Diet, Gut Microbes, and Cancer.

Gut microbes are important and may play important role in spreading cancers specially the gastrointestinal malignancies preferably colorectal cancers. Gut microbes and diet can influence the tissues in gastrointestinal tract increasing the risk of cancer spread. Insufficient nutrient intake and imbalance diet can disturb the microbiome of gastrointestinal tract causing metabolism of xenobiotics which is beneficial as well as detrimental. Dietary imbalance may also weaken the immune system which is another reason for spreading and development of cancers. The triage of gut microbiome, host immune system, and dietary patterns may help the initiation of mechanism of carcinogenesis. In addition to its role in carcinogenesis and tumor development, there is still growing evidence as to how intestinal microflora influences the efficacy and toxicity of chemotherapy and immunotherapy by the gut microbiome. It can therefore be used as a biomarker to predict treatment response or poor response and can also be modified to improve cancer treatment.

Micronutrients Importance in Cancer Prevention-Minerals.

Cancer, a non-communicable disease with diverse kinds is one of the major global problems with high incidence and no proven method to prevent or treat. Minerals including trace elements are significant micronutrients for preserving the body's typical physiological function. In contrast to extremely processed industrial food, they are rich in natural sources of food and frequently included in nutritional supplements. The daily intake, storage capacities, and homeostasis of micronutrients depend on specific dietary practices in contemporary civilization and can be disturbed by various malignancies. Varied minerals have different effects on the status of cancer depending on how they affect these pathways. The outcomes could differ depending on the mineral such as calcium's supply and the cancer's location. A mineral called zinc helps the immune system function better and aids in wound healing. On the other hand, selenium exhibits anti-oxidant functions and has a dose-response relationship with many cancer types. However, this component can make the patient's condition worse. Although the body produces free radicals when iron is deficient, anaemia affects a patient's quality of life and ability to receive therapy. This chapter compiles the knowledge of minerals connected to unusual accumulation or depletion states in various malignancies.

Dietary Pattern and Cancer.

Diet play an important role in the development of cancer. A lot of research has been done on the role of individual nutrients or phytochemicals and cancer risk. Both harmful and beneficial associations of this nutrient have been observed with cancer. However, there is an interaction of individual dietary constituents to influence disease risk. On the other hand, examining the diet as a whole as is done in dietary patterns research may produce more accurate estimates and data that can be more easily translated into dietary recommendations. Dietary patterns and cancer research are becoming increasingly common in the epidemiology literature, and novel dietary patterns are being generated at a rapid pace. However, major issues remain over whether one general "healthy" dietary pattern can be suggested for cancer prevention or whether several diets should be advocated for different forms of cancer protection. It is challenging to study typical human diet in animal model that is appropriate for cancer prevention. Some dietary patterns, such as the ketogenic diet or macronutrient composition alteration, have been investigated more extensively in animal models than in humans in terms of cancer prevention, and bigger human observational studies are now needed to advise dietary guidelines. The question of whether to adapt nutritional guidelines to population subgroups based on susceptibility factors (for example, family history, sex, age, other lifestyle factors or comorbidities, metabolomics signatures, or microbiota-based profiles) is still open and will be crucial in moving the field forward.

A Stop-gain Variant c.220C>T (p.(Gln74*)) in FLNB Segregates with Spondylocarpotarsal Synostosis Syndrome in a Consanguineous Family.

Spondylocarpotarsal synostosis (SCT) syndrome is a very rare and severe form of skeletal dysplasia. The hallmark features of SCT are disproportionate short stature, scoliosis, fusion of carpal and tarsal bones, and clubfoot. Other common manifestations are cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Homozygous variants in FLNB are known to cause SCT. This study was aimed to investigate the phenotypic and genetic basis of unique presentation of SCT syndrome segregating in a consanguineous Pakistani family. Three of the four affected siblings evaluated had severe short stature, short trunk, short neck, kyphoscoliosis, pectus carinatum, and winged scapula. The subjects had difficulty in walking and gait problems and complained of knee pain and backache. Roentgenographic examination of the eldest patient revealed gross anomalies in the axial skeleton including thoracolumbar and cervical fusion of ribs, severe kyphoscoliosis, thoracic and lumbar lordosis, coxa valga, fusion of certain carpals and tarsals, and clinodactyly. The patients had normal faces and lacked other typical features of SCT like cleft palate, conductive and sensorineural hearing loss, joint stiffness, and dental enamel hypoplasia. Whole exome sequencing (WES) of two affected siblings led to the discovery of a rare stop-gain variant c.220C>T (p.(Gln74*)) in exon 1 of the FLNB gene. The variant was homozygous and segregated with the malformation in this family. This study reports extensive phenotypic variability in SCT and expands the mutation spectrum of FLNB.

Exploring Novel 1-Hydroxynaphthalene-2-Carboxanilides Based Inhibitors Against C-Jun N-Terminal Kinases Through Molecular Dynamic Simulation and WaterSwap Analysis.

Cancer is a disease of mutation and lifestyle modifications. A large number of normal genes can transform normal cells to cancer cells due to their deregulations including overexpression and loss of expression. Signal transduction is a complex signaling process that involves multiple interactions and different functions. C-Jun N-terminal kinases (JNKs) is an important protein involved in signaling process. JNK mediated pathways can detect, integrate, and amplify various external signals that may cause alterations in gene expression, enzyme activities, and different cellular functions that affect cellular behavior like metabolism, proliferation, differentiation, and cell survival. In this study, we performed molecular docking protocol (MOE) to predict the binding interactions of some known anticancer 1-hydroxynaphthalene-2-carboxanilides candidates. A set of 10 active compounds was retrieved after initial screening on the basis of docking scores, binding energies, and number of interactions and was re-docked in the active site of JNK protein. The results were further validated through molecular dynamics simulation and MMPB/GBSA calculations. The active compounds 4p and 5 k were ranked on top. After computationally exploring interactions of 1-hydroxynaphthalene-2-carboxanilides with JNK protein, we believe compounds 4p and 5 k can serve as potential inhibitors of JNK protein. It is believed that the results of current research would help to develop novel and structurally diverse anticancer compounds that will be useful not only treat cancer but also for the medication for the other diseases caused by protein deregulation.

Introduction and Overview of Cancer Therapeutics.

Cancer is a complex disease. According to the Globocan survey, 63% deaths are due to cancer. There are some conventional methods that are used to treat cancer. However, certain treatment modalities are under clinical trials still. The success of treatment depends on type and stage of cancer, locality, and patient's response to that specific treatment. Most widely used treatments are surgery, radiotherapy, and chemotherapy. Personalized treatment approach has some promising effects, yet some of the points are still unclear. This chapter has provided the overview of some of the therapeutic modalities; however, the therapeutic potential has been discussed in details throughout the book.

Radiation Therapies in Cancer.

A crucial element of cancer treatment is radiation therapy that is used to destroy tumors and cancer cells through radiation. Another essential component is immunotherapy that helps immune system to combat cancer. The combination of both radiation therapy and immunotherapy is being focused recently for the treatment of many tumors. Chemotherapy includes the use of some chemical agent to control the growth of cancer, whereas irradiation involves the use of radiations of high energy to kill cancer cells. The union of both became the strongest practice in cancer treatment techniques. Specific chemotherapies are combined with radiation in the treatment of cancer after proper preclinical assessment of their effectiveness. Some classes of compounds include platinum-based drugs, antimicrotubules, antimetabolites (5-Fluorouracil, Capecitabine, Gemcitabine, Pemetrexed), topoisomerase I inhibitors, alkylating agents (Temozolomide), and other agents (Mitomycin-C, Hypoxic Sensitizers, Nimorazole).

Nutritional Assessment in Cancer Patients.

Malnutrition in cancer patients is highly prevalent. The metabolic and physiologic changes associated with the disease and the side effects of treatment regimens all combine together to produce a detrimental effect on the patient's nutritional status. A poor nutritional status significantly reduces the efficacy of treatment methods and the patient's overall chances of survival. Therefore, an individualized nutrition care plan is essential to counter malnutrition in cancer. Nutritional assessment is the first step of this process which sets the foundation for developing an effective intervention plan. Currently, there is no single standard method for nutritional assessment in cancer. Hence, to get a true picture of the patient's nutritional state, a comprehensive analysis of all aspects of the patient's nutritional status is the only reliable strategy. The assessment includes anthropometric measurements and evaluation of body protein status, body fat, inflammation markers, and immune markers. A thorough clinical examination which factors in the medical history and physical signs, along with the dietary intake patterns of the patient, is also important components of nutritional assessment of cancer patients. To facilitate with the process, various nutritional screening tools like patient-generated subjective global assessment (PGSGA), nutrition risk screening (NRS), and malnutrition screening tool (MST) have been developed. While these tools have their own benefits, they only give a glimpse of the nutritional problems and do not bypass the need for a complete assessment employing various methods. This chapter covers all four of the elements of nutritional assessment for cancer patients in detail.

Naturally Isolated Sesquiterpene Lactone and Hydroxyanthraquinone Induce Apoptosis in Oral Squamous Cell Carcinoma Cell Line.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide, especially in Asian countries. The emergence of its drug resistance and its side effects demands alternatives, to improve prognosis. Since the majority of cancer drugs are derived from natural sources, it provides a window to look for more biocompatible alternatives. In this study, two natural compounds, costunolide (CE) and aloe emodin (AE), were isolated from the stem of Lycium shawii. The compounds were examined for their anticancer and apoptotic potentials against OSCC (CAL 27) cells, using an in vitro analysis, such as a MTT assay, scratch assay, gene, and protein expressions. Both compounds, CE and AE, were found to be cytotoxic against the cancer cells with an IC50 value of 32 and 38 µM, respectively. Moreover, the compounds were found to be non-toxic against normal NIH-3T3 cells and comparable with the standard drug i.e., 5-fluorouracil (IC50 = 97.76 µM). These compounds were active against normal cells at higher concentrations. Nuclear staining displayed the presence of apoptosis-associated morphological changes, i.e., karyopyknosis and karyorrhexis in the treated cancer cells. Flow cytometry results further confirmed that these compounds induce apoptosis rather than necrosis, as the majority of the cells were found in the late apoptotic phase. Gene and protein expression analyses showed an increased expression of apoptotic genes, i.e., BAK, caspase 3, 6, and 9. Moreover, the compounds significantly downregulated the expression of the anti-apoptotic (BCL-2 L1), metastatic (MMP-2), and pro-inflammatory (COX-2) genes. Both compounds have shown promising anticancer, apoptotic, and anti-migratory activities against the OSCC cell line (i.e., CAL-27). However, further in vivo studies are required to explore these compounds as anticancer agents.

Anticariogenic and Mechanical Characteristics of Resin-Modified Glass Ionomer Cement Containing Lignin-Decorated Zinc Oxide Nanoparticles.

This study aims to synthesize and characterize lignin-decorated zinc oxide nanoparticles before incorporating them into resin-modified glass ionomer cement (RMGIC) to improve their anticariogenic potential and mechanical properties (shear bond strength and microhardness). Probe sonication was used to synthesize lignin-decorated zinc oxide nanoparticles which were then characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. Following characterization, these were incorporated in RMGIC (Gold label, Fuji II LC). Three major groups, experimental group A (EGA), experimental group B (EGB), and control group (CG), were outlined. EGA and EGB were divided into numbered subgroups based on the ascending concentrations of nanoparticles (5, 10, and 15%) of lignin-coated zinc oxide and zinc-oxide, respectively. CG served as a control and comprised cured RMGIC samples without any incorporation. Anticariogenic analysis was conducted on experimental RMGIC samples via disk-diffusion (n = 3) and direct contact test (n = 3) against Streptococcus mutans (ATCC 25175). Optical density values for days 1, 3, and 5 were recorded via a UV-Vis spectrophotometer. A shear bond strength test was performed using 35 premolars. The adhesive remnant index was used to estimate the site of bond failure. For the Vickers microhardness test (n = 3), 100 g of load at 10 s dwell time was set. Atomic absorption spectroscopy was performed over 28 days to determine the release of zinc from the samples. All tests were analyzed statistically. The anticariogenic potential of EGA and EGB was significantly greater (p ≤ 0.05) than that of the control. The shear bond strength test reported the highest value for EGA15 with all groups exhibiting failure at the bracket/RMGIC interface. The microhardness of EGA15 yielded the highest value (p ≤ 0.05). Release kinetics displayed a steady release with EGB15 exhibiting the highest value. The EGA and EGB samples displayed good anticariogenic potential, which was sustained for 28 days without any deleterious effect on the shear bond strength and microhardness.

2-Methoxy-6-Acetyl-7-Methyljuglone: A Bioactive Phytochemical with Potential Pharmacological Activities.

Natural products have been the focus of biomedical and pharmaceutical research to develop new therapies in recent years. 2-methoxy-6-acetyl-7-methyljuglone (2-methoxystypandrone, MAM) a natural bioactive juglone derivative, is known to have various levels of pharmacotherapeutic efficacies as an anti-inflammatory, anticancer, antioxidant, antimicrobial, and anti-HIV activities. MAM fights cancer progression by inducing apoptosis, necroptosis and deregulating signaling pathways through H2O2-induced JNK/iNOS/NO and MAPK, ERK1/2 pathways, JNK activation, and the RIP1/RIP3 complex. In this review, we summarize the pharmacological importance of MAM in the field of drug discovery. Furthermore, this review not only emphasizes the medicinal properties of MAM, but also discusses its potential efficacy in future medicinal products.

Down-regulation of ANXA7 decreases metastatic potential of human hepatocellular carcinoma cells in vitro.

We report for the first time the influence of ANXA7 gene on human hepatocellular carcinoma cells (HCC). We down-regulated ANXA7 in human HCC cell line (HepG2) using siRNA method. By Western Blot analysis, we confirmed about 70% down-regulation of the gene in the shRNA-ANXA7 transfected cells (shRNA-ANXA7-HepG2) compared to the non-specific sequence shRNA transfected cells (control-shRNA-HepG2) and the un-manipulated-HepG2 cells. We used CCK-8 cell proliferation kit and observed about 65% reduction in the shRNA-ANXA7-HepG2 cells where the two controls exhibited comparable cell proliferation rates. Also, by using PI staining followed by flow cytometry, we noticed a cell cycle arrest at G0/G1 with more than one fold reduction of shRNA-ANXA7-HepG2 cell population in the S-phase of the cell cycle. Also of particular note was a significant aneuploidy in the controls compared to zero aneuploidy in the ANXA7 down-regulated cells. Migration of the cells was detected using Boyden's transwell chamber and scratch wound healing assay which showed 50% and 30% respective reductions in shRNA-ANXA7-HepG2 cells migration. Furthermore, the control-shRNA-HepG2 cells and the un-manipulated-HepG2 cells invaded through the ECM-coated transwell plates two times more than the shRNA-ANXA7-HepG2 cells. We have found ANXA7 to be functioning like a tumour promoter in HepG2 human hepatocellular carcinoma cells and could have a potential as a therapeutic window into the management of liver cancer.

Subcellular proteomics: determination of specific location and expression levels of lymphatic metastasis associated proteins in hepatocellular carcinoma by subcellular fractionation.

BACKGROUND: Subcellular fractionation and proteomics form an ideal partnership when it comes to specific location and analysis of intracellular organelles and expression levels of multiprotein complexes. Lymphatic metastasis is the major complicated system involving multiple factors. However, to date lymphatic metastatic mechanism is poorly understood. AIM: To specifically locate expression site by subcellular fractionation, based on expression levels, interpret the involvement of different lymphatic metastasis associated proteins in hepatocellular carcinoma cell lines with different lymphatic metastasis potential. METHOD: Mouse hepatocellular cell lines Hca-F and Hca-P are used to evaluate the location and expression levels of some lymphatic metastasis-associated proteins in the cell by using subcellular fractionation kit and Western blot analysis. The proteins under studies were Gelsolin, JNK and Annexin 7. RESULTS: Gelsolin was sequestered in cytoplasm, membrane and cytoskeleton in F-cells but in P-cells, it was found in cytoplasm and cytoskeleton .JNK was located in nuclear fraction and cytoskeleton in F and P cells, Annexin7 was in cytoplasm with its two isoforms only at this location, cell membrane and cytoskeleton in F and P cells. With the high expression level of Gelsolin, JNK and Annexin 7 in Hca-F cell line than Hca-P cell line. CONCLUSION: With subcellular fractionation specific location of Gelsolin, JNK and Annexin 7 at various cell sites during lymphatic metastasis were determined. High expression levels were found in high lymphatic metastasis potential cell lines which indicate their roles according to different expression sites in the disease.