Potential Therapeutic Application of Regulatory T Cells in Diabetes Mellitus Type 1

The autoimmune reaction against the beta cells of the pancreatic islets in type 1 diabetes mellitus (T1DM) patients is active in prediabetes and during the development of the clinical manifestation of T1DM, but it decreases within a few years of the clinical manifestation of this disease. A key role in the pathogenesis of T1DM is played by regulatory T cell (Treg) deficiency or dysfunction. Immune interventions, such as potential therapeutic applications or the induction of the Treg-cell population in T1DM, will be important in the development of new types of treatment. The aim of this study was to evaluate innovative immune interventions as treatments for T1DM. After an evaluation of full-length papers from the PubMed database from 2010 to 2021, 20 trials were included for the final analysis. The analysis led to the following conclusions: Treg cells play an important role in the limitation of the development of T1DM, the activation or application of Tregs may be more effective in the early stages of T1DM development, and the therapeutic use of Treg cells in T1DM is promising but requires long-term observation in a large group of patients.

Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation

The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments.

Studies on the Synthesis of Marine Natural Product (-)-Zampanolide and its Analogues

<p>(-)-Zampanolide is a microtubule-stabilising marine natural product, with promise as a cancer drug candidate. The potential therapeutic application of zampanolide has fuelled worldwide interest in its total synthesis, but few analogue studies have been reported. Analogues afford the possibility of examining the structure-activity relationships with a view to optimising for potency and medicinal viability. This project seeks to devise a new route to zampanolide and generate a series of analogues for bioactivity evaluation. The initial approach to zampanolide and a number of designed analogues was through disconnections at C20 by an N-aldol reaction, at C1 by Yamaguchi esterification, at C8-C9 by metathesis and at C15-C16 by alkynylation. During the development of fragment syntheses, problems were encountered with protection of the secondary hydroxyl group at C19 and establishment of an aldehyde at C15. Useful natural and analogue fragments were generated during this exploratory phase. The order of connections was revised, and effort has been put towards the improvement of the synthetic efficiency. A three-component reaction involving (triphenylphosphoranylidene)-ketene, also known as Bestmann ylide, as a linchpin was envisaged to provide the dienoate of zampanolide. This is an expanded application of Bestmann ylide and therefore the scope of this linchpin reaction was investigated using simple alcohols and aldehydes. Success in the scoping study fortified this approach, and the coupling of the C3-C8 and C16-C20 fragments of zampanolide proceeded with good yields and stereoselectivity of the E,Z-geometry. The planned late stage connections were tested on model substrates. The side arm attachment by a chiral boron reagent-promoted aza-aldol reaction failed to produce desired product on a simple model. However, model substrates that better account for the functionality of the zampanolide macrocycle are proposed for subsequent studies. In case these also do not succeed, reliable alternative methods described in the literature would be used. Several methods were scanned for the asymmetric alkynylation required for the C15-C16 bond connection. That involving ProPhenol and diethylzinc produced an excellent yield with a model alkyne. Although the stereoselectivity of the alkynylation is yet to be optimized, it was also tested on the full zampanolide fragment generated from the Bestmann ylide reaction. A small amount of the desired product was isolated, establishing 16 out of the 18 carbons of the macrocycle. Formation of a macrocycle is close at hand.</p>

Studies on the Synthesis of Marine Natural Product (-)-Zampanolide and its Analogues

<p>(-)-Zampanolide is a microtubule-stabilising marine natural product, with promise as a cancer drug candidate. The potential therapeutic application of zampanolide has fuelled worldwide interest in its total synthesis, but few analogue studies have been reported. Analogues afford the possibility of examining the structure-activity relationships with a view to optimising for potency and medicinal viability. This project seeks to devise a new route to zampanolide and generate a series of analogues for bioactivity evaluation. The initial approach to zampanolide and a number of designed analogues was through disconnections at C20 by an N-aldol reaction, at C1 by Yamaguchi esterification, at C8-C9 by metathesis and at C15-C16 by alkynylation. During the development of fragment syntheses, problems were encountered with protection of the secondary hydroxyl group at C19 and establishment of an aldehyde at C15. Useful natural and analogue fragments were generated during this exploratory phase. The order of connections was revised, and effort has been put towards the improvement of the synthetic efficiency. A three-component reaction involving (triphenylphosphoranylidene)-ketene, also known as Bestmann ylide, as a linchpin was envisaged to provide the dienoate of zampanolide. This is an expanded application of Bestmann ylide and therefore the scope of this linchpin reaction was investigated using simple alcohols and aldehydes. Success in the scoping study fortified this approach, and the coupling of the C3-C8 and C16-C20 fragments of zampanolide proceeded with good yields and stereoselectivity of the E,Z-geometry. The planned late stage connections were tested on model substrates. The side arm attachment by a chiral boron reagent-promoted aza-aldol reaction failed to produce desired product on a simple model. However, model substrates that better account for the functionality of the zampanolide macrocycle are proposed for subsequent studies. In case these also do not succeed, reliable alternative methods described in the literature would be used. Several methods were scanned for the asymmetric alkynylation required for the C15-C16 bond connection. That involving ProPhenol and diethylzinc produced an excellent yield with a model alkyne. Although the stereoselectivity of the alkynylation is yet to be optimized, it was also tested on the full zampanolide fragment generated from the Bestmann ylide reaction. A small amount of the desired product was isolated, establishing 16 out of the 18 carbons of the macrocycle. Formation of a macrocycle is close at hand.</p>

Monitoring decellularization via absorbance spectroscopy during the derivation of extracellular matrix scaffolds

Extracellular matrix (ECM) is a complex structure composed of bioactive molecules representative of the specific local tissue microenvironment. Decellularized ECM biomaterials harness these biomolecules for regenerative medicine applications. One potential therapeutic application is the use of vocal fold (VF) specific ECM to restore the VFs after injury. ECM scaffolds are derived through a process of decellularization, which aims to remove unwanted immunogenic biomolecules (e.g., DNA) while preserving the composition of the ECM. The effectiveness of the decellularization is typically assessed at the end by quantifying ECM attributes such as final dsDNA content. However, batch-to-batch variability in ECM manufacturing remains a significant challenge for the process standardization, cost-effectiveness, and scale-up. The limited number of tools available for in-process control heavily restricts the uncovering of the correlations between decellularization process parameters and ECM attributes. In this study, we developed a technique applicable to both the classical batch method and semi-continuous decellularization system to trace the decellularization of two laryngeal tissues in real-time. We hypothesize that monitoring the bioreactor's effluent absorbance at 260 nm as a function of time will provide a representative DNA release profile from the tissue and thus allowing for process optimization. The DNA release profiles were obtained for laryngeal tissues and were successfully used to optimize the derivation of VF lamina propria-ECM (auVF-ECM) hydrogels. This hydrogel had comparable rheological properties to commonly used biomaterials to treat VF injuries. Also, the auVF-ECM hydrogel promoted the down-regulation of CCR7 by THP-1 macrophages upon lipopolysaccharide stimulation in vitro suggesting some anti-inflammatory properties. The results show that absorbance profiles are a good representation of DNA removal during the decellularization process thus providing an important tool to optimize future protocols.

Potential action on the central nervous system of neroli oil extracted from Citrus aurantium

The essential oil from C. aurantium has been widely studied due to its potential anxiolytic action on several receptors in the Central Nervous System (CNS). Although it presents variations in its phytochemical composition depending on its origin, we can highlight that many compounds remain present, such as linalool that demonstrated antagonistic activity on glutamatergic receptors, possible inhibitory action of noradrenaline and serotonin receptors, besides the ability to activate GABA receptors in association with some flavonoids present in the oil. It is globally known that the underlying pathology called anxiety influences worldwide as an antecedent of conflicting psychological and physical disorders, which are associated with various neuronal disorders. In this regard, the oil extracted from C. aurantium flowers shows a potential therapeutic application for the treatment of anxiety disorders. However, more studies are needed to elucidate its complete role on the CNS and to verify and prove its safety and efficacy profile.

Treating Major Depression Disorder with Psychedelics: A Potential Therapeutic Application for Psilocybin?

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Regulation of cGAS-STING pathway - Implications for systemic lupus erythematosus

Type I interferon (IFN-I) is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and the closely associated monogenic autoinflammatory disorders termed the “interferonopathies.” Recently, the cytosolic DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and its downstream signaling adaptor stimulator of interferon genes (STING) have been identified as having important, if not central, roles in driving IFN-I expression in response to self-DNA. This review highlights the many ways in which this pathway is regulated in order to prevent self-DNA recognition and underlines the importance of maintaining tight control in order to prevent autoimmune disease. We will discuss the murine and human studies that have implicated the cGAS-STING pathway as being an important contributor to breakdown in tolerance in SLE and highlight the potential therapeutic application of this knowledge for the treatment of SLE.

AZP2006, a new promising treatment for Alzheimer’s and related diseases

Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.