Long-lasting Therapeutic Effects Research Articles

Stem cell grafts enhance endogenous extracellular vesicle expression in the stroke brain

Endogenous brain repair occurs following an ischemic stroke but is transient, thus unable to fully mount a neuroprotective response against the evolving secondary cell death. Finding a treatment strategy that may render robust and long-lasting therapeutic effects stands as a clinically relevant therapy for stroke. Extracellular vesicles appear to be upregulated after stroke, which may represent a candidate target for neuroprotection. In this study, we probed whether transplanted stem cells could enhance the expression of extracellular vesicles to afford stable tissue remodeling in the ischemic stroke brain. Aged rats were initially exposed to the established ischemic stroke model of middle cerebral artery occlusion then received intravenous delivery of either bone marrow-derived mesenchymal stem cell transplantation or vehicle. A year later, the animals were assayed for brain damage, inflammation, and extracellular vesicle expression. Our findings revealed that while core infarction was not reduced, the stroke animals transplanted with stem cells displayed a significant reduction in peri-infarct cell loss that coincided with downregulated Iba1-labeled inflammatory cells and upregulated CD63-positive extracellular vesicles that appeared to be co-localized with GFAP-positive astrocytes. Interestingly, grafted stem cells were not detected at one year post-transplantation period, suggesting that the extracellular vesicles likely originated within the host brain. That long-lasting functional benefits persisted in the absence of surviving transplanted stem cells, but with upregulation of endogenous extracellular vesicles, advances the concept that transplantation of stem cells acutely after stroke propels host extracellular vesicles to the ischemic brain, altogether promoting chronic brain remodeling.

Coordinated reset stimulation of plastic neural networks with spatially dependent synaptic connections.

Abnormal neuronal synchrony is associated with several neurological disorders, including Parkinson's disease (PD), essential tremor, dystonia, and epilepsy. Coordinated reset (CR) stimulation was developed computationally to counteract abnormal neuronal synchrony. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites. Computational studies in plastic neural networks reported that CR stimulation drove the networks into an attractor of a stable desynchronized state by down-regulating synaptic connections, which led to long-lasting desynchronization effects that outlasted stimulation. Later, corresponding long-lasting desynchronization and therapeutic effects were found in animal models of PD and PD patients. To date, it is unclear how spatially dependent synaptic connections, as typically observed in the brain, shape CR-induced synaptic downregulation and long-lasting effects. We performed numerical simulations of networks of leaky integrate-and-fire neurons with spike-timing-dependent plasticity and spatially dependent synaptic connections to study and further improve acute and long-term responses to CR stimulation. The characteristic length scale of synaptic connections relative to the distance between stimulation sites plays a key role in CR parameter adjustment. In networks with short synaptic length scales, a substantial synaptic downregulation can be achieved by selecting appropriate stimulus-related parameters, such as the stimulus amplitude and shape, regardless of the employed spatiotemporal pattern of stimulus deliveries. Complex stimulus shapes can induce local connectivity patterns in the vicinity of the stimulation sites. In contrast, in networks with longer synaptic length scales, the spatiotemporal sequence of stimulus deliveries is of major importance for synaptic downregulation. In particular, rapid shuffling of the stimulus sequence is advantageous for synaptic downregulation. Our results suggest that CR stimulation parameters can be adjusted to synaptic connectivity to further improve the long-lasting effects. Furthermore, shuffling of CR sequences is advantageous for long-lasting desynchronization effects. Our work provides important hypotheses on CR parameter selection for future preclinical and clinical studies.

Therapeutic value in the time of digital brainwaves.

This article examines the value of medical technology through the case of electroencephalograms (EEGs), devices used to visualize brain activity and diagnose seizures. Drawing on ethnographic fieldwork, the article shows that EEGs are valued differently by patients and medical practitioners. While practitioners value EEGs for their clinical utility, i.e., ability to inform clinical decisions, patients value EEGs even in the absence of clinical utility. Indeed, patients derive long-lasting therapeutic effects from this diagnostic technology. These findings intervene in the utilitarian calculus of therapeutic value-a mode of reasoning that equates value with clinical utility-commonly deployed in biomedicine and engineering and call for a recognition of alternative notions such as the therapeutic value of being witnessed and cared for by medical experts via EEGs and other technologies that require time to work. Expansive notions of therapeutic value are imperative for including marginalized patients-especially low-income, disabled, and women patients-in debates on automation and the future of healthcare. Studying how multiple stakeholders value a medical technology provides insight into valuation, objectification, expertise, and other concerns central to science and technology studies.

Abstract A026: Synthesis and structure-activity studies of DNA- and RNA-binding nucleopeptides with a cell penetrating potential

Abstract In the field of modern biomedicine, significant progress has been made in countering or restoring faulty genes using exogenous nucleic acids or their mimetics (NAMs). This approach enables targeted and long-lasting therapeutic effects by circumventing the need of interventions at a protein level. Despite the boom of clinical approvals, the development of NAMs still faces crucial challenges, including susceptibility to metabolic breakdown, limited uptake by cells, self-aggregation, and the potential for immune reactions. In addition to employing advanced delivery strategies, alternative methods to address these issues involve modifying NAMs chemically or combining oligonucleotides (ONs) with cellular carriers, including cell-penetrating peptides. Against this background, herein we present the nucleopeptides (NPs) as a family of unexplored NAMs that bridge the gap between ONs and peptide structures. By incorporating two consecutive amino acids—one bearing a nucleobase on the side chain and the other remaining unaltered—we created a monomer that spans the length of a single nucleotide. This functional module possesses nucleobase recognition elements along with additional functional groups eligible to modulate physio-chemical properties. We investigated this class of macromolecules by preliminarily devising an efficient solid-phase peptide synthesis technique profitable for homo- and hetero-sequences and sparing the monomer assembly in solution. [1] The influence of the amino acid composition on target binding properties, metabolic stability, and cellular penetration, were assessed through the synthesis of a series of homothymine hexameric derivatives. This simplified model was also used to investigate the distance between the nucleobase and the backbone, the absolute configuration of the nucleobase- bearing element, and the polycationic/anionic nature of the unmodified amino acid. [2-4] We evaluated the recognition and the thermodynamic stability of NPs/DNA and NPs/RNA hetero-duplexes through circular dichroism and UV spectroscopy experiments, while we employed confocal microscopy with suitable FITC- labeled derivatives to determine the intracellular localization in target cells. [1,3] Our results suggested that NPs exhibit distinct binding properties towards complementary RNA and DNA sequences according to their aminoacidic composition, and are characterized by a higher affinity compared to ONs and PNAs, thus arising as promising cell penetrating NAMs. [1] Mercurio ME, Tomassi S, et al. J Org Chem. 2016, 81(23), 11612- 11625. [2] Tomassi S, Ieranò C, et al. Bioorg Med Chem. 2018, 26(9), 2539-2550. [3] Tomassi S, Montalban FF, et al. Symmetry 2019, 11(4), 567-582. [4] Tomassi S, Ieranò C, et al. Int J Mol Sci. 2022, 23(15), 8504-8518. Citation Format: Stefano Tomassi, Caterina Ieranò, Stefania Scala, Anna Messere, Salvatore Di Maro. Synthesis and structure-activity studies of DNA- and RNA-binding nucleopeptides with a cell penetrating potential [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A026.

PD-1 Antibody (Sintilimab) Plus Histone Deacetylase Inhibitor (Chidamide) for the Treatment of Refractory or Relapsed Extranodal Natural Killer/T Cell Lymphoma, Nasal Type (r/r ENKTL): Updates of the Phase Ib/II Scent Study

Background Extranodal natural killer/T-cell lymphoma (ENKTL) is a highly aggressive of non-Hodgkin's lymphoma (NHL) closely related to Epstein-Barr virus (EBV), with a higher incidence in Asia than in Europe and North America. Patients with r/r ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-programmed death 1 (anti-PD-1) antibody monotherapy represented a favorable treatment for the patients with rr-ENKTL. ORIENT-4 trial demonstrated sintilimab(anti-PD-1antibody ) was effective and well tolerated in r/r ENKTL. The efficacy of chidamide monotherapy, an oral subtype-selective histone deacetylase inhibitor (HDACi) was reported on the patients with rr-ENKTL . Moreover, accumulating evidences have shown the synergism between epigenetic modulator and PD-1 antibody. In 2020 ASH meeting, we reported the preliminary results of sintilimab plus chidamide (SC) for treatment of r/r ENKTL orally. This report is an update of this trial with cumulative data of approximately 40 months. Methods This multicenter, single-arm, phase Ib/II clinical trial enrolled eligible patients with histologically confirmed r/r-ENKTL failing from asparaginase-based regimen. This study consisted of a Phase Ib (dose escalation) portion followed by a Phase II expansion portion. In the Phase Ib escalation portion, a standard “3+3” design was utilized to identify the maximum tolerated dose (MTD), dose limited toxicity (DLT) and recommended Phase II dosage (RP2D) of chidamide. Patients received oral escalating doses of chidamide (20, 25, 30 mg) twice a week and 200 mg of sintilimab intravenously every 3 weeks. In the phase II expansion portion, patients received six cycles of SC every 3 weeks. Patients with complete response (CR) or partial response (PR) received SC every 3 weeks for up to 1 year, until disease progression, intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIL 2017criteria. Key secondary endpoints included time to response (TTR), duration of response (DOR) and progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). This trial was registered at ClinicalTrials.gov (NCT 03820596). Results From March 2019 to May 2020, 41 patients were screened, and 37 eligible patients were enrolled. Overall, median age 48 years (range, 20-72), 26 (70.3%) patients with Stage IV, 20 (54.1%) patients with PINK-E score ≥ 3 points, 16 (43.2%) patients received ≥ 2 lines of prior systemic therapy. RP2D of chidamide was 30 mg twice a week. Of 36 response evaluable patients, 21 patients (58.3%) achieved an objective response including 16 (44.4%) patients with CR. The median time to initial response was 6.0 weeks (range, 5.0 to12.4). Cut-off data was July 28, 2023. The median cycles of SC were 6 (range, 2 to 44). Median follow-up time of whole cohort was 38.3 (range, 0.9 to 51.5; Interquartile range [IQR] range 8.5 to 46.3) months, 3-year OS rate was 56% (95% CI: 0.44-0.75, Figure 1 A), median PFS was 23.4 months (Figure 1 B). Twenty-one patients still alive, median follow-up time for this group was 44.9 (IQR 43.2 to 49.3) months. Estimated 4-year PFS rate was 76% (95% CI: 0.51-0.89, Figure 1 C). Median follow-up time of 21 responded(CR+PR) patients was 43.4 (IQR 34.3 to 47.6) months, estimated 4-year DOR was 68% (95% CI: 0.45-0.83, Figure 1 D). Twenty-six (26, 70.3%) patients reported treatment-related AEs (TRAEs). There were no new safety signals were identified after August 2020. The most frequently observed (≥10%) TRAEs were neutropenia (21,56.8%), thrombocytopenia (17, 45.9%), transaminase increased (11, 29.7%), nausea (9, 24.3%). The most frequent Grade (G) ≥3 TRAEs were neutropenia (6, 16.2%) and thrombocytopenia (4, 10.8%). Immune-related AEs were reported in 16 (43.2%) patients including a G4 exfoliative dermatitis, and the most common irAEs were G1 hypothyroidism and rash. TEAEs that led to permanent treatment discontinuation occurred in only one (2.7%) patient. No death was related to the study drug. Conclusion Sintilimab combined with Chidamide showed long-lasting therapeutic effects with manageable toxicity in patients with r/r-ENKTL. Epigenetic modulator can synergize with anti-PD-1 antibody to enhance antitumor activity to r/r-ENKTL.

Gene therapy in spinal muscular atrophy

Infantile SMA is a neuromuscular disease caused by the motor neuron degeneration, depending on the age of appearance of clinical signs and the evolution of the disease, three types of decreasing severity have been defined. SMA is caused by mutations or deletions of the SMN1 gene and disease. Various therapies aimed at increasing SMN protein levels have been developed. Gene therapy is part of the therapeutic arsenal now available for the treatment of SMA under certain conditions. It uses the scAAV9 vector carrying a functional copy of SMN1 to restore SMN protein expression at the cellular level. Because the adeno-associated virus genome is maintained as it is an episome, a single intravenous administration is sufficient to producing a long-lasting therapeutic effect. The effectiveness of gene replacement therapy in patients with SMA has been demonstrated in various studies. It is now clear that treatment as early as possible provides better clinical results. However, this treatment must be carried out in a suitable medical environment, with close monitoring initially due to potentially serious side effects. In France, this treatment has been available since 2019. A national committee of experts involved in the treatment of pediatric SMA patients has established that pediatric patients with SMA decide on the indications for disease-modifying therapies (DMT) in children. The French Spinal Muscular Atrophy Registry (SMA France Registry) was established in January 2020. The registry includes all patients with genetically confirmed SMN1-related SMA. All patients treated with GT are systematically included in the registry. As of July 21, 2023: 72 patients with SMA have been treated with GT in France since June 2019. The arrival of new treatments reveals new clinical phenotypes of SMA which constitute a new management challenge. Treatment as early as possible is also a very important factor for a favorable outcome and calls for presymptomatic screening. However, the arrival of these new treatments, extremely expensive raises other socio-economic questions. © 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.

Gene therapy for inherited retinal diseases: exploiting new tools in genome editing and nanotechnology.

Inherited retinal diseases (IRDs) encompass a diverse group of genetic disorders that lead to progressive visual impairment and blindness. Over the years, considerable strides have been made in understanding the underlying molecular mechanisms of IRDs, laying the foundation for novel therapeutic interventions. Gene therapy has emerged as a compelling approach for treating IRDs, with notable advancements achieved through targeted gene augmentation. However, several setbacks and limitations persist, hindering the widespread clinical success of gene therapy for IRDs. One promising avenue of research is the development of new genome editing tools. Cutting-edge technologies such as CRISPR-Cas9 nucleases, base editing and prime editing provide unprecedented precision and efficiency in targeted gene manipulation, offering the potential to overcome existing challenges in gene therapy for IRDs. Furthermore, traditional gene therapy encounters a significant challenge due to immune responses to viral vectors, which remain crucial obstacles in achieving long-lasting therapeutic effects. Nanotechnology has emerged as a valuable ally in the quest to optimize gene therapy outcomes for ocular diseases. Nanoparticles engineered with nanoscale precision offer improved gene delivery to specific retinal cells, allowing for enhanced targeting and reduced immunogenicity. In this review, we discuss recent advancements in gene therapy for IRDs and explore the setbacks that have been encountered in clinical trials. We highlight the technological advances in genome editing for the treatment of IRDs and how integrating nanotechnology into gene delivery strategies could enhance the safety and efficacy of gene therapy, ultimately offering hope for patients with IRDs and potentially paving the way for similar advancements in other ocular disorders.

Rational antibiotic therapy – a choice from the point of view of innovative technologies

Innovative technologies in medicine allow the medical community to boldly respond to challenges, such was the development of the drug Cifran OD, which contains a modern topical fluoroquinolone with a special slow release in the human body. Ciprofloxacin is indicated for the treatment of bacterial infections of most organs and systems of the human body, the long-acting formula provides a quick and long-lasting therapeutic effect. At the same time, the concentration in body tissues does not reach dangerous levels, which ensures a high safety profile. Due to the convenient dosage (once a day), patients have a high commitment to treatment, which ensures compliance with the required duration of therapy, according to the protocols in each specific case. In comparative studies of regular ciprofloxacin and ciprofloxacin with a delayed release of the active substance, the effectiveness was equally high, but the frequency of side effects was lower in the treatment with ciprofloxacin of prolonged action. The choice in favor of the drug Cifran OD is a guarantee of success and safety in the treatment of infectious diseases caused by pathogens sensitive to the active substance.

Evolution Of Immunotherapy Against Pollen Allergy.

Allergic diseases have increased worldwide during the last century and are a major disease burden globally. Several substances can induce allergic sensitization and elicit allergic symptoms in sensitized individuals. Pollen grains are one of the main causes of allergic rhinitis and asthma, and the prevalence of different pollen species depends on the climate, geographical regions, flora, and season. In addition to avoiding exposure to pollens, anti-allergic drugs are commonly used to mitigate the symptoms of allergies. However, these drugs must be administered repeatedly as long as the symptoms prevail, usually life-long. Allergen immunotherapy (AIT) is currently the only disease-modifying approach that can prevent the natural progression of the disease (also known as an allergic march), provide a long-lasting therapeutic effect, and prevent the worsening of the symptoms and the occurrence of new sensitizations in allergic individuals. Since the pioneering clinical studies conducted more than 100 years ago using subcutaneously administered pollen extract to treat hay fever, significant advances have been made in the field of AIT. Starting from this pioneering approach, in this review, we have discussed the evolution of the products used for AIT with particular emphasis on pollen allergoids, the chemically modified pollen extracts characterized by lower allergenicity and comparable immunogenicity, and the different routes of administration used for AIT.

AAV-vectored base editor trans-splicing delivers dystrophin repair

AAV-vectored base editor trans-splicing delivers dystrophin repair

Exosome inspired photo-triggered gelation hydrogel composite on modulating immune pathogenesis for treating rheumatoid arthritis

Although exosome therapy has been recognized as a promising strategy in the treatment of rheumatoid arthritis (RA), sustained modulation on RA specific pathogenesis and desirable protective effects for attenuating joint destruction still remain challenges. Here, silk fibroin hydrogel encapsulated with olfactory ecto-mesenchymal stem cell-derived exosomes (Exos@SFMA) was photo-crosslinked in situ to yield long-lasting therapeutic effect on modulating the immune microenvironment in RA. This in situ hydrogel system exhibited flexible mechanical properties and excellent biocompatibility for protecting tissue surfaces in joint. Moreover, the promising PD-L1 expression was identified on the exosomes, which potently suppressed Tfh cell polarization via inhibiting the PI3K/AKT pathway. Importantly, Exos@SFMA effectively relieved synovial inflammation and joint destruction by significantly reducing T follicular helper (Tfh) cell response and further suppressing the differentiation of germinal center (GC) B cells into plasma cells. Taken together, this exosome enhanced silk fibroin hydrogel provides an effective strategy for the treatment of RA and other autoimmune diseases.

Treating Lower Urinary Tract Symptoms in Older Adults: Intravesical Options.

This article provides an overview of the diagnosis and the treatment of lower urinary tract symptoms in older adults complicated by the neurodegenerative changes in the micturition reflex and further confounded by age-related decline in hepatic and renal clearance raising the propensity of adverse drug reactions. The first-line drug treatment for lower urinary tract symptoms, orally administered antimuscarinics, fails to reach the equilibrium dissociation constant of muscarinic receptors even at their maximum plasma concentration and tends to evoke a half-maximal response at a muscarinic receptor occupancy of just 0.206% in the bladder with a minimal difference from exocrine glands, which raises the adverse drug reaction risk. On the contrary, intravesical antimuscarinics are instilled at concentrations 1000-fold higher than the oral maximum plasma concentration and the equilibrium dissociation constant erects a downhill concentration gradient that drives passive diffusion and achieves a mucosal concentration around ten-fold lower than the instilled concentration for a long-lasting occupation of muscarinic receptors in mucosa and sensory nerves. A high local concentration of antimuscarinics in the bladder triggers alternative mechanisms of action and is supposed to engage retrograde transport to nerve cell bodies for neuroplastic changes that underlie a long-lasting therapeutic effect, while an intrinsically lower systemic uptake of the intravesical route lowers the muscarinic receptor occupancy of exocrine glands to lower the adverse drug reaction relative to the oral route. Thus, the traditional pharmacokinetics and pharmacodynamics of oral treatment are upended by intravesical antimuscarinics to generate a dramatic improvement (~ 76%) noted in a meta-analysis of studies enrolling children with neurogenic lower urinary tract symptoms on the primary endpoint of maximum cystometric bladder capacity as well as the secondary endpoints of filling compliance and uninhibited detrusor contractions. The therapeutic success of intravesical multidose oxybutynin solution or oxybutynin entrapped in the polymer for sustained release in the pediatric populationbodes well for patients with lower urinary tract symptoms at the other extreme of the age spectrum. Though generally used to predict oral drug absorption, Lipinski's rule of five can also explain the ten-fold lower systemic uptake from the bladder of positively charged trospium over oxybutynin, a tertiary amine. Chemodenervation by an intradetrusor injection of onabotulinumtoxinA is merited for patients with idiopathic overactive bladder discontinuing oral treatment because of a lack of efficacy. However, age-related peripheral neurodegeneration potentiates the adverse drug reaction risk of urinary retention that motivates the quest of liquid instillation, delivering larger fraction of onabotulinumtoxinA to the mucosa as opposed to muscle by an intradetrusor injection can also probe the neurogenic and myogenic predominance of idiopathic overactive bladder. Overall, the treatment paradigm of lower urinary tract symptoms in older adults should be tailored to individual's overall health status and the risk tolerance for adverse drug reactions.

Decoupling of interacting neuronal populations by time-shifted stimulation through spike-timing-dependent plasticity.

The synaptic organization of the brain is constantly modified by activity-dependent synaptic plasticity. In several neurological disorders, abnormal neuronal activity and pathological synaptic connectivity may significantly impair normal brain function. Reorganization of neuronal circuits by therapeutic stimulation has the potential to restore normal brain dynamics. Increasing evidence suggests that the temporal stimulation pattern crucially determines the long-lasting therapeutic effects of stimulation. Here, we tested whether a specific pattern of brain stimulation can enable the suppression of pathologically strong inter-population synaptic connectivity through spike-timing-dependent plasticity (STDP). More specifically, we tested how introducing a time shift between stimuli delivered to two interacting populations of neurons can effectively decouple them. To that end, we first used a tractable model, i.e., two bidirectionally coupled leaky integrate-and-fire (LIF) neurons, to theoretically analyze the optimal range of stimulation frequency and time shift for decoupling. We then extended our results to two reciprocally connected neuronal populations (modules) where inter-population delayed connections were modified by STDP. As predicted by the theoretical results, appropriately time-shifted stimulation causes a decoupling of the two-module system through STDP, i.e., by unlearning pathologically strong synaptic interactions between the two populations. Based on the overall topology of the connections, the decoupling of the two modules, in turn, causes a desynchronization of the populations that outlasts the cessation of stimulation. Decoupling effects of the time-shifted stimulation can be realized by time-shifted burst stimulation as well as time-shifted continuous simulation. Our results provide insight into the further optimization of a variety of multichannel stimulation protocols aiming at a therapeutic reshaping of diseased brain networks.

Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin.

Psilocybin is a psychedelic with therapeutic potential. While there is growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining the impact of psilocybin on plasticity-related gene expression throughout the brain can broaden our understanding of the neural circuits involved in psychedelic-evoked neural plasticity. In this study, whole-brain serial two-photon microscopy and light sheet microscopy were employed to map the expression of the immediate early gene, c-Fos, in male and female mice. The drug-induced c-Fos expression following psilocybin administration was compared to that of subanesthetic ketamine and saline control. Psilocybin and ketamine produced acutely comparable elevations in c-Fos expression in numerous brain regions, including anterior cingulate cortex, locus coeruleus, primary visual cortex, central and basolateral amygdala, medial and lateral habenula, and claustrum. Select regions exhibited drug-preferential differences, such as dorsal raphe and insular cortex for psilocybin and the CA1 subfield of hippocampus for ketamine. To gain insights into the contributions of receptors and cell types, the c-Fos expression maps were related to brain-wide in situ hybridization data. The transcript analyses showed that the endogenous levels of Grin2a and Grin2b predict whether a cortical region is sensitive to drug-evoked neural plasticity for both ketamine and psilocybin. Collectively, the systematic mapping approach produced an unbiased list of brain regions impacted by psilocybin and ketamine. The data are a resource that highlights previously underappreciated regions for future investigations. Furthermore, the robust relationships between drug-evoked c-Fos expression and endogenous transcript distributions suggest glutamatergic receptors as a potential convergent target for how psilocybin and ketamine produce their rapid-acting and long-lasting therapeutic effects.

Nanomedicine‐boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Traditional treatments for advanced hepatocellular carcinoma (HCC), such as surgical resection, transplantation, radiofrequency ablation, and chemotherapy are unsatisfactory, and therefore the exploration of powerful therapeutic strategies is urgently needed. Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects. Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC. Encouragingly, in 2022, icaritin soft capsules were approved by the National Medical Products Administration (NMPA) of China for the immunotherapy of advanced HCC. However, the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency. Recently, functionalized drug delivery systems including stimuli-responsive nanocarriers, cell membrane-coated nanocarriers, and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs, including the low bioavailability and limited delivery efficiency as well as side effects. Taken together, the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC. Herein, we compared the different preparation methods for icaritin, interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC, and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritin-based nanomedicines for advanced HCC immunotherapy. Finally, the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

Future treatment of Diabetes - Tyrosine Kinase inhibitors.

Diabetes mellitus (DM) is a group of metabolic disorders that have an increased risk of macro and micro-vascular complications due to lipid dysfunction. The present drug treatments for the management of DM either have numerous side effects or do not have long-lasting therapeutic effects. So it is essential to find a newer class of drug for DM treatment. Broad information has been researched regarding Tyrosine kinase Inhibitors (TKIs) and their mechanism of action. They are proven for the management of various kinds of cancers. TKIs produce anti-hyperglycemic effects by acting on multiple targets such as c-Abl, Platelet-Derived Growth Factor Receptor (PDGFR), Vascular Endothelial Growth Factor Receptor (VEGFR), Epidermal Growth Factor Receptor (EGFR), and c-Kit. This family of drugs blocks numerous tyrosine kinases by acting as a partial agonist of PPAR-γ receptors and results in an anti-diabetic effect by improving insulin sensitivity and glucose disposal rate. Therefore, it is said that TKI drugs will be great potential for the treatment of Diabetes. This review summarizes the possible targets of TKIs and TKIs being a potential drug class in the management of Diabetes mellitus.

Psychedelics and Neural Plasticity: Therapeutic Implications.

Psychedelic drugs have reemerged as tools to treat several brain disorders. Cultural attitudes toward them are changing, and scientists are once again investigating the neural mechanisms through which these drugs impact brain function. The significance of this research direction is reflected by recent work, including work presented by these authors at the 2022 meeting of the Society for Neuroscience. As of 2022, there were hundreds of clinical trials recruiting participants for testing the therapeutic effects of psychedelics. Emerging evidence suggests that psychedelic drugs may exert some of their long-lasting therapeutic effects by inducing structural and functional neural plasticity. Herein, basic and clinical research attempting to elucidate the mechanisms of these compounds is showcased. Topics covered include psychedelic receptor binding sites, effects of psychedelics on gene expression, and on dendrites, and psychedelic effects on microcircuitry and brain-wide circuits. We describe unmet clinical needs and the current state of translation to the clinic for psychedelics, as well as other unanswered basic neuroscience questions addressable with future studies.

Presymptomatic macrophage targeting has a long-lasting therapeutic effect on treatment termination in a mouse model of Charcot-Marie-Tooth 1

Macrophage-mediated inflammation is a potent driver of disease progression in mouse models of Charcot-Marie-Tooth (CMT) 1 diseases. This leads to the possibility to consider these cells as therapeutic targets to dampen disease outcome in the so far non-treatable neuropathies. As a pharmacological proof-of-principle study, long-term targeting of nerve macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 showed a substantial alleviation of the neuropathy in distinct CMT1 mouse models. However, regarding translational options, clinically relevant questions emerged regarding treatment onset, duration and termination.Corroborating previous data, we here show that in a model for CMT1B, peripheral neuropathy was substantially alleviated after early continuous PLX5622 treatment in CMT1B mice, leading to preserved motor function. However, late-onset treatment failed to mitigate histopathological and clinical features, despite a similar reduction in the number of macrophages. Surprisingly, in CMT1B mice, terminating early PLX5622 treatment at six months was still sufficient to preserve motor function at 12 months of age, suggesting a long-lasting, therapeutic effect of early macrophage depletion. This novel and unexpected finding may have important translational implications, since we here show that continuous macrophage targeting appears not to be necessary for disease alleviation, provided that the treatment starts within an early, critical time window.

Health benefits of functional plant polysaccharides in metabolic syndrome: An overview

Metabolic syndrome (MetS) has become a worldwide public health problem with increasing global morbidity. Existing surgical and pharmaceutical treatments have certain side effects. Consequently, the search for anti-MetS active ingredients with long-lasting stable therapeutic effects and less toxic side effects has become a focal point of contemporary research. Functional polysaccharides with safe and excellent physiological activities have attracted more and more attention in the regulation of MetS, but a comprehensive understanding is still lacking. In this review, the effects and mechanisms of plant polysaccharides in the prevention and improvement of MetS by regulating intestinal flora, improving glucose and lipid metabolism disorders, maintaining the balance of islet internal environment and reducing systemic inflammation are summarized. Plant polysaccharides can be used to reduce the risk of metabolic diseases in a safe and dependable manner.

Janus mucosal dressing with a tough and adhesive hydrogel based on synergistic effects of gelatin, polydopamine, and nano-clay

There are many problems and challenges related to the treatment of highly prevalent oral mucosal diseases and oral drug delivery because of a large amount of saliva present in the oral cavity, the accompanying oral movements, and unconscious swallowing in the mouth. Therefore, an ideal oral dressing should possess stable adhesion and superior tough strength in the oral cavity. However, this fundamental requirement greatly limits the use of synthetic adhesive dressings for oral dressings. Here, we developed a mussel-inspired Janus gelatin-polydopamine-nano-clay (GPC) hydrogel with controlled adhesion and toughness through the synergistic physical and chemical interaction of gelatin (Gel), nano-clay, and dopamine (DA). The hydrogel not only exhibits strong wet adhesion force (63 kPa) but also has high toughness (1026 ± 100 J m−3). Interfacial adhesion of hydrogels is achieved by modulating the interaction of catechol groups of the hydrogel with specific functional groups (e.g., NH2, SH, OH, and COOH) on the tissue surface. The matrix dissipation of the hydrogel is regulated by physical crosslinking of gelatin, chemical crosslinking of gelatin with polydopamine (Michael addition and Schiff base formation), and nano-clay-induced constraint of the molecular chain. In addition, the GPC hydrogel shows high cell affinity and favors cell adhesion and proliferation. The hydrogel's instant and strong mucoadhesive properties provide a long-lasting therapeutic effect of the drug, thereby enhancing the healing of oral ulcers. Therefore, mussel-inspired wet-adhesion Janus GPC hydrogels can be used as a platform for mucosal dressing and drug delivery systems. Statement of significanceIt is a great challenge to treat oral mucosal diseases due to the large amount of saliva present in the oral cavity, the accompanying oral movements, unconscious swallowing, and flushing of drugs in the mouth. To overcome the significant limitations of clinical bioadhesives, such as weakness, toxicity, and poor usage, in the present study, we developed a simple method through the synergistic effects of gelatin, polydopamine, and nano-clay to prepare an optimal mucosal dressing (Janus GPC) that integrates Janus, adhesion, toughness, and drug release property. It fits effectively in the mouth, resists saliva flushing and oral movements, provides oral drug delivery, and reduces patient discomfort. The Janus GPC adhesive hydrogels have great commercial potential to support further the development of innovative therapies for oral mucosal diseases.