Mechanism Of Inhibition Research Articles

Synthesis, Characterization, Theoretical, and evaluation of Eco-Friendly benzimidazolylmethyl-pyrazole carboxylate Schiff Bases corrosion inhibitors for mild steel

In this study, benzimidazolylmethyl-pyrazole carboxylate derivatives were synthesized via a 1,3-dipolar cycloaddition reaction and characterized using IR, HRMS and NMR spectroscopy. Three derivatives, namely ethyl 5-((3-(cyclohex-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1-phenyl-1H-pyrazole-3-carboxylate (Ph-BPC), ethyl 5-((3-(cyclohex-1-en-1-yl)-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-1-yl)methyl)-1-(p-tolyl)-1H-pyrazole-3-carboxylate (CH3Ph-BPC), and ethyl 1-(4-chlorophenyl)-5-((3-(cyclohex-1-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1H-pyrazole-3-carboxylate (ClPh-BPC), were evaluated as corrosion inhibitors for mild steel (MS) in a 1 M HCl solution. Potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) measurements revealed high inhibition efficiencies of 98.5 %, 98.2 %, and 97.7 % for ClPh-BPC, Ph-BPC, and CH3Ph-BPC, respectively, at a concentration of 10-4 M. Scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) and X-ray diffraction (XRD) analyses confirmed the formation of protective surface layers, significantly reducing corrosion rates. Thermodynamic analysis indicated that the adsorption of these inhibitors follows the Langmuir isotherm model with adsorption energies of −50.12 kJ/mol for ClPh-BPC, −50.52 kJ/mol for Ph-BPC, and −51.62 kJ/mol for CH3Ph-BPC, suggesting chemisorption. Computational studies, including Monte Carlo (MC), density functional theory (DFT), and molecular dynamics (MD) simulations, showed strong agreement with experimental results, further validating the adsorption behavior and corrosion inhibition mechanisms of these compounds.

Computational Study on the Inhibition Mechanisms of the Ziegler-Natta Catalyst in the Propylene Polymerization Process: Part 1 Effects of Acetylene and Methylacetylene

Acetylene and methylacetylene are impurities commonly found in the raw materials used for the production of polymers such as polypropylene and polyethylene. Experimental evidence indicates that both acetylene and methylacetylene can decrease the productivity of the Ziegler-Natta catalyst and alter the properties of the resulting polymer. However, there is still a lack of understanding regarding the mechanisms through which these substances affect this process. Therefore, elucidating these mechanisms is crucial to develop effective solutions to this problem. In this study, the inhibition mechanisms of the Ziegler-Natta catalyst by acetylene and methylacetylene are presented and compared with the incorporation of the first propylene monomer (chain initiation) to elucidate experimental effects. The Density Functional Theory (DFT) method was used, along with the B3LYP-D3 functional and the 6-311++G(d,p) basis set. The recorded adsorption energies were −11.10, −13.99, and −0.31 kcal mol−1, while the activation energies were 1.53, 2.83, and 28.36 kcal mol−1 for acetylene, methylacetylene, and propylene, respectively. The determined rate constants were 4.68 × 1011, 5.29 × 1011, and 2.3 × 10−8 M−1 s−1 for acetylene, methylacetylene, and propylene, respectively. Based on these values, it is concluded that inhibition reactions are more feasible than propylene insertion only if an ethylene molecule has not been previously adsorbed, as such an event reinforces propylene adsorption.

Naphthyl-functionalized acetamide derivatives: Promising agents for cholinesterase inhibition and antioxidant therapy in Alzheimer’s disease

This study presents the synthesis and characterization of a series of 13 novel acetamides. These were subjected to Ellman’s assay to determine the efficacy of the AChE and BChE inhibitors. Finally, we report their antioxidant activity as an alternative approach for the search for drugs to treat AD. These studies revealed that compounds 1a–1k and 2l–2m were obtained in moderate yield. Four amides (1h, 1j, 1k, and 2l) were selective for one of the enzymes (BChE); thus, those that inhibited BChE were more active than the positive control (galantamine) and showed better IC50 values (3.30–5.03 µM). The theoretical free binding energies calculated by MM-GBSA indicated that all inhibitors were more stable than rivastigmine, and the inhibition mechanisms involved the entire active site: peripheral anionic site, oxyanion hole, acyl-binding pockets, and catalytic site. We examined the cytotoxicity of compounds 1h, 1j, 1k, and 2l in human dermal cells and found that they did not exhibit any toxic effects under the tested conditions. Additionally, these compounds, which also inhibited BChE, displayed mixed inhibition and did not exhibit hemolytic effects on human erythrocytes. Furthermore, the ABTS and DPPH assays indicated that, although none of the compounds showed activity in the DPPH assay, the EC50 values for radical trapping by the ABTS method showed that compounds 1a, 1d, 1e, and 1g had EC50 values lower than 10 µg/mL, indicating their strong radical scavenging capacity. We also report the crystal structures of compounds 1c, 1d, 1f, and 1g, which are found in monoclinic crystal systems.

GPCR Inhibitors Have Antiviral Properties against JC Polyomavirus Infection.

JC polyomavirus (JCPyV) infects the majority of the population and initially establishes a persistent but asymptomatic infection of the kidneys. In healthy individuals, the infection remains controlled by the host immune system, but for individuals experiencing prolonged immunosuppression, the infection can reactivate and spread to the brain, where it causes progressive multifocal leukoencephalopathy (PML), which is a fatal neurodegenerative disease. Currently, there are no approved therapies to treat PML, and affected individuals suffer rapid motor weakness and cognitive deterioration. To identify novel therapeutic treatments for JCPyV infection, receptor agonists/antagonists identified in a previously published drug screen were evaluated for their antiviral properties. Seven drugs were selected and validated using infectivity assays, and the mechanism of inhibition was further explored for G protein coupled receptor (GPCR)-associated inhibitors due to the role of the GPCR 5-hydroxytryptamine 2 receptors (5-HT2Rs) in JCPyV entry. The inhibitors cetirizine and paroxetine both reduced infection early in the JCPyV infectious cycle. Paroxetine specifically reduced viral internalization through altering the receptor density of 5-HT2CR, inhibiting β-arrestin recruitment to the receptor, and reducing MAPK signaling through ERK. These findings highlight the potential of receptor signaling and viral entry mechanisms as possible targets for antiviral drug development. Further, this research suggests that FDA-approved receptor agonists/antagonists currently used to treat other medical conditions could be repurposed into antivirals for the possible treatment of JCPyV infection and the fatal disease PML.

Effect of the mRNA decapping enzyme scavenger (DCPS) inhibitor RG3039 on glioblastoma.

Patients with glioblastoma (GBM) have a poor prognosis and limited treatment options. The mRNA decapping enzyme scavenger (DCPS) is a cap-hydrolyzing enzyme. The DCPS inhibitor RG3039 exhibited excellent central nervous system bioavailability in vivo and was safe and well tolerated in healthy volunteers in a phase 1 clinical trial. In this study, we investigated the expression of DCPS in GBM and the anti-tumor activity of RG3039 in various preclinical models of GBM. DCPS expression was examined in human GBM and paired peritumoral tissues. Its prognostic role was evaluated together with clinicopathological characteristics of patients. The anti-GBM effect of RG3039 was determined using GBM cell lines, patient-derived organoids, and orthotopic mouse models. The therapeutic mechanisms of DCPS inhibition were explored. DCPS is overexpressed in GBM and is associated with poor survival of patients with GBM. The DCPS inhibitor RG3039 exhibited robust anti-GBM activities in GBM cell lines, patient-derived organoids and orthotopic mouse models, with drug exposure achievable in humans. Mechanistically, RG3039 downregulated STAT5B expression, thereby suppressing proliferation, survival and colony formation of GBM cells. DCPS is a promising target for GBM. Inhibition of DCPS with RG3039 at doses achievable in humans downregulates STAT5B expression and reduces proliferation, survival and colony formation of GBM cells. Given the excellent anti-cancer activity and central nervous system bioavailability in vivo and good tolerance in humans, RG3039 warrants further study as a potential GBM therapy.

Synergistic inhibition kinetics and mechanisms of polyethylene glycol – citric acid on non-caking coal oxidation at low temperature

ABSTRACT Focused on the insufficient efficacy of conventional flame retardants in mitigating coal spontaneous combustion (CSC), a novel composite flame retardant synthesized from polyethylene glycol (PEG) 2000 and citric acid (CA) is proposed. Through Differential Scanning Calorimetry (DSC) and Fourier Transform Infrared Spectroscopy (FTIR) experiments, the inhibitory kinetics and mechanisms were conducted. By enhancing heat absorption rate and enthalpy, with a significant increase by 90 kJ·mol−1 of activation energy, CSC resistance is improved. CA-metal ion interaction raises activation energy to inhibit methyl/methylene oxidation, while PEG disrupts aromatic oxidation by generating H ions upon hydration. This composite retardant offers a promising avenue for CSC mitigation in coal, enhancing coal fire safety.

Study on the Mechanism of Effect of Protein on Starch Digestibility in Fermented Barley.

Previous studies have shown that fermented barley has a lower digestion rate. However, it remains unclear whether the antidigestibility of starch in fermented barley is affected by other nonstarch components. In this paper, the removal of protein, lipid, and β-glucan improved the hydrolysis rate of starch and the protein showed the greatest effect. Subsequently, the inhibitory mechanism of protein on starch digestion was elucidated from the perspective of starch physicochemical properties and structural changes. The removal of protein increased the swelling power of starch from 10.09 to 11.14%. The short-range molecular ordered structure and the helical structure content decreased. The removal of protein reduced the coating and particle size of the starch particles, making the Maltese cross more dispersed. In summary, protein in fermented barley enhanced the ordered structure of starch by forming a physical barrier around starch and prevented the expansion of starch, which inhibited the hydrolysis of starch.

Low temperature and high humidity affect dynamics of chlorophyll biosynthesis and secondary metabolites in Cucumber.

During the cold season, low temperature (LT) and high relative humidity (HRH) are significant environmental factors in greenhouses and plastic tunnels, often hindering plant growth and development. The chlorophyll (Chl) biosynthesis inhibitory mechanisms under LT and HRH stress are still widely unclear. To understand how cucumbers seedlings respond to LT and HRH stress, we investigated the impact of these stressors on Chl biosynthesis. Our results revealed that individual LT, HRH and combined LT + HRH stress conditions affected chlorophyll a, b, total chlorophyll and carotenoid content, reducing the levels of these pigments. The levels of Chlorophyll precursors were also markedly reduced under LT and HRH stresses, with the greatest reduction observed in cucumber seedlings exposed to LT + HRH conditions (9/5℃, 95%HRH). The activities of glutamate-1-semialdehyde transaminase (GSA-AT), ALA dehydratase (ALAD), Mg-chelatase, and protochlorophyllide oxidoreductase (POR) were increased under individual LT, HRH, conditions but decreased by combination of LT + HRH stress condition. In addition, Chl biosynthesis related genes (except PBG) were upregulated by the HRH stress but were significantly downregulated under the LT + HRH stress condition in cucumber seedlings. Furthermore, the content of phenols, flavonoids and phenolic acids (cinnamic acid and caffeic acid) were significantly surged under LT + HRH treatment over the control. Histochemical observation showed higher O2- and H2O2 content in cucumber leaves during the LT and HRH stress. The results indicate that LT + HRH stress significantly impairs chlorophyll biosynthesis in cucumber seedlings by drastically reducing pigment accumulation, altering enzyme activity and gene expression. Additionally, LT + HRH stress induces oxidative damage, which further exacerbates the decline in chlorophyll content and affects overall cucumber metabolism.

In Vitro And In Silico Studies Of Lawsone On Inflammation-Induced Skin Cells For Development Of Skin Anti-Inflammatory Treatment

Lawsone, an active phytoconstituent of Lawsonia inermis sp., is proposed as a safer alternative for the current skin anti-inflammatory treatments that are mainly steroidal with unwanted side effects which does not conform to the concept of halalan toyyiban in medicine. This study aims to investigate the inhibitory mechanism of lawsone on pro-inflammatory cytokine, TNF (tumour necrosis factor)-α through in silico and in vitro methods. The inhibitory mechanism of lawsone were investigated via molecular docking and molecular dynamics which were performed via AutoDock Vina and GROMACS softwares, respectively. The results were then analysed via PyMol, Proteins Plus, RMSD and RMSF graphs. Subsequently, cytotoxicity of lawsone towards A431 skin epidermoid and 3T3 fibroblast cells, was determined via MTT assay. Lawsone was further tested on A431 cells stimulated with ethanol (200 mM) or hydrogen peroxide (250 µM) for 24 hours (acute) and 48 hours (chronic) to induce pro-inflammatory cytokine (TNF-α) release. Cell viabilities were determined via MTT assay and expression of TNF-α were measured via ELISA. In silico works predicted lawsone’s ability to bind to TNF-α with good binding affinity without disruption to the protein’s structure stability.Lawsone is proven to be safe towards non-pathological cells. Lawsone exhibited significant anti-inflammatory effect on inflammation induced A431 epidermoid cells. ELISA results were not as expected as compared to previous in silico study, but an anti-inflammatory pattern can be observed in the chronic ethanol-induced treatment groups. In conclusion, lawsone is shown to have potential to be developed as a halalan-toyyiban alternative for skin anti-inflammatory treatment.

Distinct Inhibitory Control Mechanisms Underlie Selective Social Inferences

ABSTRACT We investigated the role of distinct inhibitory processes as 4- to 6-year-olds from the Northeastern United States (N = 48, Mage = 68.27 months, 22 boys, 26 girls; 63% White, 6% Black, 4% Asian, 2% Hispanic, 8% more than one race, with 17% not reporting) and adults evaluated accurate or deceptive information from human or non-human (arrow) cues indicating particular locations in space. We achieved this by tracking the trajectories of our participants’ manual responses in 3D space over time. This approach allowed us to isolate inhibitory mechanisms that monitor for conflict between stimuli and representations from inhibitory mechanisms that resolve that conflict to make a response. Regardless of the cue’s accuracy, the participants we tested needed more inhibitory resources to monitor human cues that indicated the location of a hidden object than arrows. The inhibitory resources the children we tested needed to control their response (i.e., respond where the cue was pointing when it was accurate or respond alternatively when it was deceptive) was stable across the trials when the cue was a human pointing. When it was an arrow, older children needed fewer resources. These data suggest that there is continuity in participants' use of the resources necessary to monitor human information for deception, but development in the resources needed to resolve such information when learning selectively.

New Insights on the Understanding of Sulfur-Containing Coal Flotation Desulfurization

The clean and efficient utilization of coal is a promising way to achieve carbon neutrality. Coking coal is a scarce resource and an important raw material in the steel industry. However, the presence of pyrite sulfur affects its clean utilization. Nonetheless, this pyrite could be removed using depressants during flotation. Commonly used organic depressants (sodium lignosulfonate (SL), calcium lignosulfonate (CL), and pyrogallol (PY)) and inorganic depressants (calcium oxide (CaO) and calcium hypochlorite (Ca(ClO)2)) were chosen in this study. Their inhibition mechanism was discussed using FTIR, XPS, and molecular dynamics (MD) methods. The desulfurization ability of organic depressants was shown to be better than inorganic ones. Among the organic depressants, PY proved to be advantageous in terms of low dosage. Physical adsorption was identified as the main interaction form of SL, CL, and PY onto the surface of pyrite, as evidenced from FTIR and XPS analyses. Similarly, MD simulation results showed that hydrogen bonds played a proactive role in the interactions between PY and pyrite. The diffusion coefficient of water molecules on the pyrite surface was also observed to decrease when organic depressants were present, indicating an increase in the hydrophilicity of pyrite. This research is of great significance to utilize sulfur-containing coal and minerals.

Transcription factor SlSTOP1 regulates Small Auxin-Up RNA Genes for tomato root elongation under aluminum stress.

Aluminum (Al) stress, a prevalent constraint in acidic soils, inhibits plant growth by inhibiting root elongation through restricted cell expansion. The molecular mechanisms of Al-induced root inhibition, however, are not fully understood. This study aimed to elucidate the role of Small Auxin-up RNAs (SlSAURs), which function downstream of the key Al stress-responsive transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (SlSTOP1) and its enhancer STOP1-INTERACTING ZINC-FINGER PROTEIN 1 (SlSZP1), in modulating root elongation under Al stress in tomato (Solanum lycopersicum). Our findings demonstrated that tomato lines with knocked out SlSAURs exhibited shorter root lengths when subjected to Al stress. Further investigation into the underlying mechanisms revealed that SlSAURs interact with Type 2C Protein Phosphatases (SlPP2Cs), specifically D-clade Type 2C Protein Phosphatases (SlPP2C.Ds). This interaction was pivotal as it suppresses the phosphatase activity, leading to the degradation of SlPP2C.D's inhibitory effect on plasma membrane H+-ATPase. Consequently, this promoted cell expansion and root elongation under Al stress. These findings increase our understanding of the molecular mechanisms by which Al ions modulate root elongation. The discovery of the SlSAUR-SlPP2C.D interaction and its impact on H+-ATPase activity also provides a perspective on the adaptive strategies employed by plants to cope with Al toxicity, which may lead to the development of tomato cultivars with enhanced Al stress tolerance, thereby improving crop productivity in acidic soils.

The profile of plant bioactive compounds in Xinjiang, China unifloral safflower honey and their inhibitory on ACE, and determination of the mechanism of inhibition

Investigating the plant bioactive compounds in unifloral safflower honey from Xinjiang, China, is helpful for verifying its botanical origin and evaluating its functional properties. Therefore, this study quantifying hydroxysafflor yellow A (HSYA), anhydroxysafflor yellow B (ASYB), quercetin, kaempferol, rutin, myricetin, hyperoside, gallic acid, quinic acid, and ferulic acid in safflower honey by high-performance liquid chromatography; HSYA and ASYB accounted for 16.12–28.83% and 13.63–33.09%, respectively, of the quantified plant bioactive compounds and were considered characteristic markers for authentication. These compounds also exhibit angiotensin converting enzyme (ACE) inhibitory activity; the IC50 ranges from 13.33 to 132.45 μmol L−1, and the inhibition constant (Ki) is between 17.13 and 121.34 μmol L−1. HSYA (IC50 = 20.24 μmol L−1, Ki = 19.63 μmol L−1) and ASYB (IC50 = 19.33 μmol L−1, Ki = 17.13 μmol L−1) exhibited the strongest inhibitory effects. Molecular simulation studies have shown that these bioactive compounds bind key residues in the active pocket of ACE through hydrogen bonding and hydrophobic interactions, leading to ACE inhibition. Overall, HSYA and ASYB could be considered bioactive chemical markers for verifying the botanical origin of Xinjiang, China, unifloral safflower honey, and safflower honey may be a potential functional food by inhibiting ACE.

Symmetrical 2,7-disubstituted 9H-fluoren-9-one as a novel and promising scaffold for selective targeting of SIRT2.

Sirtuin 2 (SIRT2) belongs to the family of silent information regulators (sirtuins), which comprises nicotinamide adenine dinucleotide (NAD+)-dependent protein lysine deacetylases. With a distribution across numerous tissues and organs of the human body, SIRT2 is involved in a wide range of physiological and pathological processes, such as regulating the cell cycle, energy metabolism, DNA repair, and tumorigenesis. Aberrant expression of SIRT2 has been closely associated with particular etiologies of human diseases, positioning SIRT2 as a promising therapeutic target. Herein, we detail the design overview and findings of novel symmetrical 2,7-disubstituted 9H-fluoren-9-one derivatives targeting SIRT2. SG3 displayed the most potent SIRT2-selective inhibitory profile, with an IC50 value of 1.95 , and reduced the cell viability of human breast cancer MCF-7 cells accompanied by hyperacetylation of α-tubulin. Finally, molecular docking, molecular dynamics simulations, and binding free energy calculations using molecular mechanics/generalized born surface area method were performed to verify the binding ability of SG3 to SIRT2. Taken together, these results could enhance our understanding of the structural elements necessary for inhibiting SIRT2 and shed light on the mechanism of inhibition.

Mechanism of non-competitive inhibition of the SARS-CoV-2 3CL protease dimerization: Therapeutic and clinical promise of the lichen secondary metabolite perlatolinic acid

In response to the COVID-19 pandemic, identifying effective treatments against SARS-CoV-2 has become of utmost importance. This study elucidates the mechanism by which perlatolinic acid, a lichen-derived secondary metabolite, non-competitively inhibits the dimerization of the SARS-CoV-2 3CL protease, a pivotal enzyme in the virus lifecycle. Utilising a combination of kinetic parameter determination, inhibition assays, and molecular docking studies, we demonstrate that perlatolinic acid effectively disrupts the enzymatic function by binding at the dimer interface with a measured Ki value of 0.67 μM, thereby impeding the protease catalytic activity essential for viral replication. Molecular docking studies further corroborate the binding specificity of perlatolinic acid to the dimer interface, which is attributed to the loss of key interactions essential for dimerization, consequently impairing catalytic activity, highlighting its potential as a scaffold for developing broad-spectrum antiviral drugs.Despite a dose-dependent cytotoxicity of perlatolinic acid, its TC50 is approximately 43 times higher than the Ki value.Our findings suggest that perlatolinic acid holds significant promise as a lead compound for the development of new therapeutics against COVID-19, warranting further investigation and clinical evaluation.In conclusion, the study sheds light on the therapeutic potential of natural compounds in combating SARS-CoV-2, paving the way for the exploration of lichen secondary metabolites as a reservoir of potential antiviral agents.

Phenolic Compositions of Different Fractions from Coffee Silver Skin and Their Antioxidant Activities and Inhibition towards Carbohydrate-Digesting Enzymes.

Seeking food-derived antioxidants and inhibitors of α-glucosidase and α-amylase has been recognized as an effective way for managing diabetes. Coffee silver skin (CSS) is rich in phenolic compounds, which may be potential agents as antioxidants and for α-glucosidase and α-amylase inhibition. But whether phenolics in different forms show similar bioactivity remains unknown. In this study, phenolic compounds in CSS were extracted as free phenolics (FPs), esterified phenolics (EPs), and bound phenolics (BPs). The phenolic profiles and antioxidant activities of them were investigated. Their inhibitory effects on α-glucosidase and α-amylase were analyzed, and the inhibitory mechanisms were elucidated by molecular docking and molecular dynamic simulation. Results showed that FPs exhibited the best antioxidant ability and inhibitory effects on α-glucosidase and α-amylase. A total of 17 compounds were identified in FPs with 3-caffeoylquinic acid, 4-feruloylquinic acid, and dicaffeoylquinic acids as the dominant ones. Typical phenolics in FPs could bind to α-glucosidase and α-amylase through hydrogen bonds and form hydrophobic interaction with several key amino acid residues. In addition, 3,4-dicaffeoylquinic acid and 3-caffeoylquinic acid might be the principal components that account for the inhibitory effect of FPs on α-glucosidase. The results of this study may provide some scientific support for CSS utilization as a health-beneficial component in functional food development for type 2 diabetes mellitus management.

Biochemical Characterization and Inhibitor Discovery for Pf Sir2A - New Tricks for An Old Enzyme.

The Sir2 enzyme from Plasmodium falciparum ( Pf Sir2A) is essential for the antigenic variation of this parasite, and its inhibition is expected to have therapeutic effects for malaria. Selective Pf Sir2A inhibitors are not available yet, partially due to the fact that this enzyme demonstrates extremely weak in vitro deacetylase activity, making the characterization of its inhibitors rather challenging. In the current study, we report the biochemical characterization and inhibitor discovery for this enzyme. Pf Sir2A exhibits greater enzymatic activity in the presence of DNA for both the peptide and histone protein substrates, suggesting that nucleosomes may be the real substrates of this enzyme. Indeed, it demonstrates robust deacetylase activity against nucleosome substrates, stemming primarily from the tight binding interactions with the nucleosome. In addition to DNA/nucleosome, free fatty acids (FFAs) are also identified as endogenous Pf Sir2A regulators. Myristic acid, a biologically relevant FFA, shows differential regulation of the two distinct activities of Pf Sir2A: activates deacetylation, but inhibits defatty-acylation. The structural basis of this differential regulation was further explored. Moreover, synthetic small molecule inhibitors of Pf Sir2A were discovered through the screening of a library of human sirtuin regulators. The mechanism of inhibition of the lead compounds were investigated. Collectively, the mechanistic insights and inhibitors described in this study will facilitate the future development of small molecule Pf Sir2A inhibitors as antimalarial agents.

Crosslinking of Ly6a metabolically reprograms CD8 T cells for cancer immunotherapy

T cell inhibitory mechanisms prevent autoimmune reactions, while cancer immunotherapy aims to remove these inhibitory signals. Chronic ultraviolet (UV) exposure attenuates autoimmunity through promotion of poorly understood immune-suppressive mechanisms. Here we show that mice with subcutaneous melanoma are not responsive to anti-PD1 immunotherapy following chronic UV irradiation, given prior to tumor injection, due to the suppression of T cell killing ability in skin-draining lymph nodes. Using mass cytometry and single-cell RNA-sequencing analyzes, we discover that skin-specific, UV-induced suppression of T-cells killing activity is mediated by upregulation of a Ly6ahigh T-cell subpopulation. Independently of the UV effect, Ly6ahigh T cells are induced by chronic type-1 interferon in the tumor microenvironment. Treatment with an anti-Ly6a antibody enhances the anti-tumoral cytotoxic activity of T cells and reprograms their mitochondrial metabolism via the Erk/cMyc axis. Treatment with an anti-Ly6a antibody inhibits tumor growth in mice resistant to anti-PD1 therapy. Applying our findings in humans could lead to an immunotherapy treatment for patients with resistance to existing treatments.

Inhibitory mechanisms in the prefrontal-cortex differentially mediate Putamen activity during valence-based learning.

Learning from appetitive and aversive stimuli involves interactions between the prefrontal cortex and subcortical structures. Preclinical and theoretical studies indicate that inhibition is essential in regulating the relevant neural circuitry. Here, we demonstrate that GABA, the main inhibitory neurotransmitter in the central nervous system, differentially affects how the dACC interacts with subcortical structures during appetitive and aversive learning in humans. Participants engaged in tasks involving appetitive and aversive learning, while using functional magnetic resonance spectroscopy (MRS) at 7T to track GABA concentrations in the dACC, alongside whole-brain fMRI scans to assess BOLD activation. During appetitive learning, dACC GABA concentrations were negatively correlated with learning performance and BOLD activity measured from the dACC and the Putamen. These correlations were absent during aversive learning, where dACC GABA concentrations negatively correlated with the connectivity between the dACC and the Putamen. Our results show that inhibition in the dACC mediates appetitive and aversive learning in humans through distinct mechanisms.

Lannea microcarpa Leaves Extract as Corrosion Inhibitor for Aluminium Metal in Acid Medium

Techniques for weight loss, electrochemistry, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) were used to investigate the inhibitory impact of Lannea microcarpa leaves extract. The weight loss data showed that the plant extract's ability to suppress corrosion increased with higher concentrations and decreased with higher temperatures and HCl acid concentrations. According to the electrochemical data, the plant extract uses a mixed type mechanism to limit both cathodic and anodic reaction rates. Calculated activation energies were found to be higher in inhibited systems than in uninhibited systems, indicating physisorption, while negative values of ∆G point to a process that is both possible and spontaneous. The inhibitory mechanism was demonstrated by FTIR spectra to be an adsorption process through the functional groups present in the phytochemicals of the plant extract onto the surface of Al metal. SEM surface morphology study demonstrated the protection that the extract provided on the metal surface. Compared to other isotherm models that were examined, the adsorption data were found to be more reliable and suited the Langmuir isotherm well.