت الثنائي فانة يمتلك شكل رباعي السطوح. استخدام برنامج  Hyper Chem-8.0.7لتوقع الشكل الهندسي للمركبات جنبًا إلى جنب مع حرارة التكوين (°ΔH f) ، طاقة الربط (ΔEb) ، عزم ثنائي القطب (µ) ، ترددات FT-IR في الحالة الغازية . تم فحص هذه المركبات ونشاطهاالحيوي كمضادات للجراثيم والفطريات.               In this paper, the complexes of Shiff base of Methyl -6-[2-(diphenylmethylene)amino)-2-(4-hydroxyphenyl)acetamido]-2,2-dimethyl-5-oxo-1-thia-4-azabicyclo[3.2.0]heptane-3-carboxylate (L) with Cobalt(II), Nickel(II), Cupper(II) and Zinc(II) have been prepared. The compounds have been characterized by different means such as FT-IR, UV-Vis, magnetic moment, elemental microanalyses (C.H.N), atomic absorption, and molar conductance. It is obvious when looking at the spectral study that the overall complexes obtained as monomeric structure as well as the metals center moieties are two-coordinated with octahedral geometry excepting Co complexes that existed as a tetrahedral geometry. Hyper Chem-8.0.7 program was employed, after calculating the heat of formation (ΔH°f), binding energy (ΔEb), dipole moment( µ ), and FT-IR frequencies are carried out in gas phase, the geometric shape is suggested. The compounds have been also screened for their bioactivity to antibacterial and antifungal.

Simultaneous determination of paracetamol, caffeine and codeine in tablets and human plasma by micellar liquid chromatography

A simple, rapid, sensitive and eco-friendly liquid chromatographic method was developed and validated for the simultaneous determination of paracetamol (PAR), caffeine (CAF) and codeine (COD). The separation was performed on cyano column using a micellar mobile phase consists of 140 mM sodium dodecyl sulfate, 25 mM phosphate buffer and 10% acetonitrile at pH = 3. The analysis was performed at a flow rate of 1 mL/min and a column temperature of 30 °C under direct UV detection at 210 nm. Total analysis time was below 6 min. Baclofen (BCF) was used as an internal standard. The validation was performed according to the ICH guidelines. The proposed method was linear over the ranges of 0.2-100.0, 0.02-12.0 and 0.2-12.0 µg/mL for PAR, CAF and COD, respectively. The limits of detection were 0.031, 0.007 and 0.054 µg/mL and limits of quantification 0.103, 0.02 and 0.164 µg/mL for PAR, CAF and COD, respectively. The results show that the procedure is suitable for the routine analysis of drugs in tablet dosage forms. The method was further extended to the determination of the studied drugs in spiked human plasma with mean percentage recoveries of 99.61±0.530, 99.28±0.523 and 99.52±0.385 for PAR, CAF and COD, respectively

Discovery of novel phthalimide analogs

In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a–i, 5a–f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target enzymes