As biomedical scientists we know, the uterus is centre stage in the teaching of reproduction. The uterus accepts an implanting embryo, protects and nurtures it, and at parturition, undergoes prolonged muscular activity to deliver the neonate. We also acknowledge that we cannot answer all the questions our students or patients may have in terms of its physiology. Why does the uterus not accept so many embryos? What determines the timing of parturition? Why do so many human labours require medical interventions? There remains a great need to better the physiology of reproduction.
My research focuses on the myometrium and its physiology and pathology. Despite being vital, there is still much that we do not understand about this unique smooth muscle. This limits our ability to predict, prevent and treat conditions which are major killers of mothers and babies – preterm deliveries and dysfunctional labours. Studies from my group have shown how myometrial blood flow, biochemistry and function are all intimately linked. In my presentation I will discuss what we know about the causes of, and effects of low pH on uterine contractions, and the clear link to dysfunctional labours. I will also report on a small randomized clinical trial which indicates that correction of the acidity by oral bicarbonate, can greatly improve delivery outcomes, and reduce the need for, potentially dangerous surgical interventions.
The global biomimic technology has made breakthroughs in recent years. We have also reconstituted in vitro lung models, lung-on-a-chip (LoC), respiratory system and intelligent detection technologies, aiming to replace animal experiments and achieve more accurate and reliable preclinical experimental data. These platforms include alveolar and airway models and simulated respiratory systems. We have also completed health assessments of air pollution and viral infections, and established in vitro disease models of chronic pulmonary obstructive disease and pulmonary fibrosis, and it also established the operation of lung tissue for more than 45 days in vitro, realizing the functions of inflammatory response, barrier damage, particle penetration, and integrated artificial intelligence image analysis. It can even simulate different breathing patterns to explore the therapeutic evaluation of inhaled nano-based therapeutics.
In recent years, the application of digital twins (DTs) in technology has received increasing attention and has been shown to reduce medical development time and costs. Therefore, we combine the innovative concepts of LoC and DTs, deepen the application of blockchain with LoC, integrate the personal health data database platform we created: Anivance AI, and build digital personalized virtual lungs: Lungteller, extending from real-world organs-on-chips to organs-on-cards of the metaverse. We hope that this biomimic platform will popularize daily health management in the future, assist doctors in diagnosis and improve the accuracy of medication, and promote the global health industry market, so as to achieve the vision of using digital medicine to change the traditional healthcare model.
In the early 1950, It revealed how complex carbohydrates are synthesized from, and broken down into simple sugars, and pathways for biosynthesis of pentose, and the catabolism of fatty acids. The Glucose-lipid metabolism is always mentioned as the Randle cycle, also known as glucose-fatty acid cycle. This process involves the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.
The laboratory evaluation of glucose metabolism includes glucagon, arginine, and oral glucose tolerance test to evaluate insulin secretion; HOMA and glucose clamp to evaluate the degree of resistance. We have studied insulin secretion by using oral glucose tolerance and arginine test and glucose clamp to evaluate insulin resistance in the patients with hyperthyroidism.
Although acetyl-CoA is both an end point of fatty acid catabolism and starting substrate for fatty synthesis, but entirely taking place in a different compartment of the cell. During starvation, severe insulin deficiency, the transfer of acyl-CoA from extra mitochondria to mitochondria through the action of carnitine acyl transferase, which glucagon playing an important role and ketone bodies formation through a numerous step in the process of beta oxidation.
On the other hand, for lipid metabolism especially triglyceride one, there are several types of lipases got involved including pancreatic lipase in patient with acute pancreatitis, hormone sensitive lipase in adipose tissue and lipoprotein lipase in blood vessel endothelium. So far, we also studied lipoprotein lipase activity and mass in the patients with hypertriglyceridemia.
In summary, from biochemical perspective in the process of glucose and lipid metabolic derangement, it may manifest a numerous aspects of laboratory test spectrum.
Precision medicine takes prevention and treatment strategies with individual variabilities into consideration. It chooses cancer as the top diseases target. Diabetes and CVD are also high in priority. Currently, the drawback of precision medicine is the lack of effective therapy for individual patients. Before the drug development can catch up, precision nutrition may help. Precision nutrition is defined as a field that leverages human individuality to promote nutritional strategies in disease prevention and treatment, particularly in type 2 diabetes (T2D) and cardiovascular disease (CVD). This lecture will briefly outline the metabolomic characteristics of these diseases and highlight why they are most helpful in precision medicine and precision nutrition.
Diabetes is the common soil for cardiometabolic disease, which is the most prevalent degenerative disease in humans. We propose that for achieving whole-body wellness, individual should avoid diabetes and its complications, maintain functional energy metabolism, and achieve healthy gut microbiota. Starting with insulin resistance, obesity, metabolic syndrome, T2D and its complications, such as CVD and diabetic nephropathy (DN), a new trend of their detection has shifted from elevated plasma glucose to elevated muscle protein wasting. Elevations of branched-chain amino acids (BCAAs; Val, Leu, and Ile) in the plasma, due to muscle protein breakdown, and aromatic amino acids (Trp, Phe, Tyr and His) have become the new targets to delineate prediabetes, early T2D and CVD. Muscle sets the pace of aging of other tissues. Sarcopenia, commonly found in T2D patients, is a disease in losing muscle mass and function. Precision medicine allows us to monitor these diseases. Precision nutrition may help us manage them more effectively.
Elevation of triacylglycerols (TG) and decrease in HDL-C, not LDL-C, is a sign for entering metabolic syndrome and T2D. The disease progression of metabolic syndrome, T2D, CVD and DN remains correlated with plasma BCAAs and their short-chain organic acids as catabolic metabolites. Diabetes patients have a higher risk for developing several types of cancer, especially liver, colorectal, breast, and prostate cancers. Current genomic and epigenomic analyses have identified many risk loci and the metabolomic platform has identified many onco-metabolites. Combination of genomics and metabolomics is the best approach to explore the potential portfolio of omics-based biomarkers.
Skin, the largest organ of human body, plays a key role in protecting the body against environmental pathogens and with numerous glands under the skin continually releasing metabolites and wastes onto the skin’s surface. Even some of these metabolites may be potential biomarkers for diseases, current analytical techniques are unable to efficiently characterize them for the difficulties in sampling, sample pretreatment, and their presence in extremely low quantity. In this study, an ambient ionization mass spectrometric technique—thermal desorption electrospray ionization tandem mass spectrometry (TD-ESI/MS/MS) was developed and applied to rapidly characterize trace drugs and potential metabolic biomarkers on skin without sample pretreatment, blood withdrawals, or urine collection. A stainless steel probe was used to gently scrap the skin surface for noninvasively skin sampling; the probe was then inserted into the ionization source to thermally desorb the analytes on it. The analytes were subsequently delivered by a nitrogen stream into an electrospray plume, where the analytes were ionized by reacting with the charged solvent species in the plume. Each analysis took less than 30 seconds to complete. With the features of simple, rapid and highly sensitive, TD-ESI/MS/MS was applied to determine metabolites profiles of patients with different diseases and normal controls. The results are helpful in understanding the relationship between skin metabolites and diseases.
Several drugs for targeted therapy of lung cancer patients were detected on patients’ skin. Detection of these drugs on skin without blood withdrawals or urine collection has the advantages for rapidly evaluating the effectiveness of the drugs and determination of individual pharmacokinetic profiles of drug on skin has the potential for precision medicine. The influence of physical therapy on the neurotransmitters on skin was studied. It was found that different individuals reacted differently on physical therapy. For some patients, it was found that certain metabolites were successfully stimulated on skin by physical therapy.
To explore the distribution of a metabolite or drug on whole body skin, three dimensional molecular imaging of skin metabolites were constructed from the data generated by multiple probe sampling (1400 probes) and TD-ESI/MS/MS analysis. The color of each sampling spot was assigned based on the intensity of the targeted metabolite signals. The molecular imaging reveal the distribution of drugs and nonpolar metabolites such as cholesterol and squalene on the surface of whole body.
Advances in stem cell research have given rise to organoid technology for generation of in vitro self-assembling three-dimensional cellular structures that stably retain key characteristics of the respective organs, can be generated either from adult tissue stem cells or induced pluripotent stem cells (iPSCs) of patients. In fact, cancer patient-derived organoids (PDOs) that have been shown to recapitulate the structures, specific functions, molecular characteristics, genomic alterations, expression profiles, and tumor microenvironment of primary tumors. The finding suggests cancer PDOs may be ideal platforms to not only be used to understand cancer mechanisms but also to identify and assess the efficacy of drugs for patients.
Although the five-year survival rate of colorectal cancer (CRC) is significantly high with localized stage (90%), only 38% of the patients are diagnosed at this stage. Therefore, finding high risk factors of CRC could prevent the disease at the early stage. Obesity and high-fat diet consumption are risk factors of CRC. In detail, oleic acids (OA) were found to accumulate in the adipose tissues of obese patients as well as being the most common long chain fatty acid in dietary lipid. The role of OA in colorectal cancer development is still controversary. in order to dissect how long chain fatty acid can contribute to malignant transformation of Kras-mutant colonic epithelia, organoids, derived from Lgr5+-EGFP mice (normal colon control), Lgr5+-EGFP-creER;LSL-KrasG12D mice (colonic epithelium harbored KrasG12D mutation) and AOM/DSS-induced CRC mice (cancerous colon control) were generated. We discovered that oleic acid can promote the malignant transformation of Kras-mutant colonic organoids through NFATc-relating pathway. The expansion of tumorigenic stem cells via induction of abnormal Paneth cell, possibly contribute to the potential of cancer-toward metaplasia in Kras-mutant organoids when exposing to high levels of oleic acid.
Clinically, addition of oxaliplatin to adjuvant 5-FU, such as FOLFOX (leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin), has significantly improved the disease-free survival in advanced colorectal cancer (CRC) patients, and serves as the first line adjuvant chemotherapy. However, more than 40% of patients remains refractory to oxaliplatin-based treatment. It is urgent to be able to predict the responsiveness toward oxaliplatin and to improve the efficacy in the resistant patients. Initially, we have established organoid lines from the biopsies of CRC patients, and performed drug sensitivity against oxaliplatin using patients-derived organoids. Notably, oxaliplatin sensitivity assessed in PDO lines in vitro was correlated to oxaliplatin sensitivity in PDO-xenografted tumors in vivo. In summary, our findings suggest organoid technologies can possibly be used to dissect role of metabolic reprogramming in development of CRC and PDOs are useful in informing decision-making on chemotherapy and in designing personalized chemotherapy for CRC patients.
Background
Increased ER stress has been implicated in the pathogenesis of organ fibrosis and atherosclerosis. The underlying molecular mechanisms by which ER stress contributes to fibrogenesis and atherogenesis, however, remain incompletely understood.
Approach
Using an approach of combined system biology and transcriptome profiling of human/mouse fibrotic and atherosclerotic tissue, we identified an ER protein thioredoxin domain containing 5 (TXNDC5) as a potentially important mediator of tissue fibrosis and atherosclerosis. We conducted a series of in vitro and in vivo experiments to determine the molecular mechanisms by which TXNDC5 mediates the development of organ fibrosis and atherogenesis.
Results
TXNDC5 was found to be both required and sufficient to promote organ (heart, lung , kidney and liver) fibrosis and disturbed flow-induced atherosclerosis. TXNDC5 promotes tissue fibrosis through enhancing the folding and stability of TGFBR1 and extracellular matrix (ECM) proteins, leading to the augmentation of fibrogenic TGFβ signaling, fibroblast activation and ECM production. TGFβ induces TXNDC5 upregulation in tissue fibroblasts through increased ER stress level and ATF6-mediated transcriptional control. Conditional knockout of TXNDC5 in tissue fibroblasts significantly mitigates cardiac, lung, kidney and liver fibrosis in response to injury. On the other hand, TXNDC5 is induced in arterial endothelial cells in response to disturbed flow under the regulation of mechanical sensing transcription factor KLF2, leading to endothelial dysfunction and atherogenesis by downregulating eNOS through HSF1-HSP90 signaling axis. Conditional knockout of endothelial TXNDC5 and treatment with TXNDC5-targeting CRISPR-nanoparticles both mitigates atherosclerosis in vivo.
Significance
This series of investigations identified a critical yet previously unidentified function of ER protein TXNDC5 in the pathogenesis of organ fibrosis and atherosclerosis. Targeting TXNDC5 can be a novel and powerful therapeutic approach against fibrosis-related organ dysfunction and atherogenesis.
Clinically, small molecules are most commonly quantified using spectrophotometry and immunoassays. There are instances when these approaches are limited with respect to sensitivity, specificity, and accuracy. Many laboratories have developed alternative solutions using LC-MS/MS to improve patient care. This presentation will describe work in our laboratory and others that builds a firm foundation for the widespread application of this superior technology to meet the needs of care providers and potentially expand our clinical use of the multiplexed measurement of small molecule metabolites.
