The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Heat shock proteins (HSPs) serve to correct proteins’ conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis—a “passive approach”. On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells;on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the “active approach”. On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain “mysteries” behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.

The Integrative Five-Fluid Circulation System in the Human Body

Water is the key medium to transport numerous constituents and to provide a platform for physiological processes to take place in the living organisms in general;it also participates actively in many of these processes. In humans, there are different vehicles to contain water and its constituents. Our objective is to find out whether there is an overall water-base circulation system in the human body by analyzing the updated findings of different research groups on the physiological functions of various seemingly isolated fluid systems. By 1963, there were five separate fluid systems discovered in mammalians: (i) The Primo Vasculature Fluid (PVF) with protein precursors and micro cells held in the Primo Vasculature System (PVS). (ii) Blood with its constituents held in the cardio vasculature. (iii) Extracranial interstitial fluid (ISF) whose vehicle had a very irregular structure—the interstitium all over the body. (iv) The cerebrospinal fluid had been considered to be within the brain ventricles and spinal canal. (v) The extra-cranial lymphatic system which drained ISF, and had been known to join the subclavian vein. Fluid (i) was first reported in 1963 and fluids (ii) to (v) have been known for many decades, but the failure to detect a lymphatic system inside the skull has also been a mystery for many decades. The intra-cranial ISF (which we name as BISF) has drawn little attention, apart from discussing the mechanism of the blood-brain-barrier. During the past decade, there has been direct evidence indicating that CSF and BISF are actually mixed. After that, the intracranial lymphatic system was discovered and confirmed in animal models only slightly over one year back, and we called such fluid as glymphatic-fluid. After reviewing the stated “classical” five fluid systems together with the new findings in Sections 2 - 7, we propose, for the first time, that the PVF, the blood, ISF, a mixture of CSF-BISF, and a mixture of glymphatic-fluid and lymph form an integrative circulation system in water base in the human and other mammalian bodies, as schematically represented in the last section. In this paper, we point out the positive correlation of chronic neuro degenerative diseases such as Alzheimer’s disease, Parkinson’s diseases and the insufficient brain wastes clearance by the glymphatic system. We also discuss the role played by the venous vessels as part of such clearance in upright posture. Moreover, simple non-invasive maneuver techniques are introduced here, as one example of enhancement of glymphatic fluid flow out of the skull to join the lymphatic system. A series of questions are raised in Section 8, the answers to which would help us to understand the transition from physio- to pathological states in the development of many diseases. Detailed analysis of this paper leads us to consider that research in understanding this integrative circulation system is only at the infancy stage, and fluid dynamics investigation seems to be the plausible modality of approach in the near future.

New Insights on Stimulating the Lung Meridian Based on Modern Neurophysiology

Chronic obstructive pulmonary diseases (COPD) caused 3.2 million deaths worldwide in 2015 [1]. Therapeutic treatments, including acupuncture & herbal medicine have been applied to handle this disease with certain efficacies in the domain of traditional Chinese Medicine. However, very few analyses on the mechanisms behind the efficacies can be found in literature. Without understanding the basic mechanisms behind any medical treatment is the bottle-neck to advancement of possibly effective therapy of any kind. Based on this argument, we start off a series of studies on the neurophysiological consequence of acupuncture/acupressure applied to the Lung Meridian. We explain how the sensory signals (by sympathetic nerves) follow the spinothalamic tracts to the thalamus and then to the primary sensory cortex. The neurons of these ascending tracts synapse the motor neurons which activate some of the different organs of the respiratory system—diaphragm, nose, larynx, scalene muscles, trachea, lungs, intercostal and supporting abdominal muscles. The sensory signals at the neo-cortex are then passed on to the motor neurons in the primary motor cortex. The activated neurons project mainly along two descending tracts: anterior and lateral corticospinal tracts. Neurons of these tracts project to activate again some of the respiratory organs, plus the motors neurons related to the digestive system, including the large intestine. On the other hand, an intrinsic, automatic breathing system in the brainstem sends rhythmic signals through the bulbospinal tract system, which contains a special type of neurons—the pre-sympathetic neurons. These neurons, via interneuron relay, synapse motor neurons which mobilize the organs of the respiratory organs to function. Since the “Lung Meridian induced” signals and the intrinsic signals are sent by different types of neurons, we propose that stimulating the Lung Meridian might activate/supplement the action of the intrinsic system during some pathological states. Though the initial suggestion is supported by in vitro/(in vivo) experiments in detailed steps, clinical trials await future development.

Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (I) Basics and the Diseases of Tendon

We analyze the crucial biochemical and biophysical properties of the basic constituents—connective tissues (CT), and interstitial fluid (IF) constituting the non-cellular part of the fascia. We provide ample evidence that the resident cells and cells in transit in the fascia are continuously interacting with the non-cellular constituents to form an active organ with well-defined functions. We show evidence that pathological states of diseases of internal organs, as well as that of the constituents of the fascia itself, manifest in certain CTIF domains of the fascia. Numerous diseases originate from imbalance of the digestion and synthesis of the native collagen triple helices. Review on the scanning electron microscopy examination of cross-section of tendons indicates that micro-fibrils of collagen I form regular geometrical structures, supporting the hypothesis that the collagen fibrils assemble like liquid crystals. Information on the age of Achilles tendons has been reported, based on dating of the 14C atoms generated from the nuclear bomb tests in 1955-1963. The causes of spontaneous tendon rupture and tendinopathy are analyzed. Plausible clinical measures to treat tendinopathy are briefly discussed, including the application of synthetic mechano-growth factor, glyceryl trinitrate patch (to supply nitric oxide), platelet rich plasma, proteomic profile analysis and microRNA 29a therapy.

A Novel Apprehension of the Primary Lung Meridian, Sinew Channel, Divergent Channel, Luo-Connecting Channel Acting as a Single Unit System to Serve Respiration Function Based on Modern Neurophysiology and Kinesiology

The TCM philosophy of a meridian and associated channels pertains to the specific function of one or more organs. We define the Lung Primary Meridian (LUM) together with the Lung Sinew (LUSC), Divergent (LUDC), Luo-connecting (LULCC) Channels as a system of routes plus some parts of the body (such as muscles) to fulfil respiration, as a main function under different situations. There is very limited information about the Lung associated channels in classical literature of TCM. With a clear focus on the function of respiration, we have carried out a detailed analysis of the biomedical consequence of stimulating the LUM, analysed the roles played by LUSC, LUDC, and LULCC. The updated LUM and LUDC include acupoints of other meridians, serving the same purpose of performing satisfactory respiration starting from checking the quality of the inflow through the nose. The LUSC includes the respiratory muscles (plus the associated connective tissues) extending to various parts of the body. The muscles of the limb (as part of the LUSC) embrace the nerves that provide routes for somatosensory reflexes and play the role of locomotion, providing voluntary respiration via the pectoralis muscles. The muscles of LUSC are bounded by stiff connective tissue layers, forming compartments, and are part of the pulley system for various body locomotions. Within a compartment, the interstitial fluid, blood, lymph flows must be potent to protect the associated nerves related to LUM;the healthy state of the LUSC also provides freedom of various types of locomotion. The LULCC exists because the vagus nerve has a part of it passing through the spinal cords all the way down to the sacrum domain, with exiting nerve innervating two-third of the large intestine. The crucial steps of our deductions are supported by experimental evidence based on modern neurophysiology and kinesiology. We discover that all the four channels stated above work as a unit system to allow respiration to be possible under various postures/conditions. The complexity of structures and processes is eased off by providing 29 figures and 13 tables for the relevant muscles and nerves. In addition to respiration, the Lung system in TCM context includes interaction of this system with the sweat gland and neuroendocrine system;such aspects will be left to another study.

Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (II) From Pancreatitis to Pancreatic Cancer Invasion, Formation of Stroma around the Primary Tumor in the Fascia, to Early Detection of Non-Coding microRNAs in Body Fluids and Development of Drugs to Treat Different Stages of Pancreatic Cancer

Patients suffering from pancreatic ductal adenocarcinoma (PDAC) have an average survival time of 4 - 6 months after confirmed diagnosis. The primary tumor is surrounded by a thick interstitial fluid with high pressure and dense distribution of collagen, forming a huge stroma, rendering the tumor resistant to chemo- and radiotherapy. From the genetic point of view, pancreatic carcinogenesis is driven by mutations, resulting in common activation of the oncogene KRAS, and/or inactivation of one or more of the tumor suppressor genes CDKN2A, TP53, SMAD4 [1]. The pancreas is a mixed exocrine and autocrine organ, with different cell types building up the organ. The pathogenesis involves more than 13 signaling pathways at different stages. Off-balance of the function of the proteins in these pathways due to the stated 4 plus other mutations could readily lead to carcinogenesis. We first present the basic mechanism of these 13 relevant pathways. We then provide a detailed analysis of the progression of this disease, from pancreatitis to tumor formation and metastasis, with special attention on the roles played by the newly discover calcium channel Piezo, stellate cells, stem-cell-like cells, and the concept invadopodium. Thirty potential drugs, based on in vitro and xenograft experiments from different groups, are discussed, including vitamins A, Tocotrienols-E, and D, chemical compounds, non-coding micro RNAs, circular RNA, piwi-interacting RNAs. The recent detection of exosomes enclosing many of these RNAs in body fluids gives us hope of developing early detection methodology because these RNAs carry messages for cell-cell communication at a distance. Delivery of potent drugs by nanoparticles gives us chance to send drugs through the stroma to target the tumor. Since body fluids form a circulating system, together with the connective tissues (where the tumor is associated) form the largest organ—the fascia, we conclude that manifestation of successive pathological states of pancreatic carcinogenesis can be found in compartments of the fascia. We present 17 figures, hoping to ease off the complexity of the pathogenesis of this most lethal cancer disease.