Dual Activity Research Articles

Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials.

Novel antimalarial compounds targeting both the pathogenic and transmissible stages of the human malaria parasite, Plasmodium falciparum, would greatly benefit malaria elimination strategies. However, most compounds affecting asexual blood stage parasites show severely reduced activity against gametocytes. The impact of this activity loss on a compound's transmission-blocking activity is unclear. Here, we report the systematic evaluation of the activity loss against gametocytes and investigate the confounding factors contributing to this. A threshold for acceptable activity loss between asexual blood stage parasites and gametocytes was defined, with near-equipotent compounds required to prevent continued gametocyte maturation and onward transmission. Target abundance is not predictive of gametocytocidal activity, but instead, lipoidal uptake is the main barrier of dual activity and is influenced by distinct physicochemical properties. This study provides guidelines for the required profiles of potential dual-active antimalarial agents and facilitates the development of effective transmission-blocking compounds.

Dual activation of soybean resistance against Phytophthora sojae by pectin lyase and degraded pectin oligosaccharides.

Phytophthora pathogens secrete numerous apoplastic effectors to manipulate host immunity. Herein, we identified a polysaccharide lyase 1 protein, PsPL1, which acts as an essential virulence factor of P. sojae infection in soybean. However, the overexpression of PsPL1 in P. sojae reduced infection and triggered enhanced immune responses in soybean. PsPL1 exhibited pectin lyase activity and degraded plant pectin to generate pectin oligosaccharides (POSs) with a polymerization degree of 3-14, exhibiting different levels of acetylation and methylation modifications. PsPL1 and the degraded pectin products triggered immune responses in soybean and different Solanaceous plants. The PsPL1-triggered immune responses required RSPL1, a membrane-localized leucine-rich repeat receptor-like protein, which is essential for Phytophthora resistance. Conversely, the PsPL1-degraded product-triggered immune responses depended on the membrane-localized lysin motif receptor-like kinase CERK1. This study reveals that the pectin lyase exhibits a dual immunogenic role during P. sojae infection, which activates plant resistance through different immune receptors and provides novel insights into the function of pectin lyase in host-pathogen interactions.

Dual Benefits of Tirzepatide: Anti-Obesity and Antidiabetic Efficacy: A Mini review

Background: Diabetes mellitus and obesity are two linked conditions that have reached epidemic proportions globally. According to a study published in 2023 by the Indian Council of Medical Research (ICMR) , India has 10.1 crore people with diabetes. The prevalence of obesity, especially abdominal obesity is increasing continuously due to the intake of foods that are high in carbohydrates and processed foods. Obesity can cause inflammation, insulin resistance, and pancreas overload which lead to diabetes mellitus. Main Body: The present - review focuses on the medicinal chemistry, organic chemistry and pharmacological aspects of trizepatide. Trizepatide is a new chemical moiety that shows dual agonist activity of glucagon-like peptide-1(GLP-1) receptors and glucose-dependent insulinotropic polypeptide(GIP).Trizepatide is a synthetic peptide that constitutes 39 amino acids. Trizepatide has a potent hypoglycemic effect , and it has antiobesity effects because of its adverse effect. Conclusion : Trizepatide's capacity to lower blood sugar and promote weight loss makes it an effective treatment for these conditions. Further research will confirm its safety and long-term advantages. Keywords : Trizepatide , Diabetes mellitus , Obesity, Hypoglycaemia

EXTH-78. A NOVEL BISPECIFIC S100A4/TFR ANTIBODY TO REPROGRAM THE GLIOMA TUMOR MICROENVIRONMENT AND TARGET GLIOMA STEM CELLS

Abstract GBM (glioblastoma) is the most common and aggressive primary brain tumor in adults. While immunotherapy is a promising treatment modality for GBM, most clinical trials have thus far only provided a modest benefit to GBM patients. We propose that enhancing the efficacy of immunotherapy for GBM requires approaches that increase T cell infiltration and reprogram the myeloid cells to a more pro-inflammatory state. S100A4 is a major regulator of stemness, epithelial-mesenchymal transition, and a critical regulator of immune suppressive myeloid and T cell phenotypes in GBM. Targeting S100A4 in either glioma or stromal cells is sufficient to reprogram the tumor immune landscape and extend survival of glioma bearing mice, indicating that S100A4 is a promising immunotherapy target. We recently developed a S100A4 blocking monoclonal antibody; however, this antibody does not cross the blood brain barrier (BBB) efficiently to confer significant therapeutic benefit, limiting its efficacy in treating GBM. To overcome this challenge, we generated a bispecific S100A4-TfR antibody (BsA) that allows robust BBB penetration, and tested this in a pre-clinical syngeneic, orthotopic mouse model of GBM. Using ELISA, confocal immunofluorescent microscopy, flow cytometry, and bulk RNA sequencing, we report that systemic administration of the S100A4-TfR BsA results in increased immune cell infiltration with a preferential increase in CD4 T cell infiltration, and potent immune remodeling of the tumor microenvironment to a more pro-inflammatory state. Furthermore, the BsA is taken up by glioma cells intracellularly, which is correlated with depletion of intracellular S100A4 and decreased nuclear SOX2 localization, which would reduce stemness of glioma cells. Functionally, in vitro BsA treatment of primary glioma cell cultures shows decreased S100A4 expression, proliferation, and self-renewal. Our results suggest that S100A4-TfR BsA is a novel dual activity inhibitor to simultaneously reprogram the GBM immune landscape and reduce glioma stemness.

COF-SO3H-Catalyzed Synthesis of Pyrazoline-Pyridine Hybrids with Dual Antioxidant and Anti-Inflammatory Activity Targeting PDE4B.

This study explores new anti-inflammatory agents by synthesizing pyrazoline-pyridine hybrids with N-butylsulfonated covalent organic framework (COF-SO3H) as a recyclable catalyst, achieving excellent yields in just one minute. The protocol was successfully scaled up to a multi-gram scale, highlighting its robustness and efficiency, and it operates without the need for column chromatography. Among the synthesized hybrids, compound 5d, a pyrazoline-pyridine hybrid bearing an indole moiety, emerged as a potent anti-inflammatory and antioxidant agent. It effectively inhibited PDE4B activation with an IC50 value of 99.38 nM, without adversely affecting HEK cells. Compound 5d demonstrated its dual activity by significantly reducing ROS production and restoring mitochondrial health in LPS-stimulated A549 and HEK cells, while also downregulating IL-1β and NF-ĸB/p65 expression in LPS-stimulated A549 cells. In silico studies confirmed compound 5d's strong binding to PDE4B, with stable RMSD and RMSF values, indicating its potential as a stable and effective PDE4B inhibitor. The compound exhibited favorable physicochemical properties, met drug-likeness criteria, and showed low toxicity as predicted in silico. These findings suggest that compound 5d has significant potential as a therapeutic agent for inflammatory diseases due to its dual anti-inflammatory and antioxidant activities.

Catalytic Concerted SNAr Reactions of Fluoroarenes by an Organic Superbase.

We herein propose that the catalytic concerted SNAr reaction is a powerful method to prepare functionalized aromatic scaffolds. Classic stepwise SNAr reactions involving addition/elimination processes require the use of electron-deficient aromatic halides to stabilize Meisenheimer intermediates, despite their widespread use in medicinal chemistry research. Recent efforts have been made to develop concerted SNAr reactions involving a single transition state, allowing the use of electron-rich substrates based on the use of stoichiometric amounts of strong bases or reactive nucleophiles. This study demonstrates that, without the use of such reagents, the organic superbase t-Bu-P4 efficiently catalyzes the concerted SNAr reactions of aryl fluorides regardless of their electronic nature. The key to establishing this system is the dual activation of aryl fluoride and anionic nucleophiles by the t-Bu-P4 catalyst. Furthermore, this catalysis allows excellent functional group tolerance, utilization of diverse nucleophiles, and late-stage functionalization of bioactive compound derivatives. These findings make possible diverse applications in chemical synthesis and pharmaceutical development.

EXECUTER1 and singlet oxygen signaling: A reassessment of nuclear activity.

Chloroplasts are recognized as environmental sensors, capable of translating environmental fluctuations into diverse signals to communicate with the nucleus. Among the reactive oxygen species produced in chloroplasts, singlet oxygen (1O2) has been extensively studied due to its dual roles, encompassing both damage and signaling activities, and the availability of conditional mutants overproducing 1O2 in chloroplasts. In particular, investigating the Arabidopsis (Arabidopsis thaliana) mutant known as fluorescent (flu) has led to the discovery of EXECUTER1 (EX1), a plastid 1O2 sensor residing in the grana margin of the thylakoid membrane. 1O2-triggered EX1 degradation is critical for the induction of 1O2-responsive nuclear genes (SOrNGs). However, a recent study showed that EX1 relocates from chloroplasts to the nucleus upon 1O2 release, where it interacts with WRKY18 and WRKY40 (WRKY18/40) transcription factors to regulate SOrNG expression. In this study, we challenge this assertion. Our confocal microscopy analysis and subcellular fractionation assays demonstrate that EX1 does not accumulate in the nucleus. While EX1 appears in nuclear fractions, subsequent thermolysin treatment assays indicate that it adheres to the outer nuclear region rather than localizing inside the nucleus. Furthermore, luciferase complementation imaging and yeast two-hybrid assays reveal that EX1 does not interact with nuclear WRKY18/40. Consequently, our study refines the current model of 1O2 signaling by ruling out the nuclear relocation of intact EX1 as a means of communication between the chloroplast and nucleus.

Analyte-Induced Specific Regulation of Light-Responsive COF-Cu Nanozyme Activity for Ultrafast Thiram Colorimetric Sensing.

A light-responsive covalent-organic framework (COF) nanozyme, which integrates the advantages of the COF structure and light-stimulated nanozyme catalysis, is a class of sensing star materials with wide application prospects. However, the sensing methods based on light-responsive COF nanozymes are relatively single at present. Therefore, it is necessary to develop new sensing strategies to broaden its application in chemical sensing and achieve highly efficient detection. Here, a Cu2+-modified COF composite material (TpDA-Cu) was rationally designed. The addition of Cu significantly inhibits the excellent light-responsive nanozyme activity of TpDA itself. However, because of the restoration of the enzyme activity by thiram (Tr) and the oxidase mimic activity of the newly formed Cu/Tr complex, TpDA-Cu/Tr exhibits stronger light-responsive nanozyme activity. Enzyme kinetic data show that compared with TpDA, TpDA-Cu/Tr has a larger Vmax value, which can achieve efficient catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB). In addition, the strong coordination effect of Tr and TpDA-Cu also plays a key role in achieving ultrafast, sensitive, and selective colorimetric detection of Tr. This work develops a dual activity regulation strategy of light-responsive COF nanozymes based on analyte induction and provides a new perspective for the application of light-responsive COF nanozymes in the field of sensing.

Triplet Harvesting in Trifluoromethyl Quinoxaline Derivatives via TADF and RTP Mechanisms

In this study, we explore the impact of donor strength on the photophysical properties of novel trifluoromethyl quinoxaline derivatives, which incorporate various electron-donating moieties exhibiting distinct conformational characteristics. The triplet harvesting mechanisms within these quinoxaline systems are facilitated through thermally activated delayed fluorescence (TADF) and room-temperature phosphorescence (RTP), both of which can be modulated by subtle structural alterations in the donor unit. The derivatives demonstrate varying photophysical properties, including pure RTP activity, dual activity (exhibiting both TADF and RTP), and pure TADF, contingent upon the nature of the electron-donating moieties employed. Notably, the intersystem crossing (ISC) rates are significantly higher than the rates of radiative decay, leading to diminished fluorescence quantum yields (ΦDF) of the compounds in toluene solutions. However, embedding the TADF compounds within a rigid polystyrene (PS) matrix results in a remarkable enhancement of ΦDF due to significant reduction of nonradiative pathways related to intramolecular twisting. A considerable conformational disorder of the polymer doped films was observed resulting in non-exponential fluorescence decay and significant shifts of prompt and delayed fluorescence in time-resolved spectra.

The Effect of Donepezil Hydrochloride in the Twitcher Mouse Model of Krabbe Disease.

Krabbe disease (KD) is a rare demyelinating disorder characterized by demyelination caused by mutations in the GALC gene, resulting in toxic accumulation of psychosine. Psychosine has been identified as detrimental to oligodendrocytes, leading to demyelination through diverse hypothesized pathways. Reducing demyelination is essential to maintain neurological function in KD; however, therapeutic interventions are currently limited. Acetylcholinesterase inhibitors (AChEi) are commonly used for symptomatic management of Alzheimer's Disease and are suggested to have potential disease-modifying effects, including regulating myelin state. In particular, donepezil, an AChEi, has demonstrated promising effects in cellular and animal models, including promotion of the expression of myelin-related genes and reduction of glial cell reactivity. This drug also acts as an agonist for sigma-1 receptors (Sig-1R), which are implicated in demyelination diseases. In the context of drug repurposing, here, we demonstrate that administration of donepezil has protective effects in the twitcher mouse model of KD. We provide data showing that donepezil preserves myelin and reduces glial cell reactivity in the brains of twitcher mice. Moreover, donepezil also improves behavioral phenotypes and increases lifespan in twitcher animals. These findings suggest that donepezil, with its dual activity as an AChE inhibitor and Sig-1R agonist, may hold promise as a therapeutic candidate for demyelinating diseases, including KD.

Semisynthetic p-Coumaric Acid Derivatives as Lead Dual Inhibitors Against DPP-IV and GSK-3β for Antidiabetic Therapy.

Type 2 diabetes mellitus is a dramatically increasing global public health challenge. The prevalence is projected almost double, from 194 million in 2003 to 333 million in 2025 with type 2 diabetes mellitus representing approximately 90%-95% of cases. Dual inhibitors for antidiabetic targets is still novel and promising strategy for discovery of more effective therapies. Ester and triazole derivatives of p-coumaric acid were obtained from Williamson synthesis and Microwave-assisted click reaction, respectively. Chemical structures were finely characterized through IR, 1H, and 13C NMR and HRMS. They were tested for their dual inhibitory activity against GSK-3β kinase and DPP-IV. The complexes resulting from docking were used for all-atom molecular dynamics simulations, including the enzymes in the apo form, using the GROMACS 2022.3. Two inhibitors 2 and 5 demonstrated promising inhibition at low and submicromolar against both proteins. Molecular Dynamic simulations revealed that the binding pattern of the control inhibitors were reproduced by p-coumaric acid derivatives 2 and 5 with crucial interactions involving the same residues. The p-coumaric skeleton can be considered as a promising core for GSK-3β kinase and DPP-IV dual inhibitors.

A spatial proteomic study of platinum-refractory, high-grade serous ovarian cancer implicates dual AKT and WNT activity linked to an immunosuppressive tumor microenvironment

A spatial proteomic study of platinum-refractory, high-grade serous ovarian cancer implicates dual AKT and WNT activity linked to an immunosuppressive tumor microenvironment

Self-adaptive carbon nanozyme regulation of ROS balance for bacteria-infected wound therapy

Nanozymes sterilizing drug-resistant (DR) bacteria by generating reactive oxygen species (ROS) have emerged as a promising approach for treating infected wounds. However, designing biocompatible adaptive ROS balance therapeutic platform for DR bacteria-infected wounds remains a great challenge. Herein, biocompatible lignin-based carbon dot nanomaterials (LCDs-OA) with more CO and COOH functional groups on the surface were prepared by hydrothermal organic acid co-processing and used as a dual enzyme-like active nanozyme for the therapy of wounds infected by DR bacteria. Experimental and theoretical calculations demonstrated that the CO and COOH functional groups in LCDs-OA have site-switching roles in the dual enzyme-like activity, which can balance reactive oxygen species (ROS) according to the changes in microenvironmental pH at the wound site, and realize the adaptive regulation of ROS generation for bactericidal and ROS scavenging for healing. Furthermore, the performance differences between different organic acid treatments were investigated and an adaptive ROS balance therapeutic platform (LCDs-OA@CaO2) was constructed to overcome the major limitation in treating DR bacterial infected wounds. The system achieved >99.6 % in vitro antimicrobial efficiency against DR bacteria and was highly biocompatible while effectively reducing oxidative damage to normal tissues, resulting in satisfactory therapeutic results in repairing wounds infected with DR bacteria.

Anti-diabetic and anti-inflammatory activities of Marrubiin isolated from Marrubium vulgare: Indications of its interaction with PPAR γ

BackgroundThe aerial parts of Marrubium vulgare L. were used for many ailments like catarrh to diabetes in many parts of Latin America and Asia. PurposeIdentifying the active principle responsible for anti-diabetic activity of methanol extract of M. vulgare leaves and to predict the possible targets. Study designAll the activity investigations were conducted simultaneously for the extract, fraction, and isolated compounds to decipher the activity profile in comparison to each other which allowed the identification of an active principle followed by use of in silico methods to identify the possible target/s. MethodsThe aerial parts of M. vulgare were extracted using methanol. A chloroform fraction was prepared. Marrubiin and marrubinone B were isolated from this fraction. The anti-hyperglycemic, hypoglycemic, and postprandial blood glucose lowering activities were investigated using streptozotocin-induced diabetic and non-diabetic rat models. Pro-inflammatory cytokine inhibitory potential was investigated using LPS induced acute-inflammatory mouse model and RAW 264.7 cells. Further, antioxidant activity was investigated using a DPPH assay. The in silico analysis, using the Swiss-target prediction tool, was carried out to predict the probable targets of the isolated molecules. ResultsMarrubiin exhibited anti-hyperglycemic effect in diabetic rats followed by hypoglycemia, and postprandial blood glucose lowering in non-diabetic rats. Methanol extract (Mv extract) and chloroform fraction (Mv fraction) showed anti-hyperglycemic and hypoglycemic effects. Moderate inhibition of IL-1β, TNF-α, and IL-6 was observed for marrubiin, marrubinone B, Mv extract, and Mv fraction, in vitro and in vivo. Neither marrubiin nor marrubinone B could quench the DPPH free radicals while Mv extract and Mv fraction could show 80 % suppression. In silico analysis has predicted that marrubiin can interact with PPAR γ but not marrubinone B. ConclusionsMarrubiin and marrubinone B were responsible for the anti-inflammatory effect of Mv extract and Mv fraction while not contributing to the antioxidant effect. Marrubiin was found to be responsible for the anti-diabetic activity of Mv extract. The predicted interaction propensity of marrubiin with PPAR γ could explain its dual activity observed in the experimental setup.

A Novel Dipterocarpol Derivative That Targets Alpha-Glucosidase and NLRP3 Inflammasome Activity for Treatment of Diabetes Mellitus.

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, chronic inflammation, impaired insulin secretion, and/or peripheral insulin resistance. Current α-glucosidase inhibitors approved for clinical use exhibit limited efficacy compared to other glucose-lowering agents. In this study, a series of mono- and bis-benzylidene derivatives were synthesized via aldol condensation of 3-oxo-dammarane triterpenoids with terephthalic aldehyde. The target mono- and bis-benzylidene derivatives, based on the dammarane triterpenoids hollongdione 1, (20S)-23,24-epoxy-25,26,27-trinordammar-3,24-dione 2, and 24(R,S)-20(S)-epoxy-25-hydroxy-dammar-3-one 3, were successfully synthesized. Several of these inhibitors demonstrated significantly greater efficacy than the reference drug acarbose. Notably, compound 4 inhibited S. cerevisiae α-glucosidase with an IC50 of 2.67 μM. Furthermore, the target compounds effectively inhibited NLRP3 inflammasome activation, reducing IL-1β production in LPS+ATP-stimulated murine peritoneal macrophages without detectable cytotoxicity. Compound 8, which exhibited dual activity, was further characterized as an inhibitor of NLRP3 activation in peripheral blood mononuclear cells, leading to the prevention of pyroptosis and IL-1β release. Additionally, compound 8 was shown to promote neuronal survival in LPS+ATP-treated rat hippocampal slices, highlighting its potential as a promising antidiabetic agent that targets both postprandial hyperglycemia and metaflammation.

Fe(II) Induced Porphyrin Nanoaggregates Assembled in the Liquid-Liquid Interface with Dual Enzyme-like Activity for Colorimetric Determination of Methimazole.

The liquid-liquid interface offers a confined space to control the growth of nanomaterials. In this study, Fe(II) (water phase) induced Meso-tetra (4-carboxyphenyl) porphyrin (H2TCPP) (CHCl3, organic phase) into nanoaggregates (Fe-TCPP) in the liquid-liquid interface. By tuning the ratio of DMF in organic solvents, Fe(II) induced H2TCPP into two nanoaggregates (Fe-TCPP-1 and Fe-TCPP-2) with different morphologies via coordination interaction occurring at the water-CHCl3 interface. Interestingly, the Fe-TCPP nanoaggregates possess dual enzyme-like activity (peroxidase-like and oxidase-like activity). In particular, both Fe-TCPP-1 and Fe-TCPP-2 demonstrate a peroxidase-/oxidase-like activity under visible light irradiation that is higher than that in the dark. Comparatively, Fe-TCPP-2 exhibits enhanced peroxide-like (POD) activity together with oxidase-like (OXD) activity compared with that of Fe-TCPP-1 under the corresponding similar conditions. The excellent enzyme mimic activity of Fe-TCPP nanozymes is ascribed to the generated hydroxyl radicals (·OH) and superoxide anions (O2•-). Remarkably, the catalytic activity of Fe-TCPP-2 remains more than 90% even in the higher temperature range of 35-40 °C, which is significant for biological detection under physiological conditions. Based on the outstanding dual enzyme-like activity of Fe-TCPP-2, a colorimetric sensing platform for methimazole (an antithyroid medicine) has been developed, demonstrating a linear detection range of 10-100 μM and a detection limit of 4.44 μM.

Natural phenol carbamates: Selective BuChE/FAAH dual inhibitors show neuroprotection in an Alzheimer's disease mouse model

FAAH inhibition can indirectly enhance endocannabinoid signaling to therapeutic levels, effectively preventing or slowing its progression of Alzheimer's disease (AD). Hence, the search for effective dual FAAH/cholinesterase inhibitors is considerable need for disease-modifying therapies. To this aim, we designed, synthesized, and tested three series of natural phenol carbamates. The majority of carbamates proved to be potent on a single target, amongst them, compound D12 containing paeonol motif was identified as an effective dual BuChE/FAAH inhibitor, with well-balanced nanomolar activity (IC50 = 81 and 400 nM for hBuChE and hFFAH, respectively). D12 possessed BBB penetrating ability, benign safety, neuroprotection and pseudo-irreversible BuChE inhibition (Kd = 2.11 μM, k2 = 2.27 min−1), showing good drug-like properties. D12 also modulated the BV2 microglial polarization to inhibit neuroinflammation. In vivo study verified that D12 improved Aβ1-41-induced learning impairments in AD mouse model for both short- and long-term memory responses. Thus, the dual activity of D12 could lead to a potentially more effective treatment for the counteraction of AD progression.

Complement factor D deficiency ameliorates adverse cardiac remodelling by inhibiting C5a-C5aR mediated ISGs+ neutrophil activation post myocardial infarction

Abstract Background Exaggerated inflammatory response after myocardial infarction (MI) exacerbates myocardial injury and adverse cardiac remodeling, leading to heart failure. Current management of MI involves myocardial protection and antifibrotic therapy but do not target the inflammatory response per se. Complement factor D (CFD) is an upstream rate-limiting enzyme of complement system activation, which is the early event of inflammatory response post MI. We hypothesize that CFD can be an important modulator of the inflammation-remodeling cascade post MI, but the specific mechanism remains elusive. Purpose To investigate the role and mechanism of CFD in regulating inflammatory expansion and adverse remodeling post MI. Methods We generated Cfd-AKO (Cfdfl/fl Adipoq-cre) mice using the Cre-LoxP recombination system, as CFD is mainly secreted by adipocytes. Immune status and cardiac remodeling progress were assessed by cardiovascular magnetic resonance (CMR), histology, flow cytometry, immunofluorescence, and ELISA. Single cell RNA sequencing (scRNA-seq) analyzed non­cardiomyocytes isolated from Cfd-AKO and WT mice post MI or sham operation. Genetic ablation and co-culture experiments dissected the functional molecular properties and intercellular communication. An CFD inhibitor ACH-4471 was used to explore the role of CFD in ischemia-reperfusion (IR) injury. Results The survival of Cfd-AKO mice was strongly improved, while ventricular arrhythmia induction rates and number of episodes were significantly reduced compared with those of WT mice. CMR imaging showed that Cfd-AKO mice had higher ejection fraction and reduced left ventricular dilation than WTs. Masson trichrome and picrosirius red staining revealed that besides smaller infarct size, the extent of fibrosis in the border and distal remote area decreased in Cfd-AKO mice. Cfd loss reduced myocardial injury, inhibited the release of inflammatory factors, and limits the amplification of complement components C3a and C5a post MI. ScRNA-seq revealed that CFD modulated neutrophil chemotactic ability and pro-inflammatory function by inducing interferon-stimulated genes expressing (ISG+) neutrophil CXCL10 expression. Mechanistically, CFD activates the ISG transcriptional profile via the C5a/C5aR dependent STAT1/2-IRF9 pathway. Activated neutrophils promote myofibroblast transformation through IL1β/IL1R dependent intercellular communication, thus facilitating pathological fibrosis. Early pharmacological blocking of CFD in mice IR injury models inhibited inflammation, reduced infarct size and ameliorated cardiac dysfunction. Conclusions We demonstrate the crucial role of CFD in cardiac remodeling post MI. This process is critically regulated by C5a-C5aR, an important component of complement-inflammation cascade. This CFD-C5a mediated neutrophil pro-inflammatory and pro-fibrotic dual activity represents a novel pathway and an attractive therapeutic window for heart failure post MI.CFD in cardiac remodelling post MI

The small molecule ZPD-2 inhibits the aggregation and seeded polymerisation of C-terminally truncated α-Synuclein.

Protein aggregation, particularly the formation of amyloid fibrils, is associated with numerous human disorders, including Parkinson's disease. This neurodegenerative condition is characterised by the accumulation of α-Synuclein amyloid fibrils within intraneuronal deposits known as Lewy bodies or neurites. C-terminally truncated forms of α-Synuclein are frequently observed in these inclusions in the brains of patients, and their increased aggregation propensity suggests a role in the disease's pathogenesis. This study demonstrates that the small molecule ZPD-2 acts as a potent inhibitor of both the spontaneous and seeded amyloid polimerisation of C-terminally truncated α-Synuclein by interfering with early aggregation intermediates. This dual activity positions this molecule as a promising candidate for therapeutic development in treating synucleinopathies.

Dual Antimicrobial Activity of HTCC and Its Nanoparticles: A Synergistic Approach for Antibacterial and Antiviral Applications Through Combined In Silico and In Vitro Studies.

N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC), a quaternized chitosan derivative, has been shown to exhibit a broad spectrum of antimicrobial activity, especially against bacteria and enveloped viruses. Despite this, molecular docking studies showing its atomic-level mechanisms against these microorganisms are scarce. Here, for the first time, we employed molecular docking analyses to investigate the potential antibacterial activity of HTCC against Staphylococcus aureus and its antiviral activity against human immunodeficiency virus 1 (HIV-1). According to the findings, HTCC exhibited promising antibacterial activity with high binding affinities; however, it had limited antiviral activity. To validate these theoretical outcomes, experimental studies were conducted. Different derivatives of HTCC were synthesized and characterized using NMR, XRD, FTIR, and DLS. The in vitro assays validated the potent antibacterial efficacy of HTCC against S. aureus, whereas the antiviral studies did not show good antiviral activity. However, our research also revealed a promising avenue for further exploration of the antimicrobial activity of HTCC nanoparticles (NPs), since, thus far, no studies have been conducted to show the antiviral activity of HTCC NPs against HIV-1. The nanosized HTCC exhibited superior antiviral performance compared to the parent polymers, with complete (100%) inhibition of HIV-1 viral activity at the highest tested concentration (0.33 mg/mL).