Beyond Skin Deep: Phospholipid-Based Nanovesicles as Game-Changers in Transdermal Drug Delivery.

Transdermal administration techniques have gained popularity due to their advantages over oral and parenteral methods. Noninvasive, self-administered delivery devices improve patient compliance and control drug release. Transdermal delivery devices struggle with the skin's barrier function. Molecules over 500 Dalton (Da) and ionized compounds don't permeate through the skin. Drug encapsulation in phospholipid-based vesicular systems is the most effective skin delivery technique. Vesicular carriers include bi-layered liposomes, ultra-deformable liposomes, ethanolic liposomes, transethosomes, and invasomes. These technologies enhance skin drug permeation by increasing formula solubilization, partitioning into the skin, and fluidizing the lipid barrier. Phospholipid-based delivery systems are safe and efficient, making them a promising pharmaceutical and cosmeceutical drug delivery technique. Still, making delivery systems requires knowledge about the physicochemical properties of the drug and carrier, manufacturing and process variables, skin delivery mechanisms, technological advances, constraints, and regulatory requirements. Consequently, this review covers recent research achievements addressing the mentioned concerns.

Effect of chitosan and curcumin nanoparticles against skeletal muscle fibrosis at early regenerative stage of glycerol-injured rat muscles.

INTRODUCTION: Chitosan and curcumin are natural products that have a wide range of beneficial effects including wound healing. However, their high molecular weight and poor water solubility limit their applications. AIMS: Therefore, the current study aims to evaluate the effects of chitosan (Cs) and curcumin (Cn) nanoparticles (NPs) on fibrosis and regeneration of glycerol-injured muscle. METHODS: Muscle injury was induced by intramuscular injection of glycerol into the tibialis anterior muscle of rats. Cs-NPs and Cn-NPs were administered at different doses intraperitoneally after injury. Injured muscles were collected at day 7 after injury, and muscle fibrosis and regeneration were assessed. RESULTS: The present results revealed that Cs-NPs and Cn-NPs treatment significantly decreased fibrosis index and increased the average myotube diameter with shifting of the distribution of myotube diameters towards larger diameters in a dose-dependent manner. Immunohistochemical analysis revealed that Cs-NPs and Cn-NPs treatment significantly decreased the number of CD-68+ cells and Col-1+ area. Results showed that Cn-NPs had a higher protective effect, in the form of attenuating muscle fibrosis and inflammation, and enhancing muscle regeneration, than that of Cs-NPs. CONCLUSIONS: To our knowledge, this is the first study to document the effects of Cs-NPs in injured muscles. The results of study might be a novel approach to attenuate muscle fibrosis in humans using curcumin and chitosan nanoparticles.

Mucoadhesive thermoreversible formulation of metoclopramide for rectal administration: a promising strategy for potential management of chemotherapy-induced nausea and vomiting.

The study aimed to investigate the feasibility of incorporation of metoclopramide hydrochloride (MCP HCl) in mucoadhesive thermoreversible liquid suppository (MCP HCl-LS) to bypass the first-pass metabolism and maximize its efficacy to be a promising substitute for parenteral therapy. MCP HCl-LS was formulated using Pluronic (PF127/PF68) and hydroxypropylmethylcellulose (HPMC) and in vitro evaluated through their gelation temperature, gel strength (GS), mucoadhesive force, and in vitro release studies. Also, the MCP HCl-LS was evaluated for its rheological behavior and examined for rectal mucosal integrity after administration. The results revealed that the MCP HCl-LS; composed of PF127/PF68/HPMC (20/7/0.5% w/w) was in the liquid state at room temperature, experienced gelation at 30.23 °C, with suitable GS of 28.66 s and rectal retention force of 43.03 × 102 dyne/cm2. The pharmacokinetic data showed that the MCP HCl-LS exhibited a significant increase (p < 0.05) in AUC0-480 (219.688 vs 172.333 ng.h.mL-1 of the marketed) and 1.3-fold increase in relative bioavailability compared to Primperan® suppository, indicating that LS formula bypassed the first-pass metabolism. Moreover, MCP HCl-LS did not cause any morphological harm to the rectal tissues suggested that the developed formulation was safe and could be a potentially useful alternative drug carrier for rectal delivery of MCP HCl in patients experiencing chemotherapy-induced nausea and vomiting.

Tolmetin sodium-loaded thermosensitive mucoadhesive liquid suppositories for rectal delivery; strategy to overcome oral delivery drawbacks.

Tolmetin sodium (TS) is a nonsteroidal anti-inflammatory drug (NSAID) indicated for treatment of musculoskeletal issues. As other NSAID, TS displays a marked side effects on the gastro-intestinal (GI) tract after oral administration. Traditional solid suppositories can cause pain and discomfort for patients, may reach the end of the colon; consequently, the drug can undergo the first-pass effect. TS liquid suppository (TS-LS) was developed to enhance patient compliance and rectal mucosal safety in high-risk patients receiving highly NSAID therapy. This work was conducted to optimize and evaluate Poloxamer P407/P188-based thermoresponsive TS-LS by using mucoadhesive polymers such as methylcellulose (MC). TS-LS was prepared by cold method and characterized their in vitro physicochemical properties as gelation temperature (GT), gel strength, bioadhesive properties, and in vitro release. The safety of the prepared suppository on rectum, stomach, and liver was evaluated histologically. Pharmacokinetic analyses were performed to compare rectal TS-LS to orally Rhumtol® capsules. The results showed that the optimized TS-LS; composed of P407/P188/MC (21/9/0.5% w/w) displayed gelation at rectum temperature ∼32.90 °C, gel strength of 21.35 s and rectal retention force at the administration site of 24.25 × 102 dyne/cm2. Moreover, TS-LS did not cause any morphological damage to the rectal tissues. Pharmacokinetic parameters of optimized TS-LS formulation revealed 4.6 fold increase in bioavailability as compared to Rhumtol® capsules. Taken together, the results demonstrated that liquid suppository is a potential and physically safe rectal delivery carrier for improvement rectal bioavailability and in vivo safety of TS.

Unusual behavior of diffuse large B-cell lymphoma as cardiac invasion with rapid spontaneous regression after fine needle aspiration cytology.

OBJECTIVE: Spontaneous regression (SR) of lymphoma is a rare phenomenon. While the precise mechanism of SR remains unknown, apoptosis may be associated with its process. Here, we present a case of a 52-year-old woman was admitted to our hospital with cough and orthopnea for 2 weeks. Multi-detector computed tomography of whole body showed anterior and middle mediastinal soft tissue mass with multiple adjacent malignant lymphadenopathy. The mediastinal mass invaded right atrium and pericardium. Another left subphrenic retro-pancreatic mass was detected. This mass surrounded upper pole of left kidney. Fine needle aspiration cytology was done and revealed lymphocytic smear with advised tru-cut biopsy. CT guided tru-cut was taken after 8 days. During CT guided technique; marked regression of left subphrenic mass was detected. Post-contrast MDCT scan was done and revealed partial response of the masses after 8 days. The partial regressive course of this disease suggests the effectiveness of fine needle aspiration cytology in initiating spontaneous regression. Tru-cut biopsy revealed non-Hodgkin lymphoma (diffuse large B-cell type). We report a case of NHL with abnormal location and spontaneous regression.

Urinary biomarkers for early detection of platinum based drugs induced nephrotoxicity.

BACKGROUND: Nephrotoxicity is a major hazard complicating the use of platinum based drugs (PBD), which can hinder using higher doses protocols to maximize the therapeutic gain. Shortage of serum creatinine level as an accurate biomarker for acute kidney injuries (AKI) necessitates searching for novel biomarkers with better sensitivity and specificity in patients on PBD. METHODS: In a prospective cohort design, 132 patients receiving PBD were selected for the study. AKI was diagnosed by continuous follow up of serum creatinine level according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 2012. Serum creatinine and urinary biomarkers (KIM-1, NGAL and cystatin C) was measured in the day of treatment and for 3 days after PBD cycle. RESULTS: AKI occurred in 35 patients (26.52% of patients). KIM-1, Cystatin C, and NGAL showed significant increase in samples collected in the day of AKI in comparison to their corresponding basal levels (P <  0.0001). In addition, significant increase in urinary levels of the biomarkers in samples collected 1 day before AKI in comparison to their basal levels (P <  0.0001, P <  0.0001, and P = 0.013 for KIM-1, NGAL and Cystatin C respectively). Furthermore KIM-1 data showed a significant increase 2 days before serum creatinine rise in comparison to the corresponding KIM-1 levels in patients who developed AKI (P = 0.001). CONCLUSIONS: Urinary KIM-1, Cystatin C and NGAL can predict PBD induced AKI in earlier stages than serum createnine. KIM-1 is the most sensitive biomarker for early detection of AKI in patients receiving PBD.

Usnic Acid Benzylidene Analogues as Potent Mechanistic Target of Rapamycin Inhibitors for the Control of Breast Malignancies.

(+)-Usnic acid (1) is a common bioactive lichen-derived secondary metabolite with a characteristic dibenzofuran scaffold. It displayed low micromolar antiproliferative activity levels and, notably, induced autophagy in a panel of diverse breast cancer cell lines, suggesting the mechanistic (formerly "mammalian") target of rapamycin (mTOR) as a potential macromolecular target. The cellular autophagic markers were significantly upregulated due to the inhibition of mTOR downstream effectors. Additionally, 1 showed an optimal binding pose at the mTOR kinase pocket aided by multiple interactions to critical amino acids. Rationally designed benzylidene analogues of 1 displayed excellent fitting into a targeted deep hydrophobic pocket at the core of the kinase cleft, through stacking with the phenolic side chain of the Tyr2225 residue. Several potent analogues were generated, including 52, that exhibited potent (nM concentrations) antiproliferative, antimigratory, and anti-invasive activities against cells from multiple breast cancer clonal lines, without affecting the nontumorigenic MCF-10A mammary epithelial cells. Analogue 52 also exhibited potent mTOR inhibition and autophagy induction. Furthermore, 52 showed potent in vivo antitumor activity in two athymic nude mice breast cancer xenograft models. Collectively, usnic acid and analogues are potential lead mTOR inhibitors appropriate for future use to control breast malignancies.

Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met.

Breast cancer is a major health problem affecting the female population worldwide. The triple-negative breast cancers (TNBCs) are characterized by malignant phenotypes, worse patient outcomes, poorest prognosis, and highest mortality rates. The proto-oncogenic receptor tyrosine kinase c-Met is usually dysregulated in TNBCs, contributing to their oncogenesis, tumor progression, and aggressive cellular invasiveness that is strongly linked to tumor metastasis. Therefore, c-Met is proposed as a promising candidate target for the control of TNBCs. Lichens-derived metabolites are characterized by their structural diversity, complexity, and novelty. The chemical space of lichen-derived metabolites has been extensively investigated, albeit their biological space is still not fully explored. The anticancer-guided fractionation of Usnea strigosa (Ach.) lichen extract led to the identification of the depsidone-derived norstictic acid as a novel bioactive hit against breast cancer cell lines. Norstictic acid significantly suppressed the TNBC MDA-MB-231 cell proliferation, migration, and invasion, with minimal toxicity to non-tumorigenic MCF-10A mammary epithelial cells. Molecular modeling, Z'-LYTE biochemical kinase assay and Western blot analysis identified c-Met as a potential macromolecular target. Norstictic acid treatment significantly suppressed MDA-MB-231/GFP tumor growth of a breast cancer xenograft model in athymic nude mice. Lichen-derived natural products are promising resources to discover novel c-Met inhibitors useful to control TNBCs.

Araguspongine C induces autophagic death in breast cancer cells through suppression of c-Met and HER2 receptor tyrosine kinase signaling.

Receptor tyrosine kinases are key regulators of cellular growth and proliferation. Dysregulations of receptor tyrosine kinases in cancer cells may promote tumorigenesis by multiple mechanisms including enhanced cell survival and inhibition of cell death. Araguspongines represent a group of macrocyclic oxaquinolizidine alkaloids isolated from the marine sponge Xestospongia species. This study evaluated the anticancer activity of the known oxaquinolizidine alkaloids araguspongines A, C, K and L, and xestospongin B against breast cancer cells. Araguspongine C inhibited the proliferation of multiple breast cancer cell lines in vitro in a dose-dependent manner. Interestingly, araguspongine C-induced autophagic cell death in HER2-overexpressing BT-474 breast cancer cells was characterized by vacuole formation and upregulation of autophagy markers including LC3A/B, Atg3, Atg7, and Atg16L. Araguspongine C-induced autophagy was associated with suppression of c-Met and HER2 receptor tyrosine kinase activation. Further in-silico docking studies and cell-free Z-LYTE assays indicated the potential of direct interaction between araguspongine C and the receptor tyrosine kinases c-Met and HER2 at their kinase domains. Remarkably, araguspongine C treatment resulted in the suppression of PI3K/Akt/mTOR signaling cascade in breast cancer cells undergoing autophagy. Induction of autophagic death in BT-474 cells was also associated with decreased levels of inositol 1,4,5-trisphosphate receptor upon treatment with effective concentration of araguspongine C. In conclusion, results of this study are the first to reveal the potential of araguspongine C as an inhibitor to receptor tyrosine kinases resulting in the induction of autophagic cell death in breast cancer cells.

Olive Oil-derived Oleocanthal as Potent Inhibitor of Mammalian Target of Rapamycin: Biological Evaluation and Molecular Modeling Studies.

The established anticancer and neuroprotective properties of oleocanthal combined with the reported role of mammalian target of rapamycin (mTOR) in cancer and Alzheimer's disease development encouraged us to examine the possibility that oleocanthal inhibits mTOR. To validate this hypothesis, we docked oleocanthal into the adenosine triphosphate binding pocket of a close mTOR protein homologue, namely, PI3K-γ. Apparently, oleocanthal shared nine out of ten critical binding interactions with a potent dual PIK3-γ/mTOR natural inhibitor. Subsequent experimental validation indicated that oleocanthal indeed inhibited the enzymatic activity of mTOR with an IC50 value of 708 nM. Oleocanthal inhibits the growth of several breast cancer cell lines at low micromolar concentration in a dose-dependent manner. Oleocanthal treatment caused a marked downregulation of phosphorylated mTOR in metastatic breast cancer cell line (MDA-MB-231). These results strongly indicate that mTOR inhibition is at least one of the factors of the reported anticancer and neuroprotective properties of oleocanthal.

Marine natural products-inspired phenylmethylene hydantoins with potent in vitro and in vivo antitumor activities via suppression of Brk and FAK signaling.

Breast and prostate cancers are among the most common cancers worldwide with devastating statistics for the metastatic, chemotherapy- and radiotherapy-resistant phenotypes. Novel therapies interfering with new and/or multiple pathways involved in the pathology of cancer are urgently needed. Preliminary results showed that the marine natural product Z-4-hydroxyphenylmethylene hydantoin (PMH, ) and its 4-ethylthio-analog (SEth, ) promoted tight junction formation and showed anti-invasive and anti-migratory activities in vitro against metastatic prostate cancer cells and inhibited tumor growth and micrometastases in distant organs in orthotopic and transgenic mice models. This study focuses on the design and synthesis of second-generation PMHs with enhanced antitumor activities. A series of substituted benzaldehydes was selected based on earlier SAR studies and reacted with hydantoin to yield 11 new compounds . Compounds were evaluated for their antiproliferative, antimigratory and anti-invasive properties in vitro against the human mammary and prostate cancer cell lines MDA-MB-231 and PC-3, respectively. A Western blot analysis of the most active analog showed its ability to suppress the expression of the total levels of c-Met and FAK, with subsequent reduction of their phosphorylated (activated) levels in MDA-MB-231 cells. In addition, also inhibited Brk, paxillin and Rac1 phosphorylation. was formulated using hydroxypropyl ß-cyclodextrin (HPCD) to improve its solubility and was further evaluated in a nude mice xenograft model using MDA-MB-231/GFP cells. PMH reduced breast tumor growth and suppressed Ki-67, CD31, p-Brk and p-FAK expression in tumor samples. Thus, is a potential lead for the control of invasive breast malignancies.

The marine-derived sipholenol A-4-O-3',4'-dichlorobenzoate inhibits breast cancer growth and motility in vitro and in vivo through the suppression of Brk and FAK signaling.

Sipholenol A is a natural sipholane triterpenoid isolated from the Red Sea sponge, Callyspongia siphonella. Previous studies showed the antimigratory and antiproliferative activities of the semisynthetic sipholenol A esters against breast cancer cell lines. This study investigated the effects of sipholenol A-4-O-3',4'-dichlorobenzoate (SPA) on the growth, migration and invasion of diverse human breast cancer cells. Results showed that SPA inhibited the growth of the human breast cancer cells, MDA-MB-231, MCF-7, BT-474 and T-47D, in a dose-dependent manner. Immunofluorescent analysis showed that SPA significantly reduced Ki-67-positive cells in MDA-MB-231 cells. Flow cytometry and Western blot analyses revealed that SPA treatment suppressed MDA-MB-231 cell growth by inducing cell cycle arrest at the G1 phase. In addition, SPA suppressed breast cancer cell migration, invasion and decreased Brk and FAK activation in a dose-dependent manner. Molecular docking study suggested a perfect fitting at the FAK's FERM domain, inhibiting the main autophosphorylation site, Y397, which was further confirmed by Western blot analysis. Most known small molecule FAK inhibitors target the kinase domain, creating several off-target side effects. The in vivo studies showed that SPA treatment suppressed breast tumor growth and Ki-67, CD31, p-Brk and p-FAK expression in orthotopic breast cancer in nude mice. In conclusion, SPA inhibited the growth, invasion and migration of breast cancer cells possibly via deactivating Brk and FAK signaling, suggesting good potential for therapeutic use to control invasive breast cancer.

A pH-sensitive silica nanoparticles for colon-specific delivery and controlled release of catechin: Optimization of loading efficiency and in vitro release kinetics.

Catechin is a naturally occurring flavonoid of the flavan-3-ol subclass with numerous biological functions; however, these benefits are diminished due to several factors, including low water solubility and degradation in the stomach's harsh environment. So, this study aimed to develop an intelligent catechin colon-targeting delivery system with a high loading capacity. This was done by coating surface-decorated mesoporous silica nanoparticles with a pH-responsive enteric polymer called Eudragit®-S100. The pristine wormlike mesoporous silica nanoparticles (< 100 nm) with high surface area and large total pore volume were effectively synthesized and modified with the NH2 group using the post-grafting strategy. Various parameters, including solvent polarity, catechin-carrier mass ratio, and adsorption time, were studied to improve the loading of catechin into the aminated silica nanoparticles. Next, the negatively charged Eudragit®-S100 was electrostatically coated onto the positively charged aminated nanocarriers to shield the loaded catechin from the acidic environment of the stomach (pH 1.9) and to facilitate site-specific delivery in the acidic environment of the colon (pH 7.4). The prepared nanomaterials were evaluated using several methods, including The Brauner-Emmett-Teller, surface area analyzer, zeta sizer, Field Emission Scanning Electron Microscope, Powder X-Ray Diffraction, Fourier Transform Infrared Spectroscopy, Energy-Dispersive X-ray Spectroscopy, and Differential Scanning Calorimetry. In vitro dissolution studies revealed that Eudragit®-S100-coated aminated nanomaterials prevented the burst release of the loaded catechin in the acidic environment, with approximately 90% of the catechin only being released at colonic pH (pH > 7) with a supercase II transport mechanism. As a result, silica nanoparticles coated with Eudragit®-S100 would provide an innovative and promising approach in targeted nanomedicine for the oral delivery of catechin and related medicines for treating diseases related to the colon, such as colorectal cancer and irritable bowel syndrome.

Formulation, and optimization of transdermal Atorvastatin Calcium-Loaded Ultra-flexible vesicles; ameliorates poloxamer 407-caused dyslipidemia.

Atorvastatin calcium (AC), a cholesterol-lowering medication, has limited oral bioavailability (14 %) and adverse impacts on the gastrointestinal tract (GIT), liver, and muscle. So, in an effort to improve the poor availability and overcome the hepatotoxicity complications attendant to peroral AC administration, transdermal transfersomal gel (AC-TFG) was developed as a convenient alternative delivery technique. The impact of utilizing an edge activator (EA) and varying the phosphatidylcholine (PC): EA molar ratio on the physico-chemical characteristics of the vesicles was optimized through a Quality by Design (QbD) strategy. The optimal transdermal AC-TFG was tested in an ex-vivo permeation study employing full-thickness rat skin, Franz cell experiments, an in-vivo pharmacokinetics and pharmacodynamics (PK/PD) evaluation, and a comparison to oral AC using poloxamer-induced dyslipidemic Wister rats. The optimized AC-loaded TF nanovesicles predicted by the 23-factorial design strategy had a good correlation with the measured vesicle diameter of 71.72 ± 1.159 nm, encapsulation efficiency of 89.13 ± 0.125 %, and cumulative drug release of 88.92 ± 3.78 % over 24 h. Ex-vivo data revealed that AC-TF outperformed a free drug in terms of permeation. The pharmacokinetic parameters of optimized AC-TFG demonstrated 2.5- and 13.3-fold significant improvements in bioavailability in comparison to oral AC suspension (AC-OS) and traditional gel (AC-TG), respectively. The transdermal vesicular technique preserved the antihyperlipidemic activity of AC-OS without increasing hepatic markers. Such enhancement was proven histologically by preventing the hepatocellular harm inflicted by statins. The results showed that the transdermal vesicular system is a safe alternative way to treat dyslipidemia with AC, especially when given over a long period of time.

Formulation and optimization of theophylline-loaded enteric-coated spanlastic nanovesicles for colon delivery; Ameliorate acetic acid-induced ulcerative colitis.

Treatment of colon diseases presents one of the most significant obstacles to drug delivery due to the inability to deliver sufficient drug concentration selectively to the colon. The goal of the proposed study was to develop, optimize, and assess an effective colon target delivery system of theophylline-based nanovesicles (TP-NVs) surrounded by a biodegradable polymeric shell of chitosan (CS) and Eudragit L100 (EL100) for the treatment of ulcerative colitis (UC). TP-loaded nanovesicles were fabricated using the ethanol injection method and coated with CS and EL100, respectively. We used a 32-factorial design approach to optimize the concentration of CS and EL100 to minimize particle size (PS) and maximize the cumulative amount of theophylline released (CTR) after 24 h. The optimized formulation was described using transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and in vitro release. In-vivo quantification of theophylline in the gastrointestinal tract and in-vivo targeting potential in a rat model of acetic acid-induced colitis were also thoroughly evaluated. The characteristics of the optimal formula predicted by the 32-factorial design approach corresponded exceptionally well with the measured PS of 271.3 nm, the zeta potential of -39.9 mV, and CTR of 3.95, and a 99.93% after 5 and 24 h, respectively. Notably, the in vivo results in the rat model of colitis showed that the formulation with an optimized coat significantly improved theophylline distribution to the colon and markedly decreased the expression of interleukin-6 and ulcerative lesions compared to a pure theophylline solution. These outcomes elucidated the feasibility of a 32-factorial design to detect the crucial interactions between the study's components. Our findings suggested that enteric-coated nanovesicles formulations with optimal coat compositions of 0.2693% (w/v) and 0.75% (w/v) of CS and EL100, respectively, were promising carriers for colonic delivery of theophylline, a rate-limiting step in the treatment of UC.

The effect of rectal distension on bladder function in patients with overactive bladder.

AIMS: To investigate the effect of rectal distension on bladder sensation volumes and the number of detrusor contractions in patients with overactive bladder (OAB) symptoms. METHODS: A prospective randomized study included patients with OAB symptoms. Multichannel urodynamic studies were completed with and without rectal balloon distension. Bladder sensation volumes and detrusor contractions were compared. RESULTS: Twenty-six patients were included in the study. The mean age was 67 years and mean BMI was 28.3 kg/m(2) . Bladder sensation volumes were lower with rectal distention as follows: normal desire to void (139 ml SD, ±114 vs. 197 ml SD ±150, P = 0.01), strong desire to void (260 ml SD ±171 vs. 330 ml SD ±172, P = 0.01), and maximum cystometric capacity (326 ml SD ±183 vs. 403 ml SD ±180, P = 0.0001). There was no difference in the number of detrusor contractions or the bladder volume at which the first detrusor contraction had occurred with and without rectal distension. CONCLUSION: Rectal distention in patients with OAB symptoms significantly lowered bladder sensation volumes (normal desire, strong desire, and maximal capacity).

Mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and sesamin treatment.

Epidemiological studies have highlighted the ability of phytochemicals to reduce the risk of breast cancer by attenuating specific intracellular signaling pathways that regulate cell proliferation and survival. γ-Tocotrienol is a natural form of vitamin E that displays potent anticancer activity at doses that have no discernible toxicity toward normal cells. Sesamin is an abundant phytochemical found in sesame seed oil that also shows antiproliferative and antiangiogenic activity against human breast cancer cells. In this study, the combined treatment of subeffective doses of γ-tocotrienol and sesamin caused a synergistic inhibition of murine +SA mammary epithelial cell growth, as determined by the MTT assay and immunofluorescent Ki-67 staining. Western blot studies revealed that combined low-dose treatment of γ-tocotrienol and sesamin caused a marked reduction in EGF-induced ErbB3 and ErbB4 receptors phosphorylation (activation) and a relatively large decrease in intracellular levels of total and/or phosphorylated c-Raf, MEK1/2, ERK1/2, PI3K, PDK1, Akt, p-NFκB, Jak1, Jak2, and Stat1, as compared to cells treated with only one compound or in the vehicle-treated control group. These findings demonstrate that the synergistic growth inhibitory effects of γ-tocotrienol and sesamin treatment are associated with suppression of EGF-dependent mitogenic signaling in mammary tumor cells and suggest that dietary supplementation with these phytochemicals may provide some benefits in the prevention and/or treatment of breast cancer.

Synthesis and Evaluation of High Functionality and Quality Cell-penetrating Peptide Conjugated Lipid for Octaarginine Modified PEGylated Liposomes In U251 and U87 Glioma Cells.

The use of peptide ligand modified PEGylated liposomes has been widely investigated for tumor targeting. Peptides are mainly inserted in the liposomal lipid bilayer using PEG2K-lipid spacer (Peptide-PEG2K-DSPE). However, a lower cellular uptake from longer nonlinear PEG2K spacer was reported, we here synthesized a high functionality and quality (HFQ) lipid with a short, linear serine-glycine repeated peptide [(SG)5] spacer. The objective of the current study is to develop novel octaarginine (R8) peptide-HFQ lipid grafted PEGylated liposomes for glioma cells targeting. In vitro liposomes characterization showed that the mean particle size of all liposomal formulations was in the nano-scale range < 120 nm, with a small PDI value (i.e. ∼0.2) and had a spherical shape under Transmission Electron Microscope, indicating a homogenous particle size distribution. The flow cytometry in vitro cellular association data with U251 MG and U87 cells revealed that 1.5% R8-(SG)5-lipid-PEGylated liposomes exhibited significantly higher cellular association of ∼15.87 and 7.59-fold than the conventional R8-PEG2K-lipid-PEGylated liposomes (10.4 and 6.19-fold), respectively, relative to the unmodified PEGylated liposomes. Moreover, intracellular distribution studies using confocal laser scanning microscopy (CLSM) corroborated the results of the in vitro cell association. The use of ligand-HFQ-lipid liposomes could be a potential alternative to ligand-PEG2K-lipid-modified liposomes as a drug delivery system for tumor targeting.

Human Endogenous Retrovirus-H Long Terminal Repeat- Associating Protein 2 (HHLA2) is a Novel Immune Checkpoint Protein in Lung Cancer which Predicts Survival.

ackground: Lung cancer is one of the most frequently diagnosed malignancies. Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a recently discovered ligand of the B7 family. Blocking this immune checkpoint has become an important treatment option for lung cancer. METHODS: The study includes 62 biopsy specimens either bronchoscopic or CT-guided biopsies diagnosed as lung cancer in Hospitals of Faculty of Medicine, Mansoura University, Egypt during the period from 2016 to 2020. Immunohistochemical Staining for HHLA2 and EGFR was performed. HHLA2 expression was assessed in different pathological types of lung Cancer, and it was correlated with other clinicopathologic parameters and patient prognosis. RESULTS: We found a significant association between HHLA2 expression and metastasis. About 83% of patients presented with metastasis showed positive expression of HHLA2 compared to 44.4% in patients with no metastasis (p=0.02). Also, results show significant mild positive correlation between expression of HHLA2 and EGFR markers (p=0.045). The mean OS time in cases with positive HHLA2 expression was nearly half that of patients with negative expression of the markers. However, this difference was not statistically significant. But, PFS of patients was significantly lower among the group with positive expression of HHLA2 compared to the group with negative expression of HHLA2 (p= 0.01). CONCLUSIONS: This study reports that recently discovered, HHLA2 is over expressed in lung cancer associating with higher stage. It is also correlated with EGFR overexpression. HHLA2 could serve as a predictor of progression and distant metastasis. Also, it has potential to be effective immune target in lung cancer immunotherapy such as checkpoint blockade and antibody-drug conjugate treatment.
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Screening of latent TB infection in patients with recently diagnosed bronchogenic carcinoma.

BACKGROUND: Cancer and pulmonary tuberculosis are major global health concerns and are associated with substantial morbidity and mortality. The association between active tuberculosis and subsequent cancer development has been investigated for many years. This study was planned to determine the prevalence of latent tuberculosis infection in patients with recently diagnosed bronchogenic carcinoma. METHODS: Sixty-four newly diagnosed primary lung cancer patients were enrolled. Diagnosis of latent tuberculosis infection was performed with QuantiFERON-TB Gold In-Tube tests, with exclusion of active tuberculosis. RESULTS: Latent tuberculosis infection was detected in 16 (25%) patients, and 8 (12.5%) had indeterminate results of the QuantiFERON-TB Gold In-Tube test. Being a current smoker was associated with a higher prevalence of latent tuberculosis (p = 0.001). Comorbidities, tumor site, and histopathology were not associated with latent tuberculosis infection. CONCLUSIONS: There is a considerable risk of concurrent latent tuberculosis in newly diagnosed primary bronchogenic carcinoma. The need for treatment of latent tuberculosis in these patients and its influence on the outcome and prognosis are issues for further investigations.