Cannabidiol and Neurodegeneration: From Molecular Mechanisms to Clinical Benefits.

Neurodegenerative disorders (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis are severe and life-threatening conditions in which significant damage of functional neurons occurs to produce malfunction of psycho-motor functions. NDs are an important cause of death in the elderly population worldwide. These disorders are commonly associated with the progression of age, oxidative stress, and environmental pollutants, which are the major etiological factors. Abnormal aggregation of specific proteins such as α-synuclein, amyloid-ß, huntingtin, and tau, and accumulation of its associated oligomers in neurons are the hallmark pathological features of NDs. Existing therapeutic options for NDs are only symptomatic relief and do not address root-causing factors, such as protein aggregation, oxidative stress, and neuroinflammation. Cannabidiol is a non-psychotic natural cannabinoid obtained from Cannabis sativa that possesses multiple pharmacological actions, including antioxidant, anti-inflammatory, and neuroprotective effects in various NDs and other neurological disorders both in vitro and in vivo. Cannabidiol has gained attention as a promising therapeutic drug candidate for the management of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by inhibiting protein aggregation, free radicals, and neuroinflammation. In parallel, CBD has shown positive results in other neurological disorders, such as epilepsy, depression, schizophrenia, and anxiety, as well as adjuvant treatment with existing standard therapeutic agents. Hence, the present review focuses on exploring the possible molecular mechanisms in controlling various neurological disorders as well as its clinical applications in NDs including epilepsy, depression and anxiety. In this way, the current review will serve as a standalone reference for the researchers working in this area.

Bone Marrow Aspirate Concentrate for Treatment of Primary Knee Osteoarthritis: A Prospective, Single-Center, Non-randomized Study with 2-Year Follow-Up.

Introduction: Knee osteoarthritis (OA) is a widespread, disabling condition with no intervention to fully restore cartilage or halt progression. Bone marrow aspirate concentrate (BMAC), an autologous product from bone marrow aspiration, has shown promise as a regenerative therapy due to its cell composition and chondrogenic effects. Our study aims to assess the functional outcomes, including pain, function, satisfaction, and complications post-BMAC injection in knee OA patients. Materials and Methods: In this prospective, single-center study, 63 patients with grade II-III knee OA (Kellgren-Lawrence (K-L) scale) unresponsive to conservative management underwent BMAC injection. The procedure involved bone marrow aspiration from the anterior iliac crest, processing to obtain a concentrate, followed by intra-articular injection. Patients were followed for 24 months, assessing outcomes using the Visual Analog Scale (VAS), International Knee Documentation Committee (IKDC) score, and MOCART 2.0 score. Results: The cohort, with a slight female predominance and predominantly aged 41-50 years, majorly comprised K-L grade III OA patients. BMAC treatment resulted in significant improvements in VAS pain scores, IKDC functional scores, and MOCART 2.0 scores over the 24-month follow-up. Conclusion: BMAC injection provides significant improvement in both pain and functional outcomes at mid-term follow-up in patients with mild-to-moderate OA of the knee. Further high-quality, adequately powered, multi-center, prospective, double-blinded, randomized controlled trials with longer follow-up are necessary to justify the routine clinical use of BMAC for treatment of patients suffering with knee OA.

Identification and Analysis of Atrial-Bronchial-Abdominal Disharmony in Patients with Isomeric Atrial Appendages.

Ideally, the morphology of atrial appendages should solely be used to identify and differentiate patients with isomeric right and left atrial appendages. However, in clinical practice, the segregation is often indirectly based on the arrangement of thoraco-abdominal structures. The correlation between thoraco-abdominal arrangement and atrial appendages, however, is imperfect. In this study, we sought to clarify the cardiovascular malformations in patients with isomeric atrial appendages with an emphasis on atrial-thoracic-abdominal disharmony. A retrospective review of all patients who underwent cardiac CT angiography between January 2014 and June 2023 and identified to have isomeric atrial appendages was performed. Of the 366 cases (median age: 2 years [interquartile range: 11 months-7 years]), 247 (67.5%) patients had isomeric right atrial appendages while 119 (32.5%) patients had isomeric left atrial appendages. In 316 (86.3%) patients, the thoraco-abdominal arrangement was as per atrial appendage morphology while the remaining 50 (13.6%) patients had disharmonious patterns. Compared to isomeric left atrial appendages, the disharmonious pattern was more frequent with isomeric right atrial appendages (5.9% vs. 17.4%; p 0.003). Irrespective of the type of isomerism, disharmony was mostly confined to the level of the abdomen. Not all patients with isomeric atrial appendages have a harmonious thoraco-abdominal arrangement. The atrial-bronchial-abdominal disharmony is more frequent with isomeric right atrial appendages and is mostly present at the level of the abdomen. A detailed sequential segmental analysis with an independent description of each organ system is, therefore, essential for the complete evaluation of patients with isomeric atrial appendages.

Electrical noise spectroscopy of magnons in a quantum Hall ferromagnet.

Collective spin-wave excitations, magnons, are promising quasi-particles for next-generation spintronics devices, including platforms for information transfer. In a quantum Hall ferromagnets, detection of these charge-neutral excitations relies on the conversion of magnons into electrical signals in the form of excess electrons and holes, but if the excess electron and holes are equal, detecting an electrical signal is challenging. In this work, we overcome this shortcoming by measuring the electrical noise generated by magnons. We use the symmetry-broken quantum Hall ferromagnet of the zeroth Landau level in graphene to launch magnons. Absorption of these magnons creates excess noise above the Zeeman energy and remains finite even when the average electrical signal is zero. Moreover, we formulate a theoretical model in which the noise is produced by equilibration between edge channels and propagating magnons. Our model also allows us to pinpoint the regime of ballistic magnon transport in our device.

In situ hydrolysis of a carbophosphazene ligand leads to one-dimensional lanthanide coordination polymers. Synthesis, structure and dynamic magnetic studies.

An in situ hydrolysis of the P-Cl bonds of the carbophosphazene [{NC(NMe2)}2{NPCl2}] (LPCl2) in the presence of hydrated lanthanide(III) nitrates in a dichloromethane and methanol (2 : 1) solvent mixture afforded a series of novel 1D coordination polymers: [{Ln(LHPO2)3(NO3)2(CH3OH)(H2O)} (Cl)]n {where Ln(III) = Gd (1), Tb (2), Dy (3), or Er (4) and LHPO2 is the hydrolyzed carbophosphazene (LPCl2) ligand}. X-ray crystallographic analysis revealed that complexes 1-4 are isostructural and crystallized in the monoclinic crystal system having P21/c space group. The coordination polymers are formed because of the involvement of the geminal P(O)(OH) moieties of the carbophosphazene ligand. Each lanthanide(III) ion is 9-coordinate (9O) in a distorted muffin geometry. Magnetic measurements revealed that both DyIII and ErIII analogues exhibit field-induced single-molecule magnet (SMM) behavior at 0.8 kOe and 2.2 k Oe, respectively. At such dc fields, the dynamic magnetic susceptibility displays complex behavior with a triple magnetic relaxation contribution for 3, while two contributions were identified for 4. The observed static and dynamic magnetic behavior for complexes 1-4 were further rationalized with the aid of BS-DFT and CASSCF/SO-RASSI/SINGLE_ANISO calculations.

Efficacy of stromal vascular fraction for knee osteoarthritis: A prospective, single-centre, non-randomized study with 2 years follow-up.

BACKGROUND: Current osteoarthritis (OA) treatments focus on symptom relief without addressing the underlying disease process. In regenerative medicine, current treatments have limitations. In regenerative medicine, more research is needed for intra-articular stromal vascular fraction (SVF) injections in OA, including dosage optimization, long-term efficacy, safety, comparisons with other treatments, and mechanism exploration. AIM: To compare the efficacy of intra-articular SVF with corticosteroid (ICS) injections in patients with primary knee OA. METHODS: The study included 50 patients with Kellgren-Lawrence grades II and III OA. Patients were randomly assigned (1:1) to receive either a single intra-articular SVF injection (group A) or a single intra-articular ICS (triamcinolone) (group B) injection. Patients were followed up at 1, 3, 6, 12, and 24 months. Visual analog score (VAS) and International Knee Documentation Committee (IKDC) scores were administered before the procedure and at all follow-ups. The safety of SVF in terms of adverse and severe adverse events was recorded. Statistical analysis was performed with SPSS Version 26.0, IBM Corp, Chicago, IL, United States. RESULTS: Both groups had similar demographics and baseline clinical characteristics. Follow-up showed minor patient loss, resulting in 23 and 24 in groups A and B respectively. Group A experienced a notable reduction in pain, with VAS scores decreasing from 7.7 to 2.4 over 24 months, compared to a minor reduction from 7.8 to 6.2 in Group B. This difference in pain reduction in group A was statistically significant from the third month onwards. Additionally, Group A showed significant improvements in knee functionality, with IKDC scores rising from 33.4 to 83.10, whereas Group B saw a modest increase from 36.7 to 45.16. The improvement in Group A was statistically significant from 6 months and maintained through 24 months. CONCLUSION: Our study demonstrated that intra-articular administration of SVF can lead to reduced pain and improved knee function in patients with primary knee OA. More adequately powered, multi-center, double-blinded, randomised clinical trials with longer follow-ups are needed to further establish safety and justify its clinical use.

Metal-free platforms for molecular thin films as high-performance supercapacitors.

Controlling chemical functionalization and achieving stable electrode-molecule interfaces for high-performance electrochemical energy storage applications remain challenging tasks. Herein, we present a simple, controllable, scalable, and versatile electrochemical modification approach of graphite rods (GRs) extracted from low-cost Eveready cells that were covalently modified with anthracene oligomers. The anthracene oligomers with a total layer thickness of ∼24 nm on the GR electrode yield a remarkable specific capacitance of ∼670 F g-1 with good galvanostatic charge-discharge cycling stability (10 000) recorded in 1 M H2SO4 electrolyte. Such a boost in capacitance is attributed mainly to two contributions: (i) an electrical double-layer at the anthracene oligomer/GR/electrolyte interfaces, and (ii) the proton-coupled electron transfer (PCET) reaction, which ensures a substantial faradaic contribution to the total capacitance. Due to the higher conductivity of the anthracene films, it possesses more azo groups (-N[double bond, length as m-dash]N-) during the electrochemical growth of the oligomer films compared to pyrene and naphthalene oligomers, which is key to PCET reactions. AC-based electrical studies unravel the in-depth charge interfacial electrical behavior of anthracene-grafted electrodes. Asymmetrical solid-state supercapacitor devices were made using anthracene-modified biomass-derived porous carbon, which showed improved performance with a specific capacitance of ∼155 F g-1 at 2 A g-1 with an energy density of 5.8 W h kg-1 at a high-power density of 2010 W kg-1 and powered LED lighting for a longer period. The present work provides a promising metal-free approach in developing organic thin-film hybrid capacitors.

Eight-coordinate mono- and dinuclear Dy(III) complexes containing a rigid equatorial plane and an anisobidentate carboxylate ligand in the axial position: synthesis, structure and magnetism.

A rigid pentadentate chelating ligand (H2L) has been utilized to synthesize a series of octacoordinate mononuclear complexes, [Dy(L)(Ph3PO)(OOCR)] (where R = C6H5 (1), C(CH3)3 (2), CF3 (3)) and a dinuclear complex, [Dy2(L)2(Ph3PO)2{(OOC)2C6H4}] (4) based on the highly anisotropic Dy(III) ion. All the complexes were structurally characterized by single-crystal X-ray diffraction studies. The complexes were formed by the coordination action of the dianionic pentadentate ligand [L]2-, one phosphine oxide, and carboxylate ligands. DC and AC magnetic measurements were performed on 1-4. Complexes 1-4 show SMM behaviour, under zero DC field for 1 and 4, and under 500 Oe and 1000 Oe DC fields for 2 and 3 respectively, with thermally activated, Raman, and Raman and quantum tunnelling dominant relaxation mechanisms for 1 and 2, 3 and 4, respectively.

Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence.

The host immune responses play a pivotal role in the establishment of long-term memory responses, which effectively aids in infection clearance. However, the prevailing anti-tuberculosis therapy, while aiming to combat tuberculosis (TB), also debilitates innate and adaptive immune components of the host. In this study, we explored how the front-line anti-TB drugs impact the host immune cells by modulating multiple signaling pathways and subsequently leading to disease relapse. Administration of these drugs led to a reduction in innate immune activation and also the cytokines required to trigger protective T cell responses. Moreover, these drugs led to activation-induced cell death in the mycobacterial-specific T cell leading to a reduced killing capacity. Furthermore, these drugs stalled the T cell differentiation into memory subsets by modulating the activation of STAT3, STAT4, FOXO1, and NFκB transcription factors and hampering the Th1 and Th17-mediated long-term host protective memory responses. These findings suggest the urgent need to augment directly observed treatment, short-course (DOTS) therapy with immunomodulatory agents to mitigate the adverse effects linked to the treatment.IMPORTANCEAs a central component of TB eradication initiatives, directly observed treatment, short-course (DOTS) therapy imparts immune-dampening effects during the course of treatment. This approach undermines the host immune system by delaying the activation process and lowering the immune response. In our investigation, we have unveiled the impact of DOTS on specific immune cell populations. Notably, the signaling pathways involving STAT3 and STAT4 critical for memory responses and NFκß associated with pro-inflammation were substantially declined due to the therapy. Consequently, these drugs exhibit limited effectiveness in preventing recurrence of the disease. These observations highlight the imperative integration of immunomodulators to manage TB infection.

Investigating the Potential Therapeutic Mechanisms of Puerarin in Neurological Diseases.

Plants and their derived phytochemicals have a long history of treating a wide range of illnesses for several decades. They are believed to be the origin of a diverse array of medicinal compounds. One of the compounds found in kudzu root is puerarin, a isoflavone glycoside commonly used as an alternative medicine to treat various diseases. From a biological perspective, puerarin can be described as a white needle crystal with the chemical name of 7-hydroxy-3-(4-hydroxyphenyl)-1-benzopyran-4-one-8-D-glucopyranoside. Besides, puerarin is sparingly soluble in water and produces no color or light yellow solution. Multiple experimental and clinical studies have confirmed the significant therapeutic effects of puerarin. These effects span a wide range of pharmacological effects, including neuroprotection, hepatoprotection, cardioprotection, immunomodulation, anticancer properties, anti-diabetic properties, anti-osteoporosis properties, and more. Puerarin achieves these effects by interacting with various cellular and molecular pathways, such as MAPK, AMPK, NF-κB, mTOR, ß-catenin, and PKB/Akt, as well as different receptors, enzymes, and growth factors. The current review highlights the molecular mechanism of puerarin as a neuroprotective agent in the treatment of various neurodegenerative and neurological diseases. Extensive cellular, animal, and clinical research has provided valuable insights into its effectiveness in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, cerebral stroke, depression, and more.

A highly anisotropic family of hexagonal bipyramidal Dy(III) unsaturated 18-crown-6 complexes exceeding the blockade barrier over 2700 K: a computational exploration.

In the present work, we have explored a series of unsaturated hexa-18-crown-6 (U18C6) ligands towards designing highly anisotropic Dy(III) based single-ion magnets (SIMs) with the general formula [Dy(U18C6)X2]+ (where U18C6 = [C12H12O6] (1), [C12H12S6] (2), [C12H12Se6] (3), [C12H12O4S2] (4), [C12H12O4Se2] (5) and X = F, Cl, Br, I, OtBu and OSiPh3). By analysing the electronic structure, bonding and magnetic properties, we find that the U18C6 ligands prefer stabilising the highly symmetric eight-coordinated hexagonal bipyramidal geometry (HBPY-8), which is the source of the near-Ising type anisotropy in all the [Dy(U18C6)X2]+ complexes. Moreover, the ability of sulfur/selenium substituted U18C6 ligands to stabilize the highly anisotropic HBPY-8 geometry makes them more promising towards engineering the equatorial ligand field compared to substituted saturated 18C6 ligands where the exodentate arrangement of the S lone pairs results in low symmetry. Magnetic relaxation analysis predicts a record barrier height over 2700 K for [Dy(C12H12O6)F2]+ and [Dy(C12H12S6)X2]+ (where X = F, OtBu and OSiPh3) complexes, nearly 23% higher than those of the top performing Dy(III) based SIMs in the literature.

Allosteric inhibition of dengue virus RNA-dependent RNA polymerase by Litsea cubeba phytochemicals: a computational study.

RNA-dependent RNA polymerase (RdRp) is considered a potential drug target for dengue virus (DENV) inhibition and has attracted attention in antiviral drug discovery. Here, we screened 121 natural compounds from Litsea cubeba against DENV RdRp using various approaches of computer-based drug discovery. Notably, we identified four potential compounds (Ushinsunine, Cassameridine, (+)-Epiexcelsin, (-)-Phanostenine) with good binding scores and allosteric interactions with the target protein. Moreover, molecular dynamics simulation studies were done to check the conformational stability of the complexes under given conditions. Additionally, we performed post-simulation analysis to find the stability of potential drugs in the target protein. The findings suggest Litsea cubeba-derived phytomolecules as a therapeutic solution to control DENV infection.Communicated by Ramaswamy H. Sarma.

Effect of diamagnetic Zn(II) ions on the SMM properties of a series of trinuclear ZnDy2 and tetranuclear Zn2Dy2 (LnIII = Dy, Tb, Gd) complexes: combined experimental and theoretical studies.

To study the effect of diamagnetic ions on magnetic interactions, utilizing a compartmental ligand (Z)-2-(hydroxymethyl)-4-methyl-6-((quinolin-8-ylimino)methyl)phenol (LH2), two different series of ZnII-LnIII complexes, namely the trinuclear series of [DyZn2(L)2(µ2-OAc)2(CH3OH)2]·NO3·MeOH (1), [TbZn2(L)2(µ2-OAc)2(CH3OH)2]·NO3·5MeOH·H2O (2), and [GdZn2(L)2(µ2-OAc)2(CH3OH)2]·NO3·MeOH·CHCl3 (3) and the tetranuclear series of [Dy2Zn2(LH)4(NO3)4(µ2OAc)]·NO3·MeOH·H2O (4), [Tb2Zn2(LH)4(NO3)4(µ2-OAc)]·NO3·MeOH·2H2O (5), and [Gd2Zn2(LH)4(NO3)4(µ2-OAc)]·NO3·MeOH·2H2O (6), were synthesized. Trinuclear ZnII-LnIII complexes 1-3 consist of one LnIII ion sandwiched between two peripheral ZnII ions forming a bent type ZnII-DyIII-ZnII array with an angle of 110.64°. Tetranuclear ZnII-LnIII complexes 4-6 are basically a combination of two dinuclear moieties of [LnZn(LH)2(NO3)2]+ connected by one bidentate bridging acetate ion in µ2-OAc coordination mode. The detailed magnetic analysis reveals that complexes 1 and 4 are single molecule magnets having energy barriers of 34.98 K and 46.71 K with relaxation times (τ0) of 5.05 × 10-4 s and 5.24 × 10-4 s, respectively. Ab initio calculations were employed to analyze the magnetic anisotropy and magnetic exchange interaction between the ZnII and LnIII centers with the aim of gaining better insights into the magnetic dynamics of complexes 1-6.

Immunomodulation by juglone alleviates acute graft-versus-host disease without compromising the graft-versus-leukaemia activity in mice.

BACKGROUND AND PURPOSE: Acute graft-versus-host disease (GVHD) remains a major barrier to successful transplantation outcomes. Recent studies have shown that pharmacotherapy for GVHD should target both the innate and adaptive inflammatory immune responses. Juglone, a redox-active phytochemical found in walnuts, has shown potent anti-inflammatory effects in models of colitis and inflammatory bowel disease. However, its effects on T-cell-mediated immune responses remain largely unknown. Considering the overlapping mediators of inflammation in GVHD and the aforementioned conditions, we investigated the use of juglone as a prophylactic agent for GVHD. EXPERIMENTAL APPROACH: Immunomodulatory activity and mechanism of action of juglone were studied using murine splenic leukocytes in vitro. The GVHD prophylactic efficacy of orally administered juglone was evaluated using a murine model of allogeneic haematopoietic stem cell transplantation based on an MHC mismatch. KEY RESULTS: Juglone exhibited immunomodulatory activity by (i) inhibiting the activation of dendritic cells and CD4+ T-cells, (ii) inhibiting cytokine secretion and lymphocyte proliferation, and (iii) inducing exhaustion of CD4+ T-cells, as shown by increased expression of CTLA-4 (CD152) and Fas (CD95). Oral administration of juglone significantly reduced mortality and morbidity associated with GVHD while maintaining graft-versus-leukaemia activity. This was accompanied by a decrease in the number of naïve CD4+ cells, and an increase in the number of CD4+ and CD8+ central memory T-cells. CONCLUSION AND IMPLICATIONS: Juglone is a potent immunomodulator for GVHD prophylaxis. Our study is the first to provide a dosage framework for the oral administration of juglone that can be used for clinical development.

Clarifying the Anatomy of Tetralogy of Fallot with S-shaped Ascending Aorta.

We recently encountered several cases of tetralogy of Fallot with an abnormally oriented S-shaped ascending aorta. In this retrospective study, we sought to clarify morphology of this unusual under-recognized variant. Databases were reviewed to identify all patients with tetralogy of Fallot having an S-shaped ascending aorta. Computed tomographic angiography was used for the assessment of cardiac morphology. Out of the 21 patients, 18 (86%) had a right aortic arch, 2 (9%) had a left aortic arch, and the remaining patient (5%) had a double aortic arch. Patients with a right aortic arch, compared to age and sex-matched patients with a right aortic arch but normally oriented ascending aorta, had lesser aortic override (29.3 ± 14% vs 54.8 ± 13.2%; p = 0.0001) and a wider ascending aorta (25.2 ± 6.9 vs 18.0 ± 3.2 mm; p = 0.0003). The S-shaped ascending aorta was located posteriorly, with a higher sterno-aortic distance (25.5 ± 7.7 vs 9.9 ± 4.5 mm; p = 0.0001). The ascending aorta among patients with tortuosity was longer (4.12 ± 1.7 vs 3.07 ± 0.82, p = 0.03) but with similar tortuosity index (1.22 ± 0.19 vs 1.15 ± 0.17, p = 0.23). Of the cases with right aortic arch and S-shaped ascending aorta, 16 (89%) had extrinsic compression of the right pulmonary artery (p = 0.0001), while 7 (39%) had crossed pulmonary arteries (p = 0.008), with no such findings among those with normally oriented ascending aorta. Tetralogy of Fallot with an S-shaped ascending aorta is a variant with lesser aortic override and a more posteriorly located ascending aorta. Compression of the right pulmonary artery and crossed pulmonary arteries is frequent in the presence of a right-sided aortic arch. These findings have important implications for optimal diagnosis and surgical repair.

Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-ß plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3ß, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.