Discovery and structure - activity relationships of 2,4,5-trimethoxyphenyl pyrimidine derivatives as selective D5 receptor partial agonists.

Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson's and Alzheimer's. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound 5c (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, 5j, 5h, and 5e. The most potent compound of this series 5j (4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine), exhibited EC50 of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that 5j is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of 5j (20 mg/kg, p.o) in C57BL/6j mice showed that 5j is readily absorbed via oral route of dosing and also enters into the brain (plasma Tmax: 1 h, Cmax: 51.10 ± 13.51 ng/ml; Brain Tmax: 0.5 h, Cmax: 22.54 ± 4.08 ng/ml). We further determined the in-vivo effect of 5j on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that 5j (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, i.p.). Furthermore, 5j did not exhibit any cytotoxicity (up to 10 µM) or in vivo acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that 5j could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.

Solvothermally Synthesized Nickel-Doped Marigold-Like SnS2 Microflowers for High-Performance Supercapacitor Electrode Materials.

Two-dimensional transition-metal dichalcogenides (TMDs) have emerged as promising capacitive materials for supercapacitors owing to their layered structure, high specific capacity, and large surface area. Herein, Ni-doped SnS2 microflowers were successfully synthesized via a facile one-step solvothermal approach. The obtained Ni-doped SnS2 microflowers exhibited a high specific capacitances of 459.5 and 77.22 F g-1 at current densities of 2 and 10 A g-1, respectively, in NaClO4 electrolyte, which was found to be higher than that of SnS2-based electrodes in various electrolytes such as KOH, KCl, Na2SO4, NaOH, and NaNO3. Additionally, these microflowers demonstrate a good specific energy density of up to 51.69 Wh kg-1, at a power density of 3204 Wkg-1. Moreover, Ni-doped SnS2 microflowers exhibit a capacity retention of 78.4% even after 5000 cycles. Better electrochemical performance of the prepared electrode may be attributed to some important factors, including the utilization of a highly ionic conductive and less viscous NaClO4 electrolyte, incorporation of Ni as a dopant, and the marigold flower-like morphology of the Ni-doped SnS2. Thus, Ni-doped SnS2 is a promising electrode material in unconventional high-energy storage technologies.

Exploring the genetic mechanisms: SELP gene's contribution to alleviating vaso-occlusive crisis in sickle cell disease.

Sickle cell disease is a catastrophic inflammatory disorder characterized by microvascular vaso-occlusion, leading to high morbidity and increased mortality. P-selectin, a cell adhesion molecule, plays a crucial role in the pathogenesis and severity of sickle cell disease. Its expression and binding with its ligand PSGL-1 is involved in various mechanisms that contribute to inflammation and immune response, resulting in complications in sickle cell disease. Preclinical data have verified the efficacy of P-Selectin inhibition in mitigating vaso-occlusive events and severity of disease. Currently clinical trials are ongoing to evaluate the safety and efficiency of P-Selectin-targeted therapies and concede the challenges and limitations associated with their use. Despite of its proven role in reducing severity in sickle cell disease, future research should focus on identifying other novel targets within the adhesion cascade and explore combination therapies. Conducting trials and addressing concerns about accessibility are crucial steps towards fully harnessing the potential of P selectin inhibitors as a groundbreaking treatment option. This review focuses on understanding the role of p selectin and its interactions with molecules involved in inflammation providing insights about the molecular etiology, pathophysiology, and potential therapeutic targets in sickle cell disease.

Anion-Relay Double Aza-Michael-Michael Cascades to Enone-Tethered Cyclohexadienones: Access to an Intricate Bridged Ring System.

An anion-relay double aza-Michael-Michael addition strategy has been reported for the synthesis of intricate scaffolds from enone-tethered cyclohexadienones and primary amines. This method discloses the base-catalyzed synthesis of highly valued bridged aza-tricyclic frameworks with a high level of product selectivity and stereoselectivity. Gram scale synthesis and synthetic transformation were shown to afford structurally diverse bridged aza-polycyclic amines. Control experiments and the kinetic profile were studied to determine a plausible reaction mechanism.

Xylooligosaccharides from lignocellulosic biomass and their applications as nutraceuticals: a review on their production, purification, and characterization.

Xylooligosaccharides (XOS) are considered a potent source of prebiotics for humans. The global prebiotic market is expanding in size, was valued at USD 6.05 billion in 2021, and is expected to grow at a 14.9% compound annual growth rate between 2022 and 2030, indicating a huge demand. These XOS are non-digestible pentose sugar oligomers comprising mainly xylose. Xylose is naturally present in the lignocellulosic biomass (LCB), fruits and vegetables. Apart from the prebiotic effect, these XOS have been reported to reduce blood cholesterol, possess antioxidant effects, increase calcium absorption, reduce colon cancer risk, and benefit diabetic patients. The primary use of XOS is reported in the feed industry followed by health, medical use, food and drinks. LCB mainly contains glucan, xylan and lignin. After glucan, xylan is the second-highest available sugar on the globe composed of xylose. Therefore, the xylan fraction of LCB has great significance in producing food, feed and energy. Glucan has been exploited for the commercial production of ethanol, xylitol, furfural, hydroxymethyl furfural and glucose. As of now, xylan has limited applications. Therefore, xylan can be exploited to convert to XOS. The production of XOS from LCB fraction not only helps to produce these at a very low price, but also helps in the reduction of greenhouse gases. Its use in food and drinks is increasing as it can be derived from the abundantly and cheaply available LCB. The article provides a review on the production, purification and characterization of XOS in view of their use as nutraceuticals. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Interferon inducible guanylate-binding protein 1 modulates the lipopolysaccharide-induced cytokines/chemokines and mitogen-activated protein kinases in macrophages.

Guanylate-binding proteins (GBPs) are a family of interferon (IFN)-inducible GTPases and play a pivotal role in the host immune response to microbial infections. These are upregulated in immune cells after recognizing the lipopolysaccharides (LPS), the major membrane component of Gram-negative bacteria. In the present study, the expression pattern of GBP1-7 was initially mapped in phorbol 12-myristate 13-acetate-differentiated human monocytes THP-1 and mouse macrophages RAW 264.7 cell lines stimulated with LPS. A time-dependent significant expression of GBP1-7 was observed in these cells. Moreover, among the various GBPs, GBP1 has emerged as a central player in regulating innate immunity and inflammation. Therefore, to study the specific role of GBP1 in LPS-induced inflammation, knockdown of the Gbp1 gene was carried out in both cells using small interfering RNA interference. Altered levels of different cytokines (interleukin [IL]-4, IL-10, IL-12ß, IFN-γ, tumor necrosis factor-α), inducible nitric oxide synthase, histocompatibility 2, class II antigen A, protein kinase R, and chemokines (chemokine (C-X-C motif) ligand 9 [CXCL9], CXCL10, and CXCL11) in GBP1 knockdown cells were reported compared to control cells. Interestingly, the extracellular-signal-regulated kinase 1/2 mitogen-activated protein (MAP) kinases and signal transducer and activator of transcription 1 (STAT1) transcription factor levels were considerably induced in knockdown cells compared to the control cells. However, no change in the level of phosphorylated nuclear factor-kB, c-Jun, and p38 transcription factors was observed in GBP1 knockdown cells compared to the control cells. This study concludes that GBP1 may alter the expression of cytokines, chemokines, and effector molecules mediated by MAP kinases and STAT1 transcription factors.

Antidiabetic Evaluation of Kigelia pinnata Root Bark Extract in Streptozotocin-Induced Type-2 Diabetes Model of Rats.

Diabetes mellitus (DM) is the most common endocrine disorder characterized by increased blood glucose levels resulting from defective insulin secretion, resistance to insulin action, or both. DM is often associated with severe complications, and there is an increasing appreciation that cognitive function declines in DM. The aim of this research work was to evaluate Kigelia pinnata root bark extract in Streptozotocin (STZ)-induced type-2 diabetes. Experimental diabetes was induced by a single administration of STZ (60 mg/kg, intraperitoneal [i.p.]), immediately after the STZ administration, and all animals were fed with normal food and water. Nicotinamide was administered (120 mg/kg, i.p.) 15 min before STZ. The development of hyperglycemia was confirmed by the elevated blood glucose levels determined at fixed intervals, which was confirmed by measuring fasting blood glucose levels in rats' blood taken from the tail vein. Supplementation with ethanolic extract of K. pinnata root bark (EEKP) significantly reduced the elevated blood glucose in STZ-induced hyperglycemia in rats. EEKP significantly restored the biochemical and antioxidant defense system. On the final day of the protocol, the extract also reduced inflammatory cytokines in the blood serum.

Renal Adverse Effects of Tenofovir Containing Regimens in HIV-Infected Children and Adolescents in North India.

OBJECTIVE: To study the prevalence of abnormal renal functions among children living with HIV (CLHIV) receiving tenofovir disoproxil fumarate (TDF) containing antiretroviral therapy (ART). METHODS: A prospective, observational study was conducted among CLHIV aged 10 years to 21 years attending the pediatric HIV clinic. We included CLHIV weighing ≥ 30 kg who had been receiving TDF-containing regimens for at least 6 months, with estimated glomerular filtration rate (eGFR) > 60 ml/min/m2 at enrolment and for whom baseline laboratory parameters were available before starting ART. Clinical and laboratory parameters like serum creatinine, serum phosphate, urinary protein and glucose estimation, CD4 count and viral load were noted from records. The mean change in serum creatinine, estimated glomerular filtration rate (eGFR), creatinine clearance, serum phosphate, and presence of urinary glucose and protein by dipstick were assessed at 3- and 12-months follow-up. RESULTS: We enrolled 70 patients with mean (SD) age 14.99 (2.45) years who had been receiving TDF-based ART for a mean (SD) duration of 14.60 (12.80) months. At 3-months and 12-months follow-up, 32.85% and 41.42% patients, respectively, had eGFR below 90 mL/min/1.73m2, while 4.2% and 2.8% patients, respectively, had eGFR between 50-60 mL/min/1.73m2. One patient had creatinine clearance below 50 mL/min/1.73m2. Four patients had hypophosphatemia at the first and last follow-up respectively, and five patients had proteinuria. There was no statistically significant change in CD4 counts, serum potassium, or serum uric acid during study duration. CONCLUSION: TDF-containing ART regimen is associated with decreased eGFR, creatinine clearance and proteinuria.

Fish cell line: depositories, web resources and future applications.

Cell lines are important bioresources to study the key biological processes in the areas like virology, pathology, immunology, toxicology, biotechnology, endocrinology and developmental biology. Cell lines developed from fish organs are utilized as a model in vitro system in disease surveillance programs, pharmacology, drug screening and resolving cases of metabolic abnormalities. During last decade, there were consistent efforts made globally to develop new fish cell lines from different organs like brain, eye muscles, fin, gill, heart, kidney, liver, skin, spleen, swim bladder, testes, vertebra etc. This increased use and development of cell lines necessitated the establishment of cell line depositories to store/preserve them and assure their availability to the researchers. These depositories are a source of authenticated and characterized cell lines with set protocols for material transfer agreements, maintenance and shipping as well as logistics enabling cellular research. Hence, it is important to cryopreserve and maintain cell lines in depositories and make them available to the research community. The present article reviews the current status of the fish cell lines available in different depositories across the world, along with the prominent role of cell lines in conservation of life on land or below water. Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-023-00601-2.

Design, synthesis and biological evaluation of novel pyrimidine derivatives as bone anabolic agents promoting osteogenesis via the BMP2/SMAD1 signaling pathway.

Anti-resorptive inhibitors such as bisphosphonates are widely used but they have limited efficacy and serious side effects. Though subcutaneous injection of teriparatide [PTH (1-34)] is an effective anabolic therapy, long-term repeated subcutaneous administration is not recommended. Henceforth, orally bio-available small-molecule-based novel therapeutics are unmet medical needs to improve the treatment. In this study, we designed, synthesized, and carried out a biological evaluation of 31 pyrimidine derivatives as potent bone anabolic agents. A series of in vitro experiments confirmed N-(5-bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-yl)hexanamide (18a) as the most efficacious anabolic agent at 1 pM. It promoted osteogenesis by upregulating the expression of osteogenic genes (RUNX2 and type 1 col) via activation of the BMP2/SMAD1 signaling pathway. In vitro osteogenic potential was further validated using an in vivo fracture defect model where compound 18a promoted the bone formation rate at 5 mg kg-1. We also established the structure-activity relationship and pharmacokinetic studies of 18a.

Nitric oxide: A potential etiological agent for vaso-occlusive crises in sickle cell disease.

Nitric oxide (NO), a vasodilator contributes to the vaso-occlusive crisis associated with the sickle cell disease (SCD). Vascular nitric oxide helps in vasodilation, controlled platelet aggregation, and preventing adhesion of sickled red blood cells to the endothelium. It decreases the expression of pro-inflammatory genes responsible for atherogenesis associated with SCD. Haemolysis and activated endothelium in SCD patients reduce the bioavailability of NO which promotes the severity of sickle cell disease mainly causes vaso-occlusive crises. Additionally, NO depletion can also contribute to the formation of thrombus, which can cause serious complications such as stroke, pulmonary embolism etc. Understanding the multifaceted role of NO provides valuable insights into its therapeutic potential for managing SCD and preventing associated complications. Various clinical trials and studies suggested the importance of artificially induced nitric oxide and its supplements in the reduction of severity. Further research on the mechanisms of NO depletion in SCD is needed to develop more effective treatment strategies and improve the management of this debilitating disease.

Polycyclic Pyrazoles from Alkynyl Cyclohexadienones and Nonstabilized Diazoalkanes via [3 + 2]-Cycloaddition/[1,5]-Sigmatropic Rearrangement/Aza-Michael Reaction Cascade.

An efficient method for the stereoselective synthesis of "all center substituted" polycyclic pyrazoles from alkynyl cyclohexa-2,5-dienones and nonstabilized diazoalkanes via sequential [3 + 2]-cycloaddition/[1,5]-sigmatropic rearrangement and aza-Michael reactions is reported. The developed process is highly regioselective and stereoselective. It employs a wide substrate scope to furnish structurally diverse linear and bridged [4.4.n.0] ring-fused pyrazoles in moderate to good yields. One-pot and gram-scale syntheses and synthetic transformations have also been showcased.

A cell line derived from heart of rainbow trout is refractory to Tilapia lake virus.

Cell lines are important in vitro models to answer biological mechanisms with less genetic variations. The present study was attempted to develop a cell line from rainbow trout, where we obtained a cell line from the heart, named "RBT-H." The cell line was authenticated using karyotyping and cytochrome c oxidase subunit I (COI) gene sequencing. The karyotype demonstrated diploid chromosome number (2n) as 62 and the sequence of partial COI gene was 99.84% similar to rainbow trout COI data set, both suggesting the origin of RBT-H from the rainbow trout. The heart cell line was mycoplasma-free and found to be refractory to infection with the Tilapia lake virus. The RBT-H cell line is deposited in the National Repository of Fish Cell Line (NRFC) at ICAR-NBFGR, Lucknow, India, with Accession no. NRFC0075 for maintenance and distribution to researchers on request for R&D.

Global distribution of ß-thalassemia mutations: An update.

One excellent illustration of how a single gene abnormality may result in a spectrum of disease incidence is the incredible phenotypic variety of ß-thalassemia, which spans from severe anemia and transfusion needs to an utterly asymptomatic sickness. However, genetic causes of ß-thalassemia and how the anemia's severity might be altered at various stages in its pathophysiology have been well investigated. There are currently known to be more than 350 mutations that cause genetic disease. However only 20 ß thalassemia mutations account for more than 80% of the ß thalassemia mutation across the globe due to phenomenon of geographical clustering where each population has a few common mutations together with a varying number of rare ones. Due to migration of the population, the spectrum of thalassemia mutation in changing from time to time. In this review, efforts are made to collate ß globin gene mutations in different countries and populations.

Determinants of tuberculosis: an example of high tuberculosis burden in the Saharia tribe.

Tuberculosis (TB) is a significant public health problem among the Saharia community, an underprivileged tribal group in the west-central part of India. There are several challenges for India's TB control program to curtail TB in the Saharia tribe. Malnutrition, poor health sector facilities, lower socio-economic status, and substance abuse are interconnected and synergistic factors contributing to a high burden of TB in the Saharia tribe. In this review, efforts are made to collate the findings of previous studies discussing the causes of high burden of TB in the Saharia tribe, social gaps for mitigating these preventable risk factors of TB in the Saharia tribe, and the plausible solutions for closing these gaps. The concept of Health in All Policies and intersectoral co-ordination is needed for the reduction of TB in the Saharia tribe and to make India TB-free by the year 2025.

GTP cyclohydroxylase1 (GCH1): Role in neurodegenerative diseases.

GCH1 gene provides directions for the synthesis of GTP cyclohydrolase 1 which regulates the formation of Tetrahydrobiopterin (BH4). BH4 is a crucial cofactor for essential neurotransmitters synthesis such as dopamine, serotonin and nitric oxide synthases. Deficiency of GCH1 limits the synthesis of BH4 which is responsible for neuropsychiatric diseases such as dopa-responsive dystonia, hyperalaninemia, Parkinson's disease and depression. Few single nucleotide polymorphisms of GCH1 gene are also responsible for pain in sickle cell disease. Furthermore, GCH1 regulates NO activity which controls the blood pressure, vasodilatory functions and oxidative stress. Understanding the therapeutic implications of targeting GCH1 which holds promise for treating various diseases. Novel therapeutic strategies could involve small molecule drugs or gene therapy techniques that enhance GCH1 expression or activity.

Modulation in the enzymatic antioxidants, MDA level and elicitation in conessine biomolecule in Holarrhena pubescens (medicinal tree) cultures exposed to different heavy metals: Ni, Co, Cr and As.

Nodal explants of Holarrhena pubescens, an important medicinal tree, were cultured on Murashige and Skoog's medium (MS) containing 15 µM BA (control) alone and on medium supplemented with different concentrations (0, 1, 5, 25, 50, 100 and 200 mg/L) of heavy metals such as NiCl2, CoCl2, As2O3 and CrO3 to study their toxic effect. After 28 days of treatments, the nodal segments were harvested to assess the average number of shoots per explants, average shoot length, malondialdehyde content, proline content, conessine accumulation and antioxidant enzymatic activity. Among all the metals tried, best morphogenic response was achieved at 5 mg/L CrO3 where 80% culture differentiated an average of 3.21 ± 0.08 shoots per explant having 0.95 ± 0.018 cm average shoot length. Highest concentration (200 mg/L) of all the heavy metals proved lethal for morphogenesis. Maximum inhibition in average shoot number and average shoot length was observed in nodal explants treated with 25 mg/L As2O3 where an average of 0.49 ± 0.047 shoots having an average shoot length of 0.3 ± 0.02 cm. Contrarily, addition of heavy metals in culture medium proved strong elicitors, exhibiting significant enhancement in the biosynthesis of conessine, an important bioactive compound. HPLC analysis of the crude extract of in vitro grown untreated nodal cultures revealed an average of 117.06 ± 2.59 µg/g d. w. of conessine, whereas those treated with 100 mg/L of CoCl2 accounted for 297.1 ± 7.76 µg/g d. w. (an increase of 156% over control). Among the heavy metals tried, CoCl2 proved to be the best for conessine enhancement which was in the order of CoCl2 > Cr2O3 > NiCl2 > As2O3 in the nodal explants. Concomitantly, MDA content, the antioxidant enzymes activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GR) and ascorbate peroxidase (APX) were also observed to be differentially expressed with the increase in the heavy metals concentration from 1 to 200 mg/L. Free proline, too, increased up to 3.5-fold over control. The results obtained during the present investigation revealed that the overall response of the nodal explants in terms of morphogenesis, conessine content and antioxidant enzyme activities was metal specific as well as dose dependent.

Observation of positive trions in α-MoO3/MoS2 van der Waals heterostructures.

Mono-layer transition metal dichalcogenides (TMDCs) have emerged as an ideal platform for the study of many-body physics. As a result of their low dimensionality, these materials show a strong Coulomb interaction primarily due to reduced dielectric screening that leads to the formation of stable excitons (bound electron-hole pairs) and higher order excitons, including trions, and bi-excitons even at room temperature. van der Waals (vdW) heterostructures (HSs) of TMDCs provide an additional degree of freedom for altering the properties of 2D materials because charge carriers (electrons) in the different atomically thin layers are exposed to interlayer coupling and charge transfer takes place between the layers of vdW HSs. Astoundingly, it leads to the formation of different types of quasi-particles. In the present work, we report the synthesis of vdW HSs, i.e., α-MoO3/MoS2, on a 300 nm SiO2/Si substrate and investigate their temperature-dependent photoluminescence (PL) spectra. Interestingly, an additional PL peak is observed in the case of the HS, along with A and B excitonic peaks. The emergence of a new PL peak in the low-energy regime has been assigned to the formation of a positive trion. The formation of positive trions in the HS is due to the high work function of α-MoO3, which enables the spontaneous transit of electrons from MoS2 to α-MoO3 and injection of holes into the MoS2 layer. In order to confirm charge transfer in the α-MoO3/MoS2 HS, systematic power and wavelength-dependent Raman and PL studies, as well as first-principle calculations using Bader charge analysis, have been carried out, which clearly validate our mechanism. We believe that this study will provide a platform towards the integration of vdW HSs for next-generation excitonic devices.

Strain relaxation in monolayer MoS2 over flexible substrate.

In this communication, we demonstrate uniaxial strain relaxation in monolayer (1L) MoS2 transpires through cracks in both single and double-grain flakes. Chemical vapour deposition (CVD) grown 1L MoS2 has been transferred onto polyethylene terephthalate (PET) and poly(dimethylsiloxane) (PDMS) substrates for low (∼1%) and high (1-6%) strain measurements. Both Raman and photoluminescence (PL) spectroscopy revealed strain relaxation via cracks in the strain regime of 4-6%. In situ optical micrographs show the formation of large micron-scale cracks along the strain axis and ex situ atomic force microscopy (AFM) images reveal the formation of smaller lateral cracks due to the strain relaxation. Finite element simulation has been employed to estimate the applied strain efficiency as well as to simulate the strain distribution for MoS2 flakes. The present study reveals the uniaxial strain relaxation mechanism in 1L MoS2 and paves the way for exploring strain relaxation in other transition metal dichalcogenides (TMDCs) as well as their heterostructures.