Class Of Agonists Research Articles

CGAS-STING Pathway Activation during Trypanosoma cruzi Infection Leads to Tissue-Dependent Parasite Control.

Host cell invasion by Trypanosoma cruzi is a markedly silent process, with limited host transcriptional changes indicative of innate immune recognition, except for a modest type I IFN (IFN-I) response. In this study, we show that T. cruzi-induced IFN-β production was nearly abolished in primary murine cGAS-/- or stimulator of IFN genes (STING)-deficient (STINGGt) macrophages and fibroblasts. T. cruzi infection did not impact the ability of IFN-regulatory factor reporter macrophages to respond to classical cGAS-STING agonists, indicating that the limited IFN-β induction is not due to active parasite suppression. cGAS-/-, STINGGt, and IFN-α/β receptor-/- (IFNAR-/-) macrophages infected with T. cruzi yielded significantly higher numbers of amastigotes compared with wild-type macrophages; however, the impact of the STING pathway during infection invivo is more complex. Despite an initial increase in parasite growth, STINGGt and IFNAR-/- mice ultimately had lower parasite burden in footpads as compared with wild-type mice, demonstrating a role for IFN-I expression in potentiating parasite growth at the infection site. STING pathway activation had little impact on parasite levels in the skeletal muscle; however, in the heart, cGAS-/- and STINGGt mice, but not IFNAR-/- mice, accumulated higher acute parasite loads, suggesting a protective role of STING sensing of T. cruzi in this organ that was independent of IFN-I. Together, these results demonstrate that host cGAS-STING senses T. cruzi infection, enhancing parasite growth at the site of entry, and contributes to acute-phase parasite restriction in the heart, a major site of tissue damage in chronic T. cruzi infection.

Fenoxycarb, a carbamate insect growth regulator, inhibits brassinosteroid action.

Brassinosteroids (BRs) are steroid hormones that regulate plant growth, development, and stress resistance. In this study, we evaluated the effect of agrochemicals on dark-induced hypocotyl elongation, which is regulated by BRs, to identify novel chemicals that regulate BR action. We found that the juvenile hormone agonist fenoxycarb inhibited dark-induced hypocotyl elongation in Arabidopsis. Treatment with the same class of juvenile hormone agonist, pyriproxyfen, did not affect hypocotyl elongation. Co-treatment with fenoxycarb and BR partly canceled the fenoxycarb-induced hypocotyl suppression. In addition, gene expression analysis revealed that fenoxycarb altered the BR-responsive gene expression. These results indicate that fenoxycarb is a BR action inhibitor.

Molecular docking analysis of PPARγ with phytochemicals from Moroccan medicinal plants.

PPARγ agonists play a crucial role in regulating metabolic homeostasis for treating type-2 diabetes (T2D). Due to the adverse side effects associated with thiazolidinediones, a class of PPARγ agonists, there is a growing interest in identifying natural compounds from medicinal plants that have the potential to bind PPARγ. In this study, we extensively investigated Moroccan phytochemicals using computational structure-based screening with the crystal structure of the PPARγ ligand-binding domain (PDB ID: 7awc) to discover novel phytochemicals targeting PPARγ. The docking results of 540 Moroccan phytochemicals were integrated into online databases for further exploitation through in-depth studies. Drug-likeness analysis was performed to assess the phytochemicals drug-like properties. Two promising phytochemicals, 3,4-dicaffeoylquinic acid and Chlorogenic acid, were identified, both exhibiting high docking affinity and unique binding site interactions compared to the established PPARγ full agonist, rosiglitazone. Molecular dynamics simulations of 100 ns were conducted to examine the stability of the complexes formed by both compounds within the PPARγ active site, and their dynamic behavior was compared to the reference structure of PPARγ alone and with rosiglitazone. Binding free energy calculations demonstrated that 3,4-dicaffeoylquinic acid and Chlorogenic acid exhibited higher binding free energy than the reference agonist, suggesting their potential as candidates for experimental validation in future drug discovery efforts targeting PPARγ for the treatment of T2D and metabolic syndrome.

Preclinical Development of Brain Permeable ERβ Agonist for the Treatment of Glioblastoma.

Glioblastoma (GBM) is the most prevalent and aggressive type of adult brain tumors with low 5-year overall survival rates. Epidemiologic data suggest that estrogen may decrease brain tumor growth, and estrogen receptor beta (ERβ) has been demonstrated to exert antitumor functions in GBM. The lack of potent, selective, and brain permeable ERβ agonist to promote its antitumor action is limiting the therapeutic promise of ERβ. In this study, we discovered that Indanone and tetralone-keto or hydroxyl oximes are a new class of ERβ agonists. Because of its high activity in ERβ reporter assays, specific binding to ERβ in polar screen assays, and potent growth inhibitory activity in GBM cells, CIDD-0149897 was discovered as a possible hit by screening a library of compounds. CIDD-0149897 is more selective for ERβ than ERα (40-fold). Treatment with CIDD-0149897 markedly reduced GBM cell viability with an IC50 of ∼7 to 15 μmol/L, while having little to no effect on ERβ-KO cells and normal human astrocytes. Further, CIDD-0149897 treatment enhanced expression of known ERβ target genes and promoted apoptosis in established and patient-derived GSC models. Pharmacokinetic studies confirmed that CIDD-0149897 has systemic exposure, and good bioavailability in the brain. Mice tolerated daily intraperitoneal treatment of CIDD-0149897 (50 mg/kg) with a 7-day repeat dosage with no toxicity. In addition, CIDD-0149897 treatment significantly decreased tumor growth in U251 xenograft model and extended the survival of orthotopic GBM tumor-bearing mice. Collectively, these findings pointed to CIDD-0149897 as a new class of ERβ agonist, offering patients with GBM a potential means of improving survival.

Alpha-2-macroglobulin prevents platelet aggregation induced by brain-derived neurotrophic factor

The brain-derived neurotrophic factor (BDNF) has been recently shown to have activating effects in isolated platelets. However, BDNF circulates in plasma and a mechanism to preclude constant activation of platelets appears necessary. Hence, we investigated the mechanism regulating BDNF bioavailability in blood.Protein-protein interactions were predicted by molecular docking and validated through immunoprecipitation. Platelet aggregation was assessed using light transmission aggregometry with washed platelets in response to classical agonists or BDNF, in the absence or presence of alpha-2-macroglobulin (α2M), and in platelet-rich plasma. BDNF signaling was assessed with phospho-blots.As little as 25% autologous plasma was sufficient to completely abolish platelet aggregation in response to BDNF. Docking predicted two forms of BDNF binding to native or activated α2M, in parallel and perpendicular arrangements, and the model suggested that the BDNF-α2M complex cannot bind to the high-affinity BDNF receptor, tropomyosin receptor kinase B (TrkB). Experimentally, native and activated α2M formed stable complexes with BDNF preventing BDNF-induced TrkB activation and signal transduction. Both native and activated α2M inhibited BDNF induced-platelet aggregation in a concentration-dependent manner with comparable half-maximal inhibitory concentrations (IC50≈ 125–150 nM).Our study implicates α2M as a physiological regulator of BDNF bioavailability, and as an inhibitor of BDNF-induced platelet activation in blood.

Effectiveness of Oral Semaglutide in Weight Loss and Glycemic Control among Type 2 Diabetes Population: A Real-world Longitudinal Study

Abstract Background: Oral semaglutide is a drug belonging to the class of glucagon-like peptide-1 receptor agonists which is known for its ability to maintain glycemic levels while reducing weight and lowering the risk of cardiovascular events. This study aims to explore the effectiveness of oral semaglutide by using real-world data from South Asia (India). Materials and Methods: The study is a real-world longitudinal study, and the data for the study were extracted from electronic medical records of a comprehensive diabetes center in Kerala. The primary outcome variables were measured at the baseline and at 6 months. The subjects who had data from March 2022 to July 2023 were included in the study while those with no follow-up data were excluded. The sample size was calculated as 52 using the sample size formula for the comparison of two dependent groups with a quantitative outcome. All the analyses were carried out at a level of significance of 5% using R version 4.3.1. Results: The clinical characteristics such as weight, systolic blood pressure, estimated glomerular filtration rate, and serum glutamic-oxaloacetic transaminase/aspartate aminotransferase were found to have a significant difference between the baseline and endpoint (P < 0.05). The mean absolute difference between the baseline and endpoint hemoglobin A1c (HbA1c) was found to be 0.65% (P < 0.001), and for body mass index (BMI), it was found to be 1.69 kg/m2 (P < 0.001). The baseline HbA1c and BMI were found to be significantly associated with the change in HbA1c and BMI, respectively (P < 0.05). Conclusion: This study is one of the first real-world studies conducted in South Asia (India) that explores the effectiveness of oral semaglutide. The study showed that the usage of oral semaglutide induced a significant reduction of weight and HbA1c among people with type 2 diabetes. Addressing the limitations can bring new insights into the diabetes management paradigm.

Discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists with anti-psoriasis activity in a mouse model

Aryl hydrocarbon receptor (AHR) is a ligand dependent transcription factor and participates in the regulation of the immune balance of Th17/22 and Treg cells. It has been found to be widely expressed in the skin, and involved in the pathology of psoriasis. Therefore, AHR is thought as a potential intervention target for psoriasis. Here, we report the discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists. Structure-activity relationship analyses led to the identification of the most active compound, 5- ((1H-indazol-3-yl)methylene) -3- (prop-2-yn-1-yl) -2-thiooimidazolidin-4-one (24e), which exhibited an EC50 value of 0.015 µM against AHR. Mechanism of action studies showed that 24e regulated the expression of CYP1A1 by activating the AHR pathway. Topical administration of 24e substantially alleviated imiquimod (IMQ)-induced psoriasis-like skin lesion. Overall, compound 24e could be a good lead compound for drug discovery against psoriasis, and hence deserving further in-depth studies.

Assessment of the structure-activity relationship and antileukemic activity of diacylpyramide compounds as human ClpP agonists

Human caseinolytic protease P (ClpP) is required for the regulatory hydrolysis of mitochondrial proteins. Allosteric ClpP agonists dysfunctionally activate mitochondrial ClpP in antileukemic therapies. We previously developed ZG111, a potent ClpP agonist derived from ICG-001, inhibits the proliferation of pancreatic ductal adenocarcinoma cell lines in vitro and in vivo by degrading respiratory chain complex proteins. Herein, we studied the structure-activity relationships of ICG-001 analogs as antileukemia agents. Compound ZG36 exhibited improved stabilization effects on the thermal stability of ClpP in acute myeloid leukemia (AML) cell lines compared with the stabilization effects of ZG111, indicating a direct binding between ZG36 and ClpP. Indeed, the resolved ZG36/ClpP structural complex reveals the mode of action of ZG36 during ClpP binding. Compound ZG36 nonselectively degrades respiratory chain complexes and decreases the mitochondrial DNA, eventually leading to the collapse of mitochondrial function and leukemic cell death. Finally, ZG36 treatment inhibited 3-D cell growth in vitro and suppressed the tumorigenesis of AML cells in xenografted mice models. Collectively, we developed a new class of human ClpP agonists that can be used as potential antileukemic therapies.

FAM3D: A gut secreted protein and its potential in the regulation of glucose metabolism

The number of diabetic patients is rising globally and concomitantly so do the diabetes associated complications. The gut secretes a variety of proteins to control blood glucose levels and/or food intake. As the drug class of GLP-1 agonists is based on a gut secreted peptide and the positive metabolic effects of bariatric surgery are at least partially mediated by gut peptides, we were interested in other gut secreted proteins which have yet to be explored. In this respect we identified the gut secreted protein FAM3D by analyzing sequencing data from L- and epithelial cells of VSG and sham operated as well as chow and HFD fed mice. FAM3D was overexpressed in diet induced obese mice via an adeno-associated virus (AAV), which resulted in a significant improvement of fasting blood glucose levels, glucose tolerance and insulin sensitivity. The liver lipid deposition was reduced, and the steatosis morphology was improved. Hyperinsulinemic clamps indicated that FAM3D is a global insulin sensitizer and increases glucose uptake into various tissues. In conclusion, the current study demonstrated that FAM3D controls blood glucose levels by acting as an insulin sensitizing protein and improves hepatic lipid deposition.

#5399 VONAFEXOR AS A NOVEL THERAPY FOR CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney diseases (CKD) are characterized by the progressive loss of renal function. The molecular mechanisms underlying this progression are still poorly characterized and probably multifactorial. Therefore, there is a real need to expand the very limited number of therapies able to slow down the rate of CKD progression. Recent findings indicate that NR1H4, a druggable nuclear receptor, might play an important role in CKD. The aim of this study was to investigate the benefit of Vonafexor, a novel small molecule and specific NR1H4 agonist in acquired and genetic models of CKD. Method Two complementary experimental models of CKD (the 75% excision of total renal mass (Subtotal Nephrectomy; Nx) and the Col4a3−/− mice, a model of Alport disease) were studied. NR1H4 and the expression of some of its downstream targets were evaluated by quantitative RT-PCR, western blot and immunohistochemistry. In the Nx model, mice were treated with Vonafexor by daily oral gavage from 5 to 8 weeks after the surgery. The possible beneficial effect was compared to that of Losartan and other NR1H4 agonists. In the Alport model, mice were treated by Vonafexor from 5 to 8 weeks after birth. In both models, group of mice were sacrificed at 5 weeks to evaluate the extent of renal lesions at baseline. Renal lesions were quantified using image J. Renal inflammation, myofibroblast activation and podocyte number were quantified after specific staining. Human biopsies were also studied. RNAseq was performed using Illumina NovaSeq6000. Results We observed that NR1H4 expression and OSTA and OSTB, two downstream targets of NR1H4, were significantly reduced in remnant kidneys of Nx FVB/N mice compared to sham-operated animals 8 weeks after surgery. Co-localization staining revealed that NR1H4 is mainly expressed in proximal tubules and, to a minor extent, in Henle loops. Renal lesions were already present at 5 weeks in both experimental models. Remarkably, Vonafexor stopped the progression of renal lesions, in terms of glomerulosclerosis and tubular dilatations and, more importantly, induced a regression of interstitial fibrosis 8 weeks after nephrectomy as compared to the 5-week baseline. Lymphocytes and macrophage infiltration, as well as activated myofibroblasts, were also significantly reduced. Similarly, podocyte loss was stopped by Vonafexor treatment. Of note, the beneficial effect of Vonafexor was unique compared to other classes of NR1H4 agonists and also higher than that of Losartan. The same beneficial curative effect was found in Col4a3−/− mice. RT-PCR confirmed the activation of several NR1H4 downstream targets in mice treated with Vonafexor, while RNAseq analysis revealed that Vonafexor impacted the pathological activation of pathways involved in cell cycle, cell signaling and metabolism. These results may be relevant to humans, since NR1H4 expression was significantly reduced in biopsies from patients with CKD of different etiologies as compared to control kidneys. Conclusion Altogether our results identified in Vonafexor a novel key drug to control CKD. This is consistent with recent results obtained in LIVIFY phase 2 clinical trial in which Vonafexor has already demonstrated beneficial effects on eGFR in NASH patients with mild to moderate CKD.

Defining the ligand-dependent proximatome of the sigma 1 receptor.

Sigma 1 Receptor (S1R) is a therapeutic target for a wide spectrum of pathological conditions ranging from neurodegenerative diseases to cancer and COVID-19. S1R is ubiquitously expressed throughout the visceral organs, nervous, immune and cardiovascular systems. It is proposed to function as a ligand-dependent molecular chaperone that modulates multiple intracellular signaling pathways. The purpose of this study was to define the S1R proximatome under native conditions and upon binding to well-characterized ligands. This was accomplished by fusing the biotin ligase, Apex2, to the C terminus of S1R. Cells stably expressing S1R-Apex or a GFP-Apex control were used to map proximal proteins. Biotinylated proteins were labeled under native conditions and in a ligand dependent manner, then purified and identified using quantitative mass spectrometry. Under native conditions, S1R biotinylates over 200 novel proteins, many of which localize within the endomembrane system (endoplasmic reticulum, Golgi, secretory vesicles) and function within the secretory pathway. Under conditions of cellular exposure to either S1R agonist or antagonist, results show enrichment of proteins integral to secretion, extracellular matrix formation, and cholesterol biosynthesis. Notably, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) displays increased binding to S1R under conditions of treatment with Haloperidol, a well-known S1R antagonist; whereas Low density lipoprotein receptor (LDLR) binds more efficiently to S1R upon treatment with (+)-Pentazocine ((+)-PTZ), a classical S1R agonist. Furthermore, we demonstrate that the ligand bound state of S1R correlates with specific changes to the cellular secretome. Our results are consistent with the postulated role of S1R as an intracellular chaperone and further suggest important and novel functionalities related to secretion and cholesterol metabolism.

Discovery of NXT-10796, an orally active, intestinally restricted EP4 agonist prodrug for the treatment of inflammatory bowel disease

A property-focused optimization strategy was employed to modify the carboxylic acid head group of a class of EP4 agonists in order to minimize its absorption upon oral administration. The resulting oxalic acid monohydrazide-derived carboxylate isostere demonstrated utility as a class of prodrug showing colon-targeted delivery of parent agonist 2, with minimal exposure observed in the plasma. Oral administration of NXT-10796 demonstrated tissue specific activation of the EP4 receptor through modulation of immune genes in the colon, without modulation of EP4 driven biomarkers in the plasma compartment. Although further in depth understanding of the conversion of NXT-10796 is required for further assessment of the developability of this series of prodrugs, using NXT-10796 as a tool molecule has allowed us to confirm that tissue-specific modulation of an EP4-modulated gene signature is possible, which allows for further evaluation of this therapeutic modality in rodent models of human disease.

Chronic tianeptine induces tolerance in analgesia and hyperlocomotion via mu-opioid receptor activation in mice.

Tianeptine is approved in some countries to treat depression and anxiety. In addition to its activity on serotonin and glutamate neurotransmission, tianeptine has been proven to be a mu-opioid receptor (MOR) agonist, but only a few preclinical studies have characterized the opioid-like behavioral effects of tianeptine. In this study, we tested tianeptine activity on G protein activation using the [S35] GTPγS binding assay in brain tissue from MOR+/+ and MOR-/- mice. Then, to determine whether tianeptine behavioral responses are MOR-dependent, we characterized the analgesic, locomotor, and rewarding responses of tianeptine in MOR+/+ and MOR-/- mice using tail immersion, hot plate, locomotor, and conditioned place preference tests. Using the [S35] GTPγS binding assay, we found that tianeptine signaling is mediated by MOR in the brain with properties similar to those of DAMGO (a classic MOR agonist). Furthermore, we found that the MOR is necessary for tianeptine's analgesic (tail immersion and hot plate), locomotor, and rewarding (conditioned place preference) effects. Indeed, these behavioral effects could only be measured in MOR+/+ mice but not in MOR-/- mice. Additionally, chronic administration of tianeptine induced tolerance to its analgesic and hyperlocomotor effects. These findings suggest that tianeptine's opioid-like effects require MOR and that chronic use could lead to tolerance.

Machine Learning Model for Screening Thyroid Stimulating Hormone Receptor Agonists Based on Updated Datasets and Improved Applicability Domain Metrics.

Machine learning (ML) models for screening endocrine-disrupting chemicals (EDCs), such as thyroid stimulating hormone receptor (TSHR) agonists, are essential for sound management of chemicals. Previous models for screening TSHR agonists were built on imbalanced datasets and lacked applicability domain (AD) characterization essential for regulatory application. Herein, an updated TSHR agonist dataset was built, for which the ratio of active to inactive compounds greatly increased to 1:2.6, and chemical spaces of structure-activity landscapes (SALs) were enhanced. Resulting models based on 7 molecular representations and 4 ML algorithms were proven to outperform previous ones. Weighted similarity density (ρs) and weighted inconsistency of activities (IA) were proposed to characterize the SALs, and a state-of-the-art AD characterization methodology ADSAL{ρs, IA} was established. An optimal classifier developed with PubChem fingerprints and the random forest algorithm, coupled with ADSAL{ρs ≥ 0.15, IA ≤ 0.65}, exhibited good performance on the validation set with the area under the receiver operating characteristic curve being 0.984 and balanced accuracy being 0.941 and identified 90 TSHR agonist classes that could not be found previously. The classifier together with the ADSAL{ρs, IA} may serve as efficient tools for screening EDCs, and the AD characterization methodology may be applied to other ML models.

Efficacy of treatment with glucagon-like peptide receptor agonists-1 in Asian patients with type 2 diabetes mellitus

The projected 68% increase in patients with type 2 diabetes mellitus (T2D) in the upcoming decades and the specific pathophysiological course of the disease are critical factors for the development of optimal disease management tactics in the Asian population. It is now known that β-cell dysfunction is dominant in the pathogenesis of T2D in Asians. In a number of Asian countries, incretin therapy is the leading therapy. To review literature on glucagon-like peptide-1 (GLP-1) secretion and clinical trial results of GLP-1 receptor agonist class (GLP-1RA) drugs as well as to evaluate their effectiveness in Asian population with T2D. A review of studies on pathophysiological aspects of GLP-1 secretion and evaluation of the efficacy of therapy with GLP-1RA preparations registered and used in clinical practice in Asian regions. Several studies in Asian countries have shown that intact GLP-1 levels were significantly lower in both T2D patients and healthy Japanese volunteers; as well as in patients with impaired glucose tolerance. It is suggested that either impaired secretion of GLP-1 in the gut, accelerated processing by dipeptidyl peptidase-4, or a combination of both are responsible for the decrease in GLP-1. The greater efficacy of GLP-1RA treatment in achieving glycemic control in Asian T2D patients was presented by Kim Y.G. et al. in a meta-analysis of 15 randomised controlled trials, the reduction in HbA1c on GLP-1RA treatment averaged -1.16% in Asian-dominated studies and -0.83% in non-Asian-dominated studies. In the PIONEER 9 clinical programme, similar results were obtained, with oral semaglutide having a more pronounced effect on glycaemic control in Japanese patients. Thus, the mean change in HbA 1c was -1.1%, 7 mg -1.5%, and 14 mg -1.7% at the 3 mg dose; whereas in the PIONEER 1 study in the global population, the mean change in HbA1c was -0.6%, -0.9% and -1.1% for 3, 7, 14 mg semaglutide, respectively. The PIONEER 10 study concluded that oral semaglutide was well tolerated by Japanese patients with T2D. Oral semaglutide reduced HbA1c (14 mg dose) and body weight (7 and 14 mg doses) more significantly compared to dulaglutide at 0.75 mg dose. Results of a pooled analysis of long-acting GLP-1RA showed a more significant reduction in cardiovascular event risk in the Asian subpopulation. The presented review describes benefits in glycemic control as well as in the reduction of relative cardiovascular event risks with GLP-1RA treatment in the Asian population, which requires further in-depth research and implies optimal management tactics in patients with T2DM.

Novel Derivatives of Eugenol as a New Class of PPARγ Agonists in Treating Inflammation: Design, Synthesis, SAR Analysis and In Vitro Anti-Inflammatory Activity.

The main objective of this research was to develop novel compounds from readily accessed natural products especially eugenol with potential biological activity. Eugenol, the principal chemical constituent of clove (Eugenia caryophyllata) from the family Myrtaceae is renowned for its pharmacological properties, which include analgesic, antidiabetic, antioxidant, anticancer, and anti-inflammatory effects. According to reports, PPARγ regulates inflammatory reactions. The synthesized compounds were structurally analyzed using FT-IR, 1HNMR, 13CNMR, and mass spectroscopy techniques. Molecular docking was performed to analyze binding free energy and important amino acids involved in the interaction between synthesized derivatives and the target protein. The development of the structure-activity relationship is based on computational studies. Additionally, the stability of the best-docked protein-ligand complexes was assessed using molecular dynamic modeling. The in-vitro PPARγ competitive binding Lanthascreen TR-FRET assay was used to confirm the affinity of compounds to the target protein. All the synthesized derivatives were evaluated for an in vitro anti-inflammatory activity using an albumin denaturation assay and HRBC membrane stabilization at varying concentrations from 6.25 to 400 µM. In this background, with the aid of computational research, we were able to design six novel derivatives of eugenol synthesized, analyzed, and utilized TR-FRET competitive binding assay to screen them for their ability to bind PPARγ. Anti-inflammatory activity evaluation through in vitro albumin denaturation and HRBC method revealed that 1f exhibits maximum inhibition of heat-induced albumin denaturation at 50% and 85% protection against HRBC lysis at 200 and 400 µM, respectively. Overall, we found novel derivatives of eugenol that could potentially reduce inflammation by PPARγ agonism.

Comparison between levosimendan versus beta agonists in preservation of renal function in cardiac surgery patients with low cardiac output syndrome

ABSTRACT Background Post cardiac surgery acute kidney injury (AKI) secondary to postoperative low cardiac output syndrome (LCOS), is a serious complication. Positive inotropic agents are the main line of treatment for LCOS with different degrees of improvement of cardiac function & nephroprotective efficacy Levosimendan is a calcium sensitizer in cardiac muscles, which has a comparable positive inotropic and nephroprotective effects to that of classic beta2 agonists. Objective To evaluate the possible nephroprotective effect of levosimendan as compared to beta agonists in cardiac surgery patients with LCOS. Patients and Methods It is a prospective, randomized and comparative study conducted at Ain Shams University Hospitals over the period from December 2020 to May 2021. A total of 60 patients with post cardiac surgery low cardiac output syndrome were divided into two groups of 30 patients each. Group A (control) received beta-agonists (dobutamine or adrenaline) and Group B (study) received levosimendan. The incidence of AKI at the diagnosis of LCOS & its progression to renal failure in both groups were assessed. Results The incidence of AKI at diagnosis of LCOS postoperative was 30% (n = 9) in each group; 44% of them in the control group (n = 4) developed renal failure at discharge from ICU and none of the study group patients developed renal failure at discharge. At the time of discharge from ICU, the incidence of renal failure in beta-agonist group was 13.3%, while the incidence in the levosimendan group was 0% with statistically significant P value of 0.038. Conclusion In comparison to beta-agonists, Levosimendan may have a better nephroprotective effect that plays a role in decreasing the incidence of kidney failure in patients with post cardiac surgery LCOS. A larger randomized, controlled trials are recommended to prove such a beneficial nephroprotective effect and its exact mechanism.

Combination of a STING Agonist and Photothermal Therapy Using Chitosan Hydrogels for Cancer Immunotherapy.

Cyclic dinucleotides (CDNs) are a promising class of immune agonists that trigger the stimulator of interferon genes (STING) to activate both innate and acquired immunity. However, the efficacy of CDNs is limited by drug delivery barriers. Therefore, we developed a combined immunotherapy strategy based on injectable reactive oxygen species (ROS)-responsive hydrogels, which sustainably release 5,6-dimethylxanthenone-4-acetic acid (DMXAA) as known as a STING agonist and indocyanine green (ICG) by utilizing a high level of ROS in the tumor microenvironment (TME). The STING agonist combined with photothermal therapy (PTT) can improve the biological efficacy of DMXAA, transform the immunosuppressive TME into an immunogenic and tumoricidal microenvironment, and completely kill tumor cells. In addition, this bioreactive gel can effectively leverage local ROS to facilitate the release of immunotherapy drugs, thereby enhancing the efficacy of combination therapy, improving the TME, inhibiting tumor growth, inducing memory immunity, and protecting against tumor rechallenge.

Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel RORγt inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak RORγt inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent RORγt inverse agonists with IC50 values in the range of 7 nM–50 nM in RORγt dual FRET assay. Among them, compound 14g displayed potent RORγt inverse agonistic activity with an IC50 value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC50 value of 0.428 μM and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC0-Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazine-based derivatives represent a new chemical class of RORγt inverse agonists as potential therapeutic agents against autoimmune diseases.

Agomelatine: A Potential Multitarget Compound for Neurodevelopmental Disorders.

Agomelatine (AGM) is one of the latest atypical antidepressants, prescribed exclusively for the treatment of depression in adults. AGM belongs to the pharmaceutical class of melatonin agonist and selective serotonin antagonist ("MASS"), as it acts both as a selective agonist of melatonin receptors MT1 and MT2, and as a selective antagonist of 5-HT2C/5-HT2B receptors. AGM is involved in the resynchronization of interrupted circadian rhythms, with beneficial effects on sleep patterns, while antagonism on serotonin receptors increases the availability of norepinephrine and dopamine in the prefrontal cortex, with an antidepressant and nootropic effect. The use of AGM in the pediatric population is limited by the scarcity of data. In addition, few studies and case reports have been published on the use of AGM in patients with attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Considering this evidence, the purpose of this review is to report the potential role of AGM in neurological developmental disorders. AGM would increase the expression of the cytoskeleton-associated protein (ARC) in the prefrontal cortex, with optimization of learning, long-term memory consolidation, and improved survival of neurons. Another important feature of AGM is the ability to modulate glutamatergic neurotransmission in regions associated with mood and cognition. With its synergistic activity a melatoninergic agonist and an antagonist of 5-HT2C, AGM acts as an antidepressant, psychostimulant, and promoter of neuronal plasticity, regulating cognitive symptoms, resynchronizing circadian rhythms in patients with autism, ADHD, anxiety, and depression. Given its good tolerability and good compliance, it could potentially be administered to adolescents and children.