Virus cracking molecules for treating Hepatitis B

Indiana University researchers have made an important step forward in the design of drugs that fight the hepatitis B virus, which can cause liver failure and liver cancer. ''The drug could attack hepatitis B virus on multiple fronts-preventing replication and killing new copies of the virus," said senior author Adam Zlotnick, a professor in the IU Bloomington College of Arts and Sciences' Department of Molecular and Cellular Biochemistry.

A virus reproduces by hijacking a host's cellular machinery to produce more of the virus. The majority of viruses protect their genetic material-DNA or RNA-inside a protein shell called a "capsid." The research leads to discovery of  a class of molecules called core protein allosteric modulators, or CpAMs, that disrupt capsid protein assembly.

CpAM molecules attack viruses by causing their shells to assemble incorrectly, interrupting the life cycle of the virus. Previously, CpAMs were seen as only able to disrupt a virus during formation of the capsid, after which its DNA was protected inside a hard casing.

To make their discovery,  researchers bound the CpAM to a chemical called TAMRA-a crimson-colored dye used in some red lipstick-to make it fluorescent and easier to detect in experiments. Using cryo-electron microscopy, they found the small CpAM molecule could make the large, soccer ball-shaped virus capsid bend and distort.

The big implication is viral capsids aren't as impenetrable,  if this type of interference works against hepatitis B virus, it might also work against other viruses. About half of known virus families have soccer ball-like capsids; examples include polio and herpes.  This study may lead to better treatments against them since the mechanisms behind capsid disruption could lead to drugs against any of them.
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New method of preventing liver cancer

Primary liver cancer is now the second leading cause of cancer-related death across the globe.In late stages of the malignancy, there are no effective treatments or drugs. While studying the pathogenic mechanisms of liver cancer, the researchers discovered that a commonly used synthetic double-stranded RNA dsRNA strongly boosts a variety of anti-tumor innate immune functions. They suggest it may have the potential to be administered as a vaccine to prevent cancer in individuals at high-risk of developing liver cancer.

The liver has unique immune tolerance, which is why existing treatments, including immunotherapy, have little to no lasting effects on liver cancer. Researchers were initially performing gene deletion to investigate how different types of cells communicate in the liver to promote or suppress cancer development when we found that this synthetic double-stranded RNA prevented liver cancer from initiating by harnessing the body's own innate immune system.

Researchers describe how dsRNA polyinosinic-polycytidylic acid pIC prevented primary liver cancer from occurring in mouse models when it was injected into the body cavity during the pre-cancer stage. Primary liver cancer is cancer that begins in the liver; metastatic liver cancer starts elsewhere in the body and spreads to the liver. The study showed that the formation of tumors or tumorgenesis was suppressed by reprogramming macrophages -specialized immune cells that destroy targeted cells and activation of natural killer cells and dendritic cells that kill tumor cells directly or boost adaptive immunity.

Mouse models with tumors induced either by chemical carcinogen or fatty liver diseases were injected with pIC at different stages. Tumor inhibition was successful in all models that received the dsRNA before tumor formation. The greatest decrease in tumor numbers and size was seen when pIC was administered at one month. At three months the impact was reduced but still significant. At five months, when tumors had already began to form, there was little inhibitory effect observed when comparing tumor numbers or sizes to control groups. The findings suggest that the drug may prevent liver cancer. Liver cancer in adults is among the leading causes of cancer mortality in the world, with more than 780,000 new cases and 740,000 deaths each year.
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Gene mutation linked with liver cancer

Presently, there is no effective treatment for the cancer found in the liver called fibrolamellar hepatocellular carcinoma, which is mainly found among children and young people. Operation of the tumour is the only treatment, some of the patients do not survive after five years.

Coupling of the two genes through a mutation causes a cancer tumour to develop in the liver. The researchers have made sure the genetic composition of the mutation in the mice is identical with the mutation found in human patients. This makes the researchers conclude that the gene mutation also leads to cancer in humans.

Sequencing the DNA of the patients tumour showed that all the patients suffering from the disease had the same mutation in their DNA. The researchers used the revolutionary technology CRISPR/Cas9 that makes it possible to 'edit' genetic material on mice.
They have produced CRISPR/Cas9 reagents, which would provoke precisely the desired fusion of the two genes.

The reagents were injected into the mice's tails and then transported through the bloodstream to the liver.
 In the liver they created a mutation identical with the human mutation, then the researchers were able to conclude that the mice developed the expected type of tumour in the liver.

In other studies, researchers deliberately damage the mice's liver to imitate a liver disease found among human patients or expose them to several different forms of mutations which may cause cancer. This was not necessary here. Because of our genetic design based on CRISPR/Cas9-technology we are certain that the main factor that can explain the cancer is the fusion of the two genes.

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Liquid biopsy for detecting liver cancer

Researchers have developed a new diagnostic and prognosis method for early detection of hepatocellular carcinoma HCC based on a simple blood sample containing circulating tumor DNA. HCC is the most common type of primary liver cancer in adults and among the leading causes of
cancer mortality in the world.

HCC and nonalcoholic steatohepatitis, have increased, early detection improves prognosis and survival rates, in part due to greater efficacy of localized treatment against systemic treatments. But current detection methods for HCC primarily rely upon imaging and a blood test for a non-specific tumor marker called alpha-fetoprotein AFP which is usually elevated when the disease is significantly advanced.

Non-invasive blood tests or liquid biopsies present a better alternative, there has been little success in developing effective blood-based methods for screening HCC. The only blood test, AFP, has limited clinical utility due to low sensitivity. Many liquid biopsies work by detecting circulating tumor DNA ctDNA which are fragments of genetic material shed into the blood by tumor cells. These biopsies offer several potential advantages over other methods of cancer detection.

ctDNA potentially represents the entire molecular picture of a patient's malignancy while a tumor biopsy may be limited to just the tested portion of the tumor. DNA methylation is a process that can regulate gene expression and extensive DNA methylation of a gene usually leads to a gene being turned off.

 Increased methylation of tumor suppressor genes is an early event in tumor development, suggesting that altered DNA methylation patterns may be a good indicator of an emerging tumor. Researchers looked at hundreds of thousands of methylation profiles of HCC patients and healthy controls.

The researchers identified a specific panel of methylation markers that correlated to HCC, then used a variety of machine learning and statistical methods to examine their efficacy at detecting and assessing HCC in HCC patients and normal controls.
Blood-based HCC diagnosis highly correlated with tumor burden, treatment response and stage of cancer.

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The use of metabolism to subtype hepatoblastoma tumors

Hepatoblastoma is a rare pediatric liver cancer, usually diagnosed in the first three years of life. There are many subtypes of hepatoblastoma, the two major ones are fetal and embryonal.
Scientists have identified new biomarkers that could accurately classify the two main subtypes of hepatoblastoma, a children liver cancer.

Different types of hepatoblastoma use different nutrients to grow. Some use glucose or fatty acids. The genetics of hepatoblastoma involves frequent mutations in the gene CTNNB1. This gene produces the protein beta-catenin, which is involved in cell-cell adhesion and gene transcription. Because of its dual function, mutations of the CTNNB1 gene can cause hepatoblastoma cancer.

Beta-catenin is a component of a signaling pathway known as Wnt/beta-catenin, which is responsible for regulating the expression of multiple genes. Many components of the Wnt/beta-catenin pathway are affected and overactive in various tumors.

Researchers examined the relationship between the CTNNB1 gene and the cell's metabolism, they discovered that beta-catenin, as part of the Wnt signaling pathway directly regulates the expression of a gene that produces a glucose transporter protein. GLUT3

They used RNA sequencing to identify molecular and metabolic features that are specific to hepatoblastoma. This approach revealed that several enzymes involved in the metabolism of glucose are overexpressed in embryonal hepatoblastoma cells as compared to fetal hepatoblastoma cells.

Embryonal hepatoblastoma cells show high levels of glucose uptake, they also discovered that these cells are very sensitive to the perturbation of an enzyme involved in the cell's use of glucose. They immunohistochemistry of the three metabolic biomarkers to distinguish embryonal from fetal components out of a large panel of human hepatoblastoma biopsies.

The study shows that the Wnt/beta-catenin pathway is important for reprograming the energy management of tumor cells. It also provides a new
metabolic classification of human hepatoblastoma that can help oncologists develop novel diagnostic methods and treatments.
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Use synbiotics for gut health

Probiotics are live bacteria that are good for digestive system. Probiotics are said to keep gut and digestion healthy by replacing the bad bacteria with good one.

Synbiotics combined a probiotic bacterial strain with prebiotics, which actually feed and increase the good bacteria in the gut.

Probiotics can not survive for a long periods of time, heat and stomach acid can kill them, making them ineffective before digestion.

 Synbiotics are the best way to ensure a maximum benefit from the ingested probiotics. It is the combination of probiotics and prebiotics to feed the human microbiome. Synbiotics could have beneficial effects on obesity and diabetes.

Research has linked our gut health to a range of conditions like obesity, depression, multiple sclerosis and rheumatoid arthritis. Probiotics may prevent and treat fatty liver disease and keep it from advancing to liver cancer.

 Pre-and pro-biotics work together to provide a combined benefit, while the probiotic settles in and pushes out the bad bacteria, the prebiotic feeds the growth of positive strains.

A healthy, balanced microbiome breaks down foods, protects human from infection, trains immune system and produces vitamins K and B12. It also controls mood, anxiety and appetite.
Imbalances in the gut are linked to a range of conditions.

The composition of human gut microbiota is determined by genes but it can also be influenced by lifestyle factors such as diet, alcohol intake, exercise, and medications.
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Tea or coffee can protect your liver

According to a new study published in the Journal of Hepatology, researchers found that drinking coffee and herbal tea may protect against liver fibrosis.

Unhealthy habits, sedentary lifestyle and consumption of processed foods cause non-alcoholic fatty liver disease NAFLD.

Coffee has health benefits on liver enzyme elevations, viral hepatitis, NAFLD, cirrhosis, and liver cancer.

Data was gathered on 2,424 participants of the Rotterdam study, a large population-based cohort study including participants 45 years or older living in a suburb of Rotterdam, The Netherlands.

All participants underwent an extensive physical work-up, including data collection for anthropometrics, blood sampling, hepatological imaging using abdominal ultrasound and Fibroscan®, which quantitatively measures liver stiffness.

Coffee and overall tea consumption was divided into three categories: none, moderate (0-3 cups per day), and frequent (more than 3 cups per day). Tea consumption was categorized by herbal, green, or black tea and further into none (0) or any (>0) consumption.

Researchers discovered that frequent coffee consumption was significantly associated with less scarring of the liver, independent of lifestyle, metabolic, and environmental traits.

When they looked at the whole range of liver stiffness values, they found that both frequent coffee and any herbal tea consumption, even in small amounts, were significantly associated with lower liver stiffness values.

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