bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Oxidative Stress and Inflammation on Nutritional Status and Neural Plasticity: New Perspectives on Post-Stroke Neurorehabilitative Outcome
Authors: Ciancarelli Irene , Morone Giovanni , Iosa Marco , Cerasa Antonio , Calabrò Rocco Salvatore , Iolascon Giovanni , Gimigliano Francesca , Tonin Paolo , Tozzi Ciancarelli Maria Giuliana
Published: December 2022

Beyond brain deficits caused by strokes, the effectiveness of neurorehabilitation is strongly influenced by the baseline clinical features of stroke patients, including a patient’s current nutritional status. Malnutrition, either as a pre-stroke existing condition or occurring because of ischemic injury, predisposes patients to poor rehabilitation outcomes. On the other hand, a proper nutritional status compliant with the specific needs required by the process of brain recovery plays a key role in post-stroke rehabilitative outcome favoring neuroplasticity mechanisms. Oxidative stress and inflammation play a role in stroke-associated malnutrition, as well as in the cascade of ischemic events in the brain area, where ischemic damage leads to neuronal death and brain infarction, and, via cell-to-cell signaling, the alteration of neuroplasticity processes underlying functional recovery induced by multidisciplinary rehabilitative treatment. Nutrition strategies based on food components with oxidative and anti-inflammatory properties may help to reverse or stop malnutrition and may be a prerequisite for supporting the ability of neuronal plasticity to result in satisfactory rehabilitative outcome in stroke patients. To expand nutritional recommendations for functional rehabilitation recovery, studies considering the evolution of nutritional status changes in post-stroke patients over time are required. The assessment of nutritional status must be included as a routine tool in rehabilitation settings for the integrated care of stroke-patients.
Lipid Parameters and the Development of Chronic Kidney Disease: A Prospective Cohort Study in Middle-Aged and Elderly Chinese Individuals
Authors: Liao Shumei , Lin Diaozhu , Feng Qiling , Li Feng , Qi Yiqin , Feng Wanting , Yang Chuan , Yan Li , Ren Meng , Sun Kan
Published: December 2022

Epidemiological evidence suggests that lipid parameters are related to the progression of chronic kidney disease (CKD). Nevertheless, prospective studies that comprehensively assess the effect of routinely available lipid measures on the development of CKD are lacking. The aim of this study was to longitudinally assess the influence of lipid metabolism indicators on the presence of CKD in a large community-based population. We conducted a prospective cohort study at Sun Yat-sen Memorial Hospital, China, with 5345 patients of 40 years or older. Cox regression models were conducted, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess lipid parameters and their relationship with the incidence of CKD. During the follow-up period, 340 (6.4%) subjects developed CKD. The incidence of CKD increased progressively with quartile values of triglyceride (TG), the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (non-HDL-C/HDL-C) and the ratio of TG to HDL-C, but decreased with HDL-C quartiles (p < 0.0001 for all trends). Pearson’s correlation analysis and multiple regression analyses indicated that these parameters were also associated with various indicators of kidney function. Moreover, we found that among all the lipid parameters, TG/HDL-C emerged as the most effective predictor of CKD. In conclusion, our findings suggest that TG/HDL-C better predicts the incidence of CKD in middle-aged and elderly Chinese individuals than other lipid parameters tested in the study.
Trajectories of the Prevalence of Sarcopenia in the Pre- and Post-Stroke Periods: A Systematic Review
Authors: Inoue Tatsuro , Ueshima Junko , Kawase Fumiya , Kobayashi Haruko , Nagano Ayano , Murotani Kenta , Saino Yoko , Maeda Keisuke
Published: December 2022

Interventions for stroke-related sarcopenia in patients with stroke are needed, but the details of the target population are unclear. This systematic review aimed to identify trajectories of the prevalence of sarcopenia in the pre- and post-stroke periods and to determine the diagnostic criteria used in patients with stroke. We searched for literature in six databases: MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, CINAHL, and Ichushi-web (in Japanese). We included 1627 studies in the primary screening, and 35 studies were finally included. Of the 35 studies, 32 (91.4%) included Asian patients, and the criteria of the Asian Working Group for Sarcopenia was mainly used as the diagnostic criteria. Nineteen studies used muscle strength and muscle mass to diagnose sarcopenia, whereas a full assessment, including physical performance, was performed in five studies. The estimated prevalences of sarcopenia in pre-stroke, within 10 days of stroke, and from 10 days to 1 month after stroke were 15.8%, 29.5%, and 51.6%, respectively. Sarcopenia increased by approximately 15% from pre-stroke to 10 days, and increased by approximately 20% from 10 days to 1 month. Healthcare providers should note that the prevalence of sarcopenia increases during the acute phase in patients with stroke.
Bioactive Substances of Potato Juice Reveal Synergy in Cytotoxic Activity against Cancer Cells of Digestive System Studied In Vitro
Authors: Kowalczewski Przemysław Łukasz , Olejnik Anna , Wieczorek Martyna Natalia , Zembrzuska Joanna , Kowalska Katarzyna , Lewandowicz Jacek , Lewandowicz Grażyna
Published: December 2022

More and more literature data indicate the health-promoting effect of potato juice (PJ). However, to date, it has not been precisely explained which of the many compounds present in PJ exhibit biological activity. The work aimed to establish the antiproliferative effect of gastrointestinal digested PJ and the products of its processing. Fresh PJs derived from three edible potato varieties, industrial side stream resulting from starch production, partially deproteinized PJ derived from feed protein production line, and three different potato protein preparations subjected to digestion in the artificial gastrointestinal tract were used in this study. The cytotoxic potential of glycoalkaloids (GAs), phenolic acids, digested PJ, and products of PJ processing was determined in human normal and cancer cells derived from the digestive system. The results showed that GAs exhibit concentration-dependent cytotoxicity against all analyzed cell lines. In contrast, phenolic acids (caffeic, ferulic, and chlorogenic acid) do not show cytotoxicity in the applied cell lines. A correlation between cytotoxic potency and GAs content was found in all PJ products studied. The most potent effects were observed under treatment with deproteinized PJ, a product of industrial processing of PJ, distinguished by the highest effective activity among the fresh juice products studied. Moreover, this preparation revealed a favorable cytotoxicity ratio towards cancer cells compared to normal cells. Statistical analysis of the obtained results showed the synergistic effect of other bioactive substances contained in PJ and its products, which may be crucial in further research on the possibility of using PJ as a source of compounds of therapeutic importance.
Association between Plasma Trace Element Concentrations in Early Pregnancy and Gestational Diabetes Mellitus in Shanghai, China
Authors: Wu Ting , Li Tao , Zhang Chen , Huang Hefeng , Wu Yanting
Published: December 2022

(1) Background: Trace elements play important roles in gestational diabetes mellitus (GDM), but the results from reported studies are inconsistent. This study aimed to examine the association between maternal exposure to V, Cr, Mn, Co, Ni, and Se in early pregnancy and GDM. (2) Methods: A nested case-control study with 403 GDM patients and 763 controls was conducted. Trace elements were measured using inductively coupled plasma-mass spectrometry in plasma collected from pregnant women in the first trimester of gestation. We used several statistical methods to explore the association between element exposure and GDM risk. (3) Results: Plasma V and Ni were associated with increased and decreased risk of GDM, respectively, in the single-element model. V and Mn were found to be positively, and Ni was found to be negatively associated with GDM risk in the multi-element model. Mn may be the main contributor to GDM risk and Ni the main protective factor against GDM risk in the quantile g computation (QGC). 6.89 μg/L~30.88 μg/L plasma Ni was identified as a safe window for decreased risk of GDM. (4) Conclusions: V was positively associated with GDM risk, while Ni was negatively associated. Ni has dual effects on GDM risk.
Postoperative Prevention of Urinary Tract Infections in Patients after Urogynecological Surgeries—Nonantibiotic Herbal (Canephron) versus Antibiotic Prophylaxis (Fosfomycin Trometamol): A Parallel-Group, Randomized, Noninferiority Experimental Trial
Authors: Wawrysiuk Sara , Rechberger Tomasz , Kubik-Komar Agnieszka , Kolodynska Aleksandra , Naber Kurt , Miotla Pawel
Published: December 2022

Introduction and hypothesis: Urinary tract infections (UTIs) are one of the most common complications of urogynecological surgeries. The risk of UTIs is increased by the catheterization of the bladder, intraoperative cystoscopy, and urine retention after the procedure. Due to increasing antibiotic resistance, there is a need to search for new methods of postoperative UTI prevention. Canephron is a mixture of century herbs, lovage roots, and rosemary leaves with diuretic, spasmolytic, anti-inflammatory, antibacterial, and nephroprotective properties. The aim of this study is to demonstrate the noninferiority of Canephron versus antibiotic prophylaxis with fosfomycin trometamol (FT), based on the collective results of postoperative urine culture analyses. Methods: One hundred and twenty-five female patients were randomized into two groups before undergoing urogynecological surgeries, including a control group (n = 67), which received one dose of 3 g of FT the day after the procedure, and a study group (n = 58), which received Canephron three times a day for 14 days, starting the day after the procedure. All the patients were assessed using the Acute Cystitis Symptom Score (ACSS). Results: UTIs were observed in 6.4% of the patients. There was no statistically significant difference between the use of FT and Canephron in terms of UTIs (Chi^2 N-1 = 0.8837; p = ns). Additional factors, such as menopausal status and the type of procedure performed, increased the risk of developing a UTI. Factors such as the body mass index (BMI) and parity had no correlation. Conclusions: Canephron is noninferior to FT in the prevention of postoperative UTIs. The use of such a phytotherapeutic drug may help to decrease antibiotic consumption, which is closely connected to the growing trend of antibiotic resistance.
Many Ways to Communicate—Crosstalk between the HBV-Infected Cell and Its Environment
Authors: Walter Annika Jasmin , van de Klundert Maarten A. , Jung Stephanie
Published: December 2022

Chronic infection with the hepatitis B virus (HBV) affects an estimated 257 million people worldwide and can lead to liver diseases such as cirrhosis and liver cancer. Viral replication is generally considered not to be cytopathic, and although some HBV proteins may have direct carcinogenic effects, the majority of HBV infection-related disease is related to chronic inflammation resulting from disrupted antiviral responses and aberrant innate immune reactions. Like all cells, healthy and HBV-infected cells communicate with each other, as well as with other cell types, such as innate and adaptive immune cells. They do so by both interacting directly and by secreting factors into their environment. Such factors may be small molecules, such as metabolites, single viral proteins or host proteins, but can also be more complex, such as virions, protein complexes, and extracellular vesicles. The latter are small, membrane-enclosed vesicles that are exchanged between cells, and have recently gained a lot of attention for their potential to mediate complex communication and their potential for therapeutic repurposing. Here, we review how HBV infection affects the communication between HBV-infected cells and cells in their environment. We discuss the impact of these interactions on viral persistence in chronic infection, as well as their relation to HBV infection-related pathology.
Modulation of Virulence Factors during Trypanosoma cruzi Differentiation
Authors: Oliveira Camila , Holetz Fabíola Barbieri , Alves Lysangela Ronalte , Ávila Andréa Rodrigues
Published: December 2022

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. This protozoan developed several mechanisms to infect, propagate, and survive in different hosts. The specific expression of proteins is responsible for morphological and metabolic changes in different parasite stages along the parasite life cycle. The virulence strategies at the cellular and molecular levels consist of molecules responsible for mediating resistance mechanisms to oxidative damage, cellular invasion, and immune evasion, performed mainly by surface proteins. Since parasite surface coat remodeling is crucial to invasion and infectivity, surface proteins are essential virulence elements. Understanding the factors involved in these processes improves the knowledge of parasite pathogenesis. Genome sequencing has opened the door to high-throughput technologies, allowing us to obtain a deeper understanding of gene reprogramming along the parasite life cycle and identify critical molecules for survival. This review therefore focuses on proteins regulated during differentiation into infective forms considered virulence factors and addresses the current known mechanisms acting in the modulation of gene expression, emphasizing mRNA signals, regulatory factors, and protein complexes.
Biological Control of Verticillium Wilt and Growth Promotion in Tomato by Rhizospheric Soil-Derived Bacillus amyloliquefaciens Oj-2.16
Authors: Pei Dongli , Zhang Qingchen , Zhu Xiaoqin , Zhang Lei
Published: December 2022

Verticillium wilt disease caused by Verticillium dahliae seriously affects tomato quality and yield. In this work, strain Oj-2.16 was isolated from rhizosphere soil of the medicinal plant Ophiopogon japonicas and identified as Bacillus amyloliquefaciens on the basis of morphological, physiological, and biochemical characteristics and 16S rDNA sequencing. Strain Oj-2.16 exhibited a high inhibition rate against V. dahliae, and the hyphae inhibited by Oj-2.16 were found to be destroyed on scanning electron microscopy. Lipopeptide and dipeptide genes were detected in the Oj-2.16 genome by PCR amplification involved in surfactin, iturin, fengycin, and bacilysin biosynthesis. In pot experiments, the biocontrol efficacy of strain Oj-2.16 against Verticillium wilt in tomato was 89.26%, which was slightly higher than the efficacy of the chemical fungicide carbendazim. Strain Oj-2.16 can produce indole acetic acid, siderophores, assimilate various carbon sources, and significantly promoted the growth of tomato seedlings by increasing plant height, root length, stem width, fresh weight, and dry weight by 44.44%, 122.22%, 80.19%, 57.65%, 64.00%, respectively. Furthermore, defense-related antioxidant CAT, SOD, POD, and PAL enzyme activities significantly increased and MDA contents significantly decreased in tomato seedlings treated with strain Oj-2.16 upon inoculation of V. dahliae compared with the pathogen-inoculated control. In summary, we concluded that B. amyloliquefaciens Oj-2.16 could be used as a promising candidate for the biocontrol of Verticillium wilt and as plant growth stimulator of tomato.
New Insights into Bacterial Pathogenesis
Authors: Biondo Carmelo
Published: December 2022

Pathogenicity, or the ability of a microorganism to cause disease, depends on several factors, among which the immune status of the host and the microbial species involved in the exposure play a key role [...]
Molecular Epidemiology of Cystic Echinococcosis in Rural Baluchistan, Pakistan: A Cross-Sectional Study
Authors: Ullah Ihsan , Sattar Sadia , Ali Ijaz , Farid Arshad , Ullah Amin , Eid Refaat A. , Samir A. Zaki Mohamed , Alaa Eldeen Muhammad , Ahmed Iftikhar , Ullah Irfan
Published: December 2022

Cystic echinococcosis (CE), or hydatid cyst disease (HCD), is a zoonosis of significant importance caused by the cestode of Echinococcus granulosus sensu lato (s. l.) that affects mainly nomadic populations and has substantial economic consequences. Due to the 76% rural and nomadic population, Baluchistan is a highly endemic region in Pakistan for CE; however, it has not yet been investigated for CE. For this purpose, this study was carried out to investigate the molecular epidemiology of CE in this region. In total, 23 human hydatid cyst samples were collected from tertiary health care units in Baluchistan and processed for DNA extraction, which was then followed by sequencing of the cox1 mitochondrial gene of all 23 collected samples, genotyping, and phylogenetic and haplotype analysis. Most subjects were livestock owners (39.13%) in rural settings (73.91%). Most patients (73.19%) were pet owners (dogs) and used water from open sources for drinking. The liver was the most affected organ (52.17%), followed by the lungs (17.39%). Sequence analysis based on the cox1 gene revealed that EG genotype 1 (G1) was the most prevalent (56.52%), followed by G3 (34.78%), while some samples (8.7%) were identified as the Echinococcus canadensis (G6/7) genotype. A total of five haplotypes were detected with high haplotype diversity (0.80) and low nucleotide diversity (0.033). Phylogenetic analysis revealed two diverse sub-clades, each of G1 and G3 isolates from Baluchistan, that were evolutionarily related to previously reported G1 and G3 isolates from Pakistan and China. On the other hand, the G6/7 isolates of this study were evolutionarily identical to the already reported G6/7 isolates from Pakistan, Turkey, and Kazakhstan. This study concludes that diverse G1 and G3 EG isolates are present in this part of Pakistan, while the G6/G7 genotype was reported for the first time from Baluchistan.
Therapeutic Strategies to Activate p53
Authors: Aguilar Angelo , Wang Shaomeng
Published: December 2022

The p53 protein has appropriately been named the “guardian of the genome”. In almost all human cancers, the powerful tumor suppressor function of p53 is compromised by a variety of mechanisms, including mutations with either loss of function or gain of function and inhibition by its negative regulators MDM2 and/or MDMX. We review herein the progress made on different therapeutic strategies for targeting p53.
Glucose Uptake Is Increased by Estradiol Dipropionate in L6 Skeletal Muscle Cells
Authors: Yao Yanhong , Yang Xinzhou , Shen Jinhua , Zhao Ping
Published: December 2022

GLUT4 is an important glucose transporter, which is closely related to insulin resistance and type 2 diabetes. In this study, we investigated the mechanism of Estradiol Dipropionate (EDP) on uptake of glucose in L6 skeletal muscle cells. In our study, we confirmed that EDP promoted uptake of glucose in L6 skeletal muscle cells in both normal and insulin resistant models. Western blot indicated that EDP accelerated GLUT4 expression and significantly activated AMPK and PKC phosphorylation; the expression of GLUT4 was significantly inhibited by AMPK inhibitor compound C and PKC inhibitor Gö6983, but not by Wortmannin (Akt inhibitor). Meanwhile, EDP boosted GLUT4 expression, and also increased intracellular Ca2+ levels. In the presence of 2 mM, 0 mM extracellular Ca2+ and 0 mM extracellular Ca2+ + BAPTA-AM, the involvement of intracellular Ca2+ levels contribute to EDP-induced GLUT4 expression and fusion with plasma membrane. Therefore, this study investigated whether EDP promoted GLUT4 expression through AMPK and PKC signaling pathways, thereby enhancing GLUT4 uptake of glucose and fusion into plasma membrane in L6 skeletal muscle cells. In addition, both EDP induced GLUT4 translocation and uptake of glucose were Ca2+ dependent. These findings suggested that EDP may be potential drug for the treatment of type 2 diabetes.
Acute Lung Functional and Airway Remodeling Effects of an Inhaled Highly Selective Phosphodiesterase 4 Inhibitor in Ventilated Preterm Lambs Exposed to Chorioamnionitis
Authors: Hütten Matthias Christian , Brokken Tim , Widowski Helene , Monaco Tobias , Schneider Jan Philipp , Fehrholz Markus , Ophelders Daan , Kramer Boris W. , Kunzmann Steffen
Published: December 2022

Phosphodiesterase (PDE) inhibition has been identified in animal studies as a new treatment option for neonatal lung injury, and as potentially beneficial for early lung development and function. However, our group could show that the inhaled PDE4 inhibitor GSK256066 could have dose-dependent detrimental effects and promote lung inflammation in the premature lung. In this study, the effects of a high and a low dose of GSK256066 on lung function, structure and alveolar development were investigated. In a triple hit lamb model of Ureaplasma-induced chorioamnionitis, prematurity, and mechanical ventilation, 21 animals were treated as unventilated (NOVENT) or 24 h ventilated controls (Control), or with combined 24 h ventilation and low dose (iPDE1) or high dose (iPDE10) treatment with inhaled GSK 256066. We found that high doses of an inhaled PDE4 inhibitor impaired oxygenation during mechanical ventilation. In this group, the budding of secondary septae appeared to be decreased in the preterm lung, suggesting altered alveologenesis. Ventilation-induced structural and functional changes were only modestly ameliorated by a low dose of PDE4 inhibitor. In conclusion, our findings indicate the narrow therapeutic window of PDE4 inhibitors in the developing lung.
A Comparative Study of Serum Pharmacochemistry of Kai-Xin-San in Normal and AD Rats Using UPLC-LTQ-Orbitrap-MS
Authors: Yang Lin , Liang Jian , Zheng Qin , Zhou Lifen , Xiong Yongchang , Wang Huijuan , Yuan Jinbin
Published: December 2022

Kai-Xin-San (KXS) is a classic formula for the treatment of Alzheimer’s disease (AD). KXS has been widely used to treat emotional diseases; however, its active components remain unknown. There have been some reports about the efficacy and metabolic analysis of KXS, which are mainly based on studying normal animals. The current work first established an AD rat model by injecting D-galactose into the abdominal cavity and injecting Aβ25–35 into the hippocampus on both sides, followed by intragastric administration of KXS for a consecutive week; then, the analytical method for ethanol extraction from the serum of normal and model rats was developed using UPLC-LTQ-Orbitrap-MS; finally, the transitional components in the blood were systematically compared and analyzed by multivariate statistical analysis. A total of 36 components of KXS were identified in the rat serum of the normal group, including 24 prototype components (including ginsenosides, triterpenoid acids of Poria cocos, polygala saponins, polygala xanthones and polygala ester) and 13 metabolites (including desugar, hydration and oxidation products of ginsenosides, triterpenoid acid hydroxylation, deoxygenation, demethylation, desaturation, and glycine-conjugated products of Poria cocos). Twenty KXS-relevant components were detected in the rat serum of the model group, including 11 prototypes and 9 metabolites. The normal group and the model group shared 12 common components, including 9 prototypes and 3 metabolites. The intestinal microecological balance of the model rats probably was destroyed, affecting the absorption/metabolism of saponins by the body, which resulted in fewer transitional components in the model group. This study reflected the drug-body interaction from an objective and accurate perspective, offering references and insights for elucidating the basis of active components and mechanism of action of KXS for treating AD.
Development and Validation of an LC-MS/MS Method for the Quantitative Determination of Contezolid in Human Plasma and Cerebrospinal Fluid
Authors: Zhang Guanxuanzi , Zhang Na , Dong Liuhan , Bai Nan , Cai Yun
Published: December 2022

To develop and verify a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining contezolid in plasma and cerebrospinal fluid (CSF). Protein precipitation was performed on samples using linezolid as the internal standard. We used an Agilent EclipsePlus C18 column operating at 0.4 mL/min in conjunction with acetonitrile and water mobile phases for the LC-MS/MS analysis. Using the precursor-product ion pairs 409.15→269.14 (contezolid) and 338.14→195.1 (linezolid), multiple reaction monitoring was used to quantify the compounds. Plasma linearity range was 50.0 to 5000 ng/mL, and CSF was 20.0 to 1000 ng/mL (r2 = 0.999). The inter-batch and intra-batch precisions were ≤2.57% and ≤5.79%, respectively. Plasma recovered 92.94%, and CSF recovered 97.83%. Plasma, CSF, hemolytic plasma, and hyperlipidemic plasma all showed a coefficient of variation ≤ 7.44%. The stability and dilution integrity of this method were also acceptable. The study also demonstrated that artificial CSF can be used as a matrix for the preparation of standard curve samples. A simple and accurate method was developed and validated for the determination of contezolid concentrations in human plasma and CSF, which may be useful for monitoring the therapeutic effect of central nervous system medications.
Changes in Pharmacokinetics and Pharmacodynamics of Losartan in Experimental Diseased Rats Treated with Curcuma longa and Lepidium sativum
Authors: Ahad Abdul , Raish Mohammad , Abdelrahman Ibrahim Abdelsalam , Jardan Yousef A. Bin , Alam Mohd Aftab , Al-Mohizea Abdullah M. , Al-Jenoobi Fahad I.
Published: December 2022

The current study investigated “pharmacodynamics and pharmacokinetics interactions” of losartan with Curcuma longa (CUR) and Lepidium sativum (LS) in hypertensive rats. Hypertension was induced by oral administration of L-NAME (40 mg/kg) for two weeks. Oral administration of CUR or LS shows some substantial antihypertensive activity. The systolic blood pressure (SBP) of hypertensive rats was decreased by 7.04% and 8.78% 12 h after treatment with CUR and LS, respectively, as compared to rats treated with L-NAME alone. LS and CUR display the ability to potentiate the blood pressure-lowering effects of losartan in hypertensive rats. A greater decrease in SBP, by 11.66% and 13.74%, was observed in hypertensive rats treated with CUR + losartan and LS + losartan, respectively. Further, both the investigated herbs, CUR and LS, caused an increase in plasma concentrations of losartan in hypertensive rats. The AUC0-t, AUC0-inf and AUMC0-inf of losartan were increased by 1.25-fold, 1.28-fold and 1.09-fold in hypertensive rats treated with CUR + losartan. A significant (p < 0.05) increase in AUC0-t (2.41-fold), AUC0-inf (3.86-fold) and AUMC0-inf (8.35-fold) of losartan was observed in hypertensive rats treated with LS + losartan. The present study affirms that interactions between CUR or LS with losartan alter both “pharmacokinetics and pharmacodynamics” of the drug. Concurrent administration of losartan with either CUR or LS would require dose adjustment and intermittent blood pressure monitoring for clinical use in hypertensive patients. Additional investigation is necessary to determine the importance of these interactions in humans and to elucidate the mechanisms of action behind these interactions.
A Guide to In Silico Drug Design
Authors: Chang Yiqun , Hawkins Bryson A. , Du Jonathan J. , Groundwater Paul W. , Hibbs David E. , Lai Felcia
Published: December 2022

The drug discovery process is a rocky path that is full of challenges, with the result that very few candidates progress from hit compound to a commercially available product, often due to factors, such as poor binding affinity, off-target effects, or physicochemical properties, such as solubility or stability. This process is further complicated by high research and development costs and time requirements. It is thus important to optimise every step of the process in order to maximise the chances of success. As a result of the recent advancements in computer power and technology, computer-aided drug design (CADD) has become an integral part of modern drug discovery to guide and accelerate the process. In this review, we present an overview of the important CADD methods and applications, such as in silico structure prediction, refinement, modelling and target validation, that are commonly used in this area.
In Vivo Safety and Efficacy of Chalcone-Loaded Microparticles with Modified Polymeric Matrix against Cutaneous Leishmaniasis
Authors: Sousa-Batista Ariane de J. , Arruda-Costa Natalia , Pacienza-Lima Wallace , Carvalho-Gondim Felipe , Santos Rosiane F. , Da-Silva Silvia A. G. , Ré Maria Inês , Rossi-Bergmann Bartira
Published: December 2022

Current chemotherapy of cutaneous leishmaniasis (CL) is based on repeated systemic or intralesional administration of drugs that often cause severe toxicity. Previously, we demonstrated the therapeutic potential of biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) loaded with 8% of the nitrochalcone CH8 (CH8/PLGA) prepared by a conventional bench method. Aiming at an industrially scalable process and increased drug loading, new MPs were prepared by spray drying: CH8/PDE with PLGA matrix and CH8/PVDE with PLGA + polyvinylpyrrolidone (PVP) matrix, both with narrower size distribution and higher drug loading (18%) than CH8/PLGA. Animal studies were conducted to evaluate their clinical feasibility. Both MP types induced transient local swelling and inflammation, peaking at 1–2 days, following a single intralesional injection. Different from CH8/PDE that released 90% of the drug in the ear tissue in 60 days, CH8/PVDE achieved that in 30 days. The therapeutic efficacy of a single intralesional injection was evaluated in BALB/c mice infected with Leishmania (Leishmania) amazonensis and golden hamsters infected with L. (Viannia) braziliensis. CH8/PVDE promoted greater reduction in parasite burden than CH8/PDE or CH8/PLGA, measured at one month and two months after the treatment. Thus, addition of PVP to PLGA MP matrix accelerates drug release in vivo and increases its therapeutic effect against CL.
Highly Polymorphic Materials and Dissolution Behaviour: The Peculiar Case of Rifaximin
Authors: Bianchera Annalisa , Nebuloni Marino , Colombo Nicola , Pirola Davide , Bettini Ruggero
Published: December 2022

Rifaximin is a locally acting antibiotic practically insoluble in water. It presents several crystal phases characterized by different degrees of hydration. The aim of this work is to investigate the dissolution behaviour of rifaximin α, β, and amorphous forms in relation to their relative thermodynamic stability to contribute to clarifying possible solvent- or humidity-mediated conversion patterns. Kinetic and intrinsic solubility were investigated along with particle size distribution, specific surface area, and external morphology. The solution and moisture mediated conversion from metastable α and amorphous forms to stable β form were elucidated by coupling intrinsic dissolution test with chemometric analysis as well as by dynamic vapour sorption measurements. The dissolution behaviour of the α form stems mainly from the transition to β form that occurs upon exposition to relative humidity higher than 40%. The α form converted more rapidly than the amorphous form due to the smaller supersaturation ratio. It can be concluded that, due to its marked tendency to transform into β form, the dissolution test for the α form, even if conducted according to compendial procedures, needs to be accompanied by a panel of further tests that allow to uniquely identify the solid phase under investigation.
Consideration of Commercially Available Hepatocytes as Cell Sources for Liver-Microphysiological Systems by Comparing Liver Characteristics
Authors: Horiuchi Shinichiro , Kuroda Yukie , Komizu Yuji , Ishida Seiichi
Published: December 2022

In recent years, microphysiological systems (MPS) have been developed to shorten the test period and reduce animal experiments for drug development. We examined cell sources for the liver-MPS, i.e., MPS mimicking liver function. For liver-MPS, liver-like cells with high liver functions are required. Cryo-preserved hepatocytes (cryoheps), the gold standard hepatocytes for in vitro drug development, present several disadvantages, including differences between lots due to individual donor variations or a limited cell supply from the same donor. As such, alternatives for cryoheps are sought. Hepatocyte-like cells derived from human induced pluripotent stem cells (hiPSC-Heps), hepatocytes derived from liver-humanized mice (PXB-cells), and human liver cancer cells (HepG2 cells) were examined as source candidates for liver-MPS. Gene expression levels of the major cytochrome P450 of hiPSC-Heps, PXB cells, and HepG2 cells were compared with 22 lots of cryoheps, and the activities of hiPSC-Heps were compared with 8 lots of cryopreserved hepatocytes. A focused DNA microarray was used for the global gene analysis of the liver-like characteristics of hiPSC-Heps, PXB-cells, cryoheps, and HepG2 cells. Gene expression data from the focused microarray were analyzed by principal component analysis, hierarchical clustering, and enrichment analysis. The results indicated the characteristics of individual hepatocyte cell source and raised their consideration points as an alternative cell source candidate for liver-MPS. The study contributes to the repetitive utilization of a robust in vitro hepatic assay system over long periods with stable functionality.
Dermal Delivery of Korean Red Ginseng Extract: Impact on Storage Stability of Different Carrier Systems and Evaluation of Rg1 and Rb1 Skin Permeation Ex Vivo
Authors: Klang Victoria , Schweiger Eva-Maria , Strohmaier Simone , Walter Verena Ina , Dekic Zorana , Tahir Ammar
Published: December 2022

The root extract of Panax ginseng C.A. Meyer (Korean red ginseng/KRG extract) is a traditional Asian remedy introduced to dermal products for its antioxidative potential. However, little is known about technological aspects or skin penetration of main ginsenosides. Thus, stable oil-in-water nanoemulsions (NEs) and hydrogels for dermal delivery of KRG extract were developed and characterised using light scattering methods, analysis of flow properties and pH measurements. In addition, Rg1 and Rb1 contents were monitored by UHPLC/MS. Different surfactants (phosphatidylcholine, monoacylphosphatidylcholine and polysorbate 80) and polymers (polyacrylic acid and hydroxyethylcellulose) were tested and compared for their compatibility with KRG extract. The results showed that incorporation of KRG extract led to a significantly reduced formulation pH in hydroxyethylcellulose gels (−22%), NEs (−15%) and carbomer gels (−4–5%). The dynamic viscosity was in the range of 24–28 Pas at 10 s−1 for carbomer gels. The highest storage stability and skin permeation were observed for a hydroalcoholic gel with carbomer 50,000 and TRIS buffer (each of 1% w/w), containing ethanol (20% w/w) and KRG extract (2% w/w). Ex vivo diffusion cell studies confirmed skin permeation of the moderately lipophilic Rg1, but not the more hydrophilic Rb1 with a larger molecular weight.
Imaging of Gαq Proteins in Mouse and Human Organs and Tissues
Authors: Voss Jan H. , Al-Hroub Haneen , Gedschold Robin , Dietrich Jennifer M. , Gaffal Evelyn , Toma Marieta , Kehraus Stefan , König Gabriele M. , Brust Peter , Fleischmann Bernd K. , Wenzel Daniela , Deuther-Conrad Winnie , Müller Christa E.
Published: December 2022

G protein-coupled receptors (GPCRs) transfer extracellular signals across cell membranes by activating intracellular heterotrimeric G proteins. Several studies suggested G proteins as novel drug targets for the treatment of complex diseases, e.g., asthma and cancer. Recently, we developed specific radiotracers, [³H]PSB-15900-FR and [³H]PSB-16254-YM, for the Gαq family of G proteins by tritiation of the macrocyclic natural products FR900359 (FR) and YM-254890 (YM). In the present study, we utilized these potent radioligands to perform autoradiography studies in tissues of healthy mice, mouse models of disease, and human tissues. Specific binding was high, while non-specific binding was extraordinarily low, giving nearly identical results for both radioligands. High expression levels of Gαq proteins were detected in healthy mouse organs showing the following rank order of potency: kidney > liver > brain > pancreas > lung > spleen, while expression in the heart was low. Organ sub-structures, e.g., of mouse brain and lung, were clearly distinguishable. Whereas an acute asthma model in mice did not result in altered Gαq protein expressions as compared to control animals, a cutaneous melanoma model displayed significantly increased expression in comparison to healthy skin. These results suggest the future development of Gαq-protein-binding radio-tracers as novel diagnostics.
Novel Tumor-Targeted Self-Nanostructured and Compartmentalized Water-in-Oil-in-Water Polyurethane-Polyurea Nanocapsules for Cancer Theragnosis
Authors: Bonelli Joaquín , Velasco-de Andrés María , Isidro Neus , Bayó Cristina , Chumillas Sergi , Carrillo-Serradell Laura , Casadó-Llombart Sergi , Mok Cheryl , Benítez-Ribas Daniel , Lozano Francisco , Rocas Josep , Marchán Vicente
Published: December 2022

Encapsulation of water-soluble bioactive compounds for enabling specific accumulation in tumor locations, while avoiding premature clearance and/or degradation in the bloodstream, is one of the main hallmarks in nanomedicine, especially that of NIR fluorescent probes for cancer theragnosis. The herein reported technology furnishes water-dispersible double-walled polyurethane-polyurea hybrid nanocapsules (NCs) loaded with indocyanine green (ICG-NCs), using a versatile and highly efficient one-pot and industrially scalable synthetic process based on the use of two different prepolymers to set up the NCs walls. Flow cytometry and confocal microscopy confirmed that both ICG-loaded NCs internalized in monocyte-derived dendritic cells (moDCs). The in vivo analysis of xenograft A375 mouse melanoma model revealed that amphoteric functionalization of NCs’ surface promotes the selective accumulation of ICG-NCs in tumor tissues, making them promising agents for a less-invasive theragnosis of cancer.
Engineered Exosomes for Tumor-Targeted Drug Delivery: A Focus on Genetic and Chemical Functionalization
Authors: Akbari Ali , Nazari-Khanamiri Fereshteh , Ahmadi Mahdi , Shoaran Maryam , Rezaie Jafar
Published: December 2022

Cancer is the main cause of death worldwide. The limitations in traditional cancer therapies provoked the advance and use of several nanotechnologies for more effective and nontoxic cancer treatment. Along with synthetic nanocarriers, extracellular vesicles (EVs)-mediated drug delivery systems have aroused substantial interest. The term EVs refers to cell-derived nanovesicles, such as exosomes, with phospholipid-bound structures, participating in cell-to-cell communication. Exosomes are 30–150 nm vesicles that can transfer many biological molecules between cells. From a drug delivery standpoint, exosomes can be loaded with various therapeutic cargo, with the several advantages of low immunogenicity, high biocompatibility, transformative, and effective tumor targeting aptitude. The exosomal surface can be functionalized to improve tumor targeting ability of them. Researchers have genetically expressed or chemically linked various molecules on the surface of exosomes. Despite extensive investigation, clinical translation of exosome-based drug delivery remains challenging. In this review, we discuss various methods used to loading exosomes with therapeutic cargo. We describe examples of functionalized exosomes surface using genetic and chemical modification methods. Finally, this review attempts to provide future outlooks for exosome-based targeted drug delivery.
Preparation and Characterization of a Novel Multiparticulate Dosage Form Carrying Budesonide-Loaded Chitosan Nanoparticles to Enhance the Efficiency of Pellets in the Colon
Authors: Soltani Fatemeh , Kamali Hossein , Akhgari Abbas , Ghasemzadeh Rahbardar Mahboobeh , Afrasiabi Garekani Hadi , Nokhodchi Ali , Sadeghi Fatemeh
Published: December 2022

An attempt was made to conquer the limitation of orally administered nanoparticles for the delivery of budesonide to the colon. The ionic gelation technique was used to load budesonide on chitosan nanoparticles. The nanoparticles were investigated in terms of size, zeta potential, encapsulation efficiency, shape and drug release. Then, nanoparticles were pelletized using the extrusion–spheronization method and were investigated for their size, mechanical properties, and drug release. Pellets were subsequently coated with a polymeric solution composed of two enteric (eudragit L and S) and time-dependent polymers (eudragit RS) for colon-specific delivery. All formulations were examined for their anti-inflammatory effect in rats with induced colitis and the relapse of the colitis after discontinuation of treatment was also followed. The size of nanoparticles ranged between 288 ± 7.5 and 566 ± 7.7 nm and zeta potential verified their positive charged surface. The drug release from nanoparticles showed an initial burst release followed by a continuous release. Pelletized nanoparticles showed proper mechanical properties and faster drug release in acidic pH compared with alkaline pH. It was interesting to note that pelletized budesonide nanoparticles released the drug throughout the GIT in a sustained fashion, and had long-lasting anti-inflammatory effects while rapid relapse was observed for those treated with conventional budesonide pellets. It seems that there is a synergistic effect of nanoformulation of budesonide and the encapsulation of pelletized nanoparticles in a proper coating system for colon delivery that could result in a significant and long-lasting anti-inflammatory effect.
3D Porous Collagen Matrices—A Reservoir for In Vitro Simultaneous Release of Tannic Acid and Chlorhexidine
Authors: Brăzdaru Lavinia , Staicu Teodora , Albu Kaya Mădălina Georgiana , Chelaru Ciprian , Ghica Corneliu , Cîrcu Viorel , Leca Minodora , Ghica Mihaela Violeta , Micutz Marin
Published: December 2022

The treatment of wounds occurring accidentally or as a result of chronic diseases most frequently requires the use of appropriate dressings, mainly to ensure tissue regeneration/healing, at the same time as treating or preventing potential bacterial infections or superinfections. Collagen type I-based scaffolds in tandem with adequate antimicrobials can successfully fulfill these requirements. In this work, starting from the corresponding hydrogels, we prepared a series of freeze-dried atelocollagen type I-based matrices loaded with tannic acid (TA) and chlorhexidine digluconate (CHDG) as active agents with a broad spectrum of antimicrobial activity and also as crosslinkers for the collagen network. The primary aim of this study was to design an original and reliable algorithm to in vitro monitor and kinetically analyze the simultaneous release of TA and CHDG from the porous matrices into an aqueous solution of phosphate-buffered saline (PBS, pH 7.4, 37 °C) containing micellar carriers of a cationic surfactant (hexadecyltrimethylammonium bromide, HTAB) as a release environment that roughly mimics human extracellular fluids in living tissues. Around this central idea, a comprehensive investigation of the lyophilized matrices (morpho-structural characterization through FT-IR spectroscopy, scanning electron microscopy, swelling behavior, resistance against the collagenolytic action of collagenase type I) was carried out. The kinetic treatment of the release data displayed a preponderance of non-Fickian–Case II diffusion behavior, which led to a general anomalous transport mechanism for both TA and CHDG, irrespective of their concentrations. This is equivalent to saying that the release regime is not governed only by the gradient concentration of the releasing components inside and outside the matrix (like in ideal Fickian diffusion), but also, to a large extent, by the relaxation phenomena of the collagen network (determined, in turn, by its crosslinking degree induced by TA and CHDG) and the dynamic capacity of the HTAB micelles to solubilize the two antimicrobials. By controlling the degree of physical crosslinking of collagen with a proper content of TA and CHDG loaded in the matrix, a tunable, sustainable release profile can be obtained.
In Vivo Toxicity, Redox-Modulating Capacity and Intestinal Permeability of Novel Aroylhydrazone Derivatives as Anti-Tuberculosis Agents
Authors: Valcheva Violeta , Simeonova Rumyana , Mileva Milka , Philipov Stanislav , Petrova Reneta , Dimitrov Simeon , Georgieva Almira , Tsvetanova Elina , Teneva Yoana , Angelova Violina T.
Published: December 2022

The emergence and spread of Mycobacterium tuberculosis strains resistant to many or all anti-tuberculosis (TB) drugs require the development of new compounds both efficient and with minimal side effects. Structure-activity-toxicity relationships of such novel, structurally diverse compounds must be thoroughly elucidated before further development. Here, we present the aroylhydrazone compounds (3a and 3b) regarding their: (i) acute and subacute toxicity in mice; (ii) redox-modulating in vivo and in vitro capacity; (iii) pathomorphology in the liver, kidney, and small intestine tissue specimens; and (iv) intestinal permeability. The acute toxicity test showed that the two investigated compounds exhibited low toxicity by oral and intraperitoneal administration. Changes in behavior, food amount, and water intake were not observed during 14 days of the oral administration at two doses of 1/10 and 1/20 of the LD50. The histological examination of the different tissue specimens did not show toxic changes. The in vitro antioxidant assays confirmed the ex vivo results. High gastrointestinal tract permeability at all tested pH values were demonstrated for both compounds. To conclude, both compounds 3a and 3b are highly permeable with low toxicity and can be considered for further evaluation and/or lead optimization.
Near-Perfect Narrow-Band Tunable Graphene Absorber with a Dual-Layer Asymmetric Meta-Grating
Authors: Liang Junfang , Hu Jinhua , Liu Xiuhong , Zhao Jijun
Published: December 2022

A near-perfect narrow-band graphene-based absorber was fabricated using a resonant system integrated with an asymmetric meta-grating at a wavelength of 1550 nm. By optimizing the gap between the two grating strips, the absorption of monolayer graphene can be increased to 99.6% owing to the strong field confinement of the bottom zero-contrast grating (ZCG). The position of the absorption spectrum could be adjusted by tailoring the grating period or the thickness of the waveguide layer. Interestingly, absorption spectrum linewidth can be tailored by changing the thickness of the spacer layer. The accidental bound states in the continuum (BICs) are then demonstrated in the structure. Moreover, the designed structure realizes the dynamic adjustment of the absorption efficiency at a specific wavelength, which has excellent potential in integrated optical devices and systems.