Updates on efficacy and safety outcomes of new and emerging disease modifying therapies and stem cell therapy for Multiple Sclerosis: A review.

Multiple Sclerosis (MS) is a chronic neurodegenerative autoimmune disorder of the central nervous system (CNS) and the most common cause of serious physical disability in working-age adults. Drug development and research in this field have rapidly evolved over the past two decades, leading to the broad array of treatment options available today. These disease-modifying therapies (DMTs) work through distinct mechanisms of action and exhibit varying safety and efficacy profiles to help manage symptoms and reduce exacerbations in MS patients. Our extensive understanding of this condition has also led to novel approaches, such as the discovery of specific biomarkers that allow us to monitor the therapeutic response towards DMTs. The development of new DMTs continues to progress quickly today, and it can be difficult for clinicians to remain up to date on the most recent advancements and new treatment options for their patients. In this comprehensive review, we provide an outline of current MS medications in the pipeline including emerging DMTs and stem cell therapy, as well as the unique characteristics of these medications, including their indications, pharmacokinetic effects, and the relevant advancements.

A comprehensive review of varicella-zoster virus, herpes simplex virus and cryptococcal infections associated with sphingosine-1-phosphate receptor modulators in multiple sclerosis patients.

Sphingosine-1-phosphate (S1P) receptor modulators are a new class of oral disease-modifying therapies used for Multiple Sclerosis (MS). These are immunomodulatory drugs and can thus increase the risk of certain infections in these patients. This paper summarizes the existing data on the most common opportunistic infections associated with the drugs in this class: Varicella Zoster Virus (VZV), Herpes Simplex Virus (HSV), and Cryptococcus neoformans. A literature review and descriptive analysis of reported cases and clinical phase III study findings on the incidences of these infections were conducted using PubMed and Google Scholar. Results regarding fingolimod, siponimod, ozanimod, and ponesimod were obtained. Overall, the incidence of these infections was found to be extremely low in MS patients treated with S1P receptor modulators. Among the four drugs in this class, the incidence rates of VZV, HSV, and cryptococcal infections were either similar or slightly higher than placebo, with some infections not reported in cases of ozanimod and ponesimod. Most of these resulted in favorable outcomes, with very few disabilities or fatalities. However, this paper highlights the increasing relevance of assessing infectious risk factors to promote the early identification of serious complications related to these drugs. Opportunistic infections should be considered in the differential diagnosis of an MS relapse in the setting of disease-modifying treatment.

Progressive multifocal leukoencephalopathy and sphingosine 1-phosphate receptor modulators used in multiple sclerosis: an updated review of literature.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious viral infection associated with disease-modifying therapies (DMT) for multiple sclerosis (MS) including sphingosine 1-phosphate receptor (S1PR) modulators. The objective of this review was to investigate the characteristics of PML in MS patients associated with drugs of the S1PR modulator. METHODS: We conducted a literature review and analysis of 24 patients from 12 publications in PubMed, SCOPUS and EMBASE. This is a descriptive analysis and study of characteristics of PML associated fingolimod and related S1PR modulator group of DMT. RESULTS: A total of 24 cases of PML in MS patients treated with fingolimod were identified. Of these, 21 cases contained data regarding changes in the expanded disability status scale (EDSS). One case of PML in association with ozanimod treatment in a clinical trial was also identified. In PML cases associated with fingolimod, the mean age at the time of PML diagnosis was 50.91 ± 11.5 years. All patients were treated with fingolimod for more than 24 months. Compared to patients who improved or were stable, in terms of EDSS, after symptomatic management of PML, the non-improved groups were significantly older. There were no fatalities in either group during the reported follow-up period. CONCLUSION: The incidence of PML appears to be extremely low in MS patients treated with S1PR modulators. Risk of PML increases with increase in duration of treatment with S1PR modulators like fingolimod, and increased age at the time of PML diagnosis is associated with worse prognosis.

Brain Mechanisms of Virtual Reality Breathing Versus Traditional Mindful Breathing in Pain Modulation: Observational Functional Near-infrared Spectroscopy Study.

BACKGROUND: Pain is a complex experience that involves sensory-discriminative and cognitive-emotional neuronal processes. It has long been known across cultures that pain can be relieved by mindful breathing (MB). There is a common assumption that MB exerts its analgesic effect through interoception. Interoception refers to consciously refocusing the mind's attention to the physical sensation of internal organ function. OBJECTIVE: In this study, we dissect the cortical analgesic processes by imaging the brains of healthy subjects exposed to traditional MB (TMB) and compare them with another group for which we augmented MB to an outside sensory experience via virtual reality breathing (VRB). METHODS: The VRB protocol involved in-house-developed virtual reality 3D lungs that synchronized with the participants' breathing cycles in real time, providing them with an immersive visual-auditory exteroception of their breathing. RESULTS: We found that both breathing interventions led to a significant increase in pain thresholds after week-long practices, as measured by a thermal quantitative sensory test. However, the underlying analgesic brain mechanisms were opposite, as revealed by functional near-infrared spectroscopy data. In the TMB practice, the anterior prefrontal cortex uniquely modulated the premotor cortex. This increased its functional connection with the primary somatosensory cortex (S1), thereby facilitating the S1-based sensory-interoceptive processing of breathing but inhibiting its other role in sensory-discriminative pain processing. In contrast, virtual reality induced an immersive 3D exteroception with augmented visual-auditory cortical activations, which diminished the functional connection with the S1 and consequently weakened the pain processing function of the S1. CONCLUSIONS: In summary, our study suggested two analgesic neuromechanisms of VRB and TMB practices-exteroception and interoception-that distinctively modulated the S1 processing of the ascending noxious inputs. This is in line with the concept of dualism (Yin and Yang).

Protein-protein interactions and metabolite channelling in the plant tricarboxylic acid cycle.

Protein complexes of sequential metabolic enzymes, often termed metabolons, may permit direct channelling of metabolites between the enzymes, providing increased control over metabolic pathway fluxes. Experimental evidence supporting their existence in vivo remains fragmentary. In the present study, we test binary interactions of the proteins constituting the plant tricarboxylic acid (TCA) cycle. We integrate (semi-)quantitative results from affinity purification-mass spectrometry, split-luciferase and yeast-two-hybrid assays to generate a single reliability score for assessing protein-protein interactions. By this approach, we identify 158 interactions including those between catalytic subunits of sequential enzymes and between subunits of enzymes mediating non-adjacent reactions. We reveal channelling of citrate and fumarate in isolated potato mitochondria by isotope dilution experiments. These results provide evidence for a functional TCA cycle metabolon in plants, which we discuss in the context of contemporary understanding of this pathway in other kingdoms.

Mitochondrial cysteine synthase complex regulates O-acetylserine biosynthesis in plants.

Cysteine synthesis is catalyzed by serine acetyltransferase (SAT) and O-acetylserine (thiol) lyase (OAS-TL) in the cytosol, plastids, and mitochondria of plants. Biochemical analyses of recombinant plant SAT and OAS-TL indicate that the reversible association of the proteins in the cysteine synthase complex (CSC) controls cellular sulfur homeostasis. However, the relevance of CSC formation in each compartment for flux control of cysteine synthesis remains controversial. Here, we demonstrate the interaction between mitochondrial SAT3 and OAS-TL C in planta by FRET and establish the role of the mitochondrial CSC in the regulation of cysteine synthesis. NMR spectroscopy of isolated mitochondria from WT, serat2;2, and oastl-C plants showed the SAT-dependent export of OAS. The presence of cysteine resulted in reduced OAS export in mitochondria of oastl-C mutants but not in WT mitochondria. This is in agreement with the stronger in vitro feedback inhibition of free SAT by cysteine compared with CSC-bound SAT and explains the high OAS export rate of WT mitochondria in the presence of cysteine. The predominant role of mitochondrial OAS synthesis was validated in planta by feeding [(3)H]serine to the WT and loss-of-function mutants for OAS-TLs in the cytosol, plastids, and mitochondria. On the basis of these results, we propose a new model in which the mitochondrial CSC acts as a sensor that regulates the level of SAT activity in response to sulfur supply and cysteine demand.

Not just a circle: flux modes in the plant TCA cycle.

The tricarboxylic acid (TCA) cycle is one of the iconic pathways in metabolism. The cycle is commonly thought of in terms of energy metabolism, being responsible for the oxidation of respiratory substrates to drive ATP synthesis. However, the reactions of carboxylic acid metabolism are embedded in a larger metabolic network and the conventional TCA cycle is only one way in which the component reactions can be organised. Recent evidence from labelling studies and metabolic network models suggest that the organisation of carboxylic acid metabolism in plants is highly dependent on the metabolic and physiological demands of the cell. Thus, alternative, non-cyclic flux modes occur in leaves in the light, in some developing oilseeds, and under specific physiological circumstances such as anoxia.