#demethylation

[whats-in-a-sentence]

A model showing how DNA demethylation, DNA methylation, and FIS-PRC2-mediated histone methylation may regulate MEG expression in the endosperm is shown in Figure 21.27.

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[caesarsaladinn]

could one hypothetically get around the adderall shortage by demethylating some methamphetamine?

[dreaminginthedeepsouth]

Hannah Critchlow

Mon 17 Jun 2024

Since the sequencing of the human genome in 2003, genetics has become one of the key frameworks for how we all think about ourselves. From fretting about our health to debating how schools can accommodate non-neurotypical pupils, we reach for the idea that genes deliver answers to intimate questions about people’s outcomes and identities.

Recent research backs this up, showing that complex traits such as temperament, longevity, resilience to mental ill-health and even ideological leanings are all, to some extent, “hardwired”. Environment matters too for these qualities, of course. Our education and life experiences interact with genetic factors to create a fantastically complex matrix of influence.

But what if the question of genetic inheritance were even more nuanced? What if the old polarised debate about the competing influences of nature and nurture was due a 21st-century upgrade?

Scientists working in the emerging field of epigenetics have discovered the mechanism that allows lived experience and acquired knowledge to be passed on within one generation, by altering the shape of a particular gene. This means that an individual’s life experience doesn’t die with them but endures in genetic form. The impact of the starvation your Dutch grandmother suffered during the second world war, for example, or the trauma inflicted on your grandfather when he fled his home as a refugee, might go on to shape your parents’ brains, their behaviours and eventually yours.

Much of the early epigenetic work was performed in model organisms, including mice. My favourite study is one that left the neuroscience community reeling when it was published in Nature Neuroscience, in 2014. Carried out by Prof Kerry Ressler at Emory University, Georgia, the study’s findings neatly dissect the way in which a person’s behaviours are affected by ancestral experience.

The study made use of mice’s love of cherries. Typically, when a waft of sweet cherry scent reaches a mouse’s nose, a signal is sent to the nucleus accumbens, causing this pleasure zone to light up and motivate the mouse to scurry around in search of the treat. The scientists exposed a group of mice first to a cherry-like smell and then immediately to a mild electric shock. The mice quickly learned to freeze in anticipation every time they smelled cherries. They had pups, and their pups were left to lead happy lives without electric shocks, though with no access to cherries. The pups grew up and had offspring of their own.

At this point, the scientists took up the experiment again. Could the acquired association of a shock with the sweet smell possibly have been transmitted to the third generation? It had. The grandpups were highly fearful of and more sensitive to the smell of cherries. How had this happened? The team discovered that the DNA in the grandfather mouse’s sperm had changed shape. This in turn changed the way the neuronal circuit was laid down in his pups and their pups, rerouting some nerve cells from the nose away from the pleasure and reward circuits and connecting them to the amygdala, which is involved in fear. The gene for this olfactory receptor had been demethylated (chemically tagged), so that the circuits for detecting it were enhanced. Through a combination of these changes, the traumatic memories cascaded across generations to ensure the pups would acquire the hard-won wisdom that cherries might smell delicious, but were bad news.

The study’s authors wanted to rule out the possibility that learning by imitation might have played a part. So they took some of the mice’s descendants and fostered them out. They also took the sperm from the original traumatised mice, used IVF to conceive more pups and raised them away from their biological parents. The fostered pups and those that had been conceived via IVF still had increased sensitivity and different neural circuitry for the perception of that particular scent. Just to clinch things, pups of mice that had not experienced the traumatic linking of cherries with shocks did not show these changes even if they were fostered by parents who had.

The most exciting thing of all occurred when the researchers set out to investigate whether this effect could be reversed so that the mice could heal and other descendants be spared this biological trauma. They took the grandparents and re-exposed them to the smell, this time without any accompanying shocks. After a certain amount of repetition of the pain-free experience, the mice stopped being afraid of the smell. Anatomically, their neural circuits reverted to their original format. Crucially, the traumatic memory was no longer passed on in the behaviour and brain structure of new generations.

Could the same thing hold true for humans? Studies on Holocaust survivors and their children carried out in 2020 by Prof Rachel Yehuda at the Icahn School of Medicine at Mount Sinai Medical School, New York, revealed that the effects of parental trauma can indeed be passed on in this way. Her first study showed that participants carried changes to a gene linked to levels of cortisol, which is involved in the stress response. In 2021, Yehuda and her team carried out more work to find expression changes in genes linked to immune-system function. These changes weaken the barrier of white blood cells, which allows the immune system to get improperly involved in the central nervous system. This interference has been linked to depression, anxiety, psychosis and autism. Since then, Ressler and Yehuda have collaborated, with others, to reveal epigenetic tags in PTSD afflicted war zone-exposed combatants. They are hoping this information could aid PTSD diagnosis or even pre-emptively screen for individuals who might be more prone to developing the condition before they enter the battlefield.

In all times and across all cultures, people have paid their dues to their ancestors and pondered the legacy they will leave for their descendants. Few of us believe any more that biology is necessarily destiny or that our bloodline determines who we are. And yet, the more we learn about how our body and mind work together to shape our experience, the more we can see that our life story is woven into our biology. It’s not just our body that keeps the score but our very genes.

Might this new understanding increase our capacity for self-awareness and empathy? If we can grasp the potential impact of our ancestors’ experiences on our own behaviour, might we be more understanding of others, who are also carrying the inherited weight of experience?

We are, as far as we know, the only animals capable of “cathedral thinking”, working on projects over many generations for the benefit of those who come after. It’s an idealistic way to think about legacy, but without it we will struggle to tackle complex multigenerational challenges such as the climate and ecological emergencies. Our knowledge of epigenetics and its potential to massively speed up evolutionary adaptation could support us to do everything we can to be the ancestors our descendants need. Conflict, neglect and trauma induce unpredictable and far-reaching changes. But so do trust, curiosity and compassion. Doing the right thing today could indeed cascade across generations.

[lucasdeocampo]

me talking about my fave white-haired anime characters:

my friend: yknow what i don't like about norman??

me: because he's a demethylated man? haha

friend:

😭 i thought it was funny i have been wanting to say that joke 😭

[creativeblogwritingideas]

Exploring Common Methylation Pathways: Understanding the Key Players in Genetic Regulation

Methylation, a crucial biochemical process, plays a pivotal role in gene regulation and expression. It involves the addition of a methyl group (CH3) to DNA molecules, primarily at cytosine bases within CpG dinucleotides, and to certain proteins. This modification influences various cellular processes, including gene transcription, chromatin structure, and DNA repair. Understanding common methylation pathways sheds light on fundamental mechanisms governing genetic regulation and holds promise for advancing personalized medicine and disease prevention.

The Significance of Methylation Pathways

Methylation pathways are essential for regulating gene expression, which impacts diverse biological functions such as cell differentiation, embryonic development, and response to environmental stimuli. Dysregulation of methylation patterns has been implicated in numerous diseases, including cancer, neurological disorders, and cardiovascular diseases. Consequently, investigating common methylation pathways offers insights into disease mechanisms and potential therapeutic targets.

Key Players in Methylation Pathways

DNA Methyltransferases (DNMTs): DNMTs catalyze the transfer of methyl groups to DNA, thereby modulating gene expression. There are several types of DNMTs, including DNMT1, DNMT3A, and DNMT3B, each with distinct roles in establishing and maintaining methylation patterns during development and cellular homeostasis.

Methyl-CpG-Binding Proteins (MBPs): MBPs recognize and bind to methylated CpG sites, mediating the effects of DNA methylation on chromatin structure and transcriptional regulation. These proteins play critical roles in epigenetic silencing and gene repression.

Ten-Eleven Translocation (TET) Proteins: TET proteins are involved in DNA demethylation processes, converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products. This enzymatic activity contributes to dynamic changes in DNA methylation patterns and gene expression.

At Home Genetic Methylation Test: Empowering Personalized Health

The emergence of at home genetic methylation test offers individuals unprecedented insights into their genetic predispositions and health risks. By analyzing DNA methylation patterns, these tests provide information about susceptibility to various diseases, response to certain medications, and lifestyle factors influencing gene expression. Additionally, they empower individuals to make informed decisions regarding lifestyle modifications, preventive measures, and personalized healthcare interventions.

Clinical Applications and Future Directions

Disease Risk Assessment: At-home genetic methylation tests enable individuals to assess their risk of developing certain diseases, facilitating early detection and intervention strategies. By identifying aberrant methylation patterns associated with specific conditions, these tests offer opportunities for targeted screening and disease prevention.

Personalized Medicine: Understanding individual variations in methylation patterns allows for personalized treatment approaches tailored to patients' genetic profiles. By incorporating methylation data into clinical decision-making, healthcare providers can optimize therapeutic outcomes and minimize adverse effects.

Lifestyle Interventions: At-home genetic methylation tests highlight the influence of lifestyle factors such as diet, exercise, and environmental exposures on gene expression and disease susceptibility. Armed with this knowledge, individuals can implement targeted lifestyle modifications to optimize their health and well-being.

In conclusion, exploring common methylation pathways provides valuable insights into genetic regulation and its implications for health and disease. The advent of at-home genetic methylation tests represents a significant advancement in personalized medicine, empowering individuals to take proactive steps towards optimizing their health based on their unique genetic profiles. By harnessing the power of epigenetics, we can pave the way for a future where healthcare is truly personalized, preventive, and precise.

[omkarpatel]

Thebaine: Nature's Gift or a Double-Edged Sword

Thebaine is an important organic compound that occurs naturally in some species of poppy plants. While it has legitimate medical uses, it also has properties that make it highly vulnerable for misuse and diversion into the illegal drug market. This article explores the history, properties, uses as well as challenges associated with thebaine. Properties and Occurrence Thebaine is an opioid alkaloid that is found in trace amounts within the unripe seed pods of select poppy varieties, including Papaver bracteatum and Papaver somniferum. It constitutes less than 3% of the total alkaloid content of these plants. Structurally, thebaine is similar to both codeine and oxycodone but has an unusual pharmacological profile that sets it apart. Its unique properties arise from a linkage that exposes tertiary amine and phenolic hydroxide functional groups. The presence of the tertiary amine makes it weakly psychoactive but highly susceptible to conversion into potent opioids. Medical Uses Despite its weak intrinsic activity, thebaine serves as an essential starting material in the semi-synthesis of many potent opioids used medically today. Through acetylation and demethylation, thebaine can be converted into hydrocodone, oxycodone, oxymorphone and nalbuphine. These opioids play important roles as painkillers and cough suppressants used to treat moderate to severe pain as well as breathing difficulties. Without thebaine as an intermediate, it would be nearly impossible to manufacture these drugs through isolation from natural sources alone. Challenges and Risks While thebaine facilitates the production of important medications, its unique properties also render it prone to misuse and diversion for illicit drug manufacture. Firstly, thebaine in its pure form holds little therapeutic value due to its weak opioid effects. This raises the potential for recreational experimentation and abuse. More significantly however, thebaine can be readily converted into highly addictive and dangerous opioids like heroin through facile chemical reductions. The conversion process can be carried out relatively easily with rudimentary equipment and reagents outside regulated facilities, allowing for widespread potential for abuse. Several clandestine laboratories disguised as legitimate pharmaceutical operations have been uncovered attempting to synthesise heroin from diverted thebaine. This underscores the compound's status as a controlled substance vulnerable to exploitation for illicit drug production if not closely monitored and regulated. Regulation and Supply Chain Integrity Given thebaine's dual-use potential, strict controls have been instituted worldwide to prevent diversion and abuse while still allowing its use in licensed medical applications. In the United States, thebaine is classified as a Schedule II controlled substance under the Controlled Substances Act, indicative of its high potential for addiction and approved medical use. Its international trade is regulated through bilateral quotas negotiated between producing and importing countries according to the Single Convention on Narcotic Drugs. Additionally, companies engaged in thebaine extraction, production and formulation are subject to rigorous oversight, record-keeping, security and auditing requirements. Secure supply chains from licensed poppy farmers to drug product manufacturers aim to eliminate opportunities for criminal diversion and misappropriation. However, the profitable illicit heroin market continues to pose challenges, meaning vigilance must remain steadfast.

[leedsomics]

Single-cell multi-omics reveals insights into differentiation of rare cell types in mucinous colorectal cancer

Neuroendocrine cells have been implicated in therapeutic resistance and worse overall survival in many cancer types. Mucinous colorectal cancer (mCRC) is uniquely enriched for enteroendocrine cells (EECs), the neuroendocrine cell of the normal colon epithelium, as compared to non-mucinous CRC. Therefore, targeting EEC differentiation may have clinical value in mCRC. Here, single cell multi-omics was used to uncover epigenetic alterations that accompany EEC differentiation, identify STAT3 as a novel regulator of EEC specification, and discover a rare cancer-specific cell type with enteric neuron-like characteristics. Further experiments demonstrated that lysine-specific demethylase 1 (LSD1) and CoREST2 mediate STAT3 demethylation and regulate STAT3 chromatin binding. Knockdown of CoREST2 in an orthotopic xenograft mouse model resulted in decreased primary tumor growth and lung metastases. In culmination, these results provide rationale for new LSD1 inhibitors that target the interaction between LSD1 with STAT3 or CoREST2, which may improve clinical outcomes for patients with mCRC. http://dlvr.it/T2NhrB

[daicelpharmastandard]

https://www.daicelpharmastandards.com/product/alcaftadine/alcaftadine-n-demethylated

[thebrokencrescent-blog]

📆 Mar 2020 📰 Toxoplasmosis and behavioural changes

Nearly one-third of the planet's population is affected by Toxoplasma gondii infection. In ophthalmology, toxoplasmosis is even considered to be the most common cause of posterior uveitis of infectious origin. Humans are only an intermediate host and T. gondii needs to infect cats for its sexual reproduction. All the elements increasing the risk of predation by the definitive host are then favourable to the parasite.

Numerous experimental animal model studies have shown that T. gondii infection is associated with predatory risk behaviours such as an attraction of infected mice to cat urine. Infection with the parasite is associated with a demethylation of the promoters of certain genes in the cerebral amygdala of the intermediate hosts, modifying dopaminergic circuits associated with fear.

Similarly, T. gondii has been linked to behavioural changes in humans. Toxoplasma infection is classically associated with the frequency of schizophrenia, suicide attempts or "road rage". A more recent study shows that toxoplasma infection prevalence was a consistent, positive predictor of entrepreneurial activity. Fear of failure would be less important in infected individuals, who are more willing than others to start their own business. These elements shed interesting light on behaviours and their possible relationship with toxoplasmosis, which is generally considered benign in adults.

[pharmaceutical0]

Avermectin B1b — CAS. №65195–56–4 — Ivermectin EP Impurity B

Avermectin B1b — CAS. №65195–56–4 — Ivermectin EP Impurity B Synonyms: Ivermectin EP Impurity B; Avermectin B1b

Chemical Name: 5-O-Demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-avermectin A1a Spiro[11,15-methano-2H,13H,17H-furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2`-[2H]pyran] Avermectin A1a

Buy Avermectin B1b from Simson Pharma Limited at best competitive price.

[utopianadaosophy]

This is a Second Design Image of the Hydra-Demethylation Telomere Derivation Machine.

[rnomics]

Biomolecules, Vol. 13, Pages 850: Emerging Role and Mechanism of the FTO Gene in Cardiovascular Diseases

The fat mass and obesity-associated (FTO) gene was the first obesity-susceptibility gene identified through a genome-wide association study (GWAS). A growing number of studies have suggested that genetic variants of FTO are strongly associated with the risk of cardiovascular diseases, including hypertension and acute coronary syndrome. In addition, FTO was also the first N6-methyladenosine (m6A) demethylase, suggesting the reversible nature of m6A modification. m6A is dynamically deposited, removed, and recognized by m6A methylases, demethylases, and m6A binding proteins, respectively. By catalyzing m6A demethylation on #mRNA, FTO may participate in various biological processes by modulating #RNA function. Recent studies demonstrated that FTO plays a pivotal role in the initiation and progression of cardiovascular diseases such as myocardial fibrosis, heart failure, and atherosclerosis and may hold promise as a potential therapeutic target for treating or preventing a variety of cardiovascular diseases. Here, we review the association between FTO genetic variants and cardiovascular disease risk, summarize the role of FTO as an m6A demethylase in cardiovascular disorders, and discuss future research directions and possible clinical implications. https://www.mdpi.com/2218-273X/13/5/850?utm_source=dlvr.it&utm_medium=tumblr

[prnlive]

Gary Null’s Show Notes 03 29 23

If you listen to Gary’s show, you know that he begins with the latest findings in natural approaches to health and nutrition. Starting this week, we will make some of those findings available each weekday to subscribers to the Gary Null Newsletter.

Tomato extract yields better skin

SAMe shows promise against breast cancer

Acupuncture holds promise for treating inflammatory disease

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Tomato extract yields better skin

Lycored Corp (US), March 6 2023. 

A study reported in the Journal of Cosmetic Dermatology found improvement in signs of skin aging among older women who supplemented with an extract of tomato that contained a standardized amount of the carotenoid lycopene.

“Carotenoids scavenge photo-induced free radicals and antioxidants, thus protecting cellular target molecules such as the cell membrane,” authors Elizabeth Tarshish, PhD, and Karin Hermoni, PhD, wrote. “Free radicals cause inflammatory responses, and by scavenging these free radicals, carotenoids can suppress cellular inflammatory response. Inflammation is one of the foremost causative factors for visible signs of aging.”

The study included 50 women aged 35 to 55 years with signs of facial aging who were not currently using carotenoid supplements. Participants consumed one capsule daily of Lycomato™ tomato extract, which provides 15 mg lycopene plus the carotenoids phytoene, phytofluene and beta-carotene, as well as vitamin E. Before and after 12 weeks of supplementation, the women’s’ skin was analyzed for pigmentary discolorations, wrinkles, texture, hydration, and firmness. The skin’s natural barrier was evaluated by measurement of transepidermal water loss.

At the end of the study, the participants’ skin barrier had significantly improved in comparison with measurements obtained before supplementing with the extract. Skin tone, facial lines and wrinkles, pore size and firmness improved as reported by the participants and by expert evaluation. Lines around the eyes were significantly reduced by 14.8% after four weeks and 26% following 12 weeks of tomato extract consumption. Skin brightness and luminosity had improved by 7.9% after four weeks and by 13.5% at the study’s conclusion. Additionally, skin inflammation was reduced, and texture visibly improved in association with supplementation. 

“These supplements can increase dermal defense against ultraviolet irradiation and environmental pollutants, thereby contributing to better skin health and appearance expressed as ‘beauty from within,’” the authors concluded. 

SAMe shows promise against breast cancer

McGill University (Montreal), February 23 2018

A research paper published in Oncotarget reveals protective effects for S-adenosylmethionine (SAM or SAMe) against cancer growth, invasion and metastasis in human breast cancer cells and in a mouse model of the disease.

“We and others have shown that several key molecules implicated in the metastatic cascade are epigenetically regulated through DNA hypomethylation,” Niaz Mahmood and colleagues. “The universal methyl donor SAM could be used in this regard as an inhibitor of demethylation/hypomethylation.”

By testing the effects of two concentrations of SAM on two highly invasive human breast cancer cell lines, a reduction in tumor cell proliferation was observed in comparison to cells treated with an inert substance. In contrast, normal human breast cells treated with the highest concentration of SAMe did not show any change in viability compared to the control cells, indicating a lack of potential adverse effects in healthy tissue. Treatment with SAM was also found to decrease the migratory ability and invasiveness of both cell lines. Further investigation determined that SAM induced apoptosis (programmed cell death) in both lines by suppressing antiapoptotic effects.

In mice that received implanted human breast tumor cells, tumor volume and metastasis were reduced in association with treatment with SAM. S-adenosylmethionine was also associated with a decrease in the expression of genes implicated in cancer metastasis and progression in breast tumor grafts as well as cancer cells.

“To our knowledge, this is the first direct evidence for the potential therapeutic effect of SAM in a well-recognized model of breast cancer,” the authors announce. “Results from these studies provide compelling evidence to evaluate the therapeutic as well as a chemopreventive potential of epigenetic-based agents such as SAM alone and in the combination setting for patients with several common cancers including breast cancer.”

Acupuncture holds promise for treating inflammatory disease

Rutgers Biomedical and Health Sciences, February 21, 2023

When acupuncture first became popular in the western hemisphere it had its doubters. It still does. But over time, through detailed observation, scientists have produced real evidence that ancient Chinese practitioners of the medical arts were onto something.

Now new research documents a direct connection between the use of acupuncture and physical processes that could alleviate sepsis, a condition that often develops in hospital intensive care units, springs from infection and inflammation, and takes an estimated 250,000 lives in the United States every year.

The researchers already knew that stimulation of one of the body's major nerves, the vagus nerve, triggers processes in the body that reduce inflammation, so they set out to see whether a form of acupuncture that sends a small electric current through that and other nerves could reduce inflammation and organ injury in septic mice. Ulloa explains that increasing the current magnifies the effect of needle placement, and notes that electrification is already FDA-approved for treating pain in human patients.

When electroacupuncture was applied to mice with sepsis, molecules called cytokines that help limit inflammation were stimulated as predicted, and half of those mice survived for at least a week. There was zero survival among mice that did not receive acupuncture.

Ulloa and his team then probed further, to figure out exactly why the acupuncture treatments had succeeded. And they made a discovery that, on its face, was very disappointing. They found that when they removed adrenal glands -- which produce hormones in the body -- the electroacpuncture stopped working. That discovery, on its face, presented a big roadblock to use of acupuncture for sepsis in humans, because most human cases of sepsis include sharply reduced adrenal function. In theory, electroacupuncture might still help a minority of patients whose adrenal glands work well, but not many others.

So the researchers dug even deeper -- to find the specific anatomical changes that occurred when electroacupuncture was performed with functioning adrenal glands. Those changes included increased levels of dopamine, a substance that has important functions within the immune system. But they found that adding dopamine by itself did not curb the inflammation. They then substituted a drug called fenoldopam that mimics some of dopamine's most positive effects, and even without acupuncture they succeeded in reducing sepsis-related deaths by 40 percent.

About Gary Null

An internationally renowned expert in the field of health and nutrition, Gary Null, Ph.D is the author of over 70 best-selling books on healthy living and the director of over 100 critically acclaimed full-feature documentary films on natural health, self-empowerment and the environment. He is the host of ‘The Progressive Commentary Hour” and “The Gary Null Show”, the country’s longest running nationally syndicated health radio talk show which can be heard daily on here on the Progressive Radio Network.

Throughout his career, Gary Null has made hundreds of radio and television broadcasts throughout the country as an environmentalist, consumer advocate, investigative reporter and nutrition educator. More than 28 different Gary Null television specials have appeared on PBS stations throughout the nation, inspiring and motivating millions of viewers. He originated and completed more than one hundred major investigations on health issues resulting in the use of material by 20/20 and 60 Minutes. Dr. Null started this network to provide his followers with a media outlet for health and advocacy. For more of Dr. Null’s Work visit the Gary Null’s Work Section or Blog.GaryNull.com In addition to the Progressive Radio Network, Dr. Null has a full line of all-natural home and healthcare products that can be purchased at his Online Store.

Find articles, videos, back radio broadcasts, books, and more at GaryNull.com.

https://garynull.com

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Disclaimer

While we have thoroughly researched the information we provide, and indicate its sources, information in this Gary Null Newsletter, and all Gary Null Newsletters, is for educational and informational purposes only, and is not intended to diagnose, treat, cure or prevent any disease or other condition. Consult your medical professional before choosing any treatment or course of action. Gary Null Newsletters are not liable for risks or issues associated with using or acting upon the information it provides.

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[lupine-publishers-ctgh]

Lupine Publishers | Different Toxicity of Aristolochic Acids in Kidney and Liver

Introduction

Aristolochic acid (AAs) is a group of nitrophenanthrene compounds comprised of AAI, AAII, AAIII and AAIV, which are widely found in Aristolochia plants and used in herbal therapy and traditional Chinese medicine [1]. Consistent use of aristolochic acids- containing drugs could lead to aristolochic acid nephropathy and subsequent urinary tract tumors [2-4]. Active metabolites of AAs form adducts with DNA, inducing characteristic A-T transversion (A:T to T:A mutation) known as AA mutational signature [5]. In 2017, a study has analyzed AA mutational signature of several datasets and concluded that AAs and their derivatives were widely implicated in liver cancers in Taiwan and throughout Asia [6]. Ever since the paper published, there has been an intensive debate on whether the prevalence of AA signature mutation is high in HCC patients and if this mutation spectra is really correlate with traditional Chinese medicine consumption in Asia. Since no case report has linked AAI to liver cancer by far, many researchers held doubts regarding AA-induced liver cancer. Herein, we summarized previous reports of animal experiments indicating the organ specified toxicity in kidney other than liver and shared our opinion about the possible reasons.

For long, several reports have linked AAs to the development of urothelial cancer, kidney and forestomach tumors in rodents [7-11]. Although AA could be bioactivated in both kidney and liver, in most studies, it only induces tumors in kidney [12]. Therefore, kidney was usually considered as the prior target organ of AAs. AA-DNA adduct is a well-known biomarker for AA exposure. Studies conducted on rat kidney and liver found that kidney had at least two-fold higher levels of DNA adducts and mutant frequency than livers inducted by AAI [13, 14]. The same dose didn’t cause liver tumor in rat, but DNA adducts were detectable at lower levels than kidney [13]. The experiment on Muta mice showed the same tendency [15]. A most recent study also indicated that although forestomach carcinoma was the main cause of death in long-term small dose (0.3-3.0 mg/ kg) AAI-treated mice, kidney was still the organ with most AA-DNA adducts accumulation compared with forestomach and liver [16].

There are several possible reasons for the tissue specificity of AA, one of which could be the ability of proximal tubules to transport and concentrate AA and their metabolites, resulting in renal toxicity. OAT family, mainly expressed on renal proximal tubules, is considered to be one of the pivotal determinants mediating the accumulation of AAI into the proximal tubules [17]. In addition, the level of enzymes catalyzing the reductive activation of AAI are varied in different cells. The activation pathway for AAI is nitroreduction catalyzed by both cytosolic and microsomal enzymes. One of the main human and rat enzymes activating AA-I toxicity was NAD(P) H:quinone oxidoreductase (NQO1), present in hepatic and renal cytosolic subcellular fractions. Other involving enzymes include NADPH: CYP reductase (POR) in kidney microsomes and protaglandin H synthase (cyclooxygenase, COX) in urothelial tissues [18]. In addition to gene expression level of the AAI activation related enzymes in liver and kidney, in vivo oxygen concentration in specific tissues might also affect the balance between AAI nitroreduction and demethylation, which in turn would influence tissue-specific toxicity or carcinogenicity [19]. A recent study also indicated that hepatocyte-specific metabolism of AA-I substantially increases its cytotoxicity toward kidney proximal tubular epithelial cells, including formation of aristolactam adducts and release of kidney injury biomarkers [20].Moreover, AA exposure could cause significantly altered gene expression profiles between kidney and liver, involving defense response, apoptosis and immune response, cell cycle etc, which might also be possible reasons for the tissue-specific toxicity and carcinogenicity of AA [12, 21].

Although the toxicity and carcinogenesis of AAs in kidney is well-defined, their role in liver damage and tumor development may be different. Besides, AA exposure as the main cause of liver cancer was not consistent with the actual scenario in Asia since hepatitis B virus infection remains as the highest risk. Therefore, we believe the toxicity of AAs in liver and kidney should be considered separately.

For more Lupine Publishers open access journals please visit our website:

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For more  Current Trends in Gastroenterology and Hepatology  articles please click here: https://lupinepublishers.com/gastroenterology-hepatology-journal/index.php