Magnetic Lipid-Based hybrid nanosystems: A combined stimuli- responsive nanocarriers for enriched chemotherapeutic potential of L-carnosine in induced breast Ehrlich ascites tumor model.

Magnetic Lipid-Based Hybrid Nanosystems (M-LCNPs) is a novel nanoplatform that can respond to magnetic stimulus and are designed for delivering L-carnosine (CN), a challenging dipeptide employed in the treatment of breast cancer. CN exhibits considerable water solubility and undergoes in-vivo degradation, hence restricting its application. Consequently, it is anticipated that the developed M-LCNPs will enhance the effectiveness of CN. To ensure the physical stability of MNPs, they were initially coated with a mixture of oleic acid and oleylamine before being included in pegylated liquid crystalline nanoparticles (PLCNPs). The proposed M-LCNPs exhibited promising in-vitro characteristics, notably a small particle size (143.5 nm ± 1.25) and a high zeta potential (-39.5 mV ± 1.54), together with superparamagnetic behavior. The in-vitro release profile exhibited a prolonged release pattern. The IC50 values of M-LCNPs were 1.57 and 1.59 times lower than these of the CN solution after 24 and 48 hours, respectively. Female BALB/C female mice with an induced breast cancer (Ehrlich Ascites tumor [EAT] model) were used to study the influence of an external magnetic field on the chemotherapeutic activity and toxicity of CN loaded in the developed M-LCNPs. Stimuli-responsive M-LCNPs exhibited no apparent systemic toxicity in addition to enhanced chemotherapeutic efficacy compared to nontargeted M-LCNPs and CN solution, as evidenced by a reduction of % tumor growth (11.7%), VEGF levels (22.95 pg/g tissue), and cyclin D1 levels (27.61 ng/g tissue), and an increase in caspase-3 level (28.9 ng/g tissue). Ultimately, the developed stimuli-responsive CN loaded M-LCNPs presented a promising nanoplatform for breast cancer therapy.

Modulation of autophagy and apoptosis can contribute to the anticancer effect of Abemaciclib/Celecoxib combination in colon cancer cells.

Drug resistance and recurrence represent a great challenge in colorectal cancer management, highlighting the urgent need for novel therapeutics. Our objective is to evaluate the influence of Abemaciclib, Celecoxib, and their combination on both the autophagic and apoptotic machinery in an attempt to unravel the interplay between them in HCT-116 and Caco-2 cell lines. The MTT assay was used to assess the GI50 of the drugs. ELIZA was used to determine the protein levels of Beclin-1, LC3, Cox-2, and Bcl-2. Active Caspase-3 was determined by a colorimetric assay. Gene expression levels of ATG5, LC3, Beclin-1, and p62 were assessed by quantitative real-time PCR. In HCT-116 cells, the GI50s for Abemaciclib and Celecoxib were 15.86 and 92.67 µM, respectively, while for Caco-2 cells, the GI50s were 7.85 and 49.02 µM for Abemaciclib and Celecoxib, respectively. Upon treatment of HCT-116 and Caco-2 cells with Abemaciclib, Celecoxib, and their combinations, ATG5, p62, LC3, and Beclin-1 gene expression levels were up-regulated. The protein levels of Beclin-1, LC3, and Caspase-3 were significantly increased, while Bcl-2 was decreased in both cell lines due to single and combined treatments. Both drugs, either alone or in combination, decreased the migration ability of the cells in both cell lines. To conclude, the treatment protocol has the potential to induce cell cycle arrest, diminish the potentiality of cells for migration, and initiate apoptotic and autophagic cell death. Further research is recommended to unravel the potential antitumor effects of Abemaciclib/Celecoxib combination in different cancer types.

Simultaneous Estimation of Berberine and Piperine in a Novel Nanoformulation for Epilepsy Control via HPLC.

Berberine (Brb) and piperine (Pip) are salient examples of bioactive nutraceuticals possessing a promising role in controlling epilepsy. However, during the development of novel nanoformulation that augments their effects, an adequate determination of each one separately was a challenge since they have nearly the same detection wavelength and diverse solubility profiles. Consequently, a tailored high-performance liquid chromatography technique was developed for their simultaneous detection in routine analyses. The chromatographic separation was achieved using a C18 column. The linear gradient flow of acetonitrile: 0.1%v/v aqueous phosphoric acid was altered from 55:45 to 80:20 v/v over 3 min at a 1.2 mL/min flow rate until the end of the run. Brb and Pip were eluted at 1.6 and 3.4 min, respectively. The linearity of the standard curves was found to be ≥0.999, and the mean % recovery for Brb and Pip lay within the accepted limit. Moreover, the percentage coefficient of variation was <2% for intra- and inter-day precision. Consequently, the developed assay was successfully applied for the quantification of both drugs rapidly with high resolution and minimum interference from each other during the different steps conducted during the nanoformulation development.

Effect of coadministration of omega-3 fatty acids with glimepiride on glycemic control, lipid profile, irisin, and sirtuin-1 in type 2 diabetes mellitus patients: a randomized controlled trial.

BACKGROUND AND OBJECTIVE: Type 2 diabetes mellitus (T2DM) is caused by insulin resistance or tissue insensitivity to insulin, as well as relative insulin insufficiency. Diabetes that is uncontrolled for an extended period of time is linked to substantial comorbidities and organ damage. The purpose of the current study is to assess the effect of coadministration of omega-3 fatty acids with glimepiride on blood glucose, lipid profile, serum irisin, and sirtuin-1 levels in T2DM patients. METHODS: This clinical trial involved 70 type 2 diabetic patients randomly assigned to glimepiride 3 mg with either omega-3 capsules contained fish oil 1000 mg, 13% of eicosapentaenoic acid (EPA) and 9% docosahexaenoic acid (DHA) (omega-3 group, n = 35) or placebo capsules contained corn oil and linoleic acid (control group, n = 35) daily for three months. Blood samples were obtained at the start of the study and 12 weeks later for biochemical examination of HbA1c%, FBG, fasting insulin, and lipid profile. In addition, the atherogenic index of plasma (AIP) was calculated. Human enzyme-linked immunosorbent assay (ELISA) kits were utilized for assessing serum irisin and sirtuin-1 levels before and after the intervention. RESULTS: Compared to the control group, omega-3 fatty acids decreased serum fasting blood glucose (FBG, p < 0.001), glycated hemoglobin percent (HbA1C%, p < 0.001), total cholesterol (TC, p < 0.001), triglycerides (TGs, p = 0.006), low density lipoprotein (LDL, p = 0.089), and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR, p = 0.021) after three months of intervention. However, a significant increase was reported in serum irisin and high density lipoprotein (HDL) between both groups after intervention (p = 0.026 and p = 0.007, respectively). The atherogenic index of plasma (AIP) increased in the control group but decreased in the omega-3 group, with significant differences between the two groups (p < 0.001). CONCLUSION: The present study found that supplementing with omega-3 fatty acids might dramatically enhance blood irisin levels, as well as improve glycemic control and lipid profile in type 2 diabetes mellitus patients using glimepiride. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under identifier NCT03917940 . (The registration date: April 17, 2019).

The Synergistic Antitumor Effect of Decitabine and Vorinostat Combination on HepG2 Human Hepatocellular Carcinoma Cell Line via Epigenetic Modulation of Autophagy-Apoptosis Molecular Crosstalk.

Hepatocellular carcinoma (HCC) is a worldwide health issue. Epigenetic alterations play a crucial role in HCC tumorigenesis. Using epigenetic modulators for HCC treatment confers a promising therapeutic effect. The aim of this study was to explore the effect of a decitabine (DAC) and vorinostat (VOR) combination on the crosstalk between apoptosis and autophagy in the HCC HepG2 cell line at 24 h and 72 h. Median inhibitory concentrations (IC50s) of VOR and DAC were assessed in the HepG2 cell line. The activity of caspase-3 was evaluated colorimetrically, and Cyclin D1(CCND1), Bcl-2, ATG5, ATG7, and P62 levels were assessed using ELISA at different time intervals (24 h and 72 h), while LC3IIB and Beclin-1gene expression were measured by using qRT-PCR. The synergistic effect of VOR and DAC was confirmed due to the observed combination indices (CIs) and dose reduction indices (DRIs). The combined treatment with both drugs inhibited the proliferation marker (CCND1), and enhanced apoptosis compared with each drug alone at 24 h and 72 h (via active caspase-3 upregulation and Bcl-2 downregulation). Moreover, the combination induced autophagy as an early event via upregulation of Beclin-1, LC3IIB, ATG5, and ATG7 gene expression. The initial induction of autophagy started to decrease after 72 h due to Beclin-1 downregulation, and there was decreased expression of LC3IIB compared with the value at 24 h. Herein, epigenetic modulation via the VOR/DAC combination showed an antitumor effect through the coordination of an autophagy-apoptosis crosstalk and promotion of autophagy-induced apoptosis, which ultimately led to the cellular death of HCC cancer cells.

The Effect of Metformin on Chemotherapy-Induced Toxicities in Non-diabetic Breast Cancer Patients: A Randomised Controlled Study.

BACKGROUND AND OBJECTIVE: Breast cancer patients treated with adriamycin-cyclophosphamide plus paclitaxel (AC-T) are often challenged with serious adverse effects for which no effective therapies are available. Here, we investigated whether metformin, an antidiabetic drug with additional pleiotropic effects could favourably offset AC-T induced toxicities. PATIENTS AND METHODS: Seventy non-diabetic breast cancer patients were randomised to receive either AC-T (adriamycin 60 mg/m2 + cyclophosphamide 600 mg/m2 × 4 cycles Q21 days, followed by weekly paclitaxel 80 mg/m2 × 12 cycles) alone or AC-T plus metformin (1700 mg/day). Patients were assessed regularly after each cycle to record the incidence and severity of adverse events based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. Moreover, baseline echocardiography and ultrasonography were done and repeated after the end of neoadjuvant therapy. RESULTS: Addition of metformin to AC-T resulted in significantly less incidence and severity of peripheral neuropathy, oral mucositis, and fatigue (p < 0.05) compared to control arm. Moreover, the left ventricular ejection fraction (LVEF%) in the control arm dropped from a mean of 66.69 ± 4.57 to 62.2 ± 5.22% (p = 0.0004) versus a preserved cardiac function in the metformin arm (64.87 ± 4.84 to 65.94 ± 3.44%, p = 0.2667). Furthermore, fatty liver incidence was significantly lower in metformin compared with control arm (8.33% vs 51.85%, p = 0.001). By contrast, haematological disturbances caused by AC-T were preserved after concurrent metformin administration (p > 0.05). CONCLUSION: Metformin offers a therapeutic opportunity for controlling toxicities caused by neoadjuvant chemotherapy in non-diabetic breast cancer patients. TRIAL REGISTRATION: This randomised controlled trial was registered on November 20, 2019 in ClinicalTrials.gov under registration number: NCT04170465.

Berberine-loaded zein/hyaluronic acid composite nanoparticles for efficient brain uptake to alleviate neuro-degeneration in the pilocarpine model of epilepsy.

Berberine hydrochloride is a plant alkaloid with versatile medicinal applications, yet it has suffered from multiple limitations in its usage. Nonetheless, the acknowledged role of berberine in controlling seizures has fuelled the need to develop a nanosystem capable of delivering it safely and efficiently to the brain. Consequently, zein and hyaluronic acid were chosen for this purpose, and about twenty formulations with different preliminary factors were screened. Afterward, three promising formulations were loaded with berberine and characterized to select an optimum formulation for further in vivo inspection. The B2 formula of particle size of 297.2 nm ± 1.86 and % entrapment efficiency of 83.75% ± 1.39 has succeeded in the increment of the brain uptake of berberine. Moreover, compared to free berberine suspension, the severity of pilocarpine-induced status epilepticus in rats was depleted after the subcutaneous administration of B2. The hippocampal tissue of rats receiving B2 showed signs of reduced neuro-degeneration, remarkably lower expression levels of COX-2 and TNF-α, and enhanced antioxidant activity. Finally, the relative safety of the developed system was determined after searching for any sign of intoxication or behavioral changes. In conclusion, the developed berberine loaded composite nanoparticles successfully delivered berberine across the BBB securely to ameliorate the deteriorating impact of pilocarpine-induced epilepsy.

Deep learning and computer vision techniques for microcirculation analysis: A review.

The analysis of microcirculation images has the potential to reveal early signs of life-threatening diseases such as sepsis. Quantifying the capillary density and the capillary distribution in microcirculation images can be used as a biological marker to assist critically ill patients. The quantification of these biological markers is labor intensive, time consuming, and subject to interobserver variability. Several computer vision techniques with varying performance can be used to automate the analysis of these microcirculation images in light of the stated challenges. In this paper, we present a survey of over 50 research papers and present the most relevant and promising computer vision algorithms to automate the analysis of microcirculation images. Furthermore, we present a survey of the methods currently used by other researchers to automate the analysis of microcirculation images. This survey is of high clinical relevance because it acts as a guidebook of techniques for other researchers to develop their microcirculation analysis systems and algorithms.

Prodigiosin-Functionalized Probiotic Ghosts as a Bioinspired Combination Against Colorectal Cancer Cells.

Lactobacillus acidophilus ghosts (LAGs) with the unique safety of a probiotic, inherent tropism for colon cells, and multiple bioactivities offer promise as drug carriers for colon targeting. Our objective was to evaluate LAGs functionalized with prodigiosin (PG), apoptotic secondary bacterial metabolite, as a bioinspired formulation against colorectal cancer (CRC). LAGs were prepared by a chemical method and highly purified by density gradient centrifugation. LAGs were characterized by microscopic and staining techniques as relatively small-sized uniform vesicles (≈1.6 µm), nearly devoid of cytoplasmic and genetic materials and having a negatively charged intact envelope. PG was highly bound to LAGs envelope, generating a physiologically stable bioactive entity (PG-LAGs), as verified by multiple microscopic techniques and lack of PG release under physiological conditions. PG-LAGs were active against HCT116 CRC cells at both the cellular and molecular levels. Cell viability data highlighted the cytotoxicity of PG and LAGs and LAGs-induced enhancement of PG selectivity for HCT116 cells, anticipating dose reduction for PG and LAGs. Molecularly, expression of the apoptotic caspase 3 and P53 biomarkers in HCT116 intracellular proteins was significantly upregulated while that of the anti-apoptotic Bcl-2 (B-cell lymphoma 2) was downregulated by PG-LAGs relative to PG and 5-fluorouracil. PG-LAGs provide a novel bacteria-based combination for anticancer biomedicine.

Leflunomide abrogates neuroinflammatory changes in a rat model of Alzheimer's disease: the role of TNF-α/NF-κB/IL-1ß axis inhibition.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is associated with disrupted cognition and behavior. Neuroinflammatory pathogenesis is the main component that contributes to AD initiation and progression through microglial activation and neuronal damage. Thus, targeting inflammatory pathways may help manage AD. In this study, for the first time, the potential prophylactic and therapeutic effects of leflunomide were investigated either alone or in combination with rivastigmine in aluminum chloride (AlCl3)-induced AD-like rats using behavioral, biochemical, and histological approaches. Thirty-six adult male albino rats were divided into two protocols: the treatment protocol, subdivided into five groups (n = 6)-(1) control group, (2) AlCl3 (50, 70, 100 mg/kg/I.P) group, (3) reference group (rivastigmine 2 mg/kg/P.O.), (4) experimental group (leflunomide 10 mg/kg/P.O.), and (5) combination group (rivastigmine + leflunomide); and the prophylactic protocol (leflunomide 10 mg/kg/P.O.), which started 2 weeks before AlCl3 induction. The results showed that AlCl3 disrupted learning and memory parameters in rats and increased amyloid-ß plaque deposition and neurofibrillary tangle aggregation. Moreover, AlCl3 administration markedly elevated acetylcholinesterase activity, nuclear factor-kappa ß, tumor necrosis factor-α, and interleukin-1 beta, and marked degenerative changes in the pyramidal neurons. However, administration of leflunomide alone or with rivastigmine in AlCl3-induced AD rats restored most of the behavioral, biochemical, and histological parameters triggered by AlCl3 in rats. Our findings suggest that leflunomide can potentially restore most of the neuronal damage in the hippocampal tissues of AlCl3-induced AD rats. However, these preclinical findings still need to be confirmed in clinical trials.

Investigation of the protective and therapeutic effects of Lactobacillus casei and Saccharomyces cerevisiae in a breast cancer mouse model.

Introduction: The development of novel strategies for cancer therapy is crucial to improve standard treatment protocols. Aim: This study aimed to determine the protective and therapeutic effects of heat-killed preparations of Lactobacillus casei and Saccharomyces cerevisiae in a breast cancer mouse model. Methods: Forty-two female BALB/c mice (7-8 weeks old) were divided into six groups (seven mice per group). Four groups were injected with 107 Ehrlich ascites tumor (EAT) cells suspended in phosphate-buffered saline (PBS) subcutaneously into the left side of the mammary fat pad. Tumor growth was monitored weekly until all animals developed a palpable tumor. The tumor-bearing mice in the experimental groups received heat-killed L. casei or S. cerevisiae three times per week for 35 days. The mice in the control group received PBS. The remaining two groups received heated L. casei or S. cerevisiae and then were injected with EAT cells. After 35 days, all mice were sacrificed to determine the immune response. Results: Animals that received heated S. cerevisiae exhibited the lowest rate of tumor growth compared with the other groups. TGF-ß and IL-4 secretion was increased in all mice, whereas the secretion of INF-γ and IL-10 was decreased in breast tissues. Moreover, at the histopathological level, the volume of viable tumor in the control group was higher than in the treated groups. Conclusion: Supplementary treatment with S. cerevisiae resulted in the best outcome in the breast cancer model compared with other treated and vaccinated groups.

Epigenetic restoration and activation of ERß: an inspiring approach for treatment of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ERß agonist DPN on ERα and ERß re-expressions in the MDA-MB-231 cells as a model of TNBC. METHODS: Using MTT assay, the IC50 of decitabine, vorinostat, and DPN on MDA-MB-231 cells were determined. The effects of all drugs alone or in combinations on MDA-MB-231 cells were evaluated. qRT-PCR was used to determine ERα & ERß gene expression. Caspase-3 activity and the protein expression levels of VEGF, Cyclin D1, and IGF-1 were assessed. RESULTS: Both ERα and ERß mRNA were re-expressed in different high levels in all treated groups, especially in the triple therapy group compared with control. Significantly, the triple drugs therapy showed the lowest levels of VEGF, Cyclin D1, and IGF-1 and the highest level of Caspase-3 activity, indicating a possible antitumor effect of ERß activation through decreasing proliferation and angiogenesis and increasing apoptosis in MDA-MB-231 cells. CONCLUSIONS: The antiproliferative effect of ERß could be retained when co-expressed with Erα using a powerful epigenetic combination of Decitabine and vorinostat with DPN.

GANT61/BI-847325 combination: a new hope in lung cancer treatment.

Despite the huge efforts employed to implement novel chemotherapeutic paradigms for lung cancer, the disease still remains a major concern worldwide. Targeting molecular pathways as Hedgehog (Hh) and Mitogen-activated protein kinase (MAPK) represent a new hope in lung cancer treatment. This work was undertaken to evaluate the antitumor effects of GANT61 (5 µM), BI-847325(30 µM), and GANT61 (5 µM)/BI-847325(30 µM) combination on A549 adenocarcinoma lung cancer cell line. The growth inhibition 50 (GI50) for both drugs was performed using MTT. The protein levels of Caspase-3, Bcl-2-associated X protein (Bax), Myeloid cell leukemia sequence 1 (MCL-1), cyclin D1, vascular endothelial growth factor (VEGF), extracellular signal-regulated kinases (ERK), p-Akt, and phosphohistone H3 (pHH3) were measured using ELISA. Glioma-associated oncogene homolog 1(Gli1) gene expression was assessed by quantitative real-time PCR. The GI50 for GANT61 and BI-8473255 were 5 µM and 30 µM, respectively. Caspase-3 and Bax protein levels were significantly elevated while MCL-1, cyclin D1, VEGF, ERK 1/2, p-Akt, and pHH3 levels were significantly reduced by both drugs and their combination relative to the control group. Gli1 gene expression was down-regulated in all groups relative to the control group. GANT61, BI-847325 and their combination inhibited proliferation and angiogenesis but activated the apoptotic pathway. Both drugs conferred a profound negative impact on the crosstalk between each of Hh and MAPK pathways and Phosphoinositide 3 -kinases (PI3K)/Akt/Mammalian target of Rapamycin (mTOR). To the best of our knowledge, the antitumor effects of BI-847325/GANT61 combination have not been tested before. Further in-vitro and in-vivo studies are warranted to support the findings.

Unraveling the therapeutic potential of GANT61/Dactolisib combination as a novel prostate cancer modality.

Aberrant activation of several signaling pathways has been implicated in prostate cancer (PCa) progression to castrate-resistant prostate cancer (CRPC). Phosphoinositide-3-kinase/Protein Kinase B/mechanistic Target of Rapamycin (PI3K/AKT/mTOR) and Hedgehog/GLI (Hh/GLI) pathways are major participants in progression to CRPC. In this sense, the current work aims to assess the potential antitumor effects resulting from co-targeting the aforementioned pathways in PC3 cells with Dactolisib as a dual PI3K/mTOR inhibitor and GANT61 as a GLI1 antagonist. Three replica of PC3 cells were assigned for four treatment groups; vehicle control, Dactolisib-treated, GANT61-treated, and combination-treated groups. GLI1 gene expression was determined by quantitative real-time PCR while active caspase-3 was determined colorimetrically. P-AKT, p70 ribosomal s6 protein kinase 1 (pS6K1), cyclin D1, vascular endothelial growth factor 1 (VEGF1), and Microtubule-associated proteins 1A/1B light chain 3 (LC3) protein levels were determined by ELISA technique. GLI1 gene expression was down-regulated as a result of Dactolisib, GANT61, and their combination. Additionally, both drugs significantly reduced p-AKT, pS6K1, cyclin D1, and VEGF1 protein levels. Dactolisib elevated LC3 protein levels and GANT61 augmented Dactolisib effect on LC3. Moreover, only Dactolisib/GANT61combination significantly increased active caspase-3 level. To sum up, Dactolisib/GANT61 combination was shown to be promising in PCa treatment. Further in-vitro and in-vivo studies are warranted to support our findings.

The Cardioprotective Effect of Vitamin D in Breast Cancer Patients Receiving Adjuvant Doxorubicin Based Chemotherapy.

PURPOSE: The primary objective of this study was to investigate the potential protective effect of Vitamin D (Vit D) on DOX induced cardio toxicity (DIC) in early breast cancer patients receiving adjuvant DOX based chemotherapy (AC). The secondary objective was to investigate the anti-inflammatory effect of Vit D by measuring serum IL-6 and its correlation with cardio toxicity. METHODS: This study was carried out on 150 newly diagnosed women with breast cancer who were planned to receive four cycles of adjuvant AC chemotherapy regimen (60 mg/m2 DOX and 600 mg/m2 cyclophosphamide) every 21 days. Study patients were randomized 1:1 into a control group treated with AC and a Vit D group treated with AC plus 0.5 µg of Vit D (Bon One 0.5 µg) orally once daily during the whole treatment course. The cardio protective effect of Vit D was assessed by measuring serum levels of Lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and anti-inflammatory Interleukin 6 (IL-6) at baseline, and after 4 cycles of AC in all study patients. RESULTS: Vit D supplementation in Vit D group patients was associated with a significant decrease (P < 0.001) in serum levels of LDH, cTnT, and IL-6 compared to the control group . CONCLUSION: The present work provides a promising clinical evidence to support the cardio protective effects of Vit D against DIC through attenuating the evoked pro-inflammatory cytokines induced by DOX.

Antitumor effects of rhamnazinon sorafenib-treated human hepatocellular carcinoma cell lines via modulation of VEGF signaling and PI3K/NF-κB p38/caspase-3 axes cross talk.

AIMS: Hepatocellular carcinoma (HCC) is the most common liver malignancy,characterized by dysregulation of multiple oncogenic signaling pathways, including the VEGF/PI3K/NF-κB and p38 MAPK axes.Sorafenib is a multikinase inhibitor that targets Raf kinases and receptor tyrosine kinases,which mediate HCC angiogenesis.Rhamnazin is a VEGFR2 signaling inhibitor, which inhibits the phosphorylation of Vascular endothelial growth factor receptor 2(VEGFR2) and its downstream signaling regulators. This study was designed to assess the antitumor effects of rhamnazin on human HCC cell lines treated with sorafenib, and to investigate the molecular mechanisms mediating this effect. MAIN METHODS: HepG2 and HUH-7 HCC cell lines were used.Cell viability was assessed by MTT assay. NF-κB, p38MAPK, VEGF, VEGFR2, PI3K, and Ki67 levels were assessed using ELISA. Caspase-3 activity was measured colorimetrically. VEGFR2 expression was detected by RT-PCR. KEY FINDINGS: MTT assay revealed that the sorafenib-rhamnazin combination showed significant cytotoxicity compared with sorafenib or rhamnazin alone. The sorafenib-rhamnazin combination also showed significant inhibition of the angiogenicVEGF/VEGFR2/PI3K/NF-κBsignaling axis associated with significant upregulation of the apoptotic p38MAPK/caspase-3 axis and inhibition of Ki67, a proliferation marker in HepG2 and HUH-7 cells. SIGNIFICANCE: Rhamnazin potentiates the chemotherapeutic effect of sorafenib via modulation ofthe VEGF/PI3K/NF-κBsignaling axis, downregulation of VEGFR2 expression, and upregulation of the p38MAPK/caspase-3 axis in human HCC cell lines.

Itraconazole for Topical Treatment of Skin Carcinogenesis: Efficacy Enhancement by Lipid Nanocapsule Formulations.

Itraconazole (ITC), an antifungal drug with anticancer activity, shows potential for oral treatment of skin cancer. There is clinical need for topical ITC for treating low-risk skin carcinogenesis. Our objective was to develop ITC nanoformulations with enhanced anticancer efficacy. Lipid nanocapsules (LNC), either unmodified (ITC/LNC) or modified with the amphiphiles miltefosine (ITC/MF-LNC) or the lipopeptide biosurfactant surfactin (ITC/SF-LNC) as bioactive additives were developed. LNC formulations showed high ITC entrapment efficiency (>98%), small diameter (42-45 nm) and sustained ITC release. Cytotoxicity studies using malignant SCC 9 cells and normal human fibroblasts (NHF) demonstrated significant enhancement of ITC anticancer activity and selectivity for cancer cells by the LNC formulations and a synergistic ITC-amphiphile interaction improving the combination performance. Treatment of intradermal tumor-bearing mice with the ITC nanoformulation gels compared with ITC and 5-FU gels achieved significant tumor growth inhibition that was remarkably enhanced by ITC/MF-LNC and ITC/SF-LNC as well as recovery of skin architecture. Molecularly, tumoral expression of Ki-67 and cytokeratin proliferative proteins was significantly suppressed by LNC formulations, the suppressive effect on cytokeratins was superior to that of 5-FU. These findings provide new evidence for effective topical treatment of low-risk skin carcinogenesis utilizing multiple approaches that involve drug repurposing, nanotechnology, and bioactive amphiphiles as formulation enhancing additives.

Omega 3 fatty acids effect on the vascular calcification biomarkers fetuin A and osteoprotegerin in hemodialysis patients.

Chronic renal failure patients on dialysis are at a high risk of death due to vascular calcification. This study aimed at investigating the effect of omega-3 fatty acids on the vascular calcification biomarkers fetuin-A and osteoprotegerin (OPG) in patients with chronic renal failure who are undergoing hemodialysis. This prospective, open-label, controlled, parallel study included 60 hemodialysis patients who were randomized to receive either omega-3 fatty acids capsule along with their standard care of treatment (omega-3 group) or their standard care of treatment only (control group). Serum levels of fetuin-A, OPG, calcium, phosphorus, hemoglobin, parathyroid hormone, blood urea nitrogen (BUN), albumin, serum creatinine (SCr), and serum triglycerides (TG) were measured at baseline and after six months of intervention and follow-up of both groups. Significantly increased levels of fetuin-A and OPG (p < 0.001) were observed in the omega-3 group six months after the intervention compared with the control group. Levels of TG, albumin, SCr, BUN, phosphorous, calcium, hemoglobin, and parathyroid hormone were not significantly different in the omega-3 group compared with the control group after six months of intervention. Our study concluded that omega-3 may have a clinically beneficial effect in decreasing cardiovascular events by increasing the levels of the protective vascular calcification inhibitors fetuin-A and osteoprotegerin in chronic renal failure patients who are undergoing hemodialysis.