Healthcare analytics, AI solutions for biological big data, providing an AI platform for the biotech, life sciences, medical and pharmaceutical industries, as well as for related technological approaches, i.e., curation and text analysis with machine learning and other activities related to AI applications to these industries.
The Payload Revolution: Redefining the Future of Antibody-Drug Conjugates (ADCs)
Curator: Dr. Sudipta Saha, Ph. D.
Antibody-Drug Conjugates (ADCs) are at the forefront of targeted cancer therapy. While much attention has focused on antibody engineering and linker technology, the real breakthrough may lie in the payload—the cytotoxic compound delivered to tumor cells.
Historically, ADC payloads have relied on microtubule inhibitors like MMAE and MMAF, and topoisomerase I inhibitors such as SN-38 and Exatecan. These payloads are potent but limited in diversity, making differentiation difficult in a crowded therapeutic landscape.
The next wave of innovation introduces unconventional payloads with novel mechanisms:
ISACs (Immune-Stimulating ADCs) activate the immune system locally.
Protein degraders eliminate cancer-critical proteins without inhibiting them directly.
Urease-based and membrane-disrupting agents affect the tumor microenvironment.
RNA polymerase inhibitors and peptide-based payloads offer precision with reduced systemic toxicity.
This shift also places new demands on linker design. Linkers must now accommodate payloads with diverse chemical properties and release them selectively at the tumor site. A payload–linker mismatch could compromise both safety and efficacy.
Ultimately, the focus is shifting toward payloads not just as cytotoxins, but as precision-guided interventions. This evolution could redefine how ADCs are developed and positioned in treatment regimens, enabling breakthroughs in resistant and heterogeneous cancers. The ADC revolution is payload-powered—and the future belongs to those who can innovate at the molecular level.
Protein Switches: The Programmable Future of Bio-therapeutics
Curator: Dr. Sudipta Saha, Ph. D.
A PNAS paper entitled “A protein therapeutic modality founded on molecular regulation” presents a pioneering approach to creating protein switches—engineered enzymes that activate only in specific molecular environments. This design introduces a new class of context-dependent therapeutics for precision medicine.
Using domain-insertion techniques, researchers inserted ligand-binding domains into scaffold proteins like β-lactamase. These proteins remain inactive until encountering a specific small molecule, which triggers a conformational change and restores enzymatic activity. This offers precise spatiotemporal control—ideal for minimizing off-target effects.
One key innovation is the systematic insertional mutagenesis that identifies functional switch sites across the protein scaffold. This enables the construction of vast protein libraries, increasing the likelihood of finding optimal switch configurations. Furthermore, the approach is modular—different binding domains and enzymes can be combined to create switches tailored to specific clinical contexts.
These smart proteins can be programmed to respond to cancer biomarkers, metabolite levels, or disease-specific molecular cues. By activating only under disease conditions, they provide a blueprint for next-generation bio-therapeutics—potent, selective, and safer.
The method also opens avenues for drug delivery systems, diagnostics, and biosensors, where conditional activation is critical. Overall, this work represents a conceptual leap in synthetic biology and bioengineering, with implications spanning oncology, infectious disease, and regenerative medicine.
Chicoric Acid: A Natural Boost for Glucose Metabolism via AMPK Activation
Reporter: Dr. Sudipta Saha, Ph.D.
The study published in Journal of Functional Foods explores the molecular mechanisms underlying chicoric acid’s (CA) role in glucose metabolism. Chicoric acid, a natural polyphenolic compound found in plants like chicory and basil, has garnered attention for its anti-inflammatory and antidiabetic properties. The researchers investigated its potential to regulate glucose uptake and insulin sensitivity, focusing on the AMP-activated protein kinase (AMPK) pathway.
The experiments demonstrated that chicoric acid significantly enhances glucose uptake in insulin-sensitive and insulin-resistant cells. This effect was primarily mediated through the activation of AMPKα, a key metabolic regulator that responds to energy stress. The phosphorylation of AMPKα triggered downstream signaling cascades, including the activation of Akt, a protein crucial for glucose transporter type 4 (GLUT4) translocation to the cell membrane, thereby facilitating glucose uptake.
Interestingly, the study also noted that inhibiting AMPK activity reduced CA-induced Akt phosphorylation, confirming that AMPK activation is essential for chicoric acid’s metabolic effects. Furthermore, CA showed potential in improving insulin sensitivity, which is impaired in type 2 diabetes, by mitigating cellular oxidative stress and inflammation.
The findings suggest that chicoric acid could serve as a promising therapeutic candidate for managing diabetes and metabolic disorders. By targeting the AMPKα-Akt signaling axis, CA offers a dual benefit of improving glucose metabolism and reducing insulin resistance, highlighting its potential as a natural alternative for metabolic health interventions.
SNU-BioTalk 2025: Symphony of Cellular Signals in Metabolism and Immune Response – International Conference at Sister Nivedita University, Kolkata, India on 16 & 17 January 2025
Joint Convenor: Dr. Sudipta Saha (Member of LPBI since 2012)
About the Conference:
The International Conference on ‘Symphony of Cellular Signals in Metabolism and Immune Response’ focuses on the complex signalling pathways governing cellular functions in health and disease. It will explore the cellular mechanisms that regulate metabolism, immune responses, and survival, highlighting advances in medical science and biotechnology. Bringing together leading experts and emerging researchers, the conference will feature keynote lectures, panel discussions, research presentations, and interactive sessions, all designed to foster collaboration and innovation. By promoting an exchange of ideas, the event aims to drive transformative insights and solutions that impact human health and sustainable healthcare practices.
The conference will also be livestreamed on YouTube and Facebook
This programme will also host I-STEM: Indian Science, Technology and Engineering facilities Map (I-STEM) is a dynamic and interactive national portal for research cooperation.
Thrust areas:
Intracellular signalling processes of cellular metabolism
Signalling pathways in physiological and pathological processes
2024 Nobel Prize in Physiology or Medicine jointly to Victor Ambros and Gary Ruvkun for the discovery of microRNA and its role in post-transcriptional gene regulation
Reporter: Aviva Lev-Ari, PhD, RN
Updated 10/22/2024
The revolution in our understanding of transcriptional regulation and dark regions of the genome
The genome of higher eukaryotes are comprised of multiple exonic and intronic regions, with coding and noncoding DNA respectively. Much of the DNA sequence between exonic regions of genes, the sequences encoding the amino acids of a polypeptide, was considered either promoter regions regulating an exonic sequence or ‘junk DNA’, which had merely separated exons and their regulatory elements. It was not considered that this dark DNA or junk DNA was important in regulating transcription of genes. It was felt that most gene regulation occurred in promoter regions by response element factors which bound to specific sequences within these regions.
MicroRNA (miRNA), originally discovered in Caenorhabditis elegans, is found in most eukaryotes, including humans [1–3]. It is predicted that miRNA account for 1-5% of the human genome and regulate at least 30% of protein-coding genes [4–8]. To date, 940 distinct miRNAs molecules have been identified within the human genome [9–12] (http://microrna.sanger.ac.uk accessed July 20, 2010). Although little is currently known about the specific targets and biological functions of miRNA molecules thus far, it is evident that miRNA plays a crucial role in the regulation of gene expression controlling diverse cellular and metabolic pathways.
MiRNA are small, evolutionary conserved, single-stranded, non-coding RNA molecules that bind target mRNA to prevent protein production by one of two distinct mechanisms. Mature miRNA is generated through two-step cleavage of primary miRNA (pri-miRNA), which incorporates into the effector complex RNA-induced silencing complex (RISC). The miRNA functions as a guide by base-pairing with target mRNA to negatively regulate its expression. The level of complementarity between the guide and mRNA target determines which silencing mechanism will be employed; cleavage of target messenger RNA (mRNA) with subsequent degradation or translation inhibition
Fig. (1). MicroRNA maturation and function.
Figure. miRNA maturation and function. Source: Macfarlane LA, Murphy PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010 Nov;11(7):537-61. doi: 10.2174/138920210793175895.
The following is an interview in the journal Journal of Cellular Biology with Dr, Victor Ambros on his discovery of miRNA.
Source: Ambros V. Victor Ambros: the broad scope of microRNAs. Interview by Caitlin Sedwick. J Cell Biol. 2013 May 13;201(4):492-3. doi: 10.1083/jcb.2014pi. PMID: 23671307; PMCID: PMC3653358.
Once, we thought we understood all there was to know about how gene expression is regulated: A cell can tinker with the expression level of a given protein’s messenger RNA by modifying the activity, abundance, and type of transcription factors in the nucleus or with the RNA’s stability once it is made. But then came a surprising story about a short RNA in C. elegans called lin-4, which didn’t encode a protein but prevented expression of the protein encoded by another gene, lin-14, through antisense binding to lin-14 mRNA (1, 2). Today, we know that lin-4 was just the first example of a large number of small RNAs, called microRNAs, which regulate the expression of various other proteins in a similar way.
Victor Ambros, whose lab published that first story about lin-4, has been studying microRNAs (3, 4) and their regulation (5, 6) ever since, pushing forward our understanding of this powerful mechanism. We called him at his office at the University of Massachusetts Medical School to get some perspective on microRNAs and his career and to learn about some of the latest developments in his lab.
“That shared discovery is one of the most precious moments in my career.”
FROM FARM TO LAB TABLE
How did you end up doing a PhD with David Baltimore?
I was the first scientist in my family. My dad was an immigrant from Poland. He came to the States just after World War II and met my mom. They got married, moved to a farm in Vermont, and started farming. My siblings and I grew up amongst the cows and pigs and helped with the haying and cutting corn, stuff like that.
When I was about nine, I got interested in science, and after that I always wanted to be a scientist. I was an amateur astronomer; I built a telescope and started to imagine that I could actually do astronomy or physics as an occupation. But I quickly changed my mind when I reached college, in part because I realized that my math skills weren’t really up to the task of being a physicist and also because I discovered molecular biology and genetics and just fell in love with both subjects. David taught one of the advanced biology classes I took as an undergraduate at MIT, and that probably had some influence on my decision to work with him. After college, I worked as a technician in David’s lab for a year. I liked it a lot and stayed on in his lab when I entered graduate school at MIT. I was lucky because I had gotten a little bit of traction on a project and continued on that as a grad student, so I ended up finishing grad school fairly efficiently.
Had you any idea at the time what the nature of the lin-4 mutant was?
The assumption was that it was a protein product. I mean, nobody ever thought that there would be any other kind of regulator. There really wasn’t any reason to imagine that there were any other kinds of molecules necessary, other than proteins, to carry out everything that’s done in a cell—especially with regard to the regulation of gene expression. The complexity of gene regulation by proteins alone was so enormous that I never imagined—and nobody I knew imagined—that we needed to look for new kinds of regulatory molecules. The realization that lin-4 was antisense to the 3′-untranslated region of lin-14 was totally the result of communication between Gary and me. That shared discovery is one of the most precious moments in my career. But at the time I didn’t realize that this might be the first example of a general mechanism for regulating gene expression because I was prone to thinking that whatever I was studying in the worm was not generally applicable. It wasn’t until genome sequences were made available that the prevalence of this mechanism became clear.
THE RIGHT CONTEXT
You’ve moved to studying processes that modulate microRNA function…
One protein we’ve studied is called Nhl-2. It’s an example of an emerging class of proteins that can modulate, positively or negatively, the RNA-induced silencing complex (RISC) that inhibits mRNAs targeted by microRNAs. This class of genes may have either general effects on RISC activity or, in some cases, more specific effects. One area of interest in the lab right now is trying to understand the specific outcomes for the regulation of particular microRNAs. Do they always interact with all their targets, or is their activity on some targets promoted or inhibited at the expense of other targets? Can their interaction with certain targets be modified depending on context? We’re using genetic and genomic approaches to identify new modulatory cofactors.
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Victor Ambros was born in 1953 in Hanover, New Hampshire, USA. He received his PhD from Massachusetts Institute of Technology (MIT), Cambridge, MA, in 1979 where he also did postdoctoral research 1979-1985. He became a Principal Investigator at Harvard University, Cambridge, MA in 1985. He was Professor at Dartmouth Medical School from 1992-2007 and he is now Silverman Professor of Natural Science at the University of Massachusetts Medical School, Worcester, MA.
Gary Ruvkun was born in Berkeley, California, USA in 1952. He received his PhD from Harvard University in 1982. He was a postdoctoral fellow at Massachusetts Institute of Technology (MIT), Cambridge, MA, 1982-1985. He became a Principal Investigator at Massachusetts General Hospital and Harvard Medical School in 1985, where he is now Professor of Genetics.
This year’s Nobel Prize honors two scientists for their discovery of a fundamental principle governing how gene activity is regulated.
The information stored within our chromosomes can be likened to an instruction manual for all cells in our body. Every cell contains the same chromosomes, so every cell contains exactly the same set of genes and exactly the same set of instructions. Yet, different cell types, such as muscle and nerve cells, have very distinct characteristics. How do these differences arise? The answer lies in gene regulation, which allows each cell to select only the relevant instructions. This ensures that only the correct set of genes is active in each cell type.
Victor Ambros and Gary Ruvkun were interested in how different cell types develop. They discovered microRNA, a new class of tiny RNA molecules that play a crucial role in gene regulation. Their groundbreaking discovery revealed a completely new principle of gene regulation that turned out to be essential for multicellular organisms, including humans. It is now known that the human genome codes for over one thousand microRNAs. Their surprising discovery revealed an entirely new dimension to gene regulation. MicroRNAs are proving to be fundamentally important for how organisms develop and function.
Ambros and Ruvkun were interested in genes that control the timing of activation of different genetic programs, ensuring that various cell types develop at the right time. They studied two mutant strains of worms, lin-4 and lin-14, that displayed defects in the timing of activation of genetic programs during development. The laureates wanted to identify the mutated genes and understand their function. Ambros had previously shown that the lin-4 gene appeared to be a negative regulator of the lin-14 gene. However, how the lin-14 activity was blocked was unknown. Ambros and Ruvkun were intrigued by these mutants and their potential relationship and set out to resolve these mysteries.
Ambros and Ruvkun performed further experiments showing that the lin-4 microRNA turns off lin-14 by binding to the complementary sequences in its mRNA, blocking the production of lin-14 protein. A new principle of gene regulation, mediated by a previously unknown type of RNA, microRNA, had been discovered! The results were published in 1993 in two articles in the journal Cell.
Ruvkun cloned let-7, a second gene encoding a microRNA. The gene is conserved in evolution, and it is now known that microRNA regulation is universal among multicellular organisms.
Andrew Z. Fire and Craig C. Mello, awarded the Nobel Prize in 2006, described RNA interference, where specific mRNA-molecules are inactivated by adding double-stranded RNA to cells.
Mutations in one of the proteins required for microRNA production result in the DICER1 syndrome, a rare but severe syndrome linked to cancer in various organs and tissues.
Armored CD7-CAR T Cells: A Fratricide-Resistant Solution for T-ALL Therapy
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
This research reported in Nature Medicine addresses the challenge of treating T-cell acute lymphoblastic leukemia (T-ALL) with CAR T-cell therapy, particularly focusing on CD7, a surface marker highly expressed on T-ALL cells. The authors develop a novel CAR T-cell therapy that targets CD7, but with a crucial innovation which is fratricide resistance.
Fratricide, a phenomenon where CAR T cells kill each other (killing sister cells) due to shared CD7 expression, has been a significant problem in using CD7-directed therapies. To overcome this, the researchers made CD7-negative CAR T cells (CD7-CAR T cells) by knocking out CD7 from the CAR T cells themselves, preventing them from attacking one another.
Their preclinical results show that these CD7-CAR T cells exhibit strong anti-leukemic activity in T-ALL models, both in vitro and in vivo.
The fratricide-resistant T cells not only maintain their potency but also display enhanced proliferation and persistence, crucial for sustained therapeutic effects. Additionally,
the study highlights the feasibility and safety of this approach by demonstrating no adverse off-target effects or side effects, making it a potentially promising treatment for T-ALL patients who have limited options.
The research presents a significant advancement in CAR T-cell therapy by addressing the challenge of fratricide, offering a new, effective, and safe therapeutic option for T-ALL patients. The development of fratricide-resistant CD7-CAR T cells could lead to more successful outcomes in clinical applications, revolutionizing the treatment for T-ALL patients.
Live Conference Coverage: International Dialogue in Gynecological Oncology, From Bench to Bedside, Ovarian Cancer
Reporter: Stephen J. Williams, Ph.D.
Join Live on Wednesday May 22, 2024 for an international discussion on the current state of ovarian cancer diagnostics and therapeutics, and potential therapies and biomarkers, and biotargets. Topics including potential new molecular targets for development of ovarian therapeutics, current changes in ovarian cancer clinical treatment protocols, chemo-resistance, and the use of Artificial Intelligence (AI) in the diagnosis and treatment of cancer will be discussed.
10/15.10 We Have Never Been Only Human: a new perspective to defeat ovarian cancer (C. Martinelli)
Molecular Section
20/15.20 DNA Repair mechanisms: understanding their role in cancer development and chemoresistance (L. Alfano)
35/15.35 Progranulins: a new target for oncological treatment (A. Morrione)
50/15.50 Modulation of gene expression and its applications (M. Cuomo)
10.05/16.05 Commanding the cell cycle: the role of CDKs (S.R. Burk
10.20/16.20 Drug development from nature (M. D’Angelo
Clinical Section
05/17.05 Core principles of Radiologic Diagnosis & Staging in Ovarian Cancer(A. Blandino)
20/17.20 Key Indications for Nuclear Medicine in Ovarian Cancer (S. Baldari)
35/17.35 Cutting Edge Decision: Understanding Surgical Indications and Outcomes in Ovarian Cancer (A. Ercoli)
50/17.50 Gold Standard in Oncology for Ovarian Cancer (N. Silvestris)
12.05/18.05 Role of Radiotherapy in Ovarian Cancer (S. Pergolizzi)
Conclusion
12.20/18.20 AI Applied to medical science (V. Carnevale)
Speakers
– Professor Alfredo Blandino: Professor Blandino holds the esteemed positions of Head of school of Radiology and director of the department of radiology at the University of Messina. He has made significant contributions to diagnostic imaging with over hundreds of publications to his name, Professor Blandino’s work exemplifies excellence and innovation in radiology.
– Professor Alfredo Ercoli, serves as the Director of the Department of Gynecology and Obstetrics at the “G. Martino” University Hospital in Messina. He is also head of school of gynecology and obstetrics at Messina University. Starting his research in France with studies on pelvic anatomy that became a cornerstone in medical literature, He is a pioneer in advanced gynecologic surgery, including laparoscopic and robotic procedures, having performed over thousands of surgical interventions. His research focuses on gynecologic oncology, advanced gynecologic surgery, and endometriosis, urogynecology. Professor Ercoli’s dedication to education and his numerous publications have significantly advanced the field of gynecology.
–Professor Sergio Baldari, an eminent figure in nuclear medicine. Professor Baldari is the Director of the department of nuclear medicine and head of school of nuclear medicine at the University of Messina. He has authored or co-authored over 500 publications, with a focus on diagnostic imaging and the use of PET and radiopharmaceuticals in cancer treatment. His leadership and expertise have been recognized through various prestigious positions and awards within the medical community.
– Professor Nicola Silvestris is the Director of UOC Oncologia Medica at the University of Messina. His extensive research in cancer, has led to over 360 peer-reviewed publications. Professor Silvestris has made significant contributions to translational research and the development of guidelines for managing complex oncological conditions. His work continues to shape the future of cancer treatment.
–Professor Stefano Pergolizzi, a leading expert in radiation oncology. Professor Pergolizzi serves as the Director of the department of radiotherapy and head of the school of radiotherapya at the University of Messina. He is also the president of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) His research focuses on advanced radiotherapy techniques for cancer treatment. With a career spanning several decades, Professor Pergolizzi has published numerous papers and has been instrumental in developing innovative therapeutic approaches. His dedication to patient care and education is exemplary.
Margherita D’angelo: Graduated in Molecular Biology with honors from the Federico II University of Naples.
Third year intern in Food Science at the Luigi Vanvitelli University of Naples.
Research intern in Molecular oncology with the project of developing novel drugs starting from food waste at the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University, Philadelphia (USA), directed by Dr A. Giordano.
Dr. Carnevale is an Associate Professor in the Institute for Computational Molecular Science in the College of Science & Technology, Temple University. He holds multiple NIH RO1 and NSF grants. Vincenzo Carnevale received B.Sc. and M.Sc. degrees in Physics from the University of Pisa and a PhD from SISSA – Scuola Internazionale Superiore di Studi Avanzati in Trieste, Italy. The Carnevale research group uses statistical physics and machine learning approaches to investigate sequence-structure-function relations in proteins. A central theme of the group’s research is how interactions give rise to collective phenomena and complex emergent behaviors. At the level of genes, the group is interested in epistasis – the complex entanglement phenomenon that causes amino acids to evolve in a concerted fashion – and how this shapes molecular evolution. At the cellular level, the group investigates how intermolecular interactions drive biomolecules toward self-organization and pattern formation. A long-term goal of the group is understanding the molecular underpinnings of electrical signaling in excitable cells. Toward these goals, the group applies and actively develops an extensive arsenal of theoretical and computational approaches including statistical (mean)field theories, Monte Carlo and molecular dynamics simulations, statistical inference of generative models, and deep learning.
Professor Andrea Morrione, Ph.D: Research Associate Professor, CST Temple University; After his studies in Biochemistry at Universita’ degli Studi Milano, Milan Italy, Dr. Morrione moved to USA in 1993 and has been working in the field of cancer biology since his postdoctoral training at the Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA in the laboratory of Dr. Renato Baserga, one of the leading experts in IGF-IR oncogenic signaling. In 1997 Dr. Morrione joined the Faculty of Thomas Jefferson University in the Department of Microbiology. In 2002 after receiving an NIH/NIDDK Career Development Award Dr. Morrione joined the Department of Urology at Jefferson where from 2008 to 2018 serves as the Director for Urology Basic Science and Associate Professor. Dr. Morrione joined the Department of Biology and the Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology as Associate Professor of Research, and he is currently professor of Research and Deputy Director of the Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology. He is a full member of the AACR.
Canio Martinelli, M.D.: Dr. Marinelli received his MD from Catholic University of the Sacred Heart in Rome, Visiting researcher at SHRO Temple University in Philadelphia, PhD candidate in Translational Molecular Medicine and Surgery & GYN-OB resident at UNIME. He has published numerous clinical papers in gynecologic oncology, risk reduction, and therapy and, most recently investigating clinical utilities of generative AI in gynecologic oncology.
Sharon Burk, Sharon Burk is a PhD student with Professor Antonio Giordano at the University of Siena, Italy in the department of Medical Biotechnologies, studying the role of Cyclin Dependent Kinase 10 in Triple Negative Breast Cancer. She received her Bachelor’s of Arts Degree from the University of California, Berkeley with a double major in molecular and cell biology and Italian studies. She is a member of AACR.
Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use
In this curation we wish to present two breaking through goals:
Goal 1:
Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer
Goal 2:
Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.
According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.
These eight subcellular pathologies can’t be measured at present time.
In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.
Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases
Glycation
Oxidative Stress
Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
Membrane instability
Inflammation in the gut [mucin layer and tight junctions]
Epigenetics/Methylation
Autophagy [AMPKbeta1 improvement in health span]
Diseases that are not Diseases: no drugs for them, only diet modification will help
Image source
Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease
These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:
Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL
In the Bioelecronics domain we are inspired by the work of the following three research sources:
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC
PENDING
THE VOICE of Stephen J. Williams, PhD
Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes
25% of US children have fatty liver
Type II diabetes can be manifested from fatty live with 151 million people worldwide affected moving up to 568 million in 7 years
A common myth is diabetes due to overweight condition driving the metabolic disease
There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
Thirty percent of ‘obese’ people just have high subcutaneous fat. the visceral fat is more problematic
there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects. Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
At any BMI some patients are insulin sensitive while some resistant
Visceral fat accumulation may be more due to chronic stress condition
Fructose can decrease liver mitochondrial function
A methionine and choline deficient diet can lead to rapid NASH development
The female reproductive lifespan is regulated by the menstrual cycle. Defined as the interval between the menarche and menopause, it is approximately 35 years in length on average. Based on current average human life expectancy figures, and excluding fertility issues, this means that the female body can bear children for almost half of its lifetime. Thus, within this time span many individuals may consider contraception at some point in their reproductive life. A wide variety of contraceptive methods are now available, which are broadly classified into hormonal and non-hormonal approaches. A normal menstrual cycle is controlled by a delicate interplay of hormones, including estrogen, progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), among others. These molecules are produced by the various glands in the body that make up the endocrine system.
Hormonal contraceptives – including the contraceptive pill, some intrauterine devices (IUDs) and hormonal implants – utilize exogenous (or synthetic) hormones to block or suppress ovulation, the phase of the menstrual cycle where an egg is released into the uterus. Beyond their use as methods to prevent pregnancy, hormonal contraceptives are also being increasingly used to suppress ovulation as a method for treating premenstrual syndromes. Hormonal contraceptives composed of exogenous estrogen and/or progesterone are commonly administered artificial means of birth control. Despite many benefits, adverse side effects associated with high doses such as thrombosis and myocardial infarction, cause hesitation to usage.
Scientists at the University of the Philippines and Roskilde University are exploring methods to optimize the dosage of exogenous hormones in such contraceptives. Their overall aim is the creation of patient-specific minimizing dosing schemes, to prevent adverse side effects that can be associated with hormonal contraceptive use and empower individuals in their contraceptive journey. Their research data showed evidence that the doses of exogenous hormones in certain contraceptive methods could be reduced, while still ensuring ovulation is suppressed. Reducing the total exogenous hormone dose by 92% in estrogen-only contraceptives, or the total dose by 43% in progesterone-only contraceptives, prevented ovulation according to the model. In contraceptives combining estrogen and progesterone, the doses could be reduced further.
Bacterial multidrug resistance problem solved by a broad-spectrum synthetic antibiotic
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
There is an increasing demand for new antibiotics that effectively treat patients with refractory bacteremia, do not evoke bacterial resistance, and can be readily modified to address current and anticipated patient needs. Recently scientists described a promising compound of COE (conjugated oligo electrolytes) family, COE2-2hexyl, that exhibited broad-spectrum antibacterial activity. COE2-2hexyl effectively-treated mice infected with bacteria derived from sepsis patients with refractory bacteremia, including a CRE K. pneumoniae strain resistant to nearly all clinical antibiotics tested. Notably, this lead compound did not evoke drug resistance in several pathogens tested. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to abrogate bacterial cell viability and the evolution of drug-resistance. Impeding these bacterial properties may occur through alteration of vital protein–protein or protein-lipid membrane interfaces – a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis. The diversity and ease of COE design and chemical synthesis have the potential to establish a new standard for drug design and personalized antibiotic treatment.
Recent studies have shown that small molecules can preferentially target bacterial membranes due to significant differences in lipid composition, presence of a cell wall, and the absence of cholesterol. The inner membranes of Gram-negative bacteria are generally more negatively charged at their surface because they contain more anionic lipids such as cardiolipin and phosphatidylglycerol within their outer leaflet compared to mammalian membranes. In contrast, membranes of mammalian cells are largely composed of more-neutral phospholipids, sphingomyelins, as well as cholesterol, which affords membrane rigidity and ability to withstand mechanical stresses; and may stabilize the membrane against structural damage to membrane-disrupting agents such as COEs. Consistent with these studies, COE2-2hexyl was well tolerated in mice, suggesting that COEs are not intrinsically toxic in vivo, which is often a primary concern with membrane-targeting antibiotics. The COE refinement workflow potentially accelerates lead compound optimization by more rapid screening of novel compounds for the iterative directed-design process. It also reduces the time and cost of subsequent biophysical characterization, medicinal chemistry and bioassays, ultimately facilitating the discovery of novel compounds with improved pharmacological properties.
Additionally, COEs provide an approach to gain new insights into microbial physiology, including membrane structure/function and mechanism of drug action/resistance, while also generating a suite of tools that enable the modulation of bacterial and mammalian membranes for scientific or manufacturing uses. Notably, further COE safety and efficacy studies are required to be conducted on a larger scale to ensure adequate understanding of the clinical benefits and risks to assure clinical efficacy and toxicity before COEs can be added to the therapeutic armamentarium. Despite these limitations, the ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. It enables the construction of a spectrum of compounds with the potential for development as a new versatile therapy for the emergence and rapid global spread of pathogens that are resistant to all, or nearly all, existing antimicrobial medicines.
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