bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Ferric Carboxymaltose Supplementation in Patients with Heart Failure with Preserved Ejection Fraction: Role of Attenuated Oxidative Stress and Improved Endothelial Function
Authors: Mollace Annachiara , Macrì Roberta , Mollace Rocco , Tavernese Annamaria , Gliozzi Micaela , Musolino Vincenzo , Carresi Cristina , Maiuolo Jessica , Nicita Martina , Caminiti Rosamaria , Paone Sara , Barillà Francesco , Volterrani Maurizio , Mollace Vincenzo
Published: November 2022

Both clinical and experimental evidence shows that iron deficiency (ID) correlates with an increased incidence of heart failure (HF). Moreover, data on iron supplementation demonstrating a beneficial effect in subjects with HF have mostly been collected in patients undergoing HF with reduced ejection fraction (HFrEF). Relatively poor data, however, exist on the potential of iron supplementation in patients with HF with preserved ejection fraction (HFpEF). Here, we report on data emerging from a multicentric, double-blind, randomized, placebo-controlled study investigating the effect of IV supplementation with a placebo or ferric carboxymaltose (FCM) on 64 subjects with HFpEF. ID was detected by the measurement of ferritin levels. These data were correlated with cardiac performance measurements derived from a 6 min walking test (6MWT) and with echocardiographic determinations of diastolic function. Moreover, an EndoPAT analysis was performed to correlate cardiac functionality with endothelial dysfunction. Finally, the determination of serum malondialdehyde (MDA) was performed to study oxidative stress biomarkers. These measurements were carried out before and 8 weeks after starting treatment with a placebo (100 mL of saline given i.v. in 10 min; n = 32) or FCM at a dose of 500 mg IV infusion (n = 32), which was given at time 0 and repeated after 4 weeks. Our data showed that a condition of ID was more frequently associated with impaired diastolic function, worse 6MWT and endothelial dysfunction, an effect that was accompanied by elevated MDA serum levels. Treatment with FCM, compared to the placebo, improved ferritin levels being associated with an improved 6MWT, enhanced cardiac diastolic function and endothelial reactivity associated with a significant reduction in MDA levels. In conclusion, this study confirmed that ID is a frequent comorbidity in patients with HFpEF and is associated with reduced exercise capacity and oxidative stress-related endothelial dysfunction. Supplementation with FCM determines a significant improvement in diastolic function and the exercise capacity of patients with HFpEF and is associated with an enhanced endothelial function and a reduced production of oxygen radical species.
Oral Administration of Branched-Chain Amino Acids Attenuates Atherosclerosis by Inhibiting the Inflammatory Response and Regulating the Gut Microbiota in ApoE-Deficient Mice
Authors: Li Ziyun , Zhang Ranran , Mu Hongna , Zhang Wenduo , Zeng Jie , Li Hongxia , Wang Siming , Zhao Xianghui , Chen Wenxiang , Dong Jun , Yang Ruiyue
Published: November 2022

Atherosclerosis (AS) is a chronic inflammatory disease that serves as a common pathogenic underpinning for various cardiovascular diseases. Although high circulating branched-chain amino acid (BCAA) levels may represent a risk factor for AS, it is unclear whether dietary BCAA supplementation causes elevated levels of circulating BCAAs and hence influences AS, and the related mechanisms are not well understood. Here, ApoE-deficient mice (ApoE−/−) were fed a diet supplemented with or without BCAAs to investigate the effects of BCAAs on AS and determine potential related mechanisms. In this study, compared with the high-fat diet (HFD), high-fat diet supplemented with BCAAs (HFB) reduced the atherosclerotic lesion area and caused a significant decrease in serum cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels. BCAA supplementation suppressed the systemic inflammatory response by reducing macrophage infiltration; lowering serum levels of inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6); and suppressing inflammatory related signaling pathways. Furthermore, BCAA supplementation altered the gut bacterial beta diversity and composition, especially reducing harmful bacteria and increasing probiotic bacteria, along with increasing bile acid (BA) excretion. In addition, the levels of total BAs, primary BAs, 12α-hydroxylated bile acids (12α-OH BAs) and non-12α-hydroxylated bile acids (non-12α-OH BAs) in cecal and colonic contents were increased in the HFB group of mice compared with the HFD group. Overall, these data indicate that dietary BCAA supplementation can attenuate atherosclerosis induced by HFD in ApoE−/− mice through improved dyslipidemia and inflammation, mechanisms involving the intestinal microbiota, and promotion of BA excretion.
The Ameliorative Effect and Mechanisms of Ruditapes philippinarum Bioactive Peptides on Obesity and Hyperlipidemia Induced by a High-Fat Diet in Mice
Authors: Song Yahui , Cai Qinling , Wang Shanglong , Li Li , Wang Yuanyuan , Zou Shengcan , Gao Xiang , Wei Yuxi
Published: November 2022

In this study, bioactive peptides (RBPs) from Ruditapes philippinarum were prepared by fermentation with Bacillus natto and the effect and mechanisms of RBPs on obesity and hyperlipidemia were explored in mice. We found that RBPs significantly reduced body weight, adipose tissue weight, accumulation of hepatic lipids, and serum levels of total cholesterol (CHO), triglyceride (TG), and low-density lipoprotein (LDL). Mechanistic studies showed that RBPs up-regulated the hepatic expression of genes related to lipolysis, such as hormone-sensitive lipase (HSL), phosphorylated AMP-activated protein kinase (p-AMPK), and peroxisome proliferator-activated receptors α (PPARα), and down-regulated the expression of peroxisome proliferator-activated receptors γ (PPARγ) which is related to lipid synthesis. In addition, RBPs could attenuate obesity and hyperlipidemia by regulating disordered gut microbiota composition, such as increasing the abundance of microflora related to the synthesis of short chain fatty acids (SCFAs) (Bacteroidetes, Prevotellaceas_UCG_001, norank_f_Muribaculaceae, and Odoribacter) and controlling those related to intestinal inflammation (reduced abundance of Deferribacteres and increased abundance of Alistipes and ASF356) to exert anti-obesity and lipid-lowering activities. Our findings laid the foundation for the development and utilization of RBPs as a functional food to ameliorate obesity and hyperlipidemia.
S-Benproperine, an Active Stereoisomer of Benproperine, Suppresses Cancer Migration and Tumor Metastasis by Targeting ARPC2
Authors: Jang Hyun-Jin , Yoon Yae Jin , Choi Jiyeon , Lee Yu-Jin , Lee Sangku , Cho Wansang , Byun Wan Gi , Park Seung Bum , Han Dong Cho , Kwon Byoung-Mog
Published: November 2022

Metastasis, in which cancer cells migrate to other tissues and form new tumors, is a major cause of both cancer death and treatment failure. In a previous study, benproperine (Benp) was identified as a cancer cell migration inhibitor and an inhibitor of actin-related protein 2/3 complex subunit 2 (ARPC2). However, Benp is a racemic mixture, and which stereoisomer is the active isomer remains unclear. In this study, we found that S-Benp is an active isomer and inhibits the migration and invasion of cancer cells much more strongly than R-Benp, with no effect on normal cells. The metastasis inhibitory effect of S-Benp was also verified in an animal model. Validating that inhibitors bind to their targets in cells and tissues has been a very challenging task in drug discovery. The direct interactions between ARPC2 and S-Benp were verified by surface plasmon resonance analysis (SPR), a cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). In the mutant study with ARPC2F225A cells, S-Benp did not bind to ARPC2F225A according to CETSA and DARTS. Furthermore, we validated that S-Benp colocalized with ARPC2 in cancer cells and directly bound to ARPC2 in tumor tissues using Cy3-conjugated S-Benp according to CETSA. Finally, actin polymerization assays and immunocytochemistry showed that S-Benp suppressed actin remodeling such as lamellipodium formation. Taken together, our data suggest that S-Benp is an active stereoisomer of Benp and a potential metastasis inhibitor via ARPC2 binding.
Design and Optimization of Lornoxicam Dispersible Tablets Using Quality by Design (QbD) Approach
Authors: Almotairi Nawaf , Mahrous Gamal M. , Al-suwayeh Saleh , Kazi Mohsin
Published: November 2022

The present study aims to design and optimize the lornoxicam dispersible tablet (LXDT) formulation using the Quality by design (QbD) approach. A randomized Box–Behnken experimental design was used to characterize the effect of the critical factors, such as filler (MCC/Mannitol) ratio, mixing time, and disintegrant concentration, and assessed for their impacts on the critical quality attributes (responses), including dispersibility time, friability, dissolution efficiency, and content uniformity, respectively. The drug-excipients interaction of the formulation was investigated using FTIR and DSC, respectively. The accelerated stability study at 40 °C/75% relative humidity was performed. FTIR revealed an absence of any significant chemical interaction in solid state. DSC thermogram suggested that LX endothermic peak was slightly decreased due to the dilution effect. LXDT formulations exhibited acceptable friability (0.2 to 0.9%). The dissolution efficiency of LXDT formulations ranged from 72.21 to 93.63%. The overall study showed that the optimum level of independent factors was found to be 3:1 MCC/Mannitol, 11 min mixing time, and 6.23% disintegrant concentration. Accelerated stability studies showed the compendial acceptable hardness, friability, and disintegration times. The application of QbD approach can help in the detailed understanding of the effect of CMAs and CPPs on the CQAs on LXDT final product.
Antiepileptic Effect of Neuroaid® on Strychnine-Induced Convulsions in Mice
Authors: Salim Mahmood Ahmed , Ammoo Afaq M. , Ali Mayssam Hussein Mohammed , Hameed Tiba M. , Al-Hussaniy Hany A. , Aljumaili Abdulla Amer Abbas , Al-Fallooji Mohammed Hussein Alaa , Kadhim Ali Hakim
Published: November 2022

NeuroAid II, a folk Chinese Medicine, is currently used in Asia for the treatment of stroke. An experimental study demonstrated that NeuroAid enables neuronal cells to be more resistant to glutamate toxicity. This research was constructed to evaluate the efficacy of NeuroAid in the prevention of epilepsy (EP). Forty healthy adult male mice were used and divided into four groups (10 mice/group): normal control group; positive control group; NeuroAid-treated group (10 mg/kg); topiramate-treated group (10 mg/kg). The treatment continued for 7 days, and on the last day, EP was induced using strychnine at a dose of 2 mg/kg via intraperitoneal (ip) administration. Seizure severity, latency to the seizure onset, the number of seizures, and the duration of each seizure episode were observed for one hour. The death and protection rates over the next twenty-four hours were recorded. Brain specimens from surviving animals were extracted and examined pathologically for quantification of glutamate receptor (GluR) gene expression in the isolated hippocampus employing real-time PCR analysis. Treatment with NeuroAid resulted in a significant reduction in seizure severity, prolonged the onset of seizures, decreased the number and duration of episodes, reduced brain insult, and decreased mortality rate. Reductions in the gene expression of GluRs in the hippocampus with minor histopathological changes were observed in the NeruoAid- and topiramate-treated groups. It is concluded that NeuroAid has a potential antiepileptic effect (EP) with the ability to prevent convulsion through its effect on the glutamate receptor.
Pharmacological Activities of Ginkgolic Acids in Relation to Autophagy
Authors: Ding Yuan , Ding Zheheng , Xu Jin , Li Yueying , Chen Min
Published: November 2022

Plant-derived natural compounds are widely used as alternative medicine in healthcare throughout the world. Ginkgolic acids, the phenolic compounds isolated from the leaves and seeds of Ginkgo biloba, are among the chemicals that have been explored the most. Ginkgolic acids exhibit cytotoxic activity against a vast number of human cancers in various preclinical models in vitro and in vivo. Additionally, the pharmacological activities of ginkgolic acids are also involved in antidiabetic, anti-bacteria, anti-virus, anti-fibrosis, and reno/neuroprotection. Autophagy as a highly conserved self-cleaning process that plays a crucial role in maintaining cellular and tissue homeostasis and has been proven to serve as a protective mechanism in the pathogenesis of many diseases, including neurodegenerative diseases, cancer, and infectious diseases. In this review, we surveyed the pharmacological activities of the major three forms of ginkgolic acids (C13:0, C15:1, and C17:1) that are linked to autophagic activity and the mechanisms to which these compounds may participate. A growing body of studies in last decade suggests that ginkgolic acids may represent promising chemical compounds in future drug development and an alternative remedy in humans.
Cyclooxygenase-2 (COX-2) as a Target of Anticancer Agents: A Review of Novel Synthesized Scaffolds Having Anticancer and COX-2 Inhibitory Potentialities
Authors: Mohsin Noor ul Amin , Aslam Sana , Ahmad Matloob , Irfan Muhammad , Al-Hussain Sami A. , Zaki Magdi E. A.
Published: November 2022

Cancer is a serious threat to human beings and is the second-largest cause of death all over the globe. Chemotherapy is one of the most common treatments for cancer; however, drug resistance and severe adverse effects are major problems associated with anticancer therapy. New compounds with multi-target inhibitory properties are targeted to surmount these challenges. Cyclooxygenase-2 (COX-2) is overexpressed in cancers of the pancreas, breast, colorectal, stomach, and lung carcinoma. Therefore, COX-2 is considered a significant target for the synthesis of new anticancer agents. This review discusses the biological activity of recently prepared dual anticancer and COX-2 inhibitory agents. The most important intermolecular interactions with the COX-2 enzyme have also been presented. Analysis of these agents in the active area of the COX-2 enzyme could guide the introduction of new lead compounds with extreme selectivity and minor side effects.
Characterization and Isolation of the Major Biologically Active Metabolites Isolated from Ficus retusa and Their Synergistic Effect with Tetracycline against Certain Pathogenic-Resistant Bacteria
Authors: Alqahtani Abdulwahab , Marrez Diaa A. , Aleraky Mohamed , Fagir Nada A. , Alqahtani Omaish , Othman Samir , El Raey Mohamed A. , Attia Hany G.
Published: November 2022

Globally, pathogenic microbes have reached a worrisome level of antibiotic resistance. Our work aims to identify and isolate the active components from the bioactive Ficus retusa bark extract and assess the potential synergistic activity of the most major compounds’ constituents with the antibiotic tetracycline against certain pathogenic bacterial strains. The phytochemical screening of an acetone extract of F. retusa bark using column chromatography led to the identification of 10 phenolic components. The synergistic interaction of catechin and chlorogenic acid as the most major compounds with tetracycline was evaluated by checkerboard assay followed by time-kill assay, against Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, and Salmonella typhi with fraction inhibitory concentration index values (FICI) of 0.38, 0.43, 0.38, 0.38, 0.38, and 0.75 for catechin and 0.38, 0.65, 0.38, 0.63, 0.38, and 0.75 for chlorogenic acid. The combination of catechin and chlorogenic acid with tetracycline significantly enhanced antibacterial action against gram-positive and gram-negative microorganisms; therefore, catechin and chlorogenic acid combinations with tetracycline could be employed as innovative and safe antibiotics to combat microbial resistance.
New 5-Aryl-1,3,4-Thiadiazole-Based Anticancer Agents: Design, Synthesis, In Vitro Biological Evaluation and In Vivo Radioactive Tracing Studies
Authors: El-Masry Rana M. , Essa Basma M. , Selim Adli A. , El-Emam Soad Z. , Mohamed Khaled O. , Sakr Tamer M. , Kadry Hanan H. , Taher Azza T. , Abou-Seri Sahar M.
Published: November 2022

A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (3), substituted piperazines (4a–g), benzyl piperidine (4i), and aryl aminothiazoles (5a–e) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds 4e and 4i displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of 4e and 4i towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound 4e or 4i induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either 4e or 4i indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound 4i proved its targeting ability to sarcoma cells in a tumor-bearing mice model.
Synthesis and Anti-Tumor Effects of Novel Pomalidomide Derivatives Containing Urea Moieties
Authors: Guo Yajie , Wang Xi , Wang Zhenzhen , Mao Longfei , Wang Jiahao , Peng Lizeng , Xu Guiqing
Published: November 2022

In order to explore novel immunomodulatory agents as anti-tumor drugs, we designed and synthesized a series of new pomalidomide derivatives containing urea moieties. Interestingly, in vitro biological experiments performed in several cancer cell lines showed that some of them displayed potent anti-tumor ability. These novel compounds 5a–5e and 6a–6e demonstrated the best cell growth inhibitive activity in human breast cancer cell lines MCF-7, but weaker inhibitive activity in human hepatocellular carcinoma cell lines Huh7. Moreover, compound 5d had the most powerful effects in this study, with an IC50 value of 20.2 μM in MCF-7. Further study indicated that compound 5d could inhibit cell growth and induce cell death in a concentration-dependent manner. Besides, compound 5d increased cellular ROS levels and induced DNA damage, thereby potentially leading to cell apoptosis. These observations suggest that the novel pomalidomide derivatives containing urea moieties may be worth further investigation to generate potential anti-tumor drugs.
A Class I HDAC Inhibitor BG45 Alleviates Cognitive Impairment through the CaMKII/ITPKA/Ca2+ Signaling Pathway
Authors: Liu Jingyun , Zhang Chenghong , Wang Jiale , Huang Yufei , Shen Di , Hu Yingqiu , Chu Haiying , Yu Xuebin , Zhang Liyuan , Ma Haiying
Published: November 2022

Alzheimer’s disease (AD) seriously endangers the health and life of elderly individuals worldwide. However, despite all scientific efforts, at the moment there are no effective clinical treatment options for AD. In this work, the effect of the class I histone deacetylase inhibitor (HDACI) BG45 on synapse-related proteins was investigated in primary neurons from APP/PS1 transgenic mice. The results showed that BG45 can upregulate the expression of synaptotagmin-1 (SYT-1) and neurofilament light chain (NF-L) in primary neurons. In vivo, the APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with BG45 (30 mg/kg) daily for 12 days. Behavioral testing of BG45-treated APP/PS1 mice showed improvements in learning and memory. BG45 can alleviate damage to the dendritic spine and reduce the deposition of Aβ. Similar to the in vitro results, synapse-related proteins in the prefrontal cortex were increased after BG45 treatment. Proteomic analysis results highlighted the differences in the biological processes of energy metabolism and calmodulin regulation in APP/PS1 mice with or without BG45 treatment. Further verification demonstrated that the effect of BG45 on synapses and learning and memory may involve the CaMKII/ITPKA/Ca2+ pathway. These results suggest that class I HDACI BG45 might be a promising drug for the early clinical treatment of AD.
Adverse Effects of Oral Cannabidiol: An Updated Systematic Review of Randomized Controlled Trials (2020–2022)
Authors: Souza José Diogo R. , Pacheco Julia Cozar , Rossi Giordano Novak , de-Paulo Bruno O. , Zuardi Antonio W. , Guimarães Francisco S. , Hallak Jaime E. C. , Crippa José Alexandre , Dos Santos Rafael G.
Published: November 2022

(1) Background: With the massive demand for the use and commercialization of medicinal cannabidiol (CBD) products, new randomized clinical trials (RCTs) are being published worldwide, with a constant need for safety and efficacy evaluation. (2) Methods: We performed an update on a systematic review published in 2020 that focused on analyzing the serious adverse effects (SAEs) of CBD in RCTs and its possible association with drug interactions. We also updated the report of the most prevalent CBD adverse effects (AEs). We systematically searched EMBASE, MEDLINE/PubMed, and Web of Science without language restriction for RCTs that reported adverse effects after repeated oral CBD administration for at least one week in healthy volunteers or clinical samples published from January 2019 to May 2022. The included studies were assessed for methodological quality by the Quality Assessment of Controlled Intervention Studies tool. The present review is registered on PROSPERO, number CRD42022334399. (3) Results: Twelve studies involving 745 randomized subjects analyzed were included (range 1.1–56.8 y). A total of 454 participants used CBD in the trials. The most common AEs of CBD were mild or moderate and included gastrointestinal symptoms (59.5%), somnolence (16.7%), loss of appetite (16.5%), and hypertransaminasemia (ALT/AST) (12.8%). Serious adverse effects include mainly hypertransaminasemia with serum levels elevations greater than three times the upper limit of the normal (6.4%), seizures (1.3%), and rash (1.1%). All SAEs reported in the studies were observed on CBD as an add-on therapy to anticonvulsant medications, including clobazam and valproate. (4) Conclusion: Recent RCTs involving oral CBD administration for at least a week suggest that CBD has a good safety and tolerability profile, confirming previous data. However, it can potentially interact with other drugs and its use should be monitored, especially at the beginning of treatment.
Cationic Surfactants Based on Arginine-Phenylalanine and Arginine-Tryptophan: Synthesis, Aggregation Behavior, Antimicrobial Activity, and Biodegradation
Authors: Pérez Lourdes , García María Teresa , Pinazo Aurora , Pérez-Matas Edgar , Hafidi Zakaria , Bautista Elena
Published: November 2022

Cationic surfactants have great potential as drug vehicles and for use in gene therapy (cationic vesicles made from cationic surfactants can encapsulate RNA or DNA for cellular transfer). They can also be used as antimicrobial and antifungal agents to treat human infections. In an era of increasing antimicrobial resistance, the development of new biocompatible surfactants suitable for application as antimicrobial agents is of high interest. In this work, a library of amino acid-based surfactants was synthesized, characterized and tested for antimicrobial activity. The head group architecture (number and type of amino acids, density of cationic charge, ionic character) and the hydrophobic moiety (alkyl chain length and position of the hydrophobic group) were systematically modified, and the effect on the surfactant biological and aggregation behavior was studied. Thus, the pKa values, micellization process, antimicrobial efficiency and biodegradability were evaluated. The critical micelle concentration values of the surfactants depended on their hydrophobic character, but changes in the polar head as well as the position and length of the alkyl chain also significantly affected activity against some of the tested microorganisms. Moreover, biodegradability was closely related to the hydrophobic character of the surfactant and attachment of the alkyl chain to the polar head. The structure–activity relationships established here may open perspectives for the design of effective biodegradable antimicrobial materials that can overcome emerging resistance.
Cytokine Therapy Combined with Nanomaterials Participates in Cancer Immunotherapy
Authors: Lian Heping , Ma Shuang , Zhao Duoyi , Zhao Wei , Cui Yan , Hua Yingqi , Zhang Zhiyu
Published: November 2022

Immunotherapy has gradually become an emerging treatment modality for tumors after surgery, radiotherapy, and chemotherapy. Cytokine therapy is a promising treatment for cancer immunotherapy. Currently, there are many preclinical theoretical bases to support this treatment strategy and a variety of cytokines in clinical trials. When cytokines were applied to tumor immunotherapy, it was found that the efficacy was not satisfactory. As research on tumor immunity has deepened, the role of cytokines in the tumor microenvironment has been further explored. Meanwhile, the study of nanomaterials in drug delivery has been fully developed in the past 20 years. Researchers have begun to think about the possibility of combining cytokine therapy with nanomaterials. Herein, we briefly review various nano-delivery systems that can directly deliver cytokines or regulate the expression of cytokines in tumor cells for cancer immunotherapy. We further discussed the feasibility of the combination of various therapies. We looked forward to the main challenges, opportunities, and prospects of tumor immunotherapy with multiple cytokines and a nano-delivery system.
An In Vitro Model to Investigate the Potential of Solid Dispersions to Form Pharmacobezoars
Authors: Gierke Hannes , Schaefer Kerstin , Gerlich Lukas , Willmann Ann-Cathrin , Bialetzki Verena , Boeck Georg , Pfrommer Teresa , Nolte Thomas , Weitschies Werner
Published: November 2022

The formation of pharmacobezoars from suspensions of spray-dried amorphous solid dispersions (SD-ASDs) of new chemical entities (NCEs) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) represents a non-compound related adverse effect in preclinical oral toxicity studies in rodents. Whereas the contribution of the insolubility of the carrier polymer to this process taking place in the acidic environment of the rodent stomach is conclusive, unawareness of the extent of in vivo pharmacobezoar formation is adverse. In order to evaluate the risk of pharmacobezoar formation before in vivo administration, we subsequently introduce an in vitro model to assess the agglomeration potential of solid dispersions. To verify that the pharmacobezoar formation potential can be assessed based on the observed agglomeration potential, we conducted a sequence of experiments with two HPMC-AS-based SD-ASD formulations. In vitro, we found their different in vivo pharmacobezoar formation potential reflected by a significantly increased agglomerated mass of formulation 1 per day compared to formulation 2. In order to find an approach to reduce the agglomeration potential of solid dispersion from suspensions, we further applied the model to investigate the impact of the viscosity of the vehicle used to prepare suspensions on agglomerate formation.
Photodynamic Opening of the Blood–Brain Barrier and the Meningeal Lymphatic System: The New Niche in Immunotherapy for Brain Tumors
Authors: Semyachkina-Glushkovskaya Oxana , Terskov Andrey , Khorovodov Alexander , Telnova Valeria , Blokhina Inna , Saranceva Elena , Kurths Jürgen
Published: November 2022

Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood–brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM.
Bioinspired Platelet-like Nanovector for Enhancing Cancer Therapy via P-Selectin Targeting
Authors: Wan Shengli , Wu Yuesong , Fan Qingze , Yang Gang , Hu Haiyang , Tima Singkome , Chiampanichayakul Sawitree , Anuchapreeda Songyot , Wu Jianming
Published: November 2022

Cancer is a major threat to the health of humans. Recently, various natural products including curcumin (CCM) have attracted enormous interest for efficacious cancer therapy. However, natural therapeutic agents still encounter certain challenges such as rapid clearance, low bioavailability, and poor tumor targeting. Recently, the platelet membrane (PM) camouflaged nanoparticle has provided a promising solution for cancer targeting therapy. Nevertheless, only limited efforts have been dedicated to systematically explore the mechanism of affinity between PM bioinspired nanoparticles and various tumor cells. Herein, a CCM-encapsulated platelet membrane biomimetic lipid vesicle (CCM@PL) with a size of 163.2 nm, zeta potential of −31.8 mV and encapsulation efficiency of 93.62% was developed. The values of the area under the concentration-time curve and mean residence time for CCM@PL were 3.08 times and 3.04 times those of CCM, respectively. Furthermore, this PM biomimetic carrier showed an excellent affinity against Huh-7, SK-OV-3 and MDA-MB-231 cell lines due to the biomolecular interaction between P-selectin on the PM and tumoral CD44 receptors. In addition, CCM@PL displayed enhanced cytotoxicity compared with free CCM and the synthetic formulation. Overall, our results suggest that this developed PM biomimetic lipid nanovector has great potential for targeted cancer treatment and natural components delivery.
In Vitro and In Vivo Characteristics of Olive Oil as Excipient for Topical Administration
Authors: Rodríguez-Torrado Marta , Kara Aytug , Torrado Susana , Romero Alejandro , Juberías Antonio , Torrado Juan J. , Serrano Dolores R.
Published: November 2022

Oily excipients are vital components of dermatological products. In this study, the in vitro and in vivo characteristics of Wild Olive Oil (WOO) were compared with two other types of olive oils: Extra Virgin Olive Oil (EVOO) and Virgin Olive Oil (VOO). This work has also included Liquid Paraffin (LP) and Rosehip Oil (RO) as reference oils. Melatonin was used in the study as a model drug to demonstrate the antioxidant capacity of the oils. The melatonin carrier capacity and antioxidant performance was related to the degree of unsaturation of the oils and was highest for RO and WOO and lowest for LP. However, the most stable oil to oxidation was LP. The in vivo performance of the oils in the skin of eight healthy volunteers was investigated with a dermoanalyser. The highest increment of oil and hydration in the skin was obtained with RO. The lowest perception of oiliness was described for WOO, which produced the highest increase in elasticity of the skin area where it was applied. An in vitro-in vivo correlation was therefore performed through multivariable analysis (MVA).
Synthesis of Dipyridylaminoperylenediimide–Metal Complexes and Their Cytotoxicity Studies
Authors: Garcés-Garcés José , Redrado Marta , Sastre-Santos Ángela , Gimeno María Concepción , Fernández-Lázaro Fernando
Published: November 2022

A new family of perylenediimide (PDI) silver and copper complexes has been successfully synthesized by reacting ortho- and bay-substituted (dipyrid-2′,2″-ylamino)perylenediimide ligands with metal phosphine fragments. The coordination of the metal center did not reveal a significant effect on the photophysical properties, which are mainly due to the PDI ligands, and in some cases quenching of the luminescence was observed. The antiproliferative effect of the free perylenediimide ligands and the metalloPDI complexes against the cervix cancer cell line HeLa was determined by MTT assay. The free perylenediimide ligands exhibited a moderate cytotoxic activity, but the coordination of silver or copper to the dypyridylamino fragment greatly enhanced the activity, suggesting a synergistic effect between the two fragments. In attempts to elucidate the cellular biodistribution of the PDIs and the complexes, a colocalization experiment using specific dyes for the lysosomes or mitochondria as internal standards revealed a major internalization inside the cell for the metal complexes, as well as a partial mitochondrial localization.
Airway Epithelial Cell Junctions as Targets for Pathogens and Antimicrobial Therapy
Authors: Gao Nannan , Rezaee Fariba
Published: November 2022

Intercellular contacts between epithelial cells are established and maintained by the apical junctional complexes (AJCs). AJCs conserve cell polarity and build epithelial barriers to pathogens, inhaled allergens, and environmental particles in the respiratory tract. AJCs consist of tight junctions (TJs) and adherens junctions (AJs), which play a key role in maintaining the integrity of the airway barrier. Emerging evidence has shown that different microorganisms cause airway barrier dysfunction by targeting TJ and AJ proteins. This review discusses the pathophysiologic mechanisms by which several microorganisms (bacteria and viruses) lead to the disruption of AJCs in airway epithelial cells. We present recent progress in understanding signaling pathways involved in the formation and regulation of cell junctions. We also summarize the potential chemical inhibitors and pharmacological approaches to restore the integrity of the airway epithelial barrier. Understanding the AJCs–pathogen interactions and mechanisms by which microorganisms target the AJC and impair barrier function may further help design therapeutic innovations to treat these infections.
Chitosan-Dextran-Glycerol Hydrogels Loaded with Iron Oxide Nanoparticles for Wound Dressing Applications
Authors: Chircov Cristina , Bejenaru Iuliana Teodora , Nicoară Adrian Ionuț , Bîrcă Alexandra Cătălina , Oprea Ovidiu Cristian , Tihăuan Bianca
Published: November 2022

Natural polymers have shown tremendous potential towards the development of hydrogels with tissue regeneration properties. Among them, chitosan and dextran are polysaccharides widely applied in the wound dressing area owing to their mucoadhesiveness, biodegradability, hemostatic potential, and intrinsic antibacterial activity, while glycerol is a well-known biocompatible solvent extensively used in the manufacture of cosmetic, pharmaceutical, medical, and personal care products. In order to enhance the properties of natural polymer-based hydrogels, the focus has currently shifted towards the addition of nanomaterials with antibacterial and regenerative potential, i.e., iron oxide nanoparticles. Thus, the aim of the present study was to develop a series of chitosan-dextran-glycerol hydrogels loaded with iron oxide nanoparticles, either readily added or formed in situ. The physicochemical properties of the so obtained hydrogels demonstrated an improved dispersibility of the in situ formed magnetite nanoparticles, which further decreases the porosity and swelling ratio of the hydrogels but increases the antimicrobial properties. Additionally, the presence of glycerol enhances the cell viability but reduces the antimicrobial potential. In this context, the results proved promising biological and antimicrobial properties, thus confirming their potential as biomaterials for wound healing and regeneration.
Hybrid Polydimethylsiloxane (PDMS) Incorporated Thermogelling System for Effective Liver Cancer Treatment
Authors: Ma Panqin , Jiang Lu , Luo Xi , Chen Jiayun , Wang Qi , Chen Ying , Ye Enyi , Loh Xian Jun , Wu Caisheng , Wu Yun-Long , Li Zibiao
Published: November 2022

For the delivery of anticancer drugs, an injectable in situ hydrogel with thermal responsiveness and prolonged drug release capabilities shows considerable potential. Here, we present a series of thermosensitive in situ hydrogels that serve as drug delivery systems for the treatment of liver cancer. These hydrogels were created by utilizing the polydimethylsiloxane (PDMS) oligomer, polyethylene glycol (PEG) and polypropylene glycol (PPG)’s chemical cross-linking capabilities. Doxorubicin (DOX) was encapsulated in a hydrogel with a hydrophobic core and hydrophilic shell to enhance DOX solubility. Studies into the behavior of in situ produced hydrogels at the microscopic and macroscopic levels revealed that the copolymer solution exhibits a progressive shift from sol to gel as the temperature rises. The hydrogels’ chemical composition, thermal properties, rheological characteristics, gelation period, and DOX release behavior were all reported. Subcutaneous injection in mice was used to confirm the injectability. Through the in vitro release of DOX in a PBS solution that mimics the tumor microenvironment, the hydrogel’s sustained drug release behavior was confirmed. Additionally, using human hepatocellular hepatoma, the anticancer efficacy of thermogel (DEP-2@DOX) was assessed (HepG2). The carrier polymer material DEP-2 was tested for cytotoxicity using HepG2 cells and its excellent cytocompatibility was confirmed. In conclusion, these thermally responsive injectable hydrogels are prominent potential candidates as drug delivery vehicles for the treatment of hepatocellular carcinoma.
Gossypol and Its Natural Derivatives: Multitargeted Phytochemicals as Potential Drug Candidates for Oncologic Diseases
Authors: Pal Dilipkumar , Sahu Pooja , Sethi Gautam , Wallace Carly E. , Bishayee Anupam
Published: November 2022

Despite the vast amounts of research and remarkable discoveries that have been made in recent decades, cancer remains a leading cause of death and a major public health concern worldwide. Gossypol, a natural polyphenolic compound derived from the seeds, roots, and stems of cotton (Gossypium hirsutum L.), was first used as a male contraceptive agent. Due to its diverse biological properties, including antifertility, antiviral, antioxidant, antibacterial, antimalarial, and most notably antitumor activities, gossypol has been the subject of numerous studies. Nevertheless, no systematic review has been performed that analyzes the antineoplastic potential of gossypol and related natural compounds in an organ-specific manner while delineating the molecular mechanisms of action. Hence, we have performed an extensive literature search for anticancer properties of gossypol and their natural derivatives against various types of cancer cells utilizing PubMed, ScienceDirect, Google Scholar, and Scopus. The sources, distribution, chemical structure, and toxicity of gossypol and its constituents are briefly reviewed. Based on emerging evidence, gossypol and related compounds exhibit significant antineoplastic effects against various cancer types through the modulation of different cancer hallmarks and signaling pathways. Additionally, the synergistic activity of gossypol and its derivatives with chemotherapeutic agents has been observed. Our evaluation of the current literature suggests the potential of gossypol and its derivatives as multitargeting drug candidates to combat multiple human malignancies.
Stability of Non-Ionic Surfactant Vesicles Loaded with Rifamycin S
Authors: Marchianò Verdiana , Matos Maria , Marcet Ismael , Cabal Maria Paz , Gutiérrez Gemma , Blanco-López Maria Carmen
Published: November 2022

These days, the eradication of bacterial infections is more difficult due to the mechanism of resistance that bacteria have developed towards traditional antibiotics. One of the medical strategies used against bacteria is the therapy with drug delivery systems. Non-ionic vesicles are nanomaterials with good characteristics for encapsulating drugs, due to their bioavailability and biodegradability, which allow the drugs to reach the specific target and reduce their side effects. In this work, the antibiotic Rifamycin S was encapsulated. The rifamycin antibiotics family has been widely used against Mycobacterium tuberculosis, but recent studies have also shown that rifamycin S and rifampicin derivatives have bactericidal activity against Staphylococcus epidermidis and Staphylococcus aureus. In this work, a strain of S. aureus was selected to study the antimicrobial activity through Minimum Inhibitory Concentration (MIC) assay. Three formulations of niosomes were prepared using the thin film hydration method by varying the composition of the aqueous phase, which included MilliQ water, glycerol solution, or PEG400 solution. Niosomes with a rifamycin S concentration of 0.13 μg/g were satisfactorily prepared. Nanovesicles with larger size and higher encapsulation efficiency (EE) were obtained when using glycerol and PEG400 in the aqueous media. Our results showed that niosomes consisting of an aqueous glycerol solution have higher stability and EE across a diversity of temperatures and pHs, and a lower MIC of rifamycin S against S. aureus.
Spanlastics as a Potential Platform for Enhancing the Brain Delivery of Flibanserin: In Vitro Response-Surface Optimization and In Vivo Pharmacokinetics Assessment
Authors: Alharbi Waleed S. , Hareeri Rawan H. , Bazuhair Mohammed , Alfaleh Mohamed A. , Alhakamy Nabil A. , Fahmy Usama A. , Alamoudi Abdullah A. , Badr-Eldin Shaimaa M. , Ahmed Osama A. , AlGhamdi Shareefa A. , Naguib Marianne J.
Published: November 2022

Flibanserin was licensed by the United States Food and Drug Administration (FDA) as an oral non-hormonal therapy for pre-menopausal women with inhibited sexual desire disorder. However, it suffers from susceptibility to first-pass metabolism in the liver, low aqueous solubility, and degradation in the acidic stomach environment. Such hurdles result in a limited oral bioavailability of 33%. Thus, the aim of the study was to utilize the principles of nanotechnology and the benefits of an intranasal route of administration to develop a formulation that could bypass these drawbacks. A response-surface randomized D-optimal strategy was used for the formulation of flibanserin spanlastics (SPLs) with reduced size and increased absolute zeta potential. Two numerical factors were studied, namely the Span 60: edge activator ratio (w/w) and sonication time (min), in addition to one categorical factor that deals with the type of edge activator. Particle size (nm) and zeta potential (mV) were studied as responses. A mathematical optimization method was implemented for predicting the optimized levels of the variables. The optimized formulation was prepared using a Span: sodium deoxycholate ratio of 8:2 w/w; a sonication time of 5 min showed particle sizes of 129.70 nm and a zeta potential of −33.17 mV. Further in vivo assessment following intranasal administration in rats showed boosted plasma and brain levels, with 2.11- and 2.23-fold increases (respectively) compared to raw FLB. The aforementioned results imply that the proposed spanlastics could be regarded as efficient drug carriers for the trans-nasal delivery of drugs to the brain.
The Application of Black Phosphorus Nanomaterials in Bone Tissue Engineering
Authors: Jing Xirui , Xiong Zekang , Lin Zian , Sun Tingfang
Published: November 2022

Recently, research on and the application of nanomaterials such as graphene, carbon nanotubes, and metal–organic frameworks has become increasingly popular in tissue engineering. In 2014, a two-dimensional sheet of black phosphorus (BP) was isolated from massive BP crystals. Since then, BP has attracted significant attention as an emerging nanomaterial. BP possesses many advantages such as light responsiveness, electrical conductivity, degradability, and good biocompatibility. Thus, it has broad prospects in biomedical applications. Moreover, BP is composed of phosphorus, which is a key bone tissue component with good biocompatibility and osteogenic repair ability. Thereby, BP exhibits excellent advantages for application in bone tissue engineering. In this review, the structure and the physical and chemical properties of BP are described. In addition, the current applications of BP in bone tissue engineering are reviewed to aid the future research and application of BP.
Polypyrrole Nanomaterials: Structure, Preparation and Application
Authors: Hao Lu , Dong Changyi , Zhang Lifeng , Zhu Kaiming , Yu Demei
Published: November 2022

In the past decade, nanostructured polypyrrole (PPy) has been widely studied because of its many specific properties, which have obvious advantages over bulk-structured PPy. This review outlines the main structures, preparation methods, physicochemical properties, potential applications, and future prospects of PPy nanomaterials. The preparation approaches include the soft micellar template method, hard physical template method and templateless method. Due to their excellent electrical conductivity, biocompatibility, environmental stability and reversible redox properties, PPy nanomaterials have potential applications in the fields of energy storage, biomedicine, sensors, adsorption and impurity removal, electromagnetic shielding, and corrosion resistant. Finally, the current difficulties and future opportunities in this research area are discussed.
Facile Synthesis of Formaldehyde-Free Bio-Based Thermoset Resins for Fabrication of Highly Efficient Foams
Authors: Li Xuehui , Liu Bowen , Zheng Lulu , Essawy Hisham , Liu Zhiyan , Liu Can , Zhou Xiaojian , Zhang Jun
Published: November 2022

Bio-based biodegradable foams were formulated from a crosslinkable network structure combining starch, furfuryl alcohol, glyoxal, and condensed tannin in the presence of p-toluenesulfonic acid (pTSA) and azodicarbonamide (AC) as a foaming agent. More importantly, the reinforcement of gelatinized starch–furanic foam using tannin, originating from forestry, resulted in an excellent compressive strength and lower pulverization ratio. Moreover, the addition of tannin guaranteed a low thermal conductivity and moderate flame retardancy. Fourier transform infrared (FTIR) spectroscopy approved the successful polycondensation of these condensing agents under the employed acidic conditions. Moreover, the catalytic effect of pTSA on the foaming agent induced liberation of gases, which are necessary for foam formation during crosslinking. Scanning electron microscopy (SEM) showed foam formation comprising closed cells with uniform cell distribution and appropriate apparent density. Meanwhile, the novel foam exhibited biodegradation under the action of Penicillium sp., as identified by the damage of cell walls of this foam over a period of 30 days.