Specific Receptors Research Articles

Endothelial estrogen - myocardial cGMP axis critically determines angiogenesis and cardiac performance during pressure-overload.

Estrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Estrogen receptor α (ERα) non-nuclear signaling confers protection against heart failure remodeling, involving myocardial cyclic guanosine monophosphate (cGMP) - cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examined the cell type-specific role of ERα non-nuclear signaling in estrogen-conferred protection against heart failure. We first assessed the tissue-specific impacts of ERα in estrogen's cardiac benefits, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3week pressure-overload (TAC). E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signaling in endothelial cells, employing animals with endothelial-specific inactivation of ERα non-nuclear signaling (ERαKI/KI/Tie2Cre+). Female OVX mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+ TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which was associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed with CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+ was rescued by myocardial PKG activation from chronic treatment with soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial-cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required co-existence of intact endothelial ERα signaling in a NOS-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of endothelial cells. An endothelial estrogen - myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure-overload.

Key characteristics of carcinogens meet hallmarks for prevention-cutting the Gordian knot

The complexity of cancer requires a comprehensive approach to understand its diverse manifestations and underlying mechanisms. Initially outlined by Hanahan and Weinberg in 2000 and updated in 2010, the hallmarks of cancer provide a conceptual basis for understanding inherent variability in cancer biology. Recent expansions have further elucidated additional hallmarks, including phenotypic plasticity and senescent cells. The International Agency for Research on Cancer (IARC) has identified the key characteristics of carcinogens (KCCs) to evaluate their carcinogenic potential. We analyzed chemicals of concern for environmental exposure that interact with specific receptors to induce genomic instability, epigenetic alterations, immune suppression, and receptor-mediated effects, thereby contributing to chronic inflammation. Despite their varying degrees of carcinogenicity, these chemicals have similar KCC profiles. Our analysis highlights the pivotal role of receptor binding in activating most other KCCs, underscoring their significance in cancer initiation. Although KCCs are associated with early molecular or cellular events, they do not encompass processes directly linked to full cellular malignancy. Thus, there is a need to integrate clear endpoints that anchor KCCs to the acquisition of a complete malignant phenotype into chemical testing. From the perspective of toxicology and cancer research, an all-encompassing strategy that incorporates both existing and novel KCCs and cancer hallmarks is essential to enable the targeted identification of prevalent carcinogens and facilitate zone-specific prevention strategies. To achieve this goal, collaboration between the KCC and cancer hallmarks communities becomes essential.

Vγ6/Vδ1+ γδ T cells protect from angiotensin II effects on blood pressure and endothelial function in mice.

γδ T cells mediate angiotensin II (AngII)-induced hypertension and vascular injury. γδ T cells expressing specific T-cell receptor (TCR) variable (V) γ chains develop in several waves in the thymus and migrate to specific or diverse tissues. We hypothesized that γδ T cells expressing specific Vγ subtypes in perivascular tissue mediate AngII hypertensive effects. C57BL/6J male mice were infused or not with AngII (490 ng/kg/min, subcutaneously) for 14 days. γδ T-cell Vγ subtypes were profiled by flow cytometry in the spleen, descending thoracic aorta with adherent perivascular adipose tissue (DTAo/PVAT) and mesenteric vessels (MV)/PVAT. Other sets of AngII-infused mice were injected with control or specific anti-Vγ6 or Vγ4 antibodies. Blood pressure (BP) was determined by telemetry, and mesenteric artery function and remodeling by pressurized myography. Vγ6/Vδ1+ γδ T cells represented more than 50% of the γδ T-cell Vγ subtypes in DTAo/PVAT and MV/PVAT, whereas Vγ1/2+, Vγ4+ and Vγ6/Vδ1+ γδ T cells were the most abundant Vγ subtypes in the spleen. The frequency of Vγ6/Vδ1+ γδ T cells was increased at least 1.5-fold in the spleen and DTAo/PVAT, and tended to increase in MV/PVAT by AngII. A majority of Vγ6/Vδ1+ γδ T cells were activated in perivascular tissues. Vγ6/Vδ1+ γδ T-cell neutralization caused a steeper BP elevation and greater mesenteric artery endothelial dysfunction in mice infused with AngII. This was associated with more than three-fold increase in activated Vγ6/Vδ1- γδ T cells in perivascular tissues. Depletion of Vγ4+ γδ T cells did not alter AngII detrimental effects. Vγ6/Vδ1+ γδ T cells reduce the BP elevation and endothelial dysfunction induced by AngII infusion.

Mesenchymal stem cell cryopreservation with cavitation-mediated trehalose treatment

Dimethylsulfoxide (DMSO) has conventionally been used for cell cryopreservation both in research and in clinical applications, but has long-term cytotoxic effects. Trehalose, a natural disaccharide, has been proposed as a non-toxic cryoprotectant. However, the lack of specific cell membrane transporter receptors inhibits transmembrane transport and severely limits its cryoprotective capability. This research presents a method to successfully deliver trehalose into mesenchymal stem cells (MSCs) using ultrasound in the presence of microbubbles. The optimised trehalose concentration was shown to be able to not only preserve membrane integrity and cell viability but also the multipotency of MSCs, which are essential for stem cell therapy. Confocal imaging revealed that rhodamine-labelled trehalose was transported into cells rather than simply attached to the membrane. Additionally, the membranes were successfully preserved in lyophilised cells. This study demonstrates that ultrasonication with microbubbles facilitated trehalose delivery, offering promising cryoprotective capability without the cytotoxicity associated with DMSO-based methods.

JAK inhibitor selectivity: new opportunities, better drugs?

Cytokines function as communication tools of the immune system, serving critical functions in many biological responses and shaping the immune response. When cytokine production or their biological activity goes awry, the homeostatic balance of the immune response is altered, leading to the development of several pathologies such as autoimmune and inflammatory disorders. Cytokines bind to specific receptors on cells, triggering the activation of intracellular enzymes known as Janus kinases (JAKs). The JAK family comprises four members, JAK1, JAK2, JAK3 and tyrosine kinase 2, which are critical for intracellular cytokine signalling. Since the mid-2010s multiple JAK inhibitors have been approved for inflammatory and haematological indications. Currently, approved JAK inhibitors have demonstrated clinical efficacy; however, improved selectivity for specific JAKs is likely to enhance safety profiles, and different strategies have been used to accomplish enhanced JAK selectivity. In this update, we discuss the background of JAK inhibitors, current approved indications and adverse effects, along with new developments in this field. We address the issue of JAK selectivity and its relevance in terms of efficacy, and describe new modalities of JAK targeting, as well as new aspects of JAK inhibitor action.

SARS-CoV-2 Genotyping Highlights the Challenges in Spike Protein Drift Independent of Other Essential Proteins.

As of 2024, SARS-CoV-2 continues to propagate and drift as an endemic virus, impacting healthcare for years. The largest sequencing initiative for any species was initiated to combat the virus, tracking changes over time at a full virus base-pair resolution. The SARS-CoV-2 sequencing represents a unique opportunity to understand selective pressures and viral evolution but requires cross-disciplinary approaches from epidemiology to functional protein biology. Within this work, we integrate a two-year genotyping window with structural biology to explore the selective pressures of SARS-CoV-2 on protein insights. Although genotype and the Spike (Surface Glycoprotein) protein continue to drift, most SARS-CoV-2 proteins have had few amino acid alterations. Within Spike, the high drift rate of amino acids involved in antibody evasion also corresponds to changes within the ACE2 binding pocket that have undergone multiple changes that maintain functional binding. The genotyping suggests selective pressure for receptor specificity that could also confer changes in viral risk. Mapping of amino acid changes to the structures of the SARS-CoV-2 co-transcriptional complex (nsp7-nsp14), nsp3 (papain-like protease), and nsp5 (cysteine protease) proteins suggest they remain critical factors for drug development that will be sustainable, unlike those strategies targeting Spike.

Specific cleavage of IGFBP-4 by papp-a in nervous tissue

Astrocytes are subtypes of glial cells involved in metabolic, structural, homeostatic, and neuroprotective processes that help neurons maintain viability. Insulin-like growth factors IGF-1 and IGF-2 are known to have neuroprotective effects on neurons and glial cells through interaction with specific receptors. IGF forms a complex with IGF-binding proteins (IGFBP) in nervous tissue and is released from the complex via IGFBP proteolysis by specific proteases. It has been reported that IGFBP-2, 5 and 6 are cleaved by specific proteases in the central nervous system (CNS), followed by IGF release; however, it was unknown whether IGFBP-4 was exposed to a particular proteolysis in nervous tissue. Using neurons and astrocytes derived from human induced pluripotent stem cell lines (hiPSC), as well as rat brain-sourced primary neuron-glia cultures, we demonstrated that IGFBP-4 is specifically cleaved in nervous tissue by the Pregnancy Associated Plasma Protein A (PAPP-A) protease and that this cleavage is IGF-dependent. Our results indicate that astrocyte rather than neuron PAPP-A cleaves IGFBP-4 in nervous tissue suggesting that this may be one of the fundamental mechanisms for IGF interchange between these two types of cells.

Medicinally Privileged Natural Chalcones: Abundance, Mechanisms of Action, and Clinical Trials.

Chalcones have been utilized for centuries as foods and medicines across various cultures and traditions worldwide. This paper concisely overviews their biosynthesis as specialized metabolites in plants and their significance, potential, efficacy, and possibility as future medicines. This is followed by a more in-depth exploration of naturally occurring chalcones and their corresponding mechanisms of action in human bodies. Based on their mechanisms of action, chalcones exhibit many pharmacological properties, including antioxidant, anti-inflammatory, anticancer, antimalarial, antiviral, and antibacterial properties. Novel naturally occurring chalcones are also recognized as potential antidiabetic drugs, and their effect on the GLUT-4 transporter is investigated. In addition, they are examined for their anti-inflammatory effects, focusing on chalcones used for future pharmaceutical utilization. Chalcones also bind to specific receptors and toxins that prevent bacterial and viral infections. Chalcones exhibit physiological protective effects on the biological degradation of different systems, including demyelinating neurodegenerative diseases and preventing hypertension or hyperlipidemia. Chalcones that are/were in clinical trials have been included as a separate section. By revealing the many biological roles of chalcones and their impact on medicine, this paper underlines the significance of naturally occurring chalcones and their extension to patient care, providing the audience with an index of topic-relevant information.

STAN, a computational framework for inferring spatially informed transcription factor activity.

Transcription factors (TFs) drive significant cellular changes in response to environmental cues and intercellular signaling. Neighboring cells influence TF activity and, consequently, cellular fate and function. Spatial transcriptomics (ST) captures mRNA expression patterns across tissue samples, enabling characterization of the local microenvironment. However, these datasets have not been fully leveraged to systematically estimate TF activity governing cell identity. Here, we present STAN ( S patially informed T ranscription factor A ctivity N etwork), a linear mixed-effects computational method that predicts spot-specific, spatially informed TF activities by integrating curated TF-target gene priors, mRNA expression, spatial coordinates, and morphological features from corresponding imaging data. We tested STAN using lymph node, breast cancer, and glioblastoma ST datasets to demonstrate its applicability by identifying TFs associated with specific cell types, spatial domains, pathological regions, and ligand‒receptor pairs. STAN augments the utility of STs to reveal the intricate interplay between TFs and spatial organization across a spectrum of cellular contexts.

Radiotracer Innovations in Breast Cancer Imaging: A Review of Recent Progress.

This review focuses on the pivotal role of radiotracers in breast cancer imaging, emphasizing their importance in accurate detection, staging, and treatment monitoring. Radiotracers, labeled with radioactive isotopes, are integral to various nuclear imaging techniques, including positron emission tomography (PET) and positron emission mammography (PEM). The most widely used radiotracer in breast cancer imaging is 18F-fluorodeoxyglucose (18F-FDG), which highlights areas of increased glucose metabolism, a hallmark of many cancer cells. This allows for the identification of primary tumors and metastatic sites and the assessment of tumor response to therapy. In addition to 18F-FDG, this review will explore newer radiotracers targeting specific receptors, such as estrogen receptors or HER2, which offer more personalized imaging options. These tracers provide valuable insights into the molecular characteristics of tumors, aiding in tailored treatment strategies. By integrating radiotracers into breast cancer management, clinicians can enhance early disease detection, monitor therapeutic efficacy, and guide interventions, ultimately improving patient outcomes. Ongoing research aimed at developing more specific and sensitive tracers will also be highlighted, underscoring their potential to advance precision medicine in breast cancer care.

Cannabidiol Modulation of Nicotine‐Induced Toxicity: Assessing Effects on Behavior, Brain‐Derived Neurotrophic Factor, and Oxidative Stress in C57BL/6 Male Mice

ABSTRACTHigh doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds' potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain‐derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward. Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti‐inflammatory properties, among others. This work aims to examine the potential anxiety‐reducing properties of CBD in a well‐established experimental mouse model of anxiety‐like behavior induced by high doses of nicotine on male C57BL/6 mice. In this context, the open‐field behavioral test was specially conducted to assess CBD's effects on anxiety‐like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood's metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro‐inflammatory cytokine assessments were conducted to evaluate redox status and immune system function. Our research suggests that CBD shows potential in reducing anxiety‐like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue's systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro‐inflammatory cytokines (TNF‐alpha and IL‐6).

Overview on Some Drugs Act on DNA and RNA Other than Anti-Viral Drugs — The Direct Cholinomimetics and Cholinergic Blocking Agents Depend on Stereo Specificity of Cholinergic Receptors

This article contains some drugs which inhibit the nucleic acids in versatile groups e.g., anti-parasites (metronidazole, chlorproguanil, quinolines, oxamniquine (anti-bilharzial)). Anti-bacterial (quinolones, actinomycins, doxorubicin, nitrofurantoin), some of them act on protein synthesis inhibition via DNA e.g., aminoglycosides antibiotics, tetracyclines, chloramphenicol, lincosamides, macrolides, fusidic acid, ketolides, streptomycin, also RNA polymerase inhibitor and DNA coiling granules inhibitor, in addition to flucytosine as anti-fungal, coumarins used as nucleic acid inhibitor, later on indirect nucleic acid via inhibition some enzymes e.g., azaserine inhibit enzyme which responsible for nucleotide formation, 6-diazo-5-oxo-l-norleucine as anti-tumor, hadacidin, mycophenolic acid which inhibits DNA and RNA guanine formation, 6-mercapto purine, 5-fluro uracil which act as anti-cancer by inhibition of nucleoside phosphorylation, ethidium, actinomycin-D, echinomycin, daunorubicin, netropsin, bleomycin, anthramycin, neocarzinostatin, most of them anti-biotic anti-cancer drugs.

Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies

Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured (“naïve”) male rats. Six-hour treatment with the specific Gαs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator forskolin induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12–24 h later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to −45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from −69 to −66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and produced trends for reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, or protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. The present results also raise the question of whether reactivation of primed signaling mechanisms by re-exposure to inflammatory mediators linked to cAMP synthesis during subsequent challenges to bodily integrity can “reconsolidate” nociceptor memory, extending the duration of persistent hyperexcitability.

Cryptic female choice in response to male pheromones in Drosophila melanogaster

Females control the paternity of their offspring by selectively mating with males they perceive to be of high quality. In species where females mate with multiple males in succession, females may bias offspring paternity by favoring the sperm of one male over another, a process known as cryptic female choice.1 While evidence of cryptic female choice exists in multiple taxa, the mechanisms underlying this process have remained difficult to unravel.2 Understanding cryptic female choice requires demonstration of a female-driven post-mating bias in sperm use and paternity and a causal link between this bias and male cues.3 In this study, we present evidence of cryptic female choice in female Drosophila melanogaster. Through experiments utilizing transgenic males expressing fluorescent sperm, we observed that exposure to attractive males between matings prompts females to expel the ejaculate of their initial mate more rapidly than in the presence of less attractive males. While doing so, females exhibit a bias in sperm storage against their first mate, thereby favoring the paternity of their subsequent mate. Our findings reveal that females adjust the timing of ejaculate expulsion in response to male pheromones in their environment, specifically heptanal and 11-cis-vaccenyl acetate, which are sensed by females through specific odorant receptors. We provide a cryptic female choice mechanism allowing a female to modulate the share of paternity of her first mate depending on the sensing of the quality of potential mates in her environment. These findings showcase that paternity can be influenced by events beyond copulation.

VEPTP inhibition with an extracellular domain targeting antibody did not restore albuminuria in a mouse model of diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. DKD is a heterogeneous disease with complex pathophysiology where early endothelial dysfunction is associated with disease progression. The Tie2 receptor and Angiopoietin 1 and 2 ligands are critical for maintaining endothelial cell permeability and integrity. Tie2 signaling is negatively regulated by the endothelial specific transmembrane receptor Vascular Endothelial Protein Tyrosine Phosphatase (VEPTP). Genetic deletion of VEPTP protects from hypertension and diabetes induced renal injury in a mouse model of DKD. Here, we show that VEPTP inhibition with an extracellular domain targeting VEPTP antibody induced Tie2 phosphorylation and improved VEGF-A induced vascular permeability both invitro and invivo. Treatment with the VEPTP blocking antibody decreased the renal expression of endothelial activation markers (Angpt2, Edn1, and Icam1) but failed to improve kidney function in db/db uninephrectomized ReninAAV DKD mice.

Unlocking the medicinal arsenal of Cissus assamica: GC-MS/MS, FTIR, and molecular docking insights.

This study investigated the biochemical components present in the leaves of Cissus assamica. The primary aim was to analyze these components using advanced techniques and assess their potential therapeutic applications. Fourier Transform Infrared (FT-IR) spectroscopy, Gas Chromatography-Mass Spectrometry (GC-MS), and Mass Spectral analysis were employed to identify and characterize the compounds in Cissus assamica leaves. The mass spectra of each compound were compared with data from the Wiley and NIST libraries to determine their names, molecular masses, and chemical structures. FT-IR analysis identified characteristic functional groups by their specific frequencies. FT-IR spectroscopic analysis revealed significant molecular vibrations at frequencies of 3265.63, 2853.81, 1638.60, 1469.21, and 1384.95 cm⁻¹, indicating the presence of specific functional groups. The GC-MS analysis identified distinct compounds, such as "aR-Turmerone," "Curlone," "7,8-Epoxylanostan-11-ol, 3-acetoxy-," "13-Docosenamide, (Z)-," "Phenol, 3,5-bis(1,1-dimethylethyl)-," "9,19-Cyclolanostan-3-ol, 24,24-epoxymethano-, acetate," and "Quinoline-5,8-dione-6-ol, 7-[[(4-cyclohexylbutyl)amino]methyl]-." These compounds exhibited potential therapeutic applications. Their cytotoxic, antimicrobial, antidiarrheal, anti-hyperglycemic, and pain-relieving properties were evaluated by comparing them with reference ligands targeting specific receptors, including dihydrofolate reductase (DHFR), epidermal growth factor receptor (EGFR), kappa opioid receptor (KOR), glucose transporter 3 (GLUT 3), and cyclooxygenase 2 (COX-2). The results of this study suggest that Cissus assamica leaves contain bioactive compounds with potential therapeutic benefits for treating infections, diarrhea, hyperglycemia, and pain. However, further research is needed to conduct comprehensive phytochemical screening and establish the precise mechanisms of action for the crude extract or the plant-derived compounds.

An efficient regioconvergent synthesis of 3-aza-obeticholic acid

Bile acids (BAs) are steroidal molecules that play important roles in nutrient absorption, distribution, and excretion. They also act on specific receptors implicated in various metabolic and inflammatory diseases demonstrating their importance as potential drug candidates. Accordingly, there has been a concerted effort to develop new BA derivatives to probe structure–activity relationships with the goal of discovering BA analogues with enhanced pharmacological properties. Among the many steroidal derivatisations reported, the formation of endocyclic azasteroids appeals due to their potential to deliver altered biological responses with minimal change to the steroidal superstructure. Here, we report the synthesis of 3-aza-obeticholic acid (6) via a regioconvergent route. Ammoniolysis of lactones, formed from an m-CPBA-mediated Baeyer-Villiger reaction on a 3-keto-OCA derivative, furnished protected intermediate amido-alcohols which were separately elaborated to amino-alcohols via Hofmann degradation with BAIB. Upon individual N-Boc-protection, these underwent annulation to the 3-aza-A-ring when subjected to either mesylation or a Dess-Martin oxidation/hydrogenation sequence. Global deprotection of the 3-aza-intermediate delivered 3-aza-OCA in ten steps and an overall yield of up to 19 %.

Unveiling the therapeutic potential of Canavalia rosea leaves: Exploring antioxidant, anti-inflammatory, anti-arthritic, and cytotoxic activities through biological and molecular docking evaluation with DFT analysis

BackgroundCanavalia rosea is a common tropical seacoast flowering plant from the family of Fabaceae which is reported as bay bean and coastal jack bean; has a wide range of therapeutic and nutraceutical properties. AimThe present research aims to explore some pharmacological insights of the methanol extract C. rosea of leaves (MECR) and its chloroform fraction (CFCR) and n-hexane fraction (NFCR) through in-vitro and in-silico approaches. MethodsDifferent fractions of C. rosea were subjected to ferric reduction assay and total phenolic and flavonoid content assay to explore their antioxidant potential. The anti-inflammatory activity was assessed on the hypotonic-induced human erythrocyte-lysis model, while the protein denaturation method was applied for screening anti-arthritis properties of plant extract; and the cytotoxic activity was evaluated by brine shrimp lethality bioassay. In the in-silico study, molecular docking, pass prediction and ADME/T, analysis was used to investigate anti-arthritic, anti-inflammatory, antioxidant and cytotoxic potency of five selected compounds of C. rosea. Finally, the quantum chemical density functional test analysis was applied to investigate the chemical and physical properties of those compounds. ResultsAll the soluble organic extracts of C. rosea demonstrated moderate toxicity with strong antioxidants potential, in which MECR manifested the peak level of scavenging activity (2.49) on ferric reduction assay. MECR, CFCR & NFCR significantly protected lysis of human erythrocyte membrane induced by hypotonic solution, whereas MECR and CFCR were exhibited partially equal inhibitory activity. The in-vitro anti-arthritis assay, MECR, NFCR and CFCR showed strongly significant (p˂0.001) inhibitory potency at 500 μg/mL & 1000 μg/mL concentrations. The molecular docking simulations revealed strong binding of all compounds to specific receptors, with Rutin showing the highest biological reactivity followed by Daucosterol, β-Sitosterol, Stigmasterol, and Guanidine. All the compounds showed favorable reactivity patterns, with O and H atoms poised for nucleophilic and electrophilic attacks in chemical density functional calculations. ConclusionThe recent investigation suggests that C. rosea could have the potential source of antioxidant, anti-inflammatory, anti-arthritis and cytotoxic activity, prompting further investigation into their mechanisms.

Genomic variation and receptor specificity of the equine adenoviruses

Genomic variation and receptor specificity of the equine adenoviruses

Synthesis of Novel Ester-Based 5-Fluorouracil Derivatives

Fluorouracil (5-Fu, 1) is an antimetabolite cancer drug and the first-line drug of anticancer administration by WHO that has been widely used worldwide for more than 50 years. The development of 5-fluorouracil is an effort to obtain higher activity, decrease side effects, and create a specific target receptor compared to 5-fluorouracil. In this research, a series of novel 5-Fluorouracil (5-Fu) derivatives has been synthesized based on a benzoylation reaction (Schotten-Baumann reaction) of N1-hydroxylated 5-Fu called compound 2, 5-fluoro-1-(hydroxymethyl)-uracil. The benzoyl chloride substituents used in this research, including 3-chlorobenzoyl (4a), 2-chlorobenzoyl (4b), 3-nitrobenzoyl (4c), 4-methoxy benzoyl (4d), 4-trifluoromethylbenzoyl (4e), 3,4-dichlorobenzoyl (4f), and 4-nitrobenzoyl (4g) chloride become (4a-4f)-5Fu. This research meticulously examined the conditions (time and reaction temperature) at the second step of the synthesis reaction (esterification), ensuring the reliability of the results. The best synthesis conditions for 4a, 4b, 4c, 4d, and 4g compounds were found to be reflux at 40°C for 6 hours, whereas 4e and 4f compounds reactions were performed in an ice bath for 11 and 17 hours, respectively. All product syntheses, 4a-4g compound, were purified using column chromatography and eluted using eluent hexane: acetone (6:4), and the yields of 4a-4g compounds were around 61-79%. The pure compounds were characterized using FTIR and 1HNMR spectrometer, further validating the research. Based on these findings, it can be concluded that all 5-Fu derivatives can be synthesized using the Schotten-Baumann reaction method.