Design of Cyclic-ADT Peptides to Improve Drug Delivery to the Brain via Inhibition of E-Cadherin Interactions at the Adherens Junction

We have developed linear cadherin peptides (i.e., HAV- and ADT peptides) that enhance brain delivery of drug molecules to the central nervous system (CNS). These peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells in the blood-brain barrier (BBB) to increase paracellular drug permeation. In this study, the goal was to design cyclic peptides (ADTC1, ADTC5, and ADTC6) derived from linear ADT6 (Ac-ADTPPV-NH2) to improve their stability and biological activity in improving paracellular delivery of drugs into the brain. The ADTC1 peptide (cyclo(1,8)Ac-CADTPPVC-NH2) was designed by adding two Cys residues at the N- and C-terminus of ADT6 peptide and a disulfide bond from thiol groups of the Cys residues. The ADTC5 peptide (cyclo(1,7)Ac-CDTPPVC-NH2) was derived from ADTC1 by deleting the alanine residue from the N-terminal region of ADTC1 and ADTC6. (Cyclo(1,6)Ac-CDTPPC-NH2) was constructed by deleting the valine residue from the C-terminal region of ADTC5. The results showed that ADTC1 has activity in inhibiting the resealing of the intercellular junctions of the MDCK cell monolayers similar to that of the linear ADT6, indicating that cyclization can maintain the peptide activity. The alanine residue deletion in ADTC5 does not reduce its activity compared to ADTC1 peptide, suggesting that the alanine residue does not have an important role in the activity of the peptide. In contrast, ADTC6 peptide does not have activity in inhibiting the junction resealing, indicating that the valine residue is important for peptide activity. ADTC5 inhibits the junction resealing of MDCK cell monolayers in a concentration-dependent manner with the saturation concentration above 0.4 mM and IC50 around 0.3 mM. Under the current experimental conditions, ADTC5 improves the delivery of 14C-mannitol to the brain about two fold compared to the vehicle negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide does not enhance the BBB passage of large polyethylene glycol molecules (i.e., PEG-1500 and PEG-40000) in an in situ rat brain perfusion model. In conclusion, formation of cyclic peptides can maintain cadherin peptide ability to modulate intercellular junctions of the BBB, and the primary sequence of ADT peptides is important for their biological activity

PENGARUH SUPERVISI AKADEMIK, KOMPETENSI PROFESIONAL DAN PEMANFAATAN MEDIA PEMBELAJARAN TERHADAP MUTU PENDIDIKAN SEKOLAH DASAR NEGERI KECAMATAN KALORAN KABUPATEN TEMANGGUNG

Laksitorini, Indriyati. 2024. Pengaruh Supervisi Akademik, Kompetensi Profesional dan Pemanfaatan Media Pembelajaran terhadap Mutu Pendidikan SD Negeri Kecamatan Kaloran Kabupaten Temanggung. Semarang: Pascasarjana Universitas PGRI Semarang. Pembimbing I:, Dr. Titik Haryati, M.Si. Pembimbing II:  Dr. Widya Kusumaningsih, M.Pd. Latar belakang masalah penelitian ini berkaitan dengan Mutu Pendidikan SD di Kecamatan Kaloran Kabupaten Temanggung yaitu berdasarkan Rapor Pendidikan Kecamatan Kaloran Kabupaten Temanggung Tahun 2022 dari empat dimensi yang mencapai kategori Hijau (Baik) rata-rata baru pada tingkat 24,05%, kategori cukup 53,73%, dan kateogir kurang 22,2%. Hal ini berarti 75,95% masih berada kategori cukup dan kurang. Mutu Pendidikan ditingkatkan dengan berbagai strategi di antaranya dengan Supervisi Akademik, meningkatkan Kompetensi Profesional guru dan Pemanfaatan Media Pembelajaran. Tujuan penelitian ini adalah untuk menganalisis dan mendeskripsikan pengaruh Supervisi Akademik, Kompetensi Profesional guru dan Pemanfaatan Media Pembelajaran sekolah terhadap Mutu Pendidikan sekolah dasar negeri di Kecamatan Kaloran. Penelitian ini menggunakan pendekatan penelitian kuantitatif korelasional. Populasi penelitian adalah semua guru sekolah dasar negeri di Kecamatan Kaloran Kabupaten Temanggung berjumlah 209 guru dan sampel penelitian 138 guru. Analisis penelitian ini meliputi analisis uji normalitas, uji linieritas, uji multikolinearitas, dan uji heteroskedastisitas. Uji hipotesis meliputi uji regresi sederhana dan uji regresi ganda, uji F (ANOVA) dan uji t. Berdasarkan hasil penelitian dapat disimpulkan sebagai berikut: (1) Supervisi Akademik berpengaruh positif dan signifikan terhadap Mutu Pendidikan, berdasar hasil Uji t, terbukti t hitung 7,966   > t tabel 1,977, dan nilai Sig (2-tailed) 0,000 < 0,05, besarnya pengaruh 31,5%; (2) Kompetensi Profesional berpengaruh positif dan signifikan terhadap Mutu Pendidikan, berdasarkan hasil uji t terbukti thitung l yaitu 7,405  ≥ 1,977, dan nilai Sig (2-tailed) 0,000 < 0,05, besarnya pengaruh adalah 28,9%, (3) Pemanfaatan Media Pembelajaran berpengaruh positif dan signifikan terhadap Mutu Pendidikan. Hal ini berdasarkan hasil uji t terbukti thitung ≥ ttabel 6,341 ≥ 1,977, dan nilai Sig (2-tailed) 0,000 < 0,05. Besarnya pengaruh Pemanfaatan Media Pembelajaran terhadap variabel Mutu Pendidikan adalah 22,9%, (4) Supervisi Akademik, Kompetensi Profesional dan Pemanfaatan Media Pembelajaran secara simultan berpengaruh terhadap variabel Mutu Pendidikan diperoleh lFhitung sebesar 46,799  dengan taraf signifikan 0.000.  Hasil penghitungan diperoleh nilai lFhitung > lFtabel (46,799 > l2,67) dan nilai signifikansinya 0,000 < 0,005. Besarnya sumbagan efektif dari ketiga variabel bebas adalah sebesar 50,3%

Optimization of 3,4-Dimethoxychalcone and Rutin Containing Gel with Simplex Lattice Design and In Vitro-In Vivo Test as a Sunscreen

3,4-Dimethoxychalcone and rutin, a flavonoid that contains chromophore groups, can absorb UV light and thus can be developed as a sunscreen. The objective of this study was to determine the optimum formula of 3,4-dimethoxychalcone and rutin containing gel, evaluate its physical stability, and activity of 3,4-dimethoxychalcone and rutin gel as a sunscreen through in vitro and in vivo tests. HPMC, CMC-Na, and methylcellulose were formulated into a gel base to obtain good adhesion and a clear appearance gel. Simplex Lattice Design (SLD) with Design Expert software version 10 was utilized to determine the optimum gel formulation. UVA-PF protection, photostability with transpore method, and acute dermal irritation test were performed to evaluate sunscreen activity of 3,4-dimethoxychalcone and rutin gel. The data were analyzed using SPSS version 25. The results showed that the optimum formula for 3,4-dimethoxychalcone-rutin gel consisted of 1.5% HPMC, 1.8% CMC-Na and 0.6% methylcellulose, which showed a pH of 6.96, viscosity of 89.10 dpa.s, and spreadability of 16.30 cm2. The pH, viscosity, and spreadability of base and 3,4-dimethoxychalcone- rutin gel was stable for 4 weeks of storage. The UVA-PF value is 6.48 which according to the FDA is included in the category of a two star (**) sunscreen label. The sunscreen did not exhibit a shift in wavelength after 6 hours of irradiation. Based on the primary irritation test, 3,4-dimethoxychalcone- rutin sunscreen produced zero (0) erythema and edema index. Thus, it did not cause irritation to the skin of experimental animals. Therefore, the gel containing 3,4-dimethoxychalcone and rutin had potential as a sunscreen product based on in vitro-in vivo tests and was safe on animal skin

Application of Hildebrand Solubility Parameter to Identify Ethanol-Free Co-Solvent for Pediatric Formulation

Formulation of active pharmaceutical ingredients into liquid dosage form is frequently limited by solubility issues. Ethanol is commonly used as a cosolvent to improve the solubility of drugs. Due to the incomplete expression of ethanol metabolizing enzyme in children under 6 years, several drug authorities such as WHO, EMA, and FDA recommend avoiding the use of ethanol in pediatric formulation whenever possible. In addition to that Muslim consumers are regulated by the halal practice where excessive use of ethanol in pharmaceutical products should be avoided. Thus, it is necessary to explore an alternative co-solvent to reduce the use of ethanol in the pediatric formulation. This study is aimed to identify an alternative co-solvent to ethanol that is safe for the pediatric using Hildebrand Solubility Parameter approach. In this study, the solubility parameter of the model drug, MH2011, was determined using Hildebrand Solubility Parameter (HSP). The solubility parameter (δ) of MH2011 was determined using two approaches. The first method is by measuring the maximum solubility of the model drugs in the binary mixture of water and 1,4 dioxane. The second approach is by calculating solubility parameters based on Fedor’s group substitution method. Using binary solvent blend, the MH2011 solubility parameter was identified to be approximately 14.0 (cal/cm3 )½. This value is in agreement with the result of the second approach using Fedor’s Group substitution method which is 14. 4 (cal/cm3) ½. With this data, an alternate co-solvent to substitute ethanol was explored. The studies also suggested that propylene glycol 7% v/v may give solubility power as those of ethanol 7% (v/v). This study suggested that Hildebrand’s Solubility Parameter can be applied to identify an alternate co-solvent to ethanol. This cosolvent is important for the research area where the alcohol-free formulation is preferred such as in halal pharmaceuticals and pediatric liquid formulation

Nanosilver Synthesis of Bromelain Isolate from Pineapple Extract: A Green Approach for Antibacterial Applications

Introduction: Silver nanoparticle technology has high bactericidal activity because silver ions can affect bacterial cell death, as well as nanoparticle size, which can increase drug bioavailability. Objectives: This study aims to synthesize and characterize silver nanoparticles from bromelain isolate of pineapple fruit and test the antibacterial activity of silver nanoparticles. Methods: Isolation was carried out to obtain bromelain enzyme isolates; isolates were tested for calculating bromelain content by spectrophotometry. The biosynthesis of silver nanoparticles was made by varying the number of isolates, silver nitrate solution, and PVA by ultrasonication method. Furthermore, characterization was carried out by visual observation, observation of wavelength, determination of particle size, polydispersity index, zeta potential, determination of functional groups by FTIR, and morphological evaluation by SEM. Then, the antibacterial activity of the diffusion method was tested against Staphylococcus aureus bacteria, and five formulations were obtained. Results: The formation of nanoparticles was characterized by a change from colourless to brownish yellow, a wavelength of 537.0 nm, and an absorbance of 1.276. The particle size was 92.90 nm ± 1.15, the polydispersity index value was 0.379±0.028, and the zeta potential was –38.8 mV ± 0.64. The functional group formed indicates –OH, C=O, and N=O at wave numbers 3325.04, 1634.55, and 1370.06 cm-1. It has a uniform cuboidal morphology. The results of the antibacterial activity test showed a clean and clear inhibition zone of 13.7 mm ± 1.5 against Staphylococcus aureus bacteria. Conclusions: Silver nanoparticles synthesized by bromelain isolate of pineapple fruit have the requirements for suitable silver nanoparticles and have antibacterial activity

Formulation and Antioxidant Activity of Gotu Kola Jelly Candy with Plant-based Polymers as a Gelling Agent

Centella asiatica or gotu kola has a long history as a brain supplement. Gotu kola supplements are sold as liquid and dried extract which is less attractive for a younger generation. Jelly candy is an alternative dosage form with better acceptability across ages. However, the use of animal-derived polymers such as pork gelatine in the candy restricts those who practice vegetarian and halal lifestyles from consuming the products. This study aims to explore plant-based polymers glucomannan and kappa-carrageenan as gelling agents in the preparation of gotu kola jelly candy. Preparation of the jelly candy formula was designed based on Simplex Lattice Design. Evaluation of physical characteristics of jelly candy includes organoleptic, weight uniformity, moisture content, pH, and elasticity. The antioxidant activity of gotu kola before and after the manufacturing process was evaluated. The results showed that a combination of kappa-carrageenan 1.33% and glucomannan 0.67% is the optimum formula. Adding more proportion of kappa-carrageenan reduced jelly elasticity and moisture content. While adding glucomannan improved its elasticity responses but increased moisture content. Evaluation of the antioxidant activity of gotu kola in jelly candy suggested that gotu kola experienced a significant reduction in antioxidant activity following the production process. The IC50 of the crude extract initially was129.23 ppm while post jelly candy manufacturing, the IC50 increased to 197.49 ppm. This study suggested that improvement in extraction and production processes is necessary to maintain gotu kola antioxidant activity

Feasibility of transdermal transport of atenolol by combination of iontophoresis and oleic acid pretreatment

Atenolol  has  a  low  oral  bioavailability  and  a  short  elimination  half-life. Therefore,  alternative  route  and  delivery  system  is  important.  Transdermal iontophoresis,  i.e.  a  systemic  drug  delivery  via  the  skin,  implementing  a  low intensity  of  electrical  current,  is  one  attractive  candidate.  This  study  evalu ated feasibility  of  atenolol  transdermal  transport  when  iontophoresis  is  applied  after enhancer  pretreatment.  There  were  4  formulas  prepared;  2  implemented iontophoresis  for  3  hours  (current  density:  0.25  mA/cm2)  while  the  others  did not  use  iontophoresis.  The  enhancer  was  oleic  acid  (5  or  10%  as  a  mixture  in propylene  glycol)  with  duration  of  pretreatment  of  one  hour.  Transport  was evaluated  in  the  diffusion  studies  across  the  fresh  rat  skin  in  a  static-vertical diffusion system. Data were analyzed based on the numeric convolution method to  obtain  simulated  Cp  profiles  as  well  as  AUC  of  Cp  profiles.  Based  on  the simulated Cp, the best transport was achieved in Formula 3, where iontophoresis is  performed  across  the  skin,  pretreated  with  5%  oleic  acid  for  one   hour.  The value  of  simulated  Cp  indicated  achievement  of  therapeutics  level  of  atenolol, suggesting the feasibility of the atenolol delivery by iontophoresis.Key words : atenolol, transdermal, iontophoresis, enhance

Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood-Brain Barrier Permeability

It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily due to the presence of the blood-brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules (e.g., 14C-mannitol, Gd-DTPA) to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in MDCK cell monolayers in a concentration-dependent manner (IC50 = 0.3 mM) with a maximal response at 0.4 mM. Under the current experimental conditions, ADTC5 improved the delivery of 14C-mannitol to the brain about twofold compared to the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously (i.v.). In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain

Application of PVP VA 64 and Poloxamer 188/407 in Solid Dispersion Technology for Improving Solubility of Valsartan

Valsartan, Biopharmaceutical Classification System (BCS) class II drug, exhibits pH-dependent solubility in the gastrointestinal tract, which increases at pH levels above 5. Its low solubility results in a bioavailability of only 23%, necessitating efforts to enhance it. This study aims to improve the solubility of valsartan using a solid dispersion system. Polyvinylpyrrolidone/vinyl acetate 64 (PVP VA 64), a hydrophilic polymer, was incorporated to inhibit the recrystallization of valsartan, while poloxamer 188 and poloxamer 407, used as surfactants, aimed to enhance valsartan’s solubility and intrinsic dissolution rate. Valsartan solid dispersions were prepared using the spray drying method, and the optimal formulation was determined using the Simplex Lattice Design (SLD). The composition of PVP VA 64, poloxamer 188, and poloxamer 407 were optimized factors, while saturated solubility, melting point, and intrinsic dissolution rate at pH 1.2 and 4.5 as optimized responses. The valsartan solid dispersions were characterized using Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, Powder X-Ray Diffractometry (PXRD), and Scanning Electron Microscopy (SEM). The optimal composition of the valsartan solid dispersion was 40 mg of valsartan, 100 mg of PVP VA 64, 10 mg of poloxamer 188, and 30 mg of poloxamer 407. The results indicated that the solubility of valsartan solid dispersion was 27 times higher than that of the pure drug. Furthermore, the intrinsic dissolution rate of the valsartan solid dispersion at pH 1.2 and 4.5 exceeded that of pure valsartan

In Vitro Antioxidant and Anti-Obesity Activities of Ethanolic Extract from Microalgae Strain MRB-2

Obesity has a 15-fold higher risk of coronary heart disease, stroke, and diabetes mellitus. Microalga isone of the natural resources that potentially treat obesity. The purpose of this study was to evaluate the total phenolic contents (TPC), antioxidant, and anti-obesity properties of ethanolic extract of microalgae strain MRB-2. The TPC was determined using the Follin-Ciocalteu method. The antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, and the anti-obesity was analyzed using an anti-lipase pancreatic assay. The morphology of microalga cells was also determined using Scanning Electron Microscopy (SEM). The results revealed that the TPC of ethanolic extract from the ultrasound extraction method was higher than the maceration method with the value of 2.75±0.26 mg GAE/g. While the scavenging activity toward DPPH radicals of ethanolic extract from the maceration method was higher than ultrasound, with a value of 38.92±1.94% at 0.8 mg/mL. The lipase inhibitory activity of extract from the maceration method was higher than ultrasound with a value of 20.81±2.24% at 0.38 mg/mL. Our results indicate that ethanolic extract of MRB-2 was potentially developed for anti-obesity foods and health-functional foods derived from new peatland microalgae