Resolving acne with optimized adapalene microspongeal gel, in vivo and clinical evaluations.

In our pursuit of enhancing acne treatment while minimizing side effects, we developed tailored Adapalene microsponges (MS) optimized using a Box-Behnken design 33. The independent variables, Eudragit RS100 percentage in the polymer mixture, organic phase volume, and drug to polymer percentage, were explored. The optimized formulation exhibited remarkable characteristics, with a 98.3% ± 1.6 production yield, 97.3% ± 1.64 entrapment efficiency, and a particle size of 31.8 ± 1.1 µm. Notably, it achieved a 24 h cumulative drug release of 75.1% ± 1.4. To delve deeper into its efficacy, we evaluated the optimized microspongeal-gel in vitro, in vivo, and clinically. It demonstrated impressive retention in the pilosebaceous unit, a target for acne treatment. Comparative studies between our optimized Adapalene microspongeal gel and marketed Adapalene revealed superior performance. In vivo studies on Propionibacterium acnes-infected mice ears showed a remarkable 97% reduction in ear thickness, accompanied by a significant decrease in inflammatory signs and NF-κB levels, as confirmed by histopathological and histochemical examination. Moreover, in preliminary clinical evaluation, it demonstrated outstanding effectiveness in reducing comedonal lesions while causing fewer irritations. This not only indicates its potential for clinical application but also underscores its ability to enhance patient satisfaction, paving the way for future commercialization.

Antiangiogenic drugs in combination with seaweed fucoidan: A mechanistic in vitro and in vivo study exploring the VEGF receptor and its downstream signaling molecules in hepatic cancer.

Hepatocellular carcinoma (HCC) is one of the most common cancers reported worldwide with poor morbidity and high mortality rates. HCC is a very vascular solid tumour as angiogenesis is not only a key driver for tumour progression but also an exciting therapeutic target. Our research investigated the use of fucoidan, a sulfated polysaccharide readily abundant in edible seaweeds commonly consumed in Asian diet due to their extensive health benefits. Fucoidan was reported to possess a strong anti-cancer activity, but its anti-angiogenic potential is still to be fully unraveled. Our research investigated fucoidan in combination with sorafenib (an anti-VEGFR tyrosine kinase inhibitor) and Avastin® (bevacizumab, an anti-VEGF monoclonal antibody) in HCC both in vitro and in vivo. In vitro on HUH-7 cells, fucoidan had a potent synergistic effect when combined with the anti-angiogenic drugs and significantly reduced HUH-7 cell viability in a dose dependent manner. Using the scratch wound assay to test cancer cell motility, sorafenib, A + F (Avastin and fucoidan) or S + F (sorafenib and fucoidan) treated cells consistently showed an unhealed wound and a significantly smaller %wound closure (50%-70%) versus untreated control (91%-100%) (p < 0.05, one-way ANOVA). Using RT-qPCR; fucoidan, sorafenib, A + F and S + F significantly reduced the expression of the pro-angiogenic PI3K/AKT/mTOR and KRAS/BRAF/MAPK pathways by up to 3 folds (p < 0.05, one-way ANOVA versus untreated control). While ELISA results revealed that in fucoidan, sorafenib, A + F and S + F treated cells, the protein levels of caspases 3, 8, and 9 was significantly increased especially in the S + F group showing 40- and 16-times higher caspase 3 and 8 protein levels, respectively (p < 0.05, one-way-ANOVA versus untreated control). Finally, in a DEN-HCC rat model, H&E staining revealed larger sections of apoptosis and necrosis in the tumour nodules of rats treated with the combination therapies and immunohistochemical analysis of the apoptotic marker caspase 3, the proliferation marker Ki67 and the marker for angiogenesis CD34 showed significant improvements when the combination therapies were used. Despite the promising findings reported herein that highlighted a promising chemomodulatory effect of fucoidan when combined with sorafenib and Avastin, further investigations are required to elucidate potential beneficial or adversary interactions between the tested agents.

Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes.

Experimental and clinical evidence implicate disrupted gut barrier integrity in provoking innate immune responses, specifically macrophages, towards the progression of non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors (PPARs), a subset of the nuclear receptor superfamily, act to fine-tune several metabolic and inflammatory processes implicated in NASH. As such, the current study was carried out to decipher the potential role of dual PPAR α/δ activation using elafibranor (ELA) on ileal macrophage polarization (MP) and its likely impact on the liver in a NASH setting. To achieve this aim, an in vitro NASH model using fat-laden HepG2 cells was first used to validate the impact of ELA on hepatic fat accumulation. Afterwards, ELA was used in a combined model of dietary NASH and chronic colitis analogous to the clinical presentation of NASH parallel with intestinal barrier dysfunction. ELA mitigated fat accumulation in vitro as evidenced by Oil Red-O staining and curbed triglyceride levels. Additionally, ELA restored the expression of tight junctional proteins, claudin-1 and occludin, along with decreasing intestinal permeability and inflammation skewing ileal macrophages towards the M2 phenotype, as indicated by boosted arginase-1 (Arg1) and curtailed inducible nitric oxide synthase (iNOS) expression levels. These changes were aligned with a modulation in hepatic toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) along with ileal interleukin-10 (IL-10)/signal transducer and activator of transcription-3 (STAT3) axes. Overall, the present findings suggest that the dual PPAR α/δ agonist, ELA, may drive MP in the ileum towards the M2 phenotype improving intestinal integrity towards alleviating NASH.

Smart biomaterials for enhancing cancer therapy by overcoming tumor hypoxia: a review.

Hypoxia is a distinctive feature of most solid tumors due to insufficient oxygen supply of the abnormal vasculature, which cannot work with the demands of the fast proliferation of cancer cells. One of the main obstacles to limiting the efficacy of cancer medicines is tumor hypoxia. Thus, oxygen is a vital parameter for controlling the efficacy of different types of cancer therapy, such as chemotherapy (CT), photodynamic therapy (PDT), photothermal therapy (PTT), immunotherapy (IT), and radiotherapy (RT). Numerous technologies have attracted much attention for enhancing oxygen distribution in humans and improving the efficacy of cancer treatment. Such technologies include treatment with hyperbaric oxygen therapy (HBO), delivering oxygen by polysaccharides (e.g., cellulose, gelatin, alginate, and silk) and other biocompatible synthetic polymers (e.g., PMMA, PLA, PVA, PVP and PCL), decreasing oxygen consumption, producing oxygen in situ in tumors, and using polymeric systems as oxygen carriers. Herein, this review provides an overview of the relationship between hypoxia in tumor cells and its role in the limitation of different cancer therapies alongside the numerous strategies for oxygen delivery using polysaccharides and other biomaterials as carriers and for oxygen generation.

Screening of Adapalene Microsponges Fabrication Parameters with Insight on the In vitro Biological Effectiveness.

Purpose: The objective of the present study was to scrutinize the microsponges (MS) as a carrier system using Adapalene (ADA) as a model drug. Methods: Data modelling was implemented using Plackett-Burman design to identify the main variables affecting the formulation of ADA-MS. The adopted method of preparation for MS was quasi-emulsion solvent diffusion method. The nominated independent variables were volume of organic phase, sonication time, stirring speed, drug percent, polymer type, emulsifier concentration, and method of organic phase addition. As for the dependent variables, they included entrapment efficiency (E.E.%), production yield (P.Y.%), particle size (P.S.) and morphology. Furthermore, selected ADA loaded microsponges (ADA-MS) were in vitro assayed for their biological activities via cytotoxicity, UVA irradiation and cell viability, and antimicrobial activity. Results: The study indicated that the drug percent, polymer type and surfactant concentration have the key significant effect on E.E.% and P.Y.%, while, the drug percent, stirring speed and volume of organic phase have had a significant effect on P.S. and their morphology. Furthermore, ADA-MS had a momentous cytotoxic effect on A431 and M10 cell-lines with exceptional enrichment when the polymer Eudragit RS100 was used. Also, the ADA-MS increased the cell viability after UVA irradiation on HFB-4 cell-line by 14% to 43%, especially when using Ethyl Cellulose as a polymer. Lastly, the antimicrobial activity of ADA against Propionibacterium acnes was boosted when incorporated into MS. Conclusion: The Plackett-Burman design proved its impact in discerning preparation variables affecting the quality of ADA-MS formulation, with heightening of the in vitro biological activities of ADA. Thus, MS was presumed to be an auspicious carrier system for ADA.

Enhanced antitumor activity of combined methotrexate and histone deacetylase inhibitor valproic acid on mammary cancer in vitro and in vivo.

Histone deacetylase inhibitors (HDACIs) act as antiproliferative agents by promoting differentiation and inducing apoptosis. Valproic acid (VPA) is a HDACI that shows promising chemotherapeutic effect in a number of tumor cells. The present study aimed to investigate the inhibitory effect of VPA on the viability of mammary cancer cells and its enhancing effect with methotrexate (MTX) in vitro and in vivo. Treatment with VPA or MTX alone induced concentration-dependent cytotoxic effects in two breast cancer cell lines. Valproic acid increased significantly the cytotoxicity of MTX three times against MCF7. Valproic acid addition to MTX, however, did not produce any significant changes on MTX cytotoxicity against MDA-MB231. VPA (150 and 200 mg/kg) significantly inhibited the growth of Ehrlich ascites carcinoma (EAC) and solid Ehrlich carcinoma (SEC) tumor mouse models and improved results were achieved for tumor inhibition when VPA was combined with MTX (1 and 2 mg/kg) in vivo. The antitumor activity was not associated with a significant increase in toxicity or mice mortality rate. All these findings suggest that the combination of MTX and VPA may have clinical and (or) adjuvant therapeutic application in the treatment of mammary cancer.

Safety and Effectiveness of COVID-19 Vaccines: Results from a Cross-Sectional Survey among Staff, Workers and Students at an Egyptian University.

Mass vaccination is the most effective strategy against the spread of the COVID-19 pandemic. However, concerns about the vaccine's safety and effectiveness remain a huge obstacle to vaccine acceptance. The aim of the present study was to explore different COVID-19 vaccine outcomes, including the development of adverse events and/or COVID-19 infection following COVID-19 vaccination. A cross-sectional study was conducted by distributing an online survey targeting staff and students at the British university in Egypt. A total of 637 participants fully completed the survey. Of these, 609 (95.6%) participants received the COVID-19 vaccine. Only 12.6% of the total vaccinated participants reported COVID-19 infection after vaccination. Of these, only 2.8% reported having severe symptoms while 9.9% reported having no or mild symptoms. The most common side effects reported after the first vs. second dose were headache (36.3% vs. 14.6%), tiredness and fatigue (26.9% vs. 10.7), and fever (25.6% vs. 6.7%). In conclusion, the present study explored different COVID-19 vaccine outcomes where the overall incidence of side effects is higher after the first dose than after the second dose. There is a relationship between COVID-19 vaccines' side effects and gastrointestinal disorders, gender, and the type of COVID-19 vaccine. Post-vaccination symptoms were more frequently reported in women compared to men and more frequent with viral vector vaccines compared to other types. The effectiveness of different types of COVID-19 vaccines was confirmed by the lower incidence rate of post-vaccination COVID-19 infection.

Obeticholic acid orchestrates the crosstalk between ileal autophagy and tight junctions in non-alcoholic steatohepatitis: Role of TLR4/TGF-ß1 axis.

An interplay exists between non-alcoholic steatohepatitis (NASH) and intestinal barrier dysfunction. A plethora of mechanisms are implicated in the regulation of intestinal integrity, among which is autophagy. Farnesoid X receptor (FXR) is a key metabolic regulator in the liver, however, its impact on ileal autophagy and barrier integrity in the context of NASH has not yet been unraveled. Accordingly, the present study aimed at investigating the impact of the FXR agonist, obeticholic acid (OCA), on modulating the aberrant ileal autophagy and barrier dysfunction in NASH, exploring the possible implication of the TLR4/TGF-ß1 axis. High-fat diet (HFD) and dextran sulfate sodium (DSS, MW ∼40 kDa) were used for 13 weeks to induce NASH with distorted intestinal integrity in Swiss albino male mice. Post-treatment with OCA (5 mg/kg/day; p.o; 4 weeks), histopathological evaluation revealed a restoration of normal hepatic and ileal architectures. OCA partially restored intestinal permeability, as evidenced by the FITC-dextran leakage assay, with no change in serum LPS or LBP levels. Meanwhile, ileal expression of the tight junctions; claudin-1, zonulin-1, and occludin, was upregulated. Hepatic and ileal TLR-4 and TGF-ß1 immunoreactivities were also decreased with no change observed in ileal phosphorylated Akt. In addition, ATG5 gene expression and LC3II/I protein ratio were upregulated in the ileum. Overall, the present study suggests a protective role of OCA on intestinal integrity in NASH, possibly through autophagy induction via interfering with the TLR4/TGF-ß1 pathway.

Diversifying the skin cancer-fighting worthwhile frontiers: How relevant are the itraconazole/ascorbyl palmitate nanovectors?

Fighting malignant neoplasms via repurposing existing drugs could be a welcome move for prosperous cancer remediations. In the current work, nanovehiculation and optimization of the repositioned itraconazole (ITZ) utilizing ascorbyl palmitate (AP) aspasomes would be an auspicious approach. Further, the optimized aspasomes were incorporated in a cream and tracked for skin deposition. The in vivo efficacy of aspasomal cream on mice subcutaneous Ehrlich carcinoma model was also assessed. The optimized aspasomes revealed nano size (67.83 ± 6.16 nm), negative charge (-79.40 ± 2.23 mV), > 95% ITZ entrapment and high colloidal stability. AP yielded substantial antioxidant capacity and pushed the ITZ cytotoxicity forward against A431 cells (IC50 = 5.3±0.27 µg/mL). An appealing privilege was the aspasomal cream that corroborated spreadability, contemplated skin permeation and potentiated in vivo anticancer competence, reflected in 62.68% reduction in the tumor weight. Such synergistic tumor probes set the foundation for futuristic clinical translation and commercialization.

Mercaptopurine-Loaded Sandwiched Tri-Layered Composed of Electrospun Polycaprolactone/Poly(Methyl Methacrylate) Nanofibrous Scaffolds as Anticancer Carrier with Antimicrobial and Antibiotic Features: Sandwich Configuration Nanofibers, Release Study and in vitro Bioevaluation Tests.

BACKGROUND: 6-Mercaptopurine (6-MP) is a potential anti-cancer agent which its therapeutic and limitation applicability due to its high toxicity. OBJECTIVE: Herein, 6-MP was loaded into tri-layered sandwich nanofibrous scaffold (the top layer composed of poly methyl methacrylate/polycaprolactone (PMMA/PCL), the middle layer was PCL/PMMA/6-MP, and the bottom layer was PCL/PMMA to improve its bioactivity, adjusting the release-sustainability and reduce its toxicity. METHODS: Electrospun tri-layered nanofibers composed of PCL/PMMA were utilized as nano-mats for controlling sustained drug release. Four groups of sandwich scaffold configurations were investigated with alteration of (PMMA: PCL) composition. RESULTS: The sandwich scaffold composed of 2%PCL/4%PMMA/1%6-MP showed the best miscibility, good homogeneity and produced the smoothest nanofibers and low crystallinity. All fabricated 6-MP-loaded-PCL/PMMA scaffolds exhibited antimicrobial properties on the bacterial and fungal organisms, where the cytotoxicity evaluation proved the safety of scaffolds on normal cells, even at high concentration. Scaffolds provided a sustained-drug release profile that was strongly dependent on (PCL: PMMA). As (PCL: PMMA) decreased, the sustained 6-MP release from PCL/PMMA scaffolds increased. Results established that ~18% and 20% of 6-MP were released after 23h from (4%PCL/4%PMMA/1%6-MP) and (2%PCL/4%PMMA/1%6-MP), respectively, where this release was maintained for more than 20 days. The anti-cancer activity of all fabricated scaffolds was also investigated using different cancerous cell lines (e.g., Caco-2, MDA, and HepG-2) results showed that 6-MP-loaded-nanofibrous mats have an anti-cancer effect, with a high selective index for breast cancer. We observed that viability of a cancer cell was dropped to about 10%, using nanofibers containing 2%PCL/4%PMMA/1%6-MP. CONCLUSION: Overall, the PCL: PMMA ratio and sandwich configuration imparts a tight control on long-term release profile and initial burst of 6-MP for anticancer treatment purposes.

Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model.

Despite the recent substantial progress in the treatment of hepatocellular carcinoma (HCC) from viral etiology, non-alcoholic steatohepatitis (NASH) is on a trajectory to become the fastest growing indication for HCC-related liver transplantation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily with multifaceted roles in several metabolic disorders, particularly NASH. Its role as a tumor suppressor was also highlighted. Herein, we investigated the effect of obeticholic acid (OCA), as an FXR agonist, on NASH-associated HCC (NASH-HCC) animal model induced by diethylnitrosamine and high fat choline-deficient diet, exploring the potential impact on the suppressor of cytokine signaling 3 (SOCS3)/Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway. Results indicated that OCA treatment upregulated FXR and its key mediator, small heterodimer partner (SHP), with remarkable amelioration in the dysplastic foci observed in the NASH-HCC group. This was paralleled with noticeable downregulation of alpha fetoprotein along with reduction in interferon gamma and transforming growth factor beta-1 hepatic levels besides caspase-3 and p53 upregulation. Moreover, sirtuin-1 (SIRT-1), a key regulator of FXR that controls the regenerative response of the liver, was elevated following OCA treatment. Modulation in the SOCS3/Jak2/STAT3 signaling axis was also reported. In conclusion, OCA attenuated the development and progression of NASH-dependent HCC possibly by interfering with SOCS3/Jak2/STAT3 pathway suggesting the potential use of FXR activators in NASH-related disorders, even at later stages of the disease, to impede its progression to the more deteriorating condition of HCC.

Management of recurrent aphthous ulcers exploiting polymer-based Muco-adhesive sponges: in-vitro and in-vivo evaluation.

Recurrent aphthous ulcer (RAU) is a well-known painful, inflammatory disease with uncertain etiology for which local symptomatic therapy is only available. The aim of this study was to formulate and characterize muco-adhesive sponges containing a mixture of tenoxicam and miconazole nitrate to manage pain, inflammation and avoid candida infection that may accompany RAU due to poor oral hygiene. Two polymers at different concentrations were used to prepare sponges applying simple freeze-drying. Medicated chitosan (2%) sponges (mC2) showed acceptable physical appearance, surface pH (6.3 ± 0.042), porosity (25.7% ± 1.8), swelling index (5.7 ± 0.11), in-vivo and ex-vivo muco-adhesion time (115 min.±0.813 and 155 min.±1.537, respectively), ex-vivo muco-adhesion force (0.09 N ± 0.002) and scanning electron microscope (SEM) images. For concurrent clear-cut determination of tenoxicam and miconazole nitrate from mC2, a new UPLC method was developed and validated. mC2 sponges exhibited superior in-vitro drug release profiles where ∼100% of tenoxicam released within 5 min for fast pain relief with a more prolonged miconazole nitrate release. Furthermore, in-vivo animal study revealed that mC2 caused a significant decrease in the acetic acid-induced ulcer size in rats after 6 days of treatment (p < .0001) compared to negative and positive controls. Additionally, histopathological examination showed faster healing with complete restoration of the normal oral histology in rats. The present study concludes that chitosan sponge loaded with a combination of tenoxicam and miconazole nitrate could improve healing of RAU cases.

Cross-Sectional Study on Awareness and Knowledge of COVID-19 Among Senior pharmacy Students.

Extraordinary actions have been implemented in an effort to control the rapid spread of the ongoing COVID-19 epidemic in Egypt. People's adherence to control measures is influenced by their knowledge, attitudes and practices towards the disease. Therefore, in the present study we assessed pharmacy senior students' knowledge, attitudes and practices towards the COVID-19 pandemic. An online questionnaire was created and it consisted of 12 questions testing their knowledge about COVID-19 clinical characteristics, transmission routes and prevention and control steps. Among senior pharmacy students (n = 238), 70% were females and 63% were living in greater Cairo. Their main source of information included social media (70%), published articles (48%) and television (48%). The overall correct knowledge score was 83%. Most of the students displayed a good COVID-19 knowledge level (72.5% of the students). The students were least informed when trying to answer questions about hyper-coagulation, as a major cause for death in patients with severe COVID-19, and about the timings on the necessity to wear masks. Assessment of students' attitudes and practices towards COVID-19 reflected that 87% of them were confident that health care teams and scientists could win the fight against the virus. In addition, 72% of students agreed that COVID-19 will be controlled successfully. The greater the students' knowledge, the more confident they felt that COVID-19 will be controlled successfully (OR 2.2, 95% confidence interval [CI] 1.03-4.72). Good behavioral practice towards COVID-19 control was confirmed when 87% of students answered that they didn't go out to any crowded place. Females were 3.6 times (95% confidence interval [CI] 1.03-3.11) more likely to avoid going out than males. Bad behavioral practice became evident when approximately 50% of students admitted that they did not wear masks when they left their house. Therefore, more efforts should be taken to protect future pharmacists from this pandemic.

Novel oxygen-generation from electrospun nanofibrous scaffolds with anticancer properties: synthesis of PMMA-conjugate PVP-H2O2 nanofibers, characterization, and in vitro bio-evaluation tests.

Released oxygen plays a critical role in reducing destructive tumor behavior. This study aims to utilize decomposed hydrogen peroxide as an oxygen source by conjugating it with polyvinylpyrrolidone (PVP). PVP-hydrogen peroxide complex (PHP) composed of different ratios of (PVP : H2O2) (0.5 : 1, 1 : 1, 1 : 1.5, 1 : 5, and 1 : 10) were successfully synthesized. PHP complex with a ratio of 1 : 1.5 was chosen as the optimized ratio, and it was incorporated into the polymethyl methacrylate (PMMA) nanofibrous scaffold via the electrospinning technique. Results have revealed that the PMMA-10% PHP complex provided a significant morphological structure of nanofibrous scaffolds. The mechanical properties of PMMA-10% PHP nanofibers showed the most suitable mechanical features such as Young's modulus, elongation-at-break (%), and maximum strength, in addition to the highest degree of swelling. All PHP complex scaffolds released oxygen in a sustained manner. However, the PMMA-10% PHP complex gave the highest concentration of released-oxygen with (∼8.9 mg L-1, after 2.5 h). PMMA-10% PHP nanofibers provided an ideal model for released-oxygen scaffold with anti-cancer effect and high selectivity for cancer cells, especially for breast cancer cells. Nanofibrous scaffolds with different composition revealed high cell viability for normal cells. Such outcomes support the suitability of using synthesized nanofibrous scaffolds as released-oxygen biomaterials to enhance cancer cells' sensitivity and maximize the treatment effect.

Crosstalk between aldehyde dehydrogenase-1 and chemoresistance in breast cancer: Insights into the role of vitamin D3.

AIMS: Aldehyde dehydrogenase-1 (ALDH-1) is considered a signature of breast cancer stem cells and is linked to poor outcomes in breast cancer patients. This study aimed at investigating the effect of vitamin D3 on enhancing the tumor responsiveness to different conventional chemotherapeutic agents, viz., cisplatin, methotrexate, and doxorubicin. MAIN METHODS: In vitro and in vivo experiments were performed using combinations of vitamin D3 and chemotherapeutic agents. Cell cycle analysis and apoptosis assays were performed. Moreover, ALDH-1 expression levels were estimated in cancer cell lines and solid tumors. For solid tumors, tumor volume and histopathological necrotic indices were estimated. Leukocyte presence was also evaluated in tumors using leukocyte common antigen (LCA). KEY FINDINGS: Results showed a synergistic interaction between vitamin D3 and each of the chemotherapeutic agents on breast cancer cell lines as well as cell cycle arrest at G2/M phase. A decrease in ALDH-1 levels was reported in both breast cancer cells and in tumor tissues. Reductions in tumor volume were also observed in the groups which received the combination therapy. An influence on necrosis rather than apoptosis was also reported, as evidenced by necrotic indices and Bcl-2 expression in tumor sections, respectively. Increased local leukocytes in tumors was also evident, as indicated by increased expression of leukocyte common antigen (LCA). SIGNIFICANCE: Overall, the present study shows that vitamin D3 has an impact on resistance to different chemotherapeutic agents which could be due to the inhibition of ALDH-1, suggesting its use as an adjuvant therapy in cancer patients receiving chemotherapy.

Inhibition of aldehyde dehydrogenase-1 and p-glycoprotein-mediated multidrug resistance by curcumin and vitamin D3 increases sensitivity to paclitaxel in breast cancer.

Treatment of breast cancer by paclitaxel (PAX) often encounters therapeutic failure most likely caused by innate/acquired resistance. Cancer stem cells (CSCs) and multidrug resistance complex (MDR-1 or P-glycoprotein) overexpression are main mechanisms implicated in chemoresistance. Increased aldehyde dehrogenase-1 (ALDH-1) was previously correlated with the stemness features of CSCs and hence is used as a marker for identification and CSCs targeting. The present study, therefore, aimed at investigating the effect of both curcumin (CUR) and vitamin D3 (D3) on MDR-1 and ALDH-1 expression and consequently the resistance to PAX both in vitro and in vivo. CUR was isolated from Turmeric rhizomes and identified using UPLC-ESI-MS/MS. For in vitro studies, the antiproliferative effect of PAX, CUR, 1,25(OH)2D3 (the active form of D3, also known as calcitriol) was determined, each alone and combined (PAX+CUR, PAX+1,25(OH)2D3, and PAX+CUR+1,25(OH)2D3) on MCF-7 breast cancer cells. Ehrlich ascites carcinoma solid tumor animal model was also used for in vivo studies. Combining CUR and/or 1,25(OH)2D3 to PAX showed synergistic cytotoxic interaction on MCF-7 cells. The apoptotic potential was also enhanced, as evidenced by a significant increase in caspase-7 and -9 as well as the pro-apoptotic Bax whereas a decrease in Bcl-2 levels was reported. Combining CUR and 1,25(OH)2D3 to PAX caused a downregulation in both MDR-1 and ALDH-1 gene expression in MCF-7 besides a decrease in their protein levels. In vivo, the triple therapy group (PAX+CUR+D3) showed the least tumor size. It also showed the lowest levels of MDR-1 and ALDH-1. PAX alone, however, showed increased levels of MDR-1 and ALDH-1 compared to control. Overall, the present study showed that PAX, as a monotherapy, demonstrated acquired resistance possibly by increasing MDR-1 expression and enriching CSCs population, as evidenced by increased ALDH-1. However, using CUR and D3 enhanced tumor response to PAX.

Author Correction: Verbascoside: Identification, Quantification, and Potential Sensitization of Colorectal Cancer Cells to 5-FU by Targeting PI3K/AKT Pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Structure-based drug design, synthesis, In vitro, and In vivo biological evaluation of indole-based biomimetic analogs targeting estrogen receptor-α inhibition.

Offering novel scaffolds targeting estrogen receptor creates huge necessity to overcome the evolving resistance developed by tumors. Structure-based drug design coupled with ring opening strategy of the steroids skeleton revealed the potential of indole-based analogs to be synthesized targeting the ligand binding domain of estrogen receptor-α. In vitro studies revealed the potential of the total sub-classes of the synthesized analogs to show anti-proliferative activity against estrogen receptor-dependent cancer cell lines at IC50 ranging from 28.23 to 57.13 µM. This was further validated by evaluating the potential of the synthesized analogs to compete along with estradiol via ER-α ELISA assay to show inhibitory profile at IC50 ranging from 1.76 to 204.75 nM. Two analogs (YMA-005 and YMA-006) showed significant reduction in tumor size at two dose levels with extensive degeneration and necrosis. Both YMA-005 and YMA-006 showed in-situ reduction of ER-α Immunohistochemical expression at both dose levels. Ultimately, novel analogs of indole-based biomimetic of estrone scaffolds were offered as estrogen receptor-α inhibitors.

Verbascoside: Identification, Quantification, and Potential Sensitization of Colorectal Cancer Cells to 5-FU by Targeting PI3K/AKT Pathway.

Colorectal cancer (CRC) is the third most common cancer mortality worldwide. Although, 5-Fluorouracil (5-FU)-based chemotherapeutic regimens remain the mainstay for treatment of CRC, intrinsic and acquired resistance to 5-FU is the main reason for treatment failure and relapse. Adjunct or add-on therapy, therefore, should be thought of to enhance responsiveness to 5-FU. Verbascoside (VER) is a phenylethanoid glycoside ingredient present in many Plantago species and was widely used in traditional medicine. VER showed antiproliferative effects in many cancer types including CRC. In the present study, VER in Plantago seeds was identified using UPLC-MS/MS and quantified using newly developed and validated UPLC-DAD followed by investigating its potential sensitization of CRC cells to 5-FU in vitro. The potential impact on PI3K/AKT pathway was also investigated. A synergistic cytotoxic interaction between 5-FU and VER besides G1 cell cycle arrest were detected. Enhanced apoptosis mainly by affecting Bax and Bcl-2 and to a lesser extent Bcl-xL and p53 was also observed. Additionally, 5-FU combined to VER was capable of significantly reducing PI3K and p-AKT/total AKT ratio. Overall, these results suggest a potential role of VER as an adjuvant treatment to decrease the resistance of CRC cells to 5-FU possibly by targeting the PI3K/AKT pathway.

Repositioning of Omarigliptin as a once-weekly intranasal Anti-parkinsonian Agent.

Drug repositioning is a revolution breakthrough of drug discovery that presents outstanding privilege with already safer agents by scanning the existing candidates as therapeutic switching or repurposing for marketed drugs. Sitagliptin, vildagliptin, saxagliptin & linagliptin showed antioxidant and neurorestorative effects in previous studies linked to DPP-4 inhibition. Literature showed that gliptins did not cross the blood brain barrier (BBB) while omarigliptin was the first gliptin that crossed it successfully in the present work. LC-MS/MS determination of once-weekly anti-diabetic DPP-4 inhibitors; omarigliptin & trelagliptin in plasma and brain tissue was employed after 2 h of oral administration to rats. The brain/plasma concentration ratio was used to deduce the penetration power through the BBB. Results showed that only omarigliptin crossed the BBB due to its low molecular weight & lipophilic properties suggesting its repositioning as antiparkinsonian agent. The results of BBB crossing will be of interest for researchers interested in Parkinson's disease. A novel intranasal formulation was developed using sodium lauryl sulphate surfactant to solubilize the lipophilic omarigliptin with penetration enhancing & antimicrobial properties. Intranasal administration showed enhanced brain/plasma ratio by 3.3 folds compared to the oral group accompanied with 2.6 folds increase in brain glucagon-like peptide-1 concentration compared to the control group.