Friday, November 11, 2022

The Role of Microbial Metabolites in the Etiology of Colon Cancer

 It has been shown that a number cancers are caused by pathogens as the table below demonstrates


Disease

Causative Agent

 

T-cell Leukemia

HTLV-1 Human Retrovirus

Cervical Cancer

Human Papilloma Virus (HPV) 

Liver Cancer

Hepatitis B and Hepatitis C Virus (HBV and HCV)

Stomach Cancer

H.pylori – a Bacteria

 


This growing evidence involving the role of pathogens in the etiology of various cancers has led to numerous studies that look at a possible role of enteric microorganisms that naturally inhabit the human gut in the etiology of colon cancer.  The result of this kind of investigation has revealed that so-called genotoxic gut bacteria, whose metabolic product(s) can damage or mutate human DNA, may well be drivers of colorectal cancer (CRC) parthenogenesis.

Moreover, it has been recently reported in the prestigious journal, Science, by Dr. Cao and his colleagues that patients presenting with inflammatory bowel disease (IBD) – a condition that can lead to CRC – show the evidence of  diverse populations of  bacterial strains that can exert genotoxic activity.

 In this study, a particular bacterium, Monganella morganii, proved pf particular interest.  This organism is a Gramnegative bacterium that was discovered as an enriched population among individuals suffering from IBD and CRC.  The organisms of this type was identified as belonging to a class of bacteria that produce indolimines.  This is of special importance since indolimines have been found to promote tumor growth in mice.

 In addition to these findings, “Among the most well-described genotoxic bacteria are enterotoxigenic Bacteroides fragilis (ETBF) (3) that produce Bacteroides fragilis toxin (BFT), strains of Escherichia coli or other bacteria that produce colibactin (4), and Campylobacter jejuni strains that express cytolethal distending toxin (CDT) (5). The DNA-damaging properties of these strains and their toxins vary considerably, ranging from alkylating DNA interstrand cross-links for colibactin to deoxyribonuclease (DNase) activity for CDT (1, 4, 5). Intriguingly, ETBF and E. coli producing colibactin have been linked to IBD and CRC development using in vitro and in vivo models.”

The contribution of Dr. Chao and his colleagues made as cited in their study was the successful elucidation and characterization of the existence of some 18 strains of strains of enteric bacteria that actively produce genotoxins out of the 122 strains that were isolated for examination.

In the final analysis, the correlation between genotoxins found in the gut and the onset of IBD and CRC is of immense value and points to an avenue for future studies that may be of profound importance in regard to the ultimate prevention and treatment of these diseases.

 

Saturday, October 1, 2022

Immunotherapeutic Methodology Designed to Treat Lupus

Lupus is a disease in which the patient manifests certain symptoms that are a result of an autoimmune disease in which the patient’s immune system is producing antibodies against the individual’s own tissue(s).

The following is an overview of this condition as described on the website of the Mayo Clinic – (https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789)

“Lupus is a disease that occurs when your body's immune system attacks your own tissues and organs (autoimmune disease). Inflammation caused by lupus can affect many different body systems — including your joints, skin, kidneys, blood cells, brain, heart and lungs.

“Lupus can be difficult to diagnose because its signs and symptoms often mimic those of other ailments. The most distinctive sign of lupus — a facial rash that resembles the wings of a butterfly unfolding across both cheeks — occurs in many but not all cases of lupus.

“Some people are born with a tendency toward developing lupus, which may be triggered by infections, certain drugs or even sunlight. While there's no cure for lupus, treatments can help control symptoms.

Symptoms

Red, butterfly-shaped rash on nose and cheeks


 No two cases of lupus are exactly alike. Signs and symptoms may come on suddenly or develop slowly, may be mild or severe, and may be temporary or permanent. Most people with lupus have mild disease characterized by episodes — called flares — when signs and symptoms get worse for a while, then improve or even disappear completely for a time.

The signs and symptoms of lupus that you experience will depend on which body systems are affected by the disease. The most common signs and symptoms include:

Fatigue

Fever

Joint pain, stiffness and swelling

Butterfly-shaped rash on the face that covers the cheeks and bridge of the nose or rashes elsewhere on the body

Skin lesions that appear or worsen with sun exposure

Fingers and toes that turn white or blue when exposed to cold or during stressful periods

Shortness of breath

Chest pain

Dry eyes

Headaches, confusion and memory loss”



Autoimmune diseases as a class of ailments have been historically exceedingly difficult to treat. However, impressive inroads have been made in recent years using the rapidly advancing techniques embodies in immunotherapy. It has been reported in a recent issue of the prestigious scientific publication, Nature Medicine, from a medical team in Germany that five patients, four women and a man, have been successfully treated with their own immune cells that have been genetically engineered.

This technique involves isolating the patient’s own T cells – a subset of the immune system’s cellular repertoire – and genetically modifying them so that they would recognize those B cells that are involved in the autoimmune response unique to lupus and attack them by binding to a specific cell surface protein (antigen). This kind approach is referred to as T cell (CAR-T) therapy.

In this case, all five patients tolerated the therapy and their lupus-caused impaired organ function either improved or was resolved. As a result, these patients were no longer required to take immune-suppressive medication.

These results are quite encouraging and certainly are promising in regard to the treatment of lupus.

Friday, May 27, 2022

The Beginning of Cellular Life on Planet Earth

A Possible Structure for a Primitive Cell- Biology Libre Texts

A necessary first step in examining the evolution of cellular-based life from the pre-biotic world is to discern what constitutes the makeup of cells in the broadest possible terms. In deconstructing cell structure from the viewpoint of prokaryotes, I propose the following necessary prerequisites for a living cell:

· Cell Membrane to delineate the cell and protect it from the local environment

· Cell infrastructure composed of the most basic structural components including actin, myosin, etc.

· Source of readily available energy

· Proteins especially enzymes involved in catabolic and anabolic activities

· Signal transduction pathways that allow for both intracellular and extra-cellular communication.

· Nucleic Acids: DNA and RNA to serve as information stores for the cell.

· Mechanisms for DNA and cellular replication.

Any attempt to propose a mechanism by which primordial cell-like structures evolved into the complex cells that exist today, strongly suggests a gradual stepwise process that took eons to accomplish. It also suggests, in my mind, that the process would involve steps in which cellular organization would grow in complexity from the level of simple molecules (substrates) through proteins and nucleic acids and finally through protein-nucleic acid interaction to the encoding of the genetic material. In this way, selection pressures and processes would enhance each succeeding step.

Taking all this into account, I propose the following model for the evolution of cellular life from primordial beginnings.

Elements of the Hypothesis:

There existed an aqueous environment (possibly shallow ponds or along coastal regions or possibly the sea floor) where there was an abundance of nucleotides, fatty acids, amino acids, peptides and polypeptides. It is possible that some of this organic material may have been seeded by meteorites.
In these organic-enriched regions, conditions were appropriate for the spontaneous formation of cell-like structures.
 
These cell-like structures developed semi-permeable membranes formed from the spontaneous assembly of proteins and lipids (probably a more primitive structure than found in present day cells) and highly permeable to dissolved organic matter in the local environment.
 
The local environment was such that amino acids, nucleotides, fatty acids and carbohydrates could readily penetrate the cell membranes of these primordial cells and concentrate there.
 
Ambient conditions including oxygen concentration, temperature, abundance of ammonia and methane made the spontaneous synthesis of proteins and nucleic acids not only possible but highly likely.
Assuming that spontaneous formation of tRNAs were a likely scenario, these tRNAs could bind to their appropriate amino acids. These amino acid carriers collided with each other and resulted in the formation of random polypeptide chains. Subsequently, polypeptides that were capable of binding to carbon sources such as glucose stabilized these small proteins and gave them a competitive advantage over more non-specific proteins. Since the metabolic pathway for glucose metabolism is universal to all life, one must assume that glucose was abundant in pre-biotic times. This same argument can be applied to the presence of ADP/ATP, since this molecule is the essential ingredient for all energy sustaining life activities.
 
Some of these selected proteins also possessed catalytic capabilities and were able to breakdown carbon rich substrates and ultimately capture energy in ATP molecules. This energy may have been used in accelerating the synthesis of more complex molecules and intra-cellular structures, the precursors of cellular organelles.  
 
There is mounting evidence that strongly suggests that RNA may have played a pivotal role in information storage in the early evolution of cellular life. As I have postulated above, tRNAs may have been abundant. Additionally, evidence for the role of RNA in information storage includes:
 
  • The discovery of RNA that possesses catalytic activity referred to as ribozymes. There is a ribozyme that has been found in the core of ribosomes.   
  • The discovery of small pieces of RNA that can readily bind to a variety of organic molecules and that are found on the ends of mRNA in prokaryotes. These pieces function as switches that can turn translation on or off and are referred to as riboswitches. 
  • Double-stranded RNA that can silence gene transcription in a complex referred to as RISC.
  • What is now referred to as the anti-codon region of tRNA may have been used to make mRNA possibly happening spontaneously utilizing an environment rich in small pieces of RNA or assisted by a ribozyme. These nascent mRNAs served as templates for the further synthesis of specific and biologically valuable proteins. Whether or not such associations are possible today in conditions that simulate the pre-biotic environment would need to be tested. It is possible that “ancient” RNA had a different structure than the current form. This early mechanism was probably inefficient and prone to error.
 
These early cells were infiltrated by a competing entity that gradually assumed a symbiotic relationship and was to become what is now referred to as ribosomes. These structures contributed a much more efficient mechanism for the synthesis of proteins.  In addition, the mitochondria found in eukaryotic cells and the chloroplasts found uniquely in plant cells have their own nucleic acid and most probably were once independent organisms that also assumed a symbiotic relationship with their host cells.
 
Messenger RNAs were no longer able to sustain the growing complexity of cell life as embodied in metabolism and energy transfer mechanisms. A more highly conserved store of information was required. The appearance of an enzyme capable of using mRNA as a template to make highly stable double-stranded DNA encouraged the further development of cellular complexity and evolution. This transition was necessitated by the fact that the extra-cellular environment was no longer as rich in nutrients and building materials as was previously the case. It has become clear that large portions of the genome of humans and other complex organisms are made up of retrotransposons. There are relatively small pieces of DNA that code for reverse transcriptases that allow for copying of these segments and ultimately inserting them in other places in the genome. These were originally discovered by McClintock and referred to as so-called “jumping genes.” Integration of these pieces in the promoter or structural regions of active genes can have profound impacts on gene expression. Certain diseases have been associated with this process. Furthermore, there are retrotransposons that have been conserved among and between organisms. This suggests that the increasing complexity of the genome as seen in evolution may be in large due to retrotransposons. In addition, retrotransposons have many characteristics similar to retroviruses suggesting that retroviruses may have played a significant role in delivering novel genetic material to the genome.
In conclusion, the particular scenario I have outlined represents one possible pathway that may have taken place that was responsible for the evolution of cellular life as we know it from prebiotic conditions that existed on planet Earth billions of years ago.

Wednesday, May 18, 2022

The Impact of Sunscreen Products Upon the Viability of Coral

It has been reported that the compound oxybenzone (shown below) that is the active ingredient in sunscreen preparations exhibits a toxicity to corals. The mechanism of this toxicity has not been fully understood.


Oxybenzone

William Mitch and his colleagues at Civil and Engineering at Stanford University, California have successfully delineated the mechanisms involved in regard to this toxicity. They have established that oxybenzone caused increased mortality of a sea anemone under conditions that simulated the natural (UV) radiation (290 to 370 nanometers). Furthermore they found that both the anemone and a mushroom coral formed oxybenzone–glucoside conjugates (see image below) that were powerful auto-oxidants. Corals are composed of layers, of calcium carbonate secreted by soft bodied animals called coral polyps. These polyps live in a symbiotic relationship with a host zooxanthellae such as algae that gives the coral its color. Corals devoid of algae are bleached as a consequence of climate change.




Algal symbionts took up these conjugates, and their mortality correlated well with the corresponding concentration of oxybenzone glucosides within the animal cells. Since many commercial sunscreens preparations contain compounds structurally analogous to oxybenzone, an understanding of the mechanism of this toxicity should enable the synthesis of more eco-friendly sunscreen products.

According to the authors of a paper published in a recent article in the prestigious journal, Science, “Research in the US Virgin Islands found no substantial settlement of coral larvae, survival of juvenile corals, or regeneration of adult tissue in induced lesions over a 5-year period in Trunk Bay, where high levels of recreational swimming resulted in up to 1.4 mg of oxybenzone per liter of seawater. Meanwhile, a thriving coral community was found at neighboring Caneel Bay, with lower recreational use but presumably the same impacts from global stressors. Exacerbation of coral declines by sunscreens washed off tourists would be ironic and particularly pernicious, given the promotion of ecotourism in the interest of protecting coral reefs.”

Finally, the authors go on to say that, “With recent moves by regulatory authorities in Hawaii and elsewhere to ban oxybenzone, understanding the mechanism(s) of its phototoxicity is important to ensure that the sunscreen components that are selected as alternatives are truly safer for corals.”

The ecological factors that promote and sustain the delicate balance in the natural world can easily be disrupted by human encroachment. It is vitally important to support the kind of scientific investigations that uncover these human factors and find ways to mitigate their impact.




Sunday, May 15, 2022

The Filovirus

One of the suspected and postulated origins of COVID-19 virus in human populations is the transfer of the virus across the species barrier i.e. from bats. This capacity to “jump” across species is of added concern given the severity of illness originating from human infection by a family of viruses referred to as filoviruses. A filovirus is a filamentous RNA virus (see image below).



 

Infection by this virus is the causative agent of so-called “hemorrhagic fevers” in humans and primates, that includes the Ebola and Marburg viruses. These viruses can result in multiple organ system involvement. The Marburg virus, for example, can produce nausea, vomiting, chest pain, a sore throat, abdominal pain, and diarrhea may appear. Symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction. These diseases are most prevalent in sub-Saharan Africa.



 

In 2002, the Lloviu filovirus was found in Schreiber bats (Miniopterus schreibersii) in northern Spain. This infection resulted in a massive die-off of these animals. Gabor Kemenesi and his colleagues from the National Laboratory of Virology at Szentagothai Research Center at the University of Pecs, Hungary successfully isolated and sequenced the Lloviu filovirus from Schreiber bats in Hungary. During a active surveillance of these bats, they found the Lloviu virus resident in these dead and living cave-dwelling bats.

Furthermore, antibody testing detected nine seropositive bats out of 74 live bats and four positives among 351 live bats sampled. The Lloviu virus is known to infect human cells in culture, but unlike the Ebola virus appears to be nonpathogenic to humans, at least for the time being.


Sunday, January 23, 2022

Epstein Barr Virus Infection May be Associated with the Onset of Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic and debilitating disease that is a result of the destruction of the myelin sheath that serves as insulation for the peripheral nerves within the central nervous system (CNS).  The loss of myelin has serious implications for the patient suffering from this syndrome – it results in a gradual deterioration of motor function. 

To date the etiology of this disease has been unclear.  It has long been suggested that Infection with the Epstein-Barr virus (EBV) may be responsible for triggering the onset of MS.  In a recent issue of the prestigious publication Science (January, 2022), Kjetil Bjornevik, from the Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, has provided compelling statistical evidence that EBV infection triggers the onset of MS.  According to the author, “analyzed EBV antibodies in serum from 801 individuals who developed MS among a cohort of >10 million people active in the US military over a 20-year period (1993–2013). Thirty-five of the 801 MS cases were initially EBV seronegative, and 34 became infected with EBV before the onset of MS. EBV seropositivity was nearly ubiquitous at the time of MS development, with only one of 801 MS cases being EBV seronegative at the time of MS onset. These findings provide compelling data that implicate EBV as the trigger for the development of MS.” 

EBV (see diagram below) preferentially attacks B cells; B cells are the part of the immune system repertoire responsible for the production of antibodies.   In MS the myelin sheath is degraded through an inflammatory response.  It has been shown that in MS the B cells responsible for this inflammatory are derived from plasmablasts that are generated in the marrow and take residence inside the brain and its internal lining.  These plasmablasts divide and produce clusters of daughter cells that produce immunoglobulins.  These immunoglobulins contain specific antibodies that target myelin-producing glial cells within the central nervous system (CNS).

EBV Virus


One of the accepted therapies that attempt to take advantage of this etiology is the use of monoclonal antibodies that target CD20 - a protein preferentially found on the surface of B cells.  However, it has significant drawbacks in so far as these monoclonals do not readily pass through the blood brain barrier (BBB) and they are unable to bind to plasmablasts.

What remains unclear, however, is the mechanism through which EBV triggers this sequence of events in MS patients.  One possibility involves what is referred to as molecular mimicry in which some EBV proteins may be similar enough in structure to myelin that the immune system is induced to produce antibodies against the infected individual’s myelin and CNS antigens – this would represent an autoimmune response.  In addition, EBV encodes an interleukin-10–like protein, which activates B cells.  The author of this study, reports that recent evidence seems to suggest that molecular mimicry may be the actual mechanism underlying the association between EBV infection and MS.

The results of these kind intensive studies of the etiology of MS are extremely important in that the product of this work may finally produce effective therapies for MS patients.