Nature: Protein OTX2 Plays a Crucial Role in Germ Cell Development

In a new study, researchers from the University of Edinburgh in Scotland, Shandong University in China, and the Institute of Genetics and Biophysics in Naples, Italy, discovered key insights into how sperm cells (ie, sperm) and egg cells (eggs) are formed, thus helping to reveal their earliest stages of development. This study is the first to show how proteins affect the fate of these cells that determine the DNA profile of the offspring. The relevant research results were published online in the Nature recently, and the paper titled "OTX2 restricts entry to the mouse germline".

These findings focus on the development of germ cells that produce sperm and eggs. During reproduction, germ cells from different sexes fuse together to form new individuals.

These researchers used mice as the research object to explore the first stage of germ cell formation. They focused on a molecule called BMP4 that was found to block the activity of Otx2, a gene regulator that directs the development of non-germ cells (called somatic cells). They demonstrated that lowering Otx2 activity by BMP4 is critical for germ cell development.

Professor Ian Chambers of the University of Edinburgh said, "Before, the study of germ cell identity focused on a series of events that occurred during germ cell development. We are now able to begin to observe early events that occur during germ cell development. These exciting discoveries open the door to a better understanding of the earliest stages of controlling the separation of germ cells from all other cells."

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Nat Commun: New Ways to Reduce the Side Effects of Cancer Drugs

Protein research is one of the hottest areas of medical research because protein-based drugs can be developed to treat diabetes, cancer and other diseases.

Although proteins have great potential, their incredibly complex chemical structures pose enormous challenges for scientists. As a result, researchers have been looking for a tool to modify them more precisely, thereby reducing the side effects of the drug.

Recently, researchers have developed a new protein modification method that can reduce the side effects of drugs and can be the key to promoting the development of protein drugs. Their research has been published in Nature Communications.

Protein structure is like an intricate yarn ball

Researchers call this method "His-tag acetylation." In addition, it can add toxic molecules to proteins that attack diseased cells in the body of cancer without attacking healthy cells.

“Protein is like a ball of yarn. When they are opened, a long chain of amino acids will appear. This new modification allows us to precisely target these intricate structures. In short, it will help the drug production, and we can make changes more confidently so that we can reduce side effects in the future," the author said.

Modified proteins must be pinpointed

His-tag acylation accurately targets these complex yarn-like protein structures, which also makes it possible to produce drugs with novel properties.

For example, researchers can now attach fluorescent molecules to proteins, allowing microscopy to track the path of proteins through cells. Since the primary function of these proteins is to transport anticancer molecules around the diseased cells, it is important to follow their path carefully throughout the body.

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Molecular Cancer: Researchers Find New Targets for Breast Cancer

A study led by Dr. Suresh Alahari, professor of biochemistry and molecular biology at the University of Louisiana Health Science Center (LSU Health), first discovered that a small piece of RNA can dysregulate cellular energy metabolism, which is a major feature of cancer. These findings have found a new target for therapeutic intervention in breast cancer, and the findings are recently published in Molecular Cancer.

MicroRNAs are a class of single-stranded small RNA molecules that play important regulatory roles in cell biology, and they bind to target genes to reduce their function. MicroRNAs can be used both as a carcinogen and as a tumor suppressor.

The research team has previously found that miR-27b is a breast cancer carcinogen, and researchers have found it to be high in breast cancer tissue. In this study, the researchers found that this molecule inhibited the production of a protein called PDHX. PDHX involves cellular metabolism, and cellular metabolism can affect cell proliferation. Lack of PDHX means that cells can rapidly produce new cells and promote tumor growth and progression. The team found a significant reduction in PDHX levels in breast cancer cells.

"Based on these data, we believe that inhibition of miR-27b is a new treatment for breast cancer," Dr. Alahari said. "Inhibition of miR-27b promotes PDHX expression, which inhibits tumor proliferation through several established metabolic cascades."

According to NCI statistics, the number of new breast cancer patients in the United States will be higher than other cancers in 2018. NCI estimates that there will be 266,120 new cases of breast cancer, and 40,920 will die from breast cancer. "The use of microRNA analogs or anti-microRNA agents will counteract their function, and reversing oncogene metabolism will be a unique cancer treatment strategy. Potential clinical applications of miRNAs include diagnostic tests, disease prevention, and prognostic markers, which make miRNAs a unique and attractive option for reducing cancer morbidity and mortality."

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CDK6—the Hot Potato in Cancer Treatment

It is well known that the formation of tumors is a multi-step process in which cells acquire genetic and epigenetic changes during tumorigenesis and eventually reach a state of complete transformation. The cell cycle kinase CDK6 has received a lot of attention in the past few years. It is not only a cell cycle-dependent kinase but also a transcriptional regulator with functional characteristics different from the same family of CDK4. CDK6 regulates the expression of many genes, and some studies have found that this molecule can promote the development of malignant blood diseases such as AML and ALL, and is also important for the self-sustaining of hematopoietic stem cells and leukemia stem cells.

Recently, researchers from Vienna reported that CDK6 is able to antagonize p53-induced responses. Previous studies have found that high and low expression of CDK6 are associated with poor prognosis, but the reasons for this have not been revealed. In this study, the researchers found that CDK6 promotes tumor formation by regulating transcriptional responses at specific stages. In the early stages of tumorigenesis, CDK6 kinase prevents p53 from acting in hematopoietic cells by inducing a complex transcriptional program. Cells lacking CDK6 kinase function require the presence of TP53 mutations to achieve a fully transformed immortal state.

The researchers found that CDK6 binds to promoters of many genes, including p53 antagonists Prmt5, Ppm1d and Mdm4. The researchers said the findings of the study were also confirmed in patients: the frequency of TP53 mutations in tumors expressing low levels of CDK6 was higher than expected. The study found that CDK6 can promote cell cycle progression to antagonize stress responses and affect the effects of p53 and RB. Specific inhibition of CDK6 kinase activity results in cells more susceptible to p53-induced cell death and also stimulates the growth of p53 mutant clones in precancerous cells.

EiF4E and Depression

A recent study about changes in the brain linked to depression paved the way for new therapies. Moreover, the study also revealed why a certain antidepressant drugs stop working in some people.

Scientists from the University of Edinburgh studied mice that were bred to have defects in their ability to activate a certain molecule, called eIF4E. And it turned out that those animals showed signs of depression, reduced levels of hormone serotonin and also disinterest in food.

Treatment with a commonly prescribed antidepressant called fluoxetine failed to produce a response in the mice. This suggests that activation of eIF4E is required for the beneficial antidepressant effects of fluoxetine, which belongs to a category of medicines called selective serotonin re-uptake inhibitors (SSRIs). (sciencedaily.com)

This, however, could help explain why some patients stop responding to SSRIS. Previous studies have shown the effect of eIF4E in regulating protein synthesis in the brain. And the defects of eIF4E are also linked to other neurological conditions. But it is the first time it has been found to be connected with depression.

Those findings, according to the scientists, could help develop novel therapy for depression, which are affecting increasing numbers of people worldwide.

Dr Christos Gkogkas, a Chancellor's Fellow in the University of Edinburgh's Center for Discovery Brain Sciences, stated: “Our investigation uncovers that changed protein synthesis through eIF4E is a key cellular process in the brain that can go amiss in depression. Imperatively it might clarify why a few people with depression wind up resistant to treatment with SSRIs. This information can enable us to plan another generation of antidepressants.”

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New Findings about IL-33 You May Want to Know

A team of researchers from the French Scientific Research Center and the National Institute of Health and Medical Research discovered that a protein acts like a sensor can detect asthma-inducing allergens in the respiratory tract. Their research, co-led by Corinne Cayrol and Jean-Philippe Girard, was recently published in Nature Immunology and has brought new breakthroughs in the treatment of allergic diseases.

What are the common features of mold, pollen, and wolfberry? Although they belong to three different organisms, they all can cause allergies in susceptible people. Although the composition varies greatly, they all contain enzymes called proteases.

The team found a human protein that reacts with environmental allergens: interleukin-33 (IL-33). When allergens enter the human respiratory tract, they release proteases that activate IL-33 to become extremely active. This triggers an allergic chain reaction.

At the same time, this mechanism has led to allergic reactions to various allergens. IL-33 can detect 14 different allergens, including environmental air (such as pollen, indoor aphids, fungal spores, etc.) and occupational asthma-related (like subtilisin found in detergents) allergens.

These findings are important because they find a direct relationship between genes and the environment. In fact, the gene encoding IL-33 is indeed one of the major genes that cause people to easily develop asthma. In addition, clinical trials targeting IL-33 are ongoing. Inhibiting the production of activated IL-33 after exposure to allergens may be an effective way to control severe allergic reactions in allergic patients.

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The Amaryllidaceae Alkaloid Helps Repress Cancer Cell Growth

Daffodil can quickly cure cancer? Scientists from the Laboratory of RNA Molecular Biology at the Liberal University School of Science and Cancer Research Center in Brussels, Belgium, conducted a preliminary exploration in this direction, and this study was published in Cell's Structure recently.

The study, led by Denis Lafontaine, extracted a natural anticancer compound from daffodil (Amaryllidaceae). They found that the compound is an alkaloid called tennis amine, which binds ribosomes. Ribosomes are nanodevices necessary for the survival of our cells because they synthesize all of our proteins. In order to maintain their own unrestricted growth, cancer cells rely on enhanced protein synthesis, so cancer cells are very sensitive to therapies that inhibit ribosome formation or inhibit ribosomal function.

In the new study, researchers also found that tennis amine can inhibit ribosome-forming proteins and therefore slow cancer cell growth. Peracetamol also inhibits the production of such nanodevices in the nucleus: the pressure on the nucleolus activates the anti-cancer watchdog pathway, leading to increased stability of the p53 protein, thereby eliminating cancer cells.

This study, for the first time, reveals the molecular mechanism of antitumor activity of daffodils, which has been used in folk medicine for hundreds of years. Pedigree is a member of a large group of natural therapeutic molecules: Many of the other alkaloids used in human care are extracted from plants such as morphine (potent analgesics), quinine (anti-malaria drugs), and ephedrine (anti-asthma Medicine) and so on.

In the near future, Denis Lafontaine's team will work with Veronique Mathieu's team to examine the effects of four Amaryllid alkaloids on ribosome formation and function. Their goal is to quickly find the most promising chemical framework, and then further develop anticancer drugs.

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JCI: Histone Protein Modifications May Regulate Human Glomerular Disease

During normal development, histone modifications control the fate of cells, whereas histone modification affects the process of cell dedifferentiation in the event of disease. In a recent study published in the international journals JCI, researchers from Canada decided to find out how dynamic changes in histone modifications can affect adult glomerular podocytes, which are usually at rest.

To do this, the researchers altered the inhibitory effect of H3K27me3 in podocytes and performed a series of analyzes. Adriamycin nephrotoxicity test and subtotal nephrectomy both showed that the level of H3K27me3 decreased after the removal of methyltransferase EZH2 with histone methylation in podocytes and the mice were susceptible to glomerular diseases. The researchers found that in podocytes H3K27me3 aggregates in the promoter region of Notch ligand Jag1, and inhibition of Jag1 by EZH2 knockdown or knockdown of EZH2 expression can promote podocyte dedifferentiation. In contrast, inhibition of the demethylase Jmjd3 and UTX increased the level of H3K27me3, decreased adriamycin nephrotoxicity experiments, subtotal nephrectomy, and diabetic-induced glomerular disease. In addition, the researchers analyzed glomerular podocytes in patients with focal segmental glomerulosclerosis and diabetic nephropathy and found that glomerular podocytes in these patients exhibited levels of H3K27me3 Decline and UTX levels increase. Similar to this observation, inhibition of Jmjd3 and UTX slows the progression of nephropathy in a mouse model of glomerular damage.

Collectively, these results indicate that chromatin modifications are not as stable as they appear to be at rest, and also undergo dynamic regulation, whereas epigenetic reprogramming or results that may improve glomerular disease.

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