Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function.

The glycocalyx component and sialomucin podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumor types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high and low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis.

Synthesis, Anticancer, Antioxidant, Anti-Inflammatory, Antimicrobial Activities, Molecular Docking, and DFT Studies of Sultams Derived from Saccharin.

A series of N-substituted saccharins namely 2-(1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl) acetonitrile (2) and (alkyl 1,1-dioxido-3-oxobenzo[d]isothiazol-2(3H)-yl) acetate (3a-g) were synthesized, in moderate to excellent yields, from commercially available starting materials by two different approaches and their chemical structures were characterized by spectroscopic techniques (1H-NMR, 13C-NMR, IR, and MS). All the synthesized compounds were evaluated for their anti-inflammatory toward IL-6 and TNF-α, antioxidant, as well as their anticancer activities against hepatic cancer cells. In addition, their anti-fungal and antibacterial activities against both Gram-positive and Gram-negative bacteria were tested. All the tested compounds have exhibited excellent (3a, d, e) to moderate anti-inflammatory activity. Additionally, esters (3b, f) and nitrile (2) showed excellent antioxidant activity. Furthermore, ester 3f, with isopropyl ester, exhibited the highest cytotoxic activity compared to the other esters. Moreover, all compounds were evaluated as selective inhibitors of the human COX-1 enzyme using molecular docking by calculating the free energy of binding, inhibition constant, and other parameters to find out the binding affinity. The molecular study showed that esters (3d, f) and nitrile (2) revealed the highest binding affinities, hence enhancing the inhibition activity with the active site of the COX-1 enzyme. All the tested compounds have more negative Gibbs free, electrostatic, and total intermolecular energies than the standard inhibitor ASA. These results indicate that, all the tested sultams are potent anti-inflammatory drugs as compared to standard inhibitors. Finally, the chemical properties and the quantum factors of synthesized sultams were calculated based on density functional theory (DFT) to predict reactivity, and then correlated with the experimental data. Ester 3f showed the lowest ionization potential and lowest energy gap (Egap = 7.5691 eV), which was correlated with its cytotoxic activity. Furthermore, the spatial electron distribution of HOMO, LUMO were computed and it clearly indicates the electron donation ability of all the tested compounds.

Ethoxyquin Inhibits the Progression of Murine Ehrlich Ascites Carcinoma through the Inhibition of Autophagy and LDH.

Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene Bcl-2 and by a significant increase in the expression of apoptotic genes (BAX and caspase-3). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials.

Highlights on selected growth factors and their receptors as promising anticancer drug targets.

Growth factor receptors (GFRs) and receptor tyrosine kinases (RTK) are groups of proteins mediating a plethora of physiological processes, including cell growth, proliferation, survival, differentiation and migration. Under certain circumstances, expression of GFRs and subsequently their downstream kinase signaling are deregulated by genetic, epigenetic, and somatic changes leading to uncontrolled cell division in many human diseases, most notably cancer. Cancer cells rely on growth factors to sustain the increasing need to cell division and metabolic reprogramming through cancer-associated activating mutations of their receptors (i.e., GFRs). In this review, we highlight the recent advances of selected GFRs and their ligands (growth factors) in cancer with emphasis on structural and functional differences. We also interrogate how overexpression and/or hyperactivation of GFRs contribute to cancer initiation, development, progression, and resistance to conventional chemo- and radiotherapies. Novel approaches are being developed as anticancer agents to target growth factor receptors and their signaling pathways in different cancers. Here, we illustrate how the current knowledge of GFRs biology, and their ligands lead to development of targeted therapies to inhibit and/or block the activity of growth factors, GFRs and downstream kinases to treat diseases such as cancer.

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells.

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity.

SP3 is associated with migration, invasion, and Akt/PKB signalling in MDA-MB-231 breast cancer cells.

Specificity proteins (SPs) have pro-oncogenic functions in cancer cells, ranging from cancer cell proliferation, migration, invasion, and angiogenesis. There is strong evidence that several antineoplastic drugs target depletion of SP proteins via different pathways. However, the mode of action of SP3 and the underlying consequences of its depletion are not well understood. Here, we demonstrate that SP3 is overexpressed in invasive breast cancer cells vs normal counterparts. The gene expression analysis from The Cancer Genome Atlas datasets indicated that SP3 is strongly correlated with Akt signalling-related proteins, G protein subunit alpha 13, and RAB33B (RAB33B, member RAS oncogene family). RNA interference of SP3 decreased active phosphorylation of Akt at serine and threonine sites. These findings indicate that SP3 exhibits a pro-oncogenic function, which clearly fits the description of an nononcogene addiction gene. Future analyses are prompted to uncover the SP3 gene regulation function and to reveal downstream targets of SP3 in breast cancer.

Serological Investigations of Bluetongue Virus (BTV) among Sheep and Goats in Kassala State, Eastern Sudan.

Bluetongue (BT) is an infectious, noncontagious, vector-borne viral disease of wild and domestic ruminants. BTV is a member of the Orbivirus genus of the family Reoviridae. The present study aimed to investigate the seroprevalence of BTV in sheep and goats in Kassala State, Sudan. It also aimed to determine risk factors associated with BTV infection. The study was carried out by a structured questionnaire survey, and a total of 809 serum samples were collected from sheep (n = 459) and goats (n = 350) from 9 different localities in Kassala state. These samples were analyzed using a competitive enzyme-linked immunosorbent assay (cELISA) for the detection of BTV antibodies. The overall seroprevalence of BTV was 91.2% (738/809). In goats, the prevalence of BTV antibodies was comparatively higher (100%) than in sheep (84.5%). The prevalence differed between localities and was the highest in the center section of Kassala and Western Kassala (100%). Animals aged 6-11 months were highly infected (93.9%) compared to 1-year-old (85.5%). Caprine species was more likely to be infected (100%) than ovine (84.5%), and females were highly infected (92.8%) than males (85.5%). BTV infections were higher in the winter season (91.4%). Risk factors that showed significant associations with cELISA positivity included locality and sex (p ≤ 0.003) and species and age (p ≤ 0.000). Factors significantly associated with cELISA positivity in multivariate analysis were localities, species, age, and sex. BTV infection is prevalent in sheep and goat populations in Kassala state.

Dual inhibition of glycolysis and autophagy as a therapeutic strategy in the treatment of Ehrlich ascites carcinoma.

Cancer cells have extra biosynthetic demands to sustain cell growth and redox homeostasis. Glycolysis and autophagy are crucial to fuel and recycle these biosynthetic demands. This plasticity of cancer cell metabolism participates in therapy resistances. The current study was designed to assess the therapeutic efficacy of dual targeting of glycolysis and autophagy in cancer. Using 3-bromopyruvate (3-BP; antiglycolytic inhibitor) and hydroxychloroquine (HCQ; autophagy inhibitor), we demonstrate their antitumor activity in Ehrlich ascites carcinoma (EAC)-bearing mice. A combination of 3-BP and HCQ significantly decreases tumor ascitic volume and cell count as compared with the EAC group and individual treatment groups. The enhanced antitumor activity is accompanied by hexokinase inactivation, inhibition of cellular protective autophagy, elevated antioxidant activity, and reduced oxidative stress levels. Together, these results suggest targeting both pathways in cancer as an effective therapeutic strategy. Further studies are required to validate this strategy in different cancer models and preclinical trials.

Combination of arsenic trioxide and cisplatin synergistically inhibits both hexokinase activity and viability of Ehrlich ascites carcinoma cells.

Hexokinase-2 is overexpressed in several carcinomas including breast cancer to sustain energy for rapidly dividing cells and associates with chemoresistance. However, the impact of chemo drugs (alone or in combination) on hexokinase activity and autophagic cell death is unclear. In this report, we used an in vivo murine adenocarcinoma model to validate the effects of As2 O3 and cisplatin on hexokinase activity and autophagic cancer cell death. We found that the two drugs inhibit hexokinase activity and induce autophagic marker, beclin 1 expression. Interestingly, combining As2 O3 with cisplatin synergistically enhanced these effects and alleviated oxidative stress often encountered in As2 O3 treatment. Altogether, our data provide direct evidence that inhibition of hexokinase activity and induction of autophagic cell death are mediating the antineoplastic effects of As2 O3 and cisplatin. Our findings raise the potential of combining As2 O3 with cisplatin as an approach to augment cisplatin-induced cell death and combat cisplatin chemoresistance in cancer.

The phospholipid PI(3,4)P2 is an apical identity determinant.

Apical-basal polarization is essential for epithelial tissue formation, segregating cortical domains to perform distinct physiological functions. Cortical lipid asymmetry has emerged as a determinant of cell polarization. We report a network of phosphatidylinositol phosphate (PIP)-modifying enzymes, some of which are transcriptionally induced upon embedding epithelial cells in extracellular matrix, and that are essential for apical-basal polarization. Unexpectedly, we find that PI(3,4)P2 localization and function is distinct from the basolateral determinant PI(3,4,5)P3. PI(3,4)P2 localizes to the apical surface, and Rab11a-positive apical recycling endosomes. PI(3,4)P2 is produced by the 5-phosphatase SHIP1 and Class-II PI3-Kinases to recruit the endocytic regulatory protein SNX9 to basolateral domains that are being remodeled into apical surfaces. Perturbing PI(3,4)P2 levels results in defective polarization through subcortical retention of apically destined vesicles at apical membrane initiation sites. We conclude that PI(3,4)P2 is a determinant of apical membrane identity.

Ubiquitination: Friend and foe in cancer.

Dynamic modulation and posttranslational modification of proteins are tightly controlled biological processes that occur in response to physiological cues. One such dynamic modulation is ubiquitination, which marks proteins for degradation via the proteasome, altering their localization, affecting their activity, and promoting or interfering with protein interactions. Hence, ubiquitination is crucial for a plethora of physiological processes, including cell survival, differentiation and innate and adaptive immunity. Similar to kinases, components of the ubiquitination system are often deregulated, leading to a variety of diseases, such as cancer and neurodegenerative disorders. In a context-dependent manner, ubiquitination can regulate both tumor-suppressing and tumor-promoting pathways in cancer. This review outlines how components of the ubiquitination systems (e.g. E3 ligases and deubiquitinases) act as oncogenes or tumor suppressors according to the nature of their substrates. Furthermore, I interrogate how the current knowledge of the differential roles of ubiquitination in cancer lead to technical advances to inhibit or reactivate the components of the ubiquitination system accordingly.

Synthesis, spectroscopic, thermal and molecular modeling studies of Zn2+, Cd2+ and UO22+ complexes of Schiff bases containing triazole moiety. Antimicrobial, anticancer, antioxidant and DNA binding studies.

A novel series of Zn2+, Cd2+ and UO22+ complexes of ligands namely 1-[(5-mercapto-1H-1,2,4-triazole-3-ylimino) methyl]naphthalene-2-ol (HL1) and [(1H-1,2,4-triazole-3-ylimino) methyl] naphthalene-2-ol (HL2) have been prepared and characterized by different analytical and spectral techniques. The stoichiometry, stereochemistry, conductivity measurements and mode of bonding of the complexes have been elucidated. Accurate comparison of the IR spectra of the ligands with their metal chelates proved the involvement of nitrogen atoms of the azomethine group and/or triazole ring in chelation in addition to the deprotonated hydroxyl oxygen. The UV-Vis and molar conductance data supported the octahedral geometry for the metal complexes. TGA technique has been used to study the thermal decomposition way of the metal complexes and the thermo kinetic parameters were estimated. Valuable information is obtained from calculations of molecular parameters using the molecular modeling techniques. The interaction between the metal complexes and CT-DNA has been studied from which the binding constants (kb) were calculated. The Schiff bases and their metal chelates have shown potent antimicrobial, antioxidant and antitumor activities. The antitumor activities of the compounds have been tested in vitro against HEPG2 cell line and in silico by the molecular docking analysis with the VEGFR-2 receptor responsible for angiogenesis.

HOXD8 exerts a tumor-suppressing role in colorectal cancer as an apoptotic inducer.

Homeobox (HOX) genes are conserved transcription factors which determine the anterior-posterior body axis patterning. HOXD8 is a member of HOX genes deregulated in several tumors such as lung carcinoma, neuroblastoma, glioma and colorectal cancer (CRC) in a context-dependent manner. In CRC, HOXD8 is downregulated in cancer tissues and metastatic foci as compared to normal tissues. Whether HOXD8 acts as a tumor suppressor of malignant progression and metastasis is still unclear. Also, the underlying mechanism of its function including the downstream targets is totally unknown. Here, we clarified the lower expression of HOXD8 in clinical colorectal cancer vs. normal colon tissues. Also, we showed that stable expression of HOXD8 in colorectal cancer cells significantly reduced the cell proliferation, anchorage-independent growth and invasion. Further, using The Cancer Genome Atlas (TCGA), we identified the genes associated with HOXD8 in order to demonstrate its function as a suppressor or a promoter of colorectal carcinoma. Among inversely related genes, apoptotic inhibitors like STK38 kinase and MYC were shown to be negatively associated with HOXD8. We demonstrated the ability of HOXD8 to upregulate executioner caspases 6 & 7 and cleaved PARP, thus inducing the apoptotic events in colorectal cancer cells.

FAM98A associates with DDX1-C14orf166-FAM98B in a novel complex involved in colorectal cancer progression.

Protein Arginine Methyl Transferase 1 (PRMT1) is deemed to be a potential oncogenic protein considering its overexpression in several malignancies including colorectal cancer. However, the molecular pathogenesis regarding PRMT1 overexpression and overall poor patient survival involved in this devastating and life threatening cancer remains obscured. In our previous study, we have identified FAM98A as a novel substrate of PRMT1 and also identified its role in ovarian cancer progression. Here, we showed that the two structural homologs FAM98A and FAM98B included in a novel complex with DDX1 and C14orf166 are required for PRMT1 expression. Analysis of the data from The Cancer Genome Atlas (TCGA) database and clinical colorectal cancer specimens also demonstrated a strong positive correlation and co-occurrence of PRMT1, FAM98A and FAM98B. These findings provide a mechanistic insight into how knockdown of FAM98A or FAM98B can suppress the malignant characteristics of cancer cells. Besides, we showed that FAM98A and FAM98B are working in the same axis as knockdown of both proteins together does not cause additional reduction in the cellular proliferation and colony formation of colorectal cancer cells.

Medical Students' Opinion Toward the Application of Complementary and Alternative Medicine in Healthcare.

CONTEXT: An accelerated approach to popularize complementary and alternative medicine (CAM) in healthcare services has led to the need to assess medical students' knowledge of CAM. Furthermore, their attitude toward its efficacy and usage will determine its growing popularity in healthcare. Another key idea is to integrate CAM with conventional medical teaching to make it a part of the mainstream medical curriculum. The objectives were to assess the medical students' perceptions about integrating CAM with conventional medicine and to assess the attitude of prescribing different CAM modalities to patients presenting with a particular disease or health disorder. SETTINGS AND DESIGN: This is a descriptive, institutional based study conducted on undergraduate 3rd year medical students. MATERIALS AND METHODS: Data were collected by a structured and pretested questionnaire to be filled in by the participants in the presence of the investigator. Statistical data were entered in SPSS software, and descriptive analysis was conducted. RESULTS: Most of the students (74%) agreed that conventional and CAM therapy can be integrated to achieve a better health care outcome. Forty-eight percent of the participants were positive that knowledge of CAM is important since many patients still prefer this option, particularly for chronic illnesses. CONCLUSIONS: The students were receptive to the introduction of a new treatment method in their curriculum, which although unconventional, presents an alternative and traditional form of treatment even if it does not have major backing from the scientific community. The participants felt that more knowledge is required to make an informed opinion about its usefulness to the community as a whole.

SATB1 and SATB2 play opposing roles in c-Myc expression and progression of colorectal cancer.

Special AT-rich sequence-binding protein 1 and 2 (SATB1/2) are nuclear matrix-associated proteins involved in chromatin remodeling and regulation of gene expression. SATB2 acts as a tumor suppressor in laryngeal squamous cell carcinoma and colon cancer, whereas SATB1 promotes the progression of numerous types of cancers. In this study, we examined the effects of SATB1 and SATB2 on the malignant characteristics of colorectal cancer cells. SATB1 and SATB2 expression were negatively correlated in colorectal cancer specimens. SATB1 expression was increased, whereas SATB2 expression was reduced, in colorectal cancer tissues compared to control tissues. Exogenous expression of SATB2 in colorectal cancer cells suppressed cell proliferation, colony formation and tumor proliferation in mice. c-Myc was reduced by SATB2 expression, and exogenous expression of c-Myc in SATB2-expressing cells restored proliferation, colony formation and in vivo tumor growth of colorectal cancer cells. We also showed that c-Myc reduction by SATB2 was mediated by the inactivation of ERK5. In contrast, SATB1 promoted c-Myc expression. The expression of SATB1 in colorectal cancer tissues was positively correlated with c-Myc expression, and SATB1 knockdown reduced c-Myc expression in colorectal cancer cells. Finally, we showed that SATB1 knockdown in colorectal cancer cells suppressed cell proliferation, colony formation and cell invasion. Our results reveal interesting features of how the structural homologs SATB1 and SATB2 exert opposing functions in colorectal tumorigenesis.

TRIP13 is expressed in colorectal cancer and promotes cancer cell invasion.

Thyroid hormone receptor interactor 13 (TRIP13) is a member of the ATPases associated with various cellular activities family of proteins and is highly conserved in a wide range of species. Recent studies have demonstrated that TRIP13 is critical for the inactivation of the spindle assembly checkpoint and is associated with the progression of certain cancers. In the present study, the role of TRIP13 in colorectal cancer (CRC) was examined. Reverse transcription-quantitative polymerase chain reaction analysis revealed that TRIP13 messenger RNA was highly expressed in multiple CRC tissues. The depletion of TRIP13 in CRC cells suppressed cell proliferation, migration and invasion. To determine whether the catalytic activity of TRIP13 was critical for cancer progression, an inactive mutant of TRIP13 was expressed in CRC cells. The invasion of cancer cells that expressed the mutant TRIP13 was significantly reduced compared with that of the wild type TRIP13-expressing cancer cells. These results indicate that TRIP13 could be a potential target for CRC treatment.

FAM98A is a novel substrate of PRMT1 required for tumor cell migration, invasion, and colony formation.

Protein arginine methylation, which is mediated by a family of protein arginine methyltransferases (PRMTs), is associated with numerous fundamental cellular processes. Accumulating studies have revealed that the expression of multiple PRMTs promotes cancer progression. In this study, we examined the role of PRMT1 in ovarian cancer cells. PRMT1 is expressed in multiple ovarian cancer cells, and the depletion of its expression suppressed colony formation, in vivo proliferation, migration, and invasion. To gain insight into PRMT1-mediated cancer progression, we searched for novel substrates of PRMT1. We found that FAM98A, whose physiological function is unknown, was arginine-methylated by PRMT1. FAM98A is expressed in numerous ovarian cancer cell lines and is important for the malignant characteristics of ovarian cancer cells. Our results indicate the possible role of the PRMT1-FAM98A pathway in cancer progression.