The Universal Non-Neuronal Nature of Parkinson's Disease: A Theory

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology of the majority of its cases remains unknown. In this manuscript, relevant published evidence is interpreted and integrated into a comprehensive hypothesis on the nature, origin, and inter-cellular mode of propagation of sporadic PD. We propose to characterize sporadic PD as a pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. A universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why ageing associated accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We propose that hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species homeostasis that arises with age in the hematopoietic stem-cell niche. We argue that cellular ageing is nevertheless unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of cellular propagation of the PD-state. We highlight recently published findings on the inter-cellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the inter-cellular transmission of the PD-state

The universal non-neuronal nature of parkinson's disease: a theory

Various recent developments of relevance to Parkinson's disease (PD) are discussed and integrated into a comprehensive hypothesis on the nature, origin and inter-cellular mode of propagation of late-onset sporadic PD. We propose to define sporadic PD as a characteristic pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. Although a universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why age accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We put forward hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue why, nonetheless, such a process is unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of propagation of the PD-state. We highlight recent findings on the intercellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the intercellular propagation of the PD-state

Current Strategies for Prevention and Treatment of Equine Postoperative Ileus: A Multimodal Approach

Equine paralytic (postoperative) ileus generally refers to an acute condition of impaired gastrointestinal motility. Paralytic ileus is most frequently seen following abdominal surgery on the small intestine in horses. Three main mechanisms are involved separately or simultaneously in its causation, namely neurogenic-endocrinic, inflammatory-endotoxic and pharmacological mechanisms. Regardless of the cause, equine paralytic ileus can be fatal, if not properly diagnosed and treated. Over the past 22 years (1997–2019), we have diagnosed and treated more than 180 horses with postoperative ileus using differing methods. Based on our results and experience, and that of others, we have developed a multimodal strategy to reduce the incidence of postoperative ileus. This has resulted in effective treatment of ileus-diagnosed patients in 94% of cases, a significant improvement in survival rates over the last 20 years. In this review, we described pre-, intra-, and postoperative multiple supplementary preventative and treatment procedures that cure this condition. These methods are dependent on individual cases but include the control of endotoxemia and inflammation, as well as using the least traumatic surgical techniques, carrying out the pelvic flexure colotomy, improved anesthesia techniques, treating with continuous postoperative peritoneal lavage, the use of fluid, antibiotic and NSAIDs therapy, according to a scheme the use of different prokinetic agents (including metoclopramide, neostigmine methylsulfate and domperidone), nasogastric decompression, management to minimize the surgical and postoperative stress reaction and judicious timing of postoperative feeding of horses

Promising Applications of Tumor Spheroids and Organoids for Personalized Medicine

One of the promising directions in personalized medicine is the use of three-dimensional (3D) tumor models such as spheroids and organoids. Spheroids and organoids are three-dimensional cultures of tumor cells that can be obtained from patient tissue and, using high-throughput personalized medicine methods, provide a suitable therapy for that patient. These 3D models can be obtained from most types of tumors, which provides opportunities for the creation of biobanks with appropriate patient materials that can be used to screen drugs and facilitate the development of therapeutic agents. It should be noted that the use of spheroids and organoids would expand the understanding of tumor biology and its microenvironment, help develop new in vitro platforms for drug testing and create new therapeutic strategies. In this review, we discuss 3D tumor spheroid and organoid models, their advantages and disadvantages, and evaluate their promising use in personalized medicine

Role of Viruses in the Pathogenesis of Multiple Sclerosis

Multiple sclerosis (MS) is an immune inflammatory disease, where the underlying etiological cause remains elusive. Multiple triggering factors have been suggested, including environmental, genetic and gender components. However, underlying infectious triggers to the disease are also suspected. There is an increasing abundance of evidence supporting a viral etiology to MS, including the efficacy of interferon therapy and over-detection of viral antibodies and nucleic acids when compared with healthy patients. Several viruses have been proposed as potential triggering agents, including Epstein-Barr virus, human herpesvirus 6, varicella-zoster virus, cytomegalovirus, John Cunningham virus and human endogenous retroviruses. These viruses are all near ubiquitous and have a high prevalence in adult populations (or in the case of the retroviruses are actually part of the genome). They can establish lifelong infections with periods of reactivation, which may be linked to the relapsing nature of MS. In this review, the evidence for a role for viral infection in MS will be discussed with an emphasis on immune system activation related to MS disease pathogenesis

Mitochondria donation by mesenchymal stem cells: current understanding and mitochondria transplantation strategies

The phenomenon of mitochondria donation is found in various tissues of humans and animals and is attracting increasing attention. To date, numerous studies have described the transfer of mitochondria from stem cells to injured cells, leading to increased ATP production, restoration of mitochondria function and rescue of recipient cells from apoptosis. Mitochondria transplantation is considered as a novel therapeutic approach for the treatment of mitochondrial diseases and mitochondrial function deficiency. Mitochondrial dysfunction affects cells with high energy needs such as neural, skeletal muscles, heart and liver cells, and plays a crucial role in type 2 diabetes, as well as Parkinson's, Alzheimer's diseases, ischemia, stroke, cancer and age-related disorders. In this review, we summarize recent findings in the field of mitochondria donation and mechanism of mitochondria transfer between cells. We review the existing clinical trials and discuss advantages and disadvantages of mitochondrial transplantation strategies based on the injection of stem cells, isolated functional mitochondria or EVs containing mitochondria

Investigation into Whether Proximal Suspensory Desmitis of the Hindlimb Could Predispose Horses to Sacroiliac Disease

Proximal suspensory desmopathy/desmitis (PSD) of the hindlimb is a well understood condition with widely accepted treatment protocols; however, there is little research demonstrating understanding or potential correlation between hindlimb PSD and sacroiliac disease (SID). Several studies have examined the co-existence of hindlimb PSD and SID each investigating unique predisposing factors. This has led to little direct correlation of cause and effect with no definitive conclusions drawn. The need to be objective is highlighted by the limited number of studies and that two studies used anecdotal evidence to support their hypothesis and thus creating the question does hindlimb proximal suspensory desmopathy predispose horses to sacroiliac disease? This review looks at the two conditions and compares the literature for each, including the incidence, biomechanics, anatomy, and treatment. The review further discusses whether one disorder predisposes horses/equids to the other

Cell Culture Based in vitro Test Systems for Anticancer Drug Screening

The development of new high-tech systems for screening anticancer drugs is one of the main problems of preclinical screening. Poor correlation between preclinical in vitro and in vivo data with clinical trials remains a major concern. The choice of the correct tumor model at the stage of in vitro testing provides reduction in both financial and time costs during later stages due to the timely screening of ineffective agents. In view of the growing incidence of oncology, increasing the pace of the creation, development and testing of new antitumor agents, the improvement and expansion of new high-tech systems for preclinical in vitro screening is becoming very important. The pharmaceutical industry presently relies on several widely used in vitro models, including two-dimensional models, three-dimensional models, microfluidic systems, Boyden’s chamber and models created using 3D bioprinting. This review outlines and describes these tumor models including their use in research, in addition to their characteristics. This review therefore gives an insight into in vitro based testing which is of interest to researchers and clinicians from differing fields including pharmacy, preclinical studies and cell biology

Canine osteosarcoma in comparative oncology: Molecular mechanisms through to treatment discovery.

Cancer is a leading cause of non-communicable morbidity and mortality throughout the world, similarly, in dogs, the most frequent cause of mortality is tumors. Some types of cancer, including osteosarcoma (OSA), occur at much higher rates in dogs than people. Dogs therefore not only require treatment themselves but can also act as an effective parallel patient population for the human disease equivalent. It should be noted that although there are many similarities between canine and human OSA, there are also key differences and it is important to research and highlight these features. Despite progress using chorioallantoic membrane models, 2D and 3D in vitro models, and rodent OSA models, many more insights into the molecular and cellular mechanisms, drug development, and treatment are being discovered in a variety of canine OSA patient populations