bluuebunny/crossref_metadata_2025 huggingface dataset:
Benzylisoquinoline Alkaloids from the Stems of Limacia scandens and Their Potential as Autophagy Inhibitors
Authors: Lee Hee-Ju , Park Eun-Jin , Ryu Byeol , Cho Hyo-Moon , Nghiem Duc-Trong , Pham Ha-Thanh-Tung , Pan Cheol-Ho , Oh Won-Keun
Published: October 2022

Limacia scandens is traditionally used to treat depression and affective disorders in Malaysia. The chemical compositions have been reported to include bisbenzylisoquinoline and aporphine-type alkaloids in the genus Limacia Lour., but studies on the components of L. scandens have rarely been reported. Therefore, this study was conducted to determine new benzylisoquinoline alkaloid derivatives with autophagy regulation activity from this plant. Bioactivity-guided isolation was applied to various column chromatography methods using RP-18, Sephadex LH-20 open column chromatography, and preparative HPLC. The chemical structures of the isolated compounds were elucidated through spectroscopic data analysis, including NMR, HR-ESI-MS, and ECD data. In addition, isolated compounds were tested for autophagy-regulating activity in HEK293 cells expressing GFP-L3. Three new dimeric benzylisoquinoline alkaloids (1−3), one new 4-hydroxybenzoic acid-conjugated benzylisoquinoline alkaloid (4), and six known compounds (5−10) were isolated from the stems of L. scandens. All compounds (1–10) were screened for autophagy regulation in HEK293 cells stably expressing the GFP-LC3 plasmid. Among the isolated compounds, 1, 2, and 4 showed autophagic regulation activity that blocked the process of combining autophagosomes and lysosomes. They also inhibit the protein degradation process from the autolysosome as inhibitors of autophagy. Novel benzylisoquinoline alkaloids from L. scandens showed potent potency for the inhibition of autophagic flux. This study provides potential candidates for developing natural autophagy inhibitors for disease prevention and treatment.
Comparative Cytotoxic Evaluation of Zygophyllum album Root and Aerial Parts of Different Extracts and Their Biosynthesized Silver Nanoparticles on Lung A549 and Prostate PC-3 Cancer Cell Lines
Authors: Abdelhameed Reda F. A. , Nafie Mohamed S. , Hal Dina M. , Nasr Ali M. , Swidan Shady A. , Abdel-Kader Maged S. , Ibrahim Amany K. , Ahmed Safwat A. , Badr Jihan M. , Eltamany Enas E.
Published: October 2022

The current work demonstrates a comparative study between aerial and root parts of Zygophyllum album L. The total phenolic (TPC) and flavonoid content (TFC), in addition to the antioxidant activity, of the crude extracts were investigated, where the aerial parts revealed a higher value overall. By means of UV–VIS and HPLC, rutin and caffeic acid were detected and then quantified as 5.91 and 0.97 mg/g of the plant extract, respectively. Moreover, the biosynthesis of AgNPs utilizing the crude extract of the arial parts and root of Z. album L. and the phenolic extracts was achieved in an attempt to enhance the cytotoxicity of the different plant extracts. The prepared AgNPs formulations were characterized by TEM and zeta potential measurements, which revealed that all of the formulated AgNPs were of a small particle diameter and were highly stable. The mean hydrodynamic particle size ranged from 67.11 to 80.04 nm, while the zeta potential ranged from 29.1 to 38.6 mV. Upon biosynthesis of the AgNPs using the extracts, the cytotoxicity of the tested samples was improved, so the polyphenolics AgNPs of the aerial parts exhibited a potent cytotoxicity against lung A549 and prostate PC-3 cancer cells with IC50 values of 6.1 and 4.36 µg/mL, respectively, compared with Doxorubicin (IC50 values of 6.19 and 5.13 µg/mL, respectively). Regarding the apoptotic activity, polyphenolics AgNPs of the aerial parts induced apoptotic cell death by 4.2-fold in PC-3 and 4.7-fold in A549 cells compared with the untreated control. The mechanism of apoptosis in both cancerous cells appeared to be via the upregulation proapoptotic genes; p53, Bax, caspase 3, 8, and 9, and the downregulation of antiapoptotic gene, Bcl-2. Hence, this formula may serve as a good source for anticancer agents against PC-3 and A549 cells.
Pyrazole-Based Thrombin Inhibitors with a Serine-Trapping Mechanism of Action: Synthesis and Biological Activity
Authors: Dunker Calvin , Imberg Lukas , Siutkina Alena I. , Erbacher Catharina , Daniliuc Constantin G. , Karst Uwe , Kalinin Dmitrii V.
Published: October 2022

New antithrombotic drugs are needed to combat thrombosis, a dangerous pathology that causes myocardial infarction and ischemic stroke. In this respect, thrombin (FIIa) represents an important drug target. We herein report the synthesis and biological activity of a series of 1H-pyrazol-5-amine-based thrombin inhibitors with a serine-trapping mechanism of action. Among synthesized compounds, flexible acylated 1H-pyrazol-5-amines 24e, 34a, and 34b were identified as potent 16–80 nM thrombin inhibitors, which showed practically no off-targeting effect against other physiologically relevant serine proteases. To prove that synthesized compounds are covalent thrombin inhibitors, the most potent derivative 24e (FIIa IC50 = 16 nM) was studied in a mass-shift assay, where it has been shown that 24e transfers its acyl moiety (pivaloyl) to the catalytic Ser195 of thrombin. Performed herein docking studies also confirmed the covalent mechanism of thrombin inhibition by synthesized compounds. Acylated aminopyrazoles found during this study showed only limited effects on plasma coagulation in activated partial thrombin time (aPTT) and prothrombin time (PT) in vitro assays. However, such thrombin inhibitors are expected to have virtually no effect on bleeding time and can be used as a starting point for developing a safer alternative to traditional non-covalent anticoagulants.
Ultra-Fast Middle-Up Reversed Phase Liquid Chromatography Analysis of Complex Bispecific Antibodies Obtained in Less Than One Minute
Authors: Murisier Amarande , D’Atri Valentina , Pirner Sebastian , Larraillet Vincent , Fekete Szabolcs , Lauber Matthew , Guillarme Davy
Published: October 2022

This work illustrates the benefits and limitations of using ultra-short reversed phase liquid chromatography (RPLC) columns for the characterization of various complex bispecific antibodies after prolonged thermal stress at the middle-up level of analysis. First, we have demonstrated that alternative organic modifiers, such as isopropanol, can be used in RPLC mode without generating excessive pressure, thanks to the prototype 10 × 2.1 mm, 2.7 µm particle column. However, compared to acetonitrile, the selectivity was not improved, at least for the selected biopharmaceutical products. Importantly, very fast separations (sub-1 min) of high quality were systematically obtained for the different samples when using a spectroscopic detector, but a severe loss of performance was observed with mass spectrometry (MS) detection due to dispersion effects. Based on these results, there is a clear need to improve the interfacing between LC and MS (shorter/thinner tubing) to mitigate band broadening.
Review of Novel Oral Amphotericin B Formulations for the Treatment of Parasitic Infections
Authors: Wasan Ellen , Mandava Tavonga , Crespo-Moran Pablo , Nagy Adrienne , Wasan Kishor M.
Published: October 2022

Amphotericin B (AmpB) is a polyene macrolide antibiotic used in the treatment of blood-borne parasitic and fungal infections. However, its use, particularly in the developing world, has been limited by dose-dependent kidney toxicity, other systemic-related toxicity issues following injection, the inconvenience of parenteral administration, and accessibility. Oral formulation approaches have focused on the dual problem of solubility and permeability of AmpB, which is poorly water soluble, amphoteric and has extremely low oral bioavailability. Therefore, to enhance oral absorption, researchers have employed micellar formulations, polymeric nanoparticles, cochleates, pro-drugs, and self-emulsifying drug delivery systems (SEDDS). This paper will highlight current uses of AmpB against parasitic infections such as leishmaniasis, preclinical and clinical formulation strategies, applications in veterinary medicine and the importance of developing a cost-effective and safe oral AmpB formulation.
Biosynthesis of Silver Nanoparticles Using Commiphora mukul Extract: Evaluation of Anti-Arthritic Activity in Adjuvant-Induced Arthritis Rat Model
Authors: Singh Anupama , Boregowda Sateesha Shivally , Moin Afrasim , Abu Lila Amr Selim , Aldawsari Mohammed F. , Khafagy El-Sayed , Alotaibi Hadil Faris , Jayaramu Rajamma Abburu
Published: October 2022

Rheumatoid arthritis (RA) is a major global public health challenge, and novel therapies are required to combat it. Silver nanoparticles (AgNPs) have been employed as delivery vehicles of anti-inflammatory drugs for RA therapy, and it has been recently realized that AgNPs have anti-inflammatory action on their own. However, their conventional synthesis processes might result in cytotoxicity and environmental hazards. Instead, the use of natural products as a reducing and stabilizing agent in the biosynthesis of silver nanoparticles has arisen as an option to decrease the cytotoxic and environmental concerns associated with chemical synthesis of AgNPs. In this study, we challenged the efficacy of Commiphora mukul (guggul) aqueous extract as a reducing and/or capping agent for the biosynthesis of AgNPs. Guggul-mediated biosynthesized silver nanoparticles (G-AgNPs) were characterized via UV-vis spectroscopy, dynamic light scattering, and scanning electron microscopy. In addition, their anti-arthritic potential was evaluated in an adjuvant-induced arthritis (AIA) model. The fabricated NPs showed an absorption peak at 412 nm, corresponding to the typical surface plasmon resonance band of AgNPs. The synthesized G-AgNPs were nearly spherical, with a particle size of 337.6 ± 12.1 nm and a negative surface charge (−18.9 ± 1.8 mV). In AIA rat model, synthesized G-AgNPs exerted a potent anti-inflammatory action, as manifested by a remarkable reduction in paw volume (>40%) along with elicitation of a minimal arthritic score, compared to control rats. In addition, when compared to arthritic rats, treatment with G-AgNPs efficiently restored the activity of antioxidant enzyme, superoxide dismutase, and catalase, indicating the efficiency of synthesized G-AgNPs in alleviating the oxidative stress associated with RA. Finally, histological examination revealed comparatively lower inflammatory cells infiltration in ankle joint tissue upon treatment with G-AgNPs. Collectively, biosynthesized G-AgNPs might represent a plausible therapeutic option for the management of RA.
Novel Salinomycin-Based Paramagnetic Complexes—First Evaluation of Their Potential Theranostic Properties
Authors: Pashkunova-Martic Irena , Kukeva Rositsa , Stoyanova Radostina , Pantcheva Ivayla , Dorkov Peter , Friske Joachim , Hejl Michaela , Jakupec Michael , Hohagen Mariam , Legin Anton , Lubitz Werner , Keppler Bernhard K. , Helbich Thomas H. , Ivanova Juliana
Published: October 2022

Combining therapeutic with diagnostic agents (theranostics) can revolutionize the course of malignant diseases. Chemotherapy, hyperthermia, or radiation are used together with diagnostic methods such as magnetic resonance imaging (MRI). In contrast to conventional contrast agents (CAs), which only enable non-specific visualization of tissues and organs, the theranostic probe offers targeted diagnostic imaging and therapy simultaneously. Methods: Novel salinomycin (Sal)-based theranostic probes comprising two different paramagnetic metal ions, gadolinium(III) (Gd(III)) or manganese(II) (Mn(II)), as signal emitting motifs for MRI were synthesized and characterized by elemental analysis, infrared spectral analysis (IR), electroparamagnetic resonance (EPR), thermogravimetry (TG) differential scanning calorimetry (DSC) and electrospray ionization mass spectrometry (ESI-MS). To overcome the water insolubility of the two Sal-complexes, they were loaded into empty bacterial ghosts (BGs) cells as transport devices. The potential of the free and BGs-loaded metal complexes as theranostics was evaluated by in vitro relaxivity measurements in a high-field MR scanner and in cell culture studies. Results: Both the free Sal-complexes (Gd(III) salinomycinate (Sal-Gd(III) and Mn(II) salinomycinate (Sal-Mn(II)) and loaded into BGs demonstrated enhanced cytotoxic efficacy against three human tumor cell lines (A549, SW480, CH1/PA-1) relative to the free salinomycinic acid (Sal-H) and its sodium complex (Sal-Na) applied as controls with IC50 in a submicromolar concentration range. Moreover, Sal-H, Sal-Gd(III), and Sal-Mn(II) were able to induce perturbations in the cell cycle of treated colorectal and breast human cancer cell lines (SW480 and MCF-7, respectively). The relaxivity (r1) values of both complexes as well as of the loaded BGs, were higher or comparable to the relaxivity values of the clinically applied contrast agents gadopentetate dimeglumine and gadoteridol. Conclusion: This research is the first assessment that demonstrates the potential of Gd(III) and Mn(II) complexes of Sal as theranostic agents for MRI. Due to the remarkable selectivity and mode of action of Sal as part of the compounds, they could revolutionize cancer therapy and allow for early diagnosis and monitoring of therapeutic follow-up.
3D-Powder-Bed-Printed Pharmaceutical Drug Product Tablets for Use in Clinical Studies
Authors: van den Heuvel Korinde A. , Berardi Alberto , Buijvoets Lisa B. , Dickhoff Bastiaan H. J.
Published: October 2022

Printing of phase 1 and 2a clinical trial formulations represents an interesting industrial application of powder bed printing. Formulations for clinical trials are challenging because they should enable flexible changes in the strength of the dosage form by varying the active pharmaceutical ingredient (API) percentage and tablet mass. The aim of this study was to investigate how powder bed 3D printing can be used for development of flexible platforms for clinical trials, suitable for both hydrophilic and hydrophobic APIs, using only conventional tableting excipients. A series of pre-formulation and formulation studies were performed to develop two platform formulations for clinical trials using acetaminophen and diclofenac sodium as model compounds and lactose and starch as excipients. The results showed that the type of starch used as the formulation binder must be optimized based on the type of API. Moreover, powder blend flow and liquid penetration ability proved to be critical material attributes (CMAs) that need to be controlled, particularly at high drug loading. Optimization of these CMAs was performed by selecting the appropriate particle size of the API or by addition of silica. A critical process parameter that had to be controlled for production of tablets of good quality was the quantity of the printing ink. After optimization of both the formulation and process parameters, two platform formulations, that is, one for each API, were successfully developed. Within each platform, drug loading from 5 up to 50% w/w and tablet mass from 50 to 500 mg were achieved. All 3D-printed tablets could be produced at tensile strength above 0.2 MPa, and most tablets could enable immediate release (i.e., >80% w/w within 30 min).
Crystal Engineering of Ionic Cocrystals Sustained by Azolium···Azole Heterosynthons
Authors: Rahmani Maryam , Kumar Vijith , Bruno-Colmenarez Julia , Zaworotko Michael J.
Published: October 2022

Crystal engineering of multi-component molecular crystals, cocrystals, is a subject of growing interest, thanks in part to the potential utility of pharmaceutical cocrystals as drug substances with improved properties. Whereas molecular cocrystals (MCCs) are quite well studied from a design perspective, ionic cocrystals (ICCs) remain relatively underexplored despite there being several recently FDA-approved drug products based upon ICCs. Successful cocrystal design strategies typically depend on strong and directional noncovalent interactions between coformers, as exemplified by hydrogen bonds. Understanding of the hierarchy of such interactions is key to successful outcomes in cocrystal design. We herein address the crystal engineering of ICCs comprising azole functional groups, particularly imidazoles and triazoles, which are commonly encountered in biologically active molecules. Specifically, azoles were studied for their propensity to serve as coformers with strong organic (trifluoroacetic acid and p-toluenesulfonic acid) and inorganic (hydrochloric acid, hydrobromic acid and nitric acid) acids to gain insight into the hierarchy of NH+···N (azolium-azole) supramolecular heterosynthons. Accordingly, we combined data mining of the Cambridge Structural Database (CSD) with the structural characterization of 16 new ICCs (11 imidazoles, 4 triazoles, one imidazole-triazole). Analysis of the new ICCs and 66 relevant hits archived in the CSD revealed that supramolecular synthons between identical azole rings (A+B−A) are much more commonly encountered, 71, than supramolecular synthons between different azole rings (A+B−C), 11. The average NH+···N distance found in the new ICCs reported herein is 2.697(3) Å and binding energy calculations suggested that hydrogen bond strengths range from 31–46 kJ mol−1. The azolium-triazole ICC (A+B−C) was obtained via mechanochemistry and differed from the other ICCs studied as there was no NH+···N hydrogen bonding. That the CNC angles in imidazoles and 1,2,4-triazoles are sensitive to protonation, the cationic forms having larger (approximately 4.4 degrees) values than comparable neutral rings, was used as a parameter to distinguish between protonated and neutral azole rings. Our results indicate that ICCs based upon azolium-azole supramolecular heterosynthons are viable targets, which has implications for the development of new azole drug substances with improved properties.
Drug Stability: ICH versus Accelerated Predictive Stability Studies
Authors: González-González Olga , Ramirez Irving O. , Ramirez Bianca I. , O’Connell Peter , Ballesteros Maria Paloma , Torrado Juan José , Serrano Dolores R.
Published: October 2022

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and the United States to facilitate the mutual acceptance of stability data that are sufficient for registration by the regulatory authorities in these jurisdictions. Overall, ICH stability studies involve a drug substance tested under storage conditions and assess its thermal stability and sensitivity to moisture. The long-term testing should be performed over a minimum of 12 months at 25 °C ± 2 °C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH. The intermediate and accelerated testing should cover a minimum of 6 months at 30 °C ± 2 °C/65% RH ± 5% RH (which is not necessary if this condition was utilized as a long-term one) and 40 °C ± 2 °C/75% RH ± 5% RH, respectively. Hence, the ICH stability testing for industrially fabricated medicines is rigorous and tedious and involves a long period of time to obtain preclinical stability data. For this reason, Accelerated Predictive Stability (APS) studies, carried out over a 3–4-week period and combining extreme temperatures and RH conditions (40–90 °C)/10–90% RH, have emerged as novel approaches to predict the long-term stability of pharmaceutical products in a more efficient and less time-consuming manner. In this work, the conventional ICH stability studies versus the APS approach will be reviewed, highlighting the advantages and disadvantages of both strategies. Furthermore, a comparison of the stability requirements for the commercialization of industrially fabricated medicines versus extemporaneous compounding formulations will be discussed.
Nanotherapeutics Plus Immunotherapy in Oncology: Who Brings What to the Table?
Authors: Timon-David Elise , Perez Carla , Rodallec Anne
Published: October 2022

While the number of oncology-related nanotherapeutics and immunotherapies is constantly increasing, cancer patients still suffer from a lack of efficacy and treatment resistance. Among the investigated strategies, patient selection and combinations appear to be of great hope. This review will focus on combining nanotherapeutics and immunotherapies together, how they can dually optimize each other to face such limits, bringing us into a new field called nano-immunotherapy. While looking at current clinical trials, we will expose how passive immunotherapies, such as antibodies and ADCs, can boost nanoparticle tumor uptake and tumor cell internalization. Conversely, we will study how immunotherapies can benefit from nanotherapeutics which can optimize their lipophilicity, permeability, and distribution (e.g., greater tumor uptake, BBB crossing, etc.), tumor, tumor microenvironment, and immune system targeting properties.
Real-World Safety Profile of Biologics Used in Rheumatology: A Six-Year Observational Pharmacovigilance Study in the Calabria Region
Authors: Gagliardi Agnese , Iaquinta Francesco Salvatore , Grembiale Rosa Daniela , De Sarro Caterina , Fabiano Antonio , Fraija Domenico , Palleria Caterina , Romeo Rossella , De Francesco Adele Emanuela , Naturale Maria Diana , Citraro Rita , Gallelli Luca , Leo Antonio , De Sarro Giovambattista
Published: October 2022

Background: The introduction of biological agents into the clinical armamentarium has modified the management of moderate-severe inflammatory arthritis (IA). However, these drugs can lead to serious adverse events (SAEs) and unpredictable adverse events (AEs) that are difficult to detect in pre-marketing clinical trials. This pharmacovigilance project aimed to study the AEs associated with biologics use in rheumatology. Methods: The current investigation is a multicenter, prospective, observational cohort study based on the Calabria Biologics Pharmacovigilance Program. Patients treated with one biologic agent from January 2016 to January 2022 were enrolled. Results: Overall, 729 (86.3%) of a total of 872 patients did not develop AEs or SAEs, whereas 143 (16.4%) patients experienced at least one AE, of which 16 (1.8%) had at least one SAE. The most common AEs were administration site conditions followed by gastrointestinal, nervous system and skin disorders. We reported a total of 173 switches and 156 swaps. Switches mainly occurred for inefficacy (136; 77.7%), whereas only 39 (22.3%) were due to the onset of an AE. Primary/secondary failure was the most frequent reason for swaps (124, 79%), while AEs onset led to 33 (21%) swaps. Conclusions: This study supports the validity of our program in monitoring and detecting AEs in the rheumatological area, confirming the positive beneficial/risk ratio of biologics.
Epidemiology of Treated Diabetes Ocular Complications in France 2008–2018—The LANDSCAPE French Nationwide Study
Authors: Creuzot-Garcher Catherine , Massin Pascale , Srour Mayer , Baudin Florian , Dot Corinne , Nghiem-Buffet Sylvia , Girmens Jean-Francois , Collin Cedric , Ponthieux Anne , Delcourt Cecile
Published: October 2022

Aim: LANDSCAPE aimed to estimate the annual incidence and prevalence of treated diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) between 2008 and 2018. Methods: This French nationwide observational study used data from the French National Health Insurance Databases covering 99% of the French population. Data about healthcare consumption were used to identify adults treated with anti-VEGFs or dexamethasone implants (for DME) and with pan-retinal photocoagulation (for PDR). All French patients newly treated between 2008 and 2018 were included. Incidence and prevalence of treated DME and PDR were estimated for the age-matched general population and the population with diabetes in France. Sociodemographic characteristics and medical history were described in both populations. Results: We identified 53,584 treated DME patients and 127,273 treated PDR patients between 2008 and 2018, and 11,901 DME and 11,996 PDR new incident patients in 2018. The treated DME incidence in 2018 was 2.5 per 10,000 in the general population and 37.3 per 10,000 in the population with diabetes. Prevalence in 2018 was 9.5 and 143.7 per 10,000 in the respective populations. Treated PDR incidence in 2018 was 2.3 per 10,000 in the general population and 31.2 per 10,000 in the population with diabetes. Prevalence in 2018 was 19.9 and 270.3 per 10,000 in the respective populations. Incidence and prevalence were not age-dependent. Incidence of treated PDR incidence was relatively stable from 2008–2018. Incidence of treated DME incidence rose from 2012–2018, probably due to widening access to newly available treatments, such as anti-VEGFs. Conclusions: We provide exhaustive nationwide data on the incidence and prevalence of treated diabetic ocular complications in France over a 10-year period.
Opportunities and Challenges of Switchable Materials for Pharmaceutical Use
Authors: Tuncaboylu Deniz Ceylan , Wischke Christian
Published: October 2022

Switchable polymeric materials, which can respond to triggering signals through changes in their properties, have become a major research focus for parenteral controlled delivery systems. They may enable externally induced drug release or delivery that is adaptive to in vivo stimuli. Despite the promise of new functionalities using switchable materials, several of these concepts may need to face challenges associated with clinical use. Accordingly, this review provides an overview of various types of switchable polymers responsive to different types of stimuli and addresses opportunities and challenges that may arise from their application in biomedicine.
Immobilization of Metronidazole on Mesoporous Silica Materials
Authors: Szentmihályi Klára , Klébert Szilvia , May Zoltán , Bódis Eszter , Mohai Miklós , Trif László , Feczkó Tivadar , Károly Zoltán
Published: October 2022

Metronidazole (MTZ) is a widely used drug, but due to its many side effects, there is a growing trend today to use a minimum dose while maintaining high efficacy. One way to meet this demand is to reduce the size of the drug particles. A relatively new method of size reduction is attaching the drug molecules to a mesoporous carrier. In this paper, we studied the fixation of MTZ molecules on mesoporous silica carriers. The drug was immobilized on two mesoporous silica materials (Syloid, SBA-15) with the use of a variety of immersion techniques and solvents. The immobilized drug was subjected to physicochemical examinations (e.g., SEM, XPS, XRD, nitrogen uptake, DSC) and dissolution studies. A significantly higher immobilization was attained on SBA-15 than on a Syloid carrier. Among the processing parameters, the type of MTZ solvent had the highest influence on immobilization. Ultrasonic agitation had a lower but still significant impact, while the concentration of MTZ in the solution made no difference. Under optimal conditions, with the application of an ethyl acetate solution, the surface coverage on SBA-15 reached as much as 91%. The immobilized MTZ exhibited a ca. 10% faster dissolution rate as compared to the pure micron-sized drug particles.
BKCa Activator NS1619 Improves the Structure and Function of Skeletal Muscle Mitochondria in Duchenne Dystrophy
Authors: Dubinin Mikhail V. , Starinets Vlada S. , Belosludtseva Natalia V. , Mikheeva Irina B. , Chelyadnikova Yuliya A. , Igoshkina Anastasia D. , Vafina Aliya B. , Vedernikov Alexander A. , Belosludtsev Konstantin N.
Published: October 2022

Duchenne muscular dystrophy (DMD) is a progressive hereditary disease caused by the absence of the dystrophin protein. This is secondarily accompanied by a dysregulation of ion homeostasis, in which mitochondria play an important role. In the present work, we show that mitochondrial dysfunction in the skeletal muscles of dystrophin-deficient mdx mice is accompanied by a reduction in K+ transport and a decrease in its content in the matrix. This is associated with a decrease in the expression of the mitochondrial large-conductance calcium-activated potassium channel (mitoBKCa) in the muscles of mdx mice, which play an important role in cytoprotection. We observed that the BKCa activator NS1619 caused a normalization of mitoBKCa expression and potassium homeostasis in the muscle mitochondria of these animals, which was accompanied by an increase in the calcium retention capacity, mitigation of oxidative stress, and improvement in mitochondrial ultrastructure. This effect of NS1619 contributed to the reduction of degeneration/regeneration cycles and fibrosis in the skeletal muscles of mdx mice as well as a normalization of sarcomere size, but had no effect on the leakage of muscle enzymes and muscle strength loss. In the case of wild-type mice, we noted the negative effect of NS1619 manifested in the inhibition of the functional activity of mitochondria and disruption of their structure, which, however, did not significantly affect the state of the skeletal muscles of the animals. This article discusses the role of mitoBKCa in the development of DMD and the prospects of the approach associated with the correction of its function in treatments of this secondary channelopathy.
Formulation and Optimization of Metronidazole and Lactobacillus spp. Layered Suppositories via a Three-Variable, Five-Level Central Composite Design for the Management of Bacterial Vaginosis
Authors: Ilomuanya Margaret O. , Salako Busayo B. , Ologunagba Modupe O. , Shonekan Omonike O. , Owodeha-Ashaka Kruga , Osahon Eseosa S. , Amenaghawon Andrew N.
Published: October 2022

Bacterial vaginosis, a polymicrobial clinical syndrome characterized by a shift in healthy vaginal microbiota due to bacterial colonization, is characterized by high recurrence rates after conventional treatment with an antimicrobial agent. This has necessitated the need to develop a formulation that has the potential to ensure Lactobacilli viability and bacterial clearance. This study seeks to develop and optimize a layered suppository using a five-level central composite design to ensure optimized metronidazole release and lactic acid viability. Layered suppositories were formulated using the fusion method using polyethylene glycol blend 1500/4000 and Ovucire® as suppository bases. Lactobacillus fermentum was incorporated in the molten mass before molding the solid body suppositories into the cavity of hollow-type suppositories and sealing the molten excipients. Artificial neural network model predictions for product optimization showed high predictive capacity, closely resembling experimental observations. The highest disintegration time recorded was 12.76 ± 0.37 min, with the optimized formulations showing lower times of 5.93 ± 0.98 min and an average weight of 1.17 ± 0.07 g. Histopathological observations determined high compatibility of suppositories with vaginal cells with no distortion or wearing of the vagina epithelium. This optimized formulation provides a safe and promising alternative to conventional suppositories in the treatment and prevention of the recurrence of bacterial vaginosis.
Searching for the Optimal Donor for Allogenic Adipose-Derived Stem Cells: A Comprehensive Review
Authors: Georgiev-Hristov Tihomir , García-Arranz Mariano , Trébol-López Jacobo , Barba-Recreo Paula , García-Olmo Damián
Published: October 2022

Adipose-derived stem cells comprise several clinically beneficial qualities that have been explored in basic research and have motivated several clinical studies with promising results. After being approved in the European Union, UK, Switzerland, Israel, and Japan, allogeneic adipose-derived stem cells (darvadstrocel) have been recently granted a regenerative medicine advanced therapy (RMAT) designation by US FDA for complex perianal fistulas in adults with Crohn’s disease. This huge scientific step is likely to impact the future spread of the indications of allogeneic adipose-derived stem cell applications. The current knowledge on adipose stem cell harvest describes quantitative and qualitative differences that could be influenced by different donor conditions and donor sites. In this comprehensive review, we summarize the current knowledge on the topic and propose donor profiles that could provide the optimal initial quality of this living drug, as a starting point for further applications and studies in different pathological conditions.
Three to Tango: Inhibitory Effect of Quercetin and Apigenin on Acetylcholinesterase, Amyloid-β Aggregation and Acetylcholinesterase-Amyloid Interaction
Authors: Álvarez-Berbel Irene , Espargaró Alba , Viayna Antonio , Caballero Ana Belén , Busquets Maria Antònia , Gámez Patrick , Luque Francisco Javier , Sabaté Raimon
Published: October 2022

One of the pathological hallmarks of Alzheimer’s disease (AD) is the formation of amyloid-β plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid-β aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on Aβ40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the Aβ40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.
Two-Dimensional Elliptical Microresonator Arrays for Wide Flat Bandwidth and Boxlike Filter Response
Authors: Guan Huan , Huang Xingrui , Tu Donghe , Yu Hang , Yin Yuxiang , Yu Zhiguo , Li Zhiyong
Published: October 2022

Based on two-dimensional elliptical microresonator arrays, we designed and fabricated a compact filter on the silicon-on-insulator platform with potential applications for on-chip optical interconnects. The fabricated optical filter exhibits a wide flat bandwidth of 951 GHz with the shape factor of 0.57 at the through port for the 3×20 arrays. The out-of-band rejection is as high as 50 dB. The crosstalk is also very low (−46 dB). The spectral shows a boxlike response. Although there are sixty rings used in the array, the insertion loss is still very small (≤1.36 dB).
Phase-Controlled Entanglement in a Four-Mode Optomechanical System
Authors: Jiang Cheng , Lu Hongxia , Zhai Zhangyin , Chen Guibin
Published: October 2022

We present a scheme for realizing phase-controlled entanglement in a microwave optomechanical system comprising two microwave cavities and two mechanical oscillators. Under specific driving conditions, we show that this optomechanical interface can be exploited to generate simultaneously the stationary cavity–cavity entanglement, mechanical–mechanical entanglement, and cavity–mechanical entanglement. Due to the closed loop interaction, we find that the entanglement can be controlled flexibly by tuning the phase difference between the optomechanical coupling strengths. The dependence of the entanglement on the amplitudes of the optomechanical coupling strengths is also explored in detail. Moreover, the bipartite entanglements are robust against temperature, and it is shown that the mechanical oscillators are cooled to the ground state in the parameter regimes for observing entanglement.
Seaweed Cosmetics under the Spotlight of Sustainability
Authors: Pagels Fernando , Arias Ana , Guerreiro Adriana , Guedes A. Catarina , Moreira Maria Teresa
Published: October 2022

Seaweeds represent a diverse and valuable source of cosmetic compounds such as vitamins, minerals, trace elements, amino acids, antioxidants, etc., with moisturizing, anti-inflammatory, and regenerative effects. The so-called “blue cosmetics” represent a line of products related to the use of natural active ingredients and an important market share in major international cosmetic brands. To be recognised as environmentally sustainable, it is essential to ensure that algae-derived products comply with environmentally sound harvesting, production, and extraction practices. In this work, Life Cycle Assessment (LCA) methodology was used to carry out an environmental impact assessment of the processing of the brown algae extract from Fucus vesiculosus and its comparative profile with the most used antioxidants in cosmetics: vitamin C and green tea extracts. Considering an equivalent formulation in antioxidant content, the results showed that seaweed has the lowest environmental load while green tea extracts have the highest environmental impact. Furthermore, to further reduce emissions from seaweed processing, the use of renewable energy sources and the valorisation of biomass residues as fertilisers in a circular economy approach are proposed.
Generalized Extended Uncertainty Principle Black Holes: Shadow and Lensing in the Macro- and Microscopic Realms
Authors: Lobos Nikko John Leo S. , Pantig Reggie C.
Published: October 2022

Motivated by the recent study about the extended uncertainty principle (EUP) black holes, we present in this study its extension called the generalized extended uncertainty principle (GEUP) black holes. In particular, we investigated the GEUP effects on astrophysical and quantum black holes. First, we derive the expression for the shadow radius to investigate its behavior as perceived by a static observer located near and far from the black hole. Constraints to the large fundamental length scale, L*, up to two standard deviations level were also found using the Event Horizont Telescope (EHT) data: for black hole Sgr. A*, L*=5.716×1010 m, while for M87* black hole, L*=3.264×1013 m. Under the GEUP effect, the value of the shadow radius behaves the same way as in the Schwarzschild case due to a static observer, and the effect only emerges if the mass, M, of the black hole is around the order of magnitude of L* (or the Planck length, lPl). In addition, the GEUP effect increases the shadow radius for astrophysical black holes, but the reverse happens for quantum black holes. We also explored GEUP effects to the weak and strong deflection angles as an alternative analysis. For both realms, a time-like particle gives a higher value for the weak deflection angle. Similar to the shadow, the deviation is seen when the values of L* and M are close. The strong deflection angle gives more sensitivity to GEUP deviation at smaller masses in the astrophysical scenario. However, the weak deflection angle is a better probe in the micro world.
How Do Plants Respond to Combined Drought and Salinity Stress?—A Systematic Review
Authors: Angon Prodipto Bishnu , Tahjib-Ul-Arif Md. , Samin Samia Islam , Habiba Ummya , Hossain M. Afzal , Brestic Marian
Published: October 2022

Plants are frequently exposed to one or more abiotic stresses, including combined salinity-drought, which significantly lowers plant growth. Many studies have been conducted to evaluate the responses of plants to combined salinity and drought stress. However, a meta-analysis-based systematic review has not been conducted yet. Therefore, this study analyzed how plants respond differently to combined salinity-drought stress compared to either stress alone. We initially retrieved 536 publications from databases and selected 30 research articles following a rigorous screening. Data on plant growth-related, physiological, and biochemical parameters were collected from these selected articles and analyzed. Overall, the combined salinity-drought stress has a greater negative impact on plant growth, photosynthesis, ionic balance, and oxidative balance than either stress alone. In some cases, salinity had a greater impact than drought stress and vice versa. Drought stress inhibited photosynthesis more than salinity, whereas salinity caused ionic imbalance more than drought stress. Single salinity and drought reduced shoot biomass equally, but salinity reduced root biomass more than drought. Plants experienced more oxidative stress under combined stress conditions because antioxidant levels did not increase in response to combined salinity-drought stress compared to individual salinity or drought stress. This study provided a comparative understanding of plants’ responses to individual and combined salinity and drought stress, and identified several research gaps. More comprehensive genetic and physiological studies are needed to understand the intricate interplay between salinity and drought in plants.
Ethyl Methane Sulfonate and Sodium Azide-Mediated Chemical and X-ray-Mediated Physical Mutagenesis Positively Regulate Peroxidase 1 Gene Activity and Biosynthesis of Antineoplastic Vinblastine in Catharanthus roseus
Authors: Mistry Vyoma , Tiwari Pragya , Patel Paresh , Vishwakarma Gajendra Singh , Lee Geung-Joo , Sharma Abhishek
Published: October 2022

Catharanthus roseus synthesizes bioactive therapeutic metabolites, known as monoterpenoid indole alkaloids (MIAs), including antineoplastic vinblastine and vincristine, which have high global demand, and antihypertensive ajmalicine, a serpentine. However, the in planta biosynthesis and accumulation of these phytopharmaceuticals are very low, attributed to their high cytotoxicity in the plant. Considering the low in planta concentration and over-harvesting of plant resources, biotechnological interventions have been undertaken to enhance the production of MIAs in plant systems. The present study was carried out to mutation through chemical and physical mutagenesis with sodium azide, ethyl methane sulfonate and X-rays, respectively, on C. roseus to determine their possible effects on the transcriptional modulation of MIA biosynthetic pathways in planta. The chemical mutagenesis resulted in delayed seed pod development in mutated C. roseus plants, with distinct leaf morphology and flower color. However, X-ray mutagenesis resulted in pollen-less sterile flowers. An HPLC analysis confirmed the higher catharanthine, vindoline and vinblastine content in sodium azide and X-ray mutants, and was further supported by higher PRX1 transcript levels estimated through real-time PCR analysis. The transcription factors WRKY1 and ORCA2 were found negatively regulated along with major MIA pathway genes in chemical mutants and their M1 generation, but showed positive regulation in X-ray M0 mutants. The induced mutagenesis of C. roseus provides a prospective strategy to modulate plant transcriptomes and enhance the biosynthesis of pharmaceutically important antineoplastic vinblastine in the plant.
Antiviral Potentialities of Chemical Characterized Essential Oils of Acacia nilotica Bark and Fruits against Hepatitis A and Herpes Simplex Viruses: In Vitro, In Silico, and Molecular Dynamics Studies
Authors: El Gendy Abd El-Nasser G. , Essa Ahmed F. , El-Rashedy Ahmed A. , Elgamal Abdelbaset M. , Khalaf Doaa D. , Hassan Emad M. , Abd-ElGawad Ahmed M. , Elgorban Abdallah M. , Zaghloul Nouf S. , Alamery Salman F. , Elshamy Abdelsamed I.
Published: October 2022

Acacia nilotica (synonym: Vachellia nilotica (L.) P.J.H.Hurter and Mabb.) is considered an important plant of the family Fabaceae that is used in traditional medicine in many countries all over the world. In this work, the antiviral potentialities of the chemically characterized essential oils (EOs) obtained from the bark and fruits of A. nilotica were assessed in vitro against HAV, HSV1, and HSV2. Additionally, the in silico evaluation of the main compounds in both EOs was carried out against the two proteins, 3C protease of HAV and thymidine kinase (TK) of HSV. The chemical profiling of the bark EOs revealed the identification of 32 compounds with an abundance of di- (54.60%) and sesquiterpenes (39.81%). Stachene (48.34%), caryophyllene oxide (19.11%), and spathulenol (4.74%) represented the main identified constituents of bark EO. However, 26 components from fruit EO were assigned, with the majority of mono- (63.32%) and sesquiterpenes (34.91%), where trans-caryophyllene (36.95%), Z-anethole (22.87%), and γ-terpinene (7.35%) represented the majors. The maximum non-toxic concentration (MNTC) of the bark and fruits EOs was found at 500 and 1000 µg/mL, respectively. Using the MTT assay, the bark EO exhibited moderate antiviral activity with effects of 47.26% and 35.98% and a selectivity index (SI) of 2.3 and 1.6 against HAV and HSV1, respectively. However, weak activity was observed via the fruits EO with respective SI values of 3.8, 5.7, and 1.6 against HAV, HSV1, and HSV2. The in silico results exhibited that caryophyllene oxide and spathulenol (the main bark EO constituents) showed the best affinities (ΔG = −5.62, −5.33, −6.90, and −6.76 kcal/mol) for 3C protease and TK, respectively. While caryophyllene (the major fruit EO component) revealed promising binding capabilities against both proteins (ΔG = −5.31, −6.58 kcal/mol, respectively). The molecular dynamics simulation results revealed that caryophyllene oxide has the most positive van der Waals energy interaction with 3C protease and TK with significant binding free energies. Although these findings supported the antiviral potentialities of the EOs, especially bark EO, the in vivo assessment should be tested in the intraoral examination for these EOs and/or their main constituents.
Bioinspired Green Synthesis of Silver Nanoparticles Using Three Plant Extracts and Their Antibacterial Activity against Rice Bacterial Leaf Blight Pathogen Xanthomonas oryzae pv. oryzae
Authors: Tian Ye , Luo Jinyan , Wang Hui , Zaki Haitham E. M. , Yu Shanhong , Wang Xiao , Ahmed Temoor , Shahid Muhammad Shafiq , Yan Chengqi , Chen Jianping , Li Bin
Published: October 2022

Rice bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is responsible for a significant reduction in rice production. Due to the small impact on the environment, biogenic nanomaterials are regarded as a new type of antibacterial agent. In this research, three colloids of silver nanoparticles (AgNPs) were synthesized with different biological materials such as Arctium lappa fruit, Solanum melongena leaves, and Taraxacum mongolicum leaves, and called Al-AgNPs, Sm-AgNPs and Tm-AgNPs, respectively. The appearance of brown colloids and the UV-Visible spectroscopy analysis proved the successful synthesis of the three colloids of AgNPs. Moreover, FTIR and XRD analysis revealed the formation of AgNPs structure. The SEM and TEM analysis indicated that the average diameters of the three synthesized spherical AgNPs were 20.18 nm, 21.00 nm, and 40.08 nm, respectively. The three botanical AgNPs had the strongest bacteriostatic against Xoo strain C2 at 20 μg/mL with the inhibition zone of 16.5 mm, 14.5 mm, and 12.4 mm, while bacterial numbers in a liquid broth (measured by OD600) decreased by 72.10%, 68.19%, and 65.60%, respectively. Results showed that the three AgNPs could inhibit biofilm formation and swarming motility of Xoo. The ultrastructural observation showed that Al-AgNPs adhered to the surface of bacteria and broke the bacteria. Overall, the three synthetic AgNPs could be used to inhibit the pathogen Xoo of rice bacterial leaf blight.