The diverse pharmacological role of dihydropyrimidinone scaffold has made it to be an interesting drug target. Because of the high incidence and mortality rate of breast cancer, there is a dire need of discovering new pharmacotherapeutic agents in managing this disease. A series of twenty-two derivatives of 6-(chloromethyl)-4-(4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3a-3k) and ethyl 6-(chloromethyl)-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a-4k) synthesized in a previous study were evaluated for their anticancer potential against breast cancer cell line. Molecular docking studies were performed to analyze the binding mode and interaction pattern of these compounds against nine breast cancer target proteins. The in vitro cell proliferation assay was performed against the breast cancer cell line MCF-7. The structure activity relationship of these compounds was further studied using QSARINS. Among nine proteins, the docking analysis revealed efficient binding of compounds 4f, 4e, 3e, 4g, and 4h against all target proteins. The in vitro cytotoxic assay revealed significant anticancer activity of compound 4f having IC50 of 2.15 μM. The compounds 4e, 3e, 4g, and 4h also showed anticancer activities with IC50 of 2.401, 2.41, 2.47 and 2.33 μM, respectively. The standard tamoxifen showed IC50 1.88 μM. The 2D qualitative structure-activity relationship (QSAR) analysis was also carried out to identify potential breast cancer targets through QSARINS. The final QSAR equation revealed good predictivity and statistical validation R2 and Q2 values for the model obtained from QSARINS was 0.98 and 0.97, respectively. The active compounds showed very good anticancer activities, and the binding analysis has revealed stable hydrogen bonding of these compounds with the target proteins. Moreover, the QSAR analysis has predicted useful information on the structural requirement of these compounds as anticancer agents with the importance of topological and autocorrelated descriptors in effecting the cancer activities.
Transdermal drug delivery systems (TDDSs) have provided many priorities over other administration routes, especially the oral route. Despite their advantages, there are some limitations regarding TDDSs, including those dedicated to the use of hydrophobic drugs. The emergence of novel nanostructures has presented various opportunities to develop advanced TDDSs to overcome the challenges on using these systems. Polymeric nanofibers present a unique structure for drug delivery applications due to their large loading capacity and ease of manipulation and functionalization. Natural-based polymeric nanofibers and synthetic polymeric nanofibers can both be used for transdermal drug delivery. Due to their favourable features, namely good biocompatibility, biodegradability, and low toxicity, natural polymeric nanofibers have attracted considerable interest over synthetic-based nanofibers. However, due to biosphere sources' scarcity and low flexibility, they are only used sparingly. Hence, the co-use of natural and synthetic polymers has been suggested to develop efficient TDDSs. So far, different methods have been proposed for polymeric nanofibers fabrication, in which electrospinning has been shown to be the most robust and flexible technique, particularly for natural polymers. This paper reviews the state-of-the art of the field of polymeric nanofibers, particularly covering TDDSs based on natural-based nanofibers.
Cancers have always been the most difficult to fight, the treatment of cancer is still not considered. Thus, exploring new anticancer drugs is still imminent. Traditional Chinese medicine has played an important role in the treatment of cancer. Polyphenol oxidase (PPO) extracted from Edible mushroom has many related reports on its characteristics, but its role in cancer treatment is still unclear. This study aims to investigate the effects of PPO extracted from Edible mushroom on the proliferation, migration, invasion, and apoptosis of cancer cells in vitro and explore the therapeutic effects of PPO on tumors in vivo. A cell counting kit-8 (CCK8) assay was used to detect the effect of PPO on the proliferation of cancer cells. The effect of PPO on cancer cell migration ability was detected by scratch test. The effect of PPO on the invasion ability of cancer cells was detected by a transwell assay. The effect of PPO on the apoptosis of cancer cells was detected by flow cytometry. Female BALB/c mice (18–25 g, 6–8 weeks) were used for in vivo experiments. The experiments were divided into control group, model group, low-dose group (25 mg/kg), and high-dose group (50 mg/kg). In vitro, PPO extracted from Edible mushroom significantly inhibited the proliferation, migration, and invasion capability of breast cancer cell 4T1, lung cancer cell A549, and prostate cancer cell C4-2, and significantly promoted the apoptosis of 4T1, A549, and C4-2. In vivo experiments showed PPO inhibitory effect on tumor growth. Collectively, the edible fungus extract PPO could play an effective role in treating various cancers, and it may potentially be a promising agent for treating cancers.
Peritoneal fibrosis (PF) is a common complication of long-term peritoneal dialysis (PD). It is considered as the main reason for dialysis inadequacy and PD withdrawal. Transforming growth factor beta (TGF-β) regulates the expression of stromal cell-derived factor 1 (SDF-1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) on human peritoneal mesothelial cells (HPMCs), resulting in an increased migratory potential of HPMCs and extracellular matrix (ECM) deposition in the scar tissue and eventually fibrosis. Because SDF-1α/CXCR4 activation has a vital role in the pathogenesis of PF, codelivery of a CXCR4-receptor targeting agent with an antifibrotic agent in a single nanocarrier can be a promising strategy for treating PF. Here, for the first time, AMD3100 (AMD), a CXCR4-receptor antagonist, was coformulated with sulfotanshinone IIA sodium (STS IIA) into a liposome (STS-AMD-Lips) to develop a CXCR4 receptor targeting form of combination therapy for PF. CXCR4 targeting increased the ability of liposomes to target fibrotic peritoneal mesothelial cells overexpressing CXCR4 and facilitated the ability of STS IIA treatment at the fibrotic site. The liposome had an average diameter of 103 nm with encapsulated efficiencies of above 50%. The in vivo studies confirmed the reversal of PD solution-induced epithelial-to-mesenchymal transition by STS-AMD-Lips in HPMCs. The in vivo studies also revealed the precise biodistribution of the liposomes to peritoneum. Significant reduction of the morphological lesions and decreased level of ECM proteins were observed in rats treated with STS-AMD-Lips, proving that the liposomal nanocarrier has excellent ability to reverse PF. It has been concluded that the STS-AMD-Lips exhibit specific peritoneal targeting ability and could be used to improve STS-AMD combination delivery for the treatment of PF.
Glioblastoma multiforme is a serious and life-threatening tumor of central nervous system, characterized by aggressive behavior, poor prognosis, and low survival rate. Despite of the availability of aggressive antitumor therapeutic regimen for glioblastoma (radiotherapy followed by chemotherapeutic dose), recovery rate, and patients' survival ratio is attributed to the lack of selectivity of therapeutic drugs and less advancement in cancer therapeutics over last decade. Moreover, tools employed in conventional diagnosis of glioblastoma are more invasive and painful, making the process excruciating for the patients. These challenges urge for the need of novel biomarkers for diagnosis, prognosis, and prediction purpose with less invasiveness and more patient compliance. This article will explore the genetic biomarkers isocitrate dehydrogenase mutation, MGMT mutations, and EGFR that can be deployed as an analytical tool in diagnosis of disease and prognosis of a therapeutic course. The review also highlights the importance of employing novel microRNAs as prognostic biomarkers. Recent clinical advancements to treat GBM and to prevent relapse of the disease are also discussed in this article in the hope of finding a robust and effective method to treat GBM.
Discovery of novel pharmacological effects of berberine hydrochloride (BH) has made its clinical application valuable. However, further development and applications of BH are hampered by its short half-life and the side effects associated with its intravenous (iv) injection. To improve the hypolipidemia efficacy and reduce side effects, we encapsulated BH into biocompatible red blood cells (RBCs) to explore its sustained-release effect by hypotonic pre-swelling method. From in vitro evaluation, BH loaded RBCs (BH-RBCs) presented similar morphology and osmotic fragility to native RBCs (NRBCs). After the loading process, the BH-RBCs maintained around 69% of Na+/K+-ATPase activity of NRBCs and phosphatidylserine externalization value of BH-RBCs was about 26.1 ± 2.9%. The survival test showed that the loaded cells could circulate in plasma for over 9 d. For in vivo evaluation, a series of tests including pharmacokinetics study and hypolipidemic effect were carried out to examine the long-acting effect of BH-RBCs. The results showed that the release of BH in the loaded cells could last for about 5 d and the hypolipidemic effect can still be observed on 5 d after injection. BH-loaded autologous erythrocytes seem to be a promising sustained releasing delivery system with long hypolipidemic effect.
Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to overcome the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. The aqueous swellable and crosslinked polymeric network structure of hydrogels is composed of various natural, synthetic and semisynthetic biodegradable polymers. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility. All these dynamic properties of hydrogels have increased the interest in their use as a carrier for peptides and proteins to be released slowly in a sustained manner. Peptide and proteins are remarkable therapeutic agents in today’s world that allow the treatment of severe, chronic and life-threatening diseases, such as diabetes, rheumatoid arthritis, hepatitis. Despite few limitations, hydrogels provide fine tuning of proteins and peptides delivery with enormous impact in clinical medicine. Novels drug delivery systems composed of smart peptides and molecules have the ability to drive self-assembly and form hydrogels at physiological pH. These hydrogels are significantly important for biological and medical fields. The primary objective of this article is to review current issues concerned with the therapeutic peptides and proteins and impact of remarkable properties of hydrogels on these therapeutic agents. Different routes for pharmaceutical peptides and proteins and superiority over other drugs candidates are presented. Recent advances based on various approaches like self-assembly of peptides and small molecules to form novel hydrogels are also discussed. The article will also review the literature concerning the classification of hydrogels on a different basis, polymers used, “release mechanisms” their physical and chemical characteristics and diverse applications.
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