Peripheral Side Research Articles

Preparation and Characterization of Poly(ethylene oxide)-b-poly(tert-butyl methacrylate) Micelles as Potential Nanocarriers for Donepezil

Polymeric micelles were prepared for the delivery of donepezil, a leading Alzheimer’s disease (AD) drug, to enhance its transport across the blood-brain barrier (BBB). Poly(ethylene glycol)-b-poly(tert-butyl methacrylate) amphiphilic block copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers were characterized by gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR) spectroscopy. Empty and donepezil loaded polymer micelles were formed using the dialysis method and characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug loading efficiency and release behavior were monitored using UV/Vis spectroscopy, and cytotoxicity was evaluated via colorimetric tests and impedance measurements. Additionally, the permeability of the nanocarriers across an in vitro BBB culture model was assessed. Drug-loaded micelles demonstrated similar permeability to free donepezil but offered sustained release and improved stability. This micellar delivery system holds significant potential for improving therapeutic outcomes in Alzheimer’s treatment by enhancing donepezil’s delivery across the BBB. Improved BBB permeability and sustained drug release could lead to more effective concentration of the drug in the brain, potentially reducing peripheral cholinergic side effects, such as nausea and vomiting, often observed with traditional donepezil administration. This could result in better patient compliance and improved cognitive outcomes, making this nanocarrier system a promising alternative for Alzheimer's therapy.

Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder

Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapt an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identify a naturally-evolved and serotype-specific interaction between the AAV9 capsid and human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density lipoprotein receptor-related protein 6 (LRP6) interactions specific to engineered capsids with enhanced blood-brain barrier crossing in non-human primates after intravenous administration. The unbiased cell microarray screening approach also allows us to identify off-target tissue binding interactions of engineered brain-enriched AAV capsids that may inform vectors’ peripheral organ tropism and side effects. Our cryo-electron tomography and AlphaFold modeling of capsid-interactor complexes reveal LRP6 and IL3 binding sites. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.

Antibody conjugated targeted nanotherapy epigenetically inhibits calpain-mediated mitochondrial dysfunction to attenuate Parkinson’s disease

Many neurodegenerative and psychiatric malignancies like Parkinson’ disease (PD) originate from an imbalance of 17β-Estradiol (E2) in the human brain. However, the peripheral side effects of the usage of E2 for PD therapy and less understanding of the molecular mechanism hinder establishing its neurotherapeutic potential. In the present work, systemic side effects were overcome by targeted delivery using Dopamine receptor D3 (DRD3) conjugated E2-loaded chitosan nanoparticles (Ab-ECSnps) that showed a promising delivery to the brain. E2 is a specific calpain inhibitor that fosters neurodegeneration by disrupting mitochondrial function, while B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), an epigenetic regulator, is crucial in preserving mitochondrial homeostasis. We showed the administration of Ab-ECSnps inhibits calpain's translocation into mitochondria while promoting the translocation of BMI1 to mitochondria, thereby conferring neurotherapeutic benefits by enhancing cell viability, increasing mitochondrial DNA copy number, and preserving mitochondrial membrane potential. Further, we showed a novel molecular mechanism of BMI1 regulation by calpain that might contribute to maintaining mitochondrial homeostasis for attenuating PD. Concomitantly, Ab-ECSnps showed neurotherapeutic potential in the in vivo PD model. We showed for the first time that our brain-specific targeted delivery might regulate calpain-mediated BMI1 expression, thereby preserving mitochondrial homeostasis to alleviate PD.

Glia at Transition Zones.

Neural cells are segregated into their distinct central nervous system (CNS) and peripheral nervous system (PNS) domains. However, at specialized regions of the nervous system known as transition zones (TZs), glial cells from both the CNS and PNS are uniquely present with other specialized TZ cells. Herein we review the current understanding of vertebrate TZ cells. The article discusses the distinct cells at vertebrate TZs with a focus on cells that are located on the peripheral side of the spinal cord TZs. In addition to the developmental origin and differentiation of these TZ cells, the functional importance and the role of TZ cells in disease are highlighted. This article also reviews the common and unique features of vertebrate TZs from zebrafish to mice. We propose challenges and open questions in the field that could lead to exciting insights in the field of glial biology.

Anticholinerge lading bij oudere volwassenen in een woonzorgcentrum: een pilootonderzoek

Older adults are more at risk for side effects from medications. Mainly anticholinergic side effects can lead to central and peripheral side effects on somatic and cognitive levels. In this study, we determined the anticholinergic load of the medication regimens of residents of a residential care center using two validated measurement scales. We also examined to which extent the class(es) of medications influence this anticholinergic load. Finally, we analyzed the association of a high anticholinergic load with incidents (urinary tract infections, falls, delirium). In this pilot study we see a high degree of polymedication and use of psychotropic drugs with an anticholinergic effect. On average we established a score of 1.67 on the ACB and a score of 0.87 on the DBI. The anticholinergic load in the ACB is mainly determined by antipsychotics (t = 6.110, p < 0.001), in the DBI an influence of all medications with anticholinergic properties is seen (F = 6.764, p < 0.001). A risk score on the DBI has a statistically significant correlation with experiencing a urinary tract infection (F = 5.877, p = 0.018). This influence remains significant after adjusting for covariates. The anticholinergic load of medication regimens in residents is high. An increased anticholinergic load is also associated with urinary tract infection. Reducing the anticholinergic load within residential care centers therefore represents an important challenge for the future.

Extensive intraocular melanoma with secondary glaucoma in a 15-month-old Thoroughbred filly.

A 15-month-old, grey, Thoroughbred filly presented for investigation of a 6-week history of corneal oedema and blepharospasm on the right eye (OD). The filly was otherwise healthy. Following ophthalmic examination, glaucoma on the OD was diagnosed. A space occupying mass within the anterior chamber was documented on transpalpebral ultrasonographic examination. This mass obliterated most of the anterior intraocular structures on the peripheral nasal side (corneal endothelium and drainage angle), leading to secondary glaucoma. After systemic and topical treatment addressing secondary glaucoma, the corneal oedema reduced. The mass was visualised as an irregularly rounded brown structure associated with the iris on the peripheral nasal side of the anterior chamber. Given the filly's signalment, location and appearance of the mass, a tentative diagnosis of intraocular melanoma was made and enucleation was performed. Histopathological evaluation of the globe revealed solid sheets of heavily pigmented melanocytic cells, disrupting the normal ciliary body architecture and extending into the iris and subretinal. The cells were pleomorphic, polyhedral to round with occasional spindle-shaped cells, and contained moderate to large amounts of granular black-brown pigment (melanin). The iridal component expanded into the anterior chamber, with cells directly opposed to Descemet's membrane, with loss of the endothelium and expanding and occluding the filtration angle in this area. The lesion infiltrated locally into the edge of the sclera, but did not extend through the sclera, though occasional perivascular clusters of melanophages were observed within the scleral stroma adjacent to the optic nerve. Diagnosis of a uveal melanocytic neoplasm was confirmed, with characteristics similar to only one reported case . This is a unique case of a rapidly growing, invasive, uveal melanoma in a young horse. Intraocular melanoma should be considered as a differential diagnoses for glaucoma in grey horses, regardless of the age and absence of melanocytic skin lesions.

Novel ligand conjugated poly(propylene imine) dendrimers for brain targeted delivery of tacrine hydrochloride

Alzheimer's disease (AD) is the most common type of neurodegenerative disorder characterized by extracellular deposition of Amyloid β and intracellular deposition of neurofibrillary tangles. One of the most common etiological factors is rapid and excessive hydrolysis of acetylcholine by acetylcholinesterase (AChE) enzyme. Tacrine is one of the most potent and first USFDA approved centrally acting AChE inhibitor recommended for treatment of AD, but it is no longer in use as it causes severe peripheral side effects, mainly hepatotoxicity. In this research work, novel dendrimeric conjugates were developed with an aim of enhancing the brain targeting efficiency of tacrine and eliminating the peripheral side effects. Poly(propyleneimine) G5.0 dendrimers were conjugated with oleic acid as a brain targeting ligand, and the conjugation was confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy and dynamic light scattering studies. Tacrine hydrochloride was loaded into the plain dendrimer as well as oleic acid conjugated dendrimer by physical encapsulation method. The in vitro AChE inhibitory study showed retention of the AChE inhibition ability of tacrine in dendrimeric conjugates. The safety of the drug loaded conjugates was confirmed by haemolytic, nasal ciliotoxicity and cytotoxicity studies. Further, cellular uptake studies in SH-SY5Y cells showed abundance of green cytoplasmic fluorescence, suggesting enhanced internalization of dendrimeric conjugates. The results of this research work support the further exploration of this novel dendrimers based conjugated delivery system for in vivo studies as a potential alternative to treat AD.

Supramolecular polymerization of [6]helicene-based cyano-luminogens: on the overall efficiency of self-assembled circularly polarized emitters.

The synthesis of the [6]helicene-based luminophores 1 and 2 is reported. These chiral systems, endowed with cyano-stilbene fragments, form supramolecular polymers by the operation of intermolecular H-bonding interactions between the amides present in the peripheral side chains. The dissimilar disubstitution of 1 and 2 plays a crucial role in their self-assembling features. Thus, 1 does not show an efficient π-stacking of the central aromatic moiety. Instead, its self-assembling process results in a zig-zag arrangement of the monomeric units to form the aggregated species. On the other hand, 2 presents an efficient overlap of the aromatic backbones that affords a co-facial arrangement of the monomeric units. The solvent-dependent studies indicate that both [6]helicenes self-assemble following a cooperative supramolecular polymerization mechanism with a higher degree of cooperativity and stability for compound 2. The enantioenriched samples of both 1 and 2 display a rich dichroic pattern that changes when the supramolecular polymerization takes place. Furthermore, the presence of the cyano-stilbene moieties gives rise to an aggregation induced emission effect. The inherent chirality of both the monomeric and aggregated species of 1 and 2 provides the systems with CPL-emitting properties, presenting a remarkable overall CPL-efficiency, quantified by the BCPL parameter, that increases upon supramolecular polymerization.

Intranasal administration of sertraline ensures sustained brain delivery and antidepressant effect in a mouse model of depression

The pursuit of more potent and efficacious antidepressant therapies is of utmost significance. Herein, the intranasal (IN) route was investigated for sertraline brain delivery, encompassing a comparative pharmacokinetic study after a single-dose administration to mice by IN, intravenous (IV) (4.87 mg/kg) and oral (10 mg/kg) routes, and an efficacy/toxicity study to explore the therapeutic effect in mice subjected to the unpredictable chronic mild stress (UCMS) protocol. Neurotransmitters and melatonin were quantified in prefrontal cortex and plasma, respectively. A different drug biodistribution behavior was unveiled for a CNS-acting drug administered by means of the IN route. For the first time, IN administration of sertraline exhibited heightened systemic exposure (bioavailability = 166 %), and a sustained drug release into the brain, in opposition to IV and oral routes, avoiding drug fluctuation. The lower lung exposition (given by normalized area under the curve) observed after IN instillation envisions the reduction of sertraline pulmonary side effects and similarly other peripheral side effects. IN sertraline treatment displayed significant efficacy in ameliorating anhedonia after one week of administration while the 14-day IN treatment regimen translated into decreased immobility time and increased swimming time in the forced swimming test, suggesting an improvement of the depressive-like behavior displayed by the animal depressive-model. Remarkably, these effects were absent with oral sertraline, despite the higher used dose. Noteworthy neurotransmitter alterations were observed, with IN sertraline markedly reducing adrenaline in the prefrontal cortex, while serotonin and melatonin increased following both administration routes. With its sustained brain delivery and serotonin- and melatonin-enhancing potential, the innovative strategy of IN sertraline holds the potential not only to effectively address depressive symptoms but also to mitigate challenges inherent to classic treatments.

Laparoscopic Anatomical Liver Resection Using Liver Mapping of Incidental Indocyanine Green Fluorescence due to Cholestasis.

Indocyanine green (ICG) fluorescence is useful in laparoscopic hepatectomy (LH) for tumor identification and staining, as well as determination of resection margins. At our Institution, patient-specific, three-dimensional simulations and rehearsal of surgical strategies are carried out preoperatively. We describe cases in which ICG administered preoperatively became stagnated and fluoresced in an area similar to the preoperatively established resection area and the pathological findings in these cases. Four patients who underwent LH at our hospital between 2020 and 2023 (due to hepatocellular carcinoma in two and colorectal liver metastasis in two) were enrolled in the present study. The ICG-fluorescing liver segments were resected laparoscopically and their pathological characteristics were examined using a fluorescence microscope. In four cases, the areas of ICG fluorescence seen intraoperatively were due to stasis of preoperatively administered ICG, which fortuitously was equivalent to the planned resection area in the preoperative patient-specific simulation. The fluorescent areas were resected; there were no cases of bile leakage or recurrence. Fluorescence microscopy revealed areas with diffuse ICG fluorescence in normal hepatocytes on the tumor's peripheral side. It was suggested that resection of the liver area that was fluorescent due to stagnation of preoperatively administered ICG was rational and justified both anatomically and oncologically. This resection may also contribute to the prevention of bile leakage and recurrence.

Probing conformational properties of conjugated polymers in dilute solutions under variable solvent quality via coarse‐grained modeling

AbstractConjugated polymers (CPs), characterized by rigid conjugation backbones and flexible peripheral side chains, hold significant promise in various organic optoelectronic applications. In this study, we employ coarse‐grained molecular dynamics (CG‐MD) simulations to investigate the intricate interplay of solvent quality, temperature, and chain architecture (e.g., side‐chain length and molecular mass) on the conformational behaviors of CPs in dilute solutions. Our research uncovers distinctive conformational behaviors under varying solvent conditions, highlighting the versatile nature of polymer chains, which can adopt extended configurations in good solvents and transition to aggregated states in poor solvents. Additionally, the mass scaling exponent , a robust structural descriptor, consistently described CPs behavior across diverse architectures and solvent conditions. Furthermore, our study shows that a CP with longer side‐chain exhibits improved solubility, which is further confirmed by experimental observations. Moreover, our analysis of the shape descriptor provided valuable insights into the symmetry and dimensionality of CPs under varying solvent conditions. These findings offer a comprehensive understanding of conformational behaviors of CPs in dilute solution, which are helpful in guiding the conformational design of polymer for specific applications.

Evodiamine attenuates oxidative stress and ferroptosis by inhibiting the MAPK signaling to improve bortezomib-induced peripheral neurotoxicity.

Bortezomib (BTZ) is a commonly used antitumor drug, but its peripheral neuropathy side effect poses a limitation on its dosage. Evodiamine (EVO) exhibits various biological activities, including antioxidant, anti-inflammatory, and anticancer effects. The purpose of this investigation is to confirm the impact of EVO on BTZ-induced peripheral neurotoxicity. GeneCards and HERB were applied to analyze the targets of peripheral neurotoxicity and EVO. The Gene Ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG)pathways enrichment analysis of the hub genes were identified by DAVID. Rat dorsal root ganglion neurons (DRGs) and rat RSC96 Schwann cells (SCs) were treated with BTZ to simulate peripheral neurotoxicity. BTZ-induced peripheral neurotoxicity was assessed by detecting cell viability, proliferation, oxidative stress, and ferroptosis in DRGs and SCs. The mitogen-activated protein kinase (MAPK) signaling was scrutinized by Western blot assay. The Venn diagram for the overlapping targets of EVO and peripheral neurotoxicity showed that EVO might regulate peripheral neurotoxicity by influencing cell oxidative stress, ferroptosis, and MAPK signaling pathway. EVO attenuated BTZ-induced toxicity in DRGs and SCs. EVO attenuated BTZ-induced oxidative stress damage in DRGs and SCs by reducing reactive oxygen species and malondialdehyde levels and enhancing glutathione level. EVO attenuated BTZ-induced ferroptosis in DRGs and SCs. EVO inhibited BTZ-induced activation of the MAPK signaling in DRGs and SCs. Activation of the MAPK signaling reversed the neuroprotective effect of EVO on BTZ-induced oxidative stress injury and ferroptosis. EVO attenuated oxidative stress and ferroptosis by inhibiting the MAPK signaling to improve BTZ-induced peripheral neurotoxicity.

Review on optic atrophy

The illness known as otic atrophy damages the eye. It causes anterior ischemic optic neuropathy, also known as gloaucoma, and strokes of the optic nerve. A change in vision, notably blurred vision, problems with peripheral (side) vision, problems with colour vision, and a loss of vision sharpness, are indications of optic atrophy. The final stage of a disease process that affects the retinogeniculate section of the visual pathway is called optic atrophy, and it is identified by the non-specific symptom of optic disc pallor. As a result, rather than acting like a real peripheral nerve, the optic nerve, with its 1.2 million fibres, functions more like a white matter tract. Pial capillaries that supply the optic nerve head experience degeneration, which contributes to the pallor of the optic disc seen in optic atrophy.

Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson’s disease

The present study hypothesises that the selective brain β2 receptor activation through β2-adrenoreceptor agonist (β2ARA), Formoterol (FMT), suppresses SNCA gene expression, a pathological hallmark of Parkinson’s disease (PD) in brain. Further, it is also hypothesized that brain targeted delivery of Formoterol via polysorbate-80 surface modified solid lipid nanoparticles of Formoterol (FMT-SLNs-PS80) can improve its stability, therapeutic efficacy and avoid/reduce peripheral off-target side effects. FMT-SLNs-PS80 was prepared by solvent injection method, the formulation was optimized by using Box–Behnken design and characterized by measuring drug content, entrapment efficacy, particle size, zeta potentials and poly dispersibility. The FMT-SLNs-PS80, significantly decreases the SNCA expression, mitochondrial membrane damage and rotenone induced changes in oxidative (SOD, CAT, GSH and ROS) stress markers in SH-SY5Y cell lines. The ex vivo permeation study of the formulation using everted chicken ileum exhibited a steady state flux. The pharmacokinetic and tissue distribution studies of the formulation in rats showed a significant improvement in the kinetic parameters when compared to naïve FMT, further the formulation also improved the brain bioavailability of FMT. The anti-Parkinson’s efficacy studies of the formulation in mice showed a significant neuroprotection against rotenone-induced changes in behavioural and biochemical parameters. Further, the histopathological analysis of mice brain confirms a significant neuroprotective benefit. The present study successfully establishes the brain targeted delivery and anti-Parkinson’s therapeutic efficacy of FMT-SLNs-PS80.

Transient septin sumoylation steers a Fir1-Skt5 protein complex between the split septin ring.

Ubiquitylation and phosphorylation control composition and architecture of the cell separation machinery in yeast and other eukaryotes. The significance of septin sumoylation on cell separation remained an enigma. Septins form an hourglass structure at the bud neck of yeast cells that transforms into a split septin double ring during mitosis. We discovered that sumoylated septins recruit the cytokinesis checkpoint protein Fir1 to the peripheral side of the septin hourglass just before its transformation into the double-ring configuration. As this transition occurs, Fir1 is released from the septins and seamlessly relocates between the split septin rings through synchronized binding to the scaffold Spa2. Fir1 binds and carries the membrane-bound Skt5 on its route to the division plane where the Fir1-Skt5 complex serves as receptor for chitin synthase III.

SIRT2 Inhibition Rescues Neurodegenerative Pathology but Increases Systemic Inflammation in a Transgenic Mouse Model of Alzheimer’s Disease

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer’s disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1β, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.Graphical

Synthesis of an insulin-loaded mucoadhesive nanoparticle designed for intranasal administration: focus on new diffusion media.

Intranasal administration is a drug delivery approach to provide a non-invasive pharmacological response in the central nervous system with relatively small peripheral side effects. To improve the residence time of intranasal drug delivery systems in the nasal mucosa, mucoadhesive polymers (e.g., chitosan) can be used. Here, insulin-loaded chitosan nanoparticles were synthesized and their physiochemical properties were evaluated based on requirements of intranasal administration. The nanoparticles were spherical (a hydrodynamic diameter of 165.3nm, polydispersity index of 0.24, and zeta potential of +21.6mV) that granted mucoadhesion without any noticeable toxicity to the nasal tissue. We applied a new approach using the Krebs-Henseleit buffer solution along with simulated nasal fluid in a Franz's diffusion cell to study this intranasal drug delivery system. We used the Krebs-Henseleit buffer because of its ability to supply glucose to the cells which serves as a novel ex vivo diffusion medium to maintain the viability of the tissue during the experiment. Based on diffusion rate and histopathological endpoints, the Krebs-Henseleit buffer solution can be a substituent solution to the commonly used simulated nasal fluid for such drug delivery systems.

Supramolecular Block Copolymers from Tricarboxamides. Biasing Co-assembly by the Incorporation of Pyridine Rings.

The synthesis of a series of triangular-shape tricarboxamides endowed with three picolin or nicotin (compounds2and3) or just one nicotine unit (compound4) is reported and their self-assembling features investigated. The pyridine rings make compounds2-4electronically complementary with our previously reported OPETA1to form supramolecular copolymers.C3-symmetric tricarboxamide2forms highly stable intramolecular five-membered pseudocycles that impedes its supramolecular polymerization intopoly-2and the co-assembly with1to yield copolymerpoly-1-co-2. On the other hand,C3-symmetric tricarboxamide3readily formpoly-3with great stability but unable to form helical supramolecular polymers despite the presence of the peripheral chiral side chains. The copolymerpoly-1-co-3can only be obtained by a previous complete disassembly of the constitutive homopolymers in CHCl3. Helicalpoly-1-co-3arises in a process involving the transfer of the helicity from racemicpoly-1topoly-3, and the amplification of asymmetry from chiralpoly-3topoly-1. Importantly,C2v-symmetric4, endowed with only one nicotinamide moiety and three chiral side chains, self-assembles intoP-type helical supramolecular polymer (poly-4) in a thermodynamically controlled cooperative process. The combination ofpoly-1andpoly-4generates chiral supramolecular copolymerpoly-1-co-4, whose blocky microstructure has been investigated by applying the supramolecular copolymerization model.

Supramolecular Block Copolymers from Tricarboxamides. Biasing Co‐assembly by the Incorporation of Pyridine Rings

AbstractThe synthesis of a series of triangular‐shaped tricarboxamides endowed with three picoline or nicotine units (compounds 2 and 3, respectively) or just one nicotine unit (compound 4) is reported, and their self‐assembling features investigated. The pyridine rings make compounds 2–4 electronically complementary with our previously reported oligo(phenylene ethynylene)tricarboxamides (OPE‐TA) 1 to form supramolecular copolymers. C3‐symmetric tricarboxamide 2 forms highly stable intramolecular five‐membered pseudocycles that impede its supramolecular polymerization into poly‐2 and the co‐assembly with 1 to yield copolymer poly‐1‐co‐2. On the other hand, C3‐symmetric tricarboxamide 3 readily forms poly‐3 with great stability but unable to form helical supramolecular polymers despite the presence of the peripheral chiral side chains. The copolymer poly‐1‐co‐3 can only be obtained by a previous complete disassembly of the constitutive homopolymers in CHCl3. Helical poly‐1‐co‐3 arises in a process involving the transfer of the helicity from racemic poly‐1 to poly‐3, and the amplification of asymmetry from chiral poly‐3 to poly‐1. Importantly, C2v‐symmetric 4, endowed with only one nicotinamide moiety and three chiral side chains, self‐assembles into a P‐type helical supramolecular polymer (poly‐4) in a thermodynamically controlled cooperative process. The combination of poly‐1 and poly‐4 generates chiral supramolecular copolymer poly‐1‐co‐4, whose blocky microstructure has been investigated by applying the previously reported supramolecular copolymerization model.

Outcomes and clinical implications of intranasal insulin on cognition in humans: A systematic review and meta-analysis.

Aberrant brain insulin signaling has been posited to lie at the crossroads of several metabolic and cognitive disorders. Intranasal insulin (INI) is a non-invasive approach that allows investigation and modulation of insulin signaling in the brain while limiting peripheral side effects. The objective of this systematic review and meta-analysis is to evaluate the effects of INI on cognition in diverse patient populations and healthy individuals. MEDLINE, EMBASE, PsycINFO, and Cochrane CENTRAL were systematically searched from 2000 to July 2021. Eligible studies were randomized controlled trials that studied the effects of INI on cognition. Two independent reviewers determined study eligibility and extracted relevant descriptive and outcome data. Twenty-nine studies (pooled N = 1,726) in healthy individuals as well as those with Alzheimer's disease (AD)/mild cognitive impairment (MCI), mental health disorders, metabolic disorders, among others, were included in the quantitative meta-analysis. Patients with AD/MCI treated with INI were more likely to show an improvement in global cognition (SMD = 0.22, 95% CI: 0.05-0.38 p = <0.00001, N = 12 studies). Among studies with healthy individuals and other patient populations, no significant effects of INI were found for global cognition. This review demonstrates that INI may be associated with pro-cognitive benefits for global cognition, specifically for individuals with AD/MCI. Further studies are required to better understand the neurobiological mechanisms and differences in etiology to dissect the intrinsic and extrinsic factors contributing to the treatment response of INI.