Biological Efficacy Research Articles

Biological Control of Potato Bacterial Wilt (Ralstonia solanacearum) Using Selected Plant Extracts

Abstract The current study evaluated the effect of methanol and water extracts of tobacco (Nicotiana tabacum L.), wild marigold (Tagetes minuta L.), and garlic (Allium sativum L.) at 50 mg·mL−1 applied at different frequencies (weekly, biweekly, and monthly) on the control of potato bacterial wilt under field conditions (two growing seasons in 2021). Weekly and biweekly application of methanol extracts from tobacco and wild marigold showed higher efficacy of biological control of the pathogen (58% and 57%) on aerial parts of potato plants than monthly application (48%). In potato tubers, weekly and biweekly application of methanol extracts caused higher biological control efficacy (75.92% and 67.39%) than monthly application (52.49%). Weekly and biweekly application of methanol extracts of tobacco and wild marigold also reduced postharvest infection and postharvest yield losses caused by potato bacterial wilt during the storage period, among other treatments. These experiments conclude that weekly or biweekly application of methanol extract from tobacco and wild marigold at 50 mg·mL−1 is a practical approach to control potato bacterial wilt in the field and storage.

Host-Parasitoid Phenology, Distribution, and Biological Control under Climate Change.

Climate change raises a serious threat to global entomofauna-the foundation of many ecosystems-by threatening species preservation and the ecosystem services they provide. Already, changes in climate-warming-are causing (i) sharp phenological mismatches among host-parasitoid systems by reducing the window of host susceptibility, leading to early emergence of either the host or its associated parasitoid and affecting mismatched species' fitness and abundance; (ii) shifting arthropods' expansion range towards higher altitudes, and therefore migratory pest infestations are more likely; and (iii) reducing biological control effectiveness by natural enemies, leading to potential pest outbreaks. Here, we provided an overview of the warming consequences on biodiversity and functionality of agroecosystems, highlighting the vital role that phenology plays in ecology. Also, we discussed how phenological mismatches would affect biological control efficacy, since an accurate description of stage differentiation (metamorphosis) of a pest and its associated natural enemy is crucial in order to know the exact time of the host susceptibility/suitability or stage when the parasitoids are able to optimize their parasitization or performance. Campaigns regarding landscape structure/heterogeneity, reduction of pesticides, and modelling approaches are urgently needed in order to safeguard populations of natural enemies in a future warmer world.

Novel Protacs Demonstrate Dual Kinase Inhibition and Degradation of HCK and BTK, and Are Highly Active in MYD88 Mutated WM and ABC DLBCL Cells

Background: Activating mutations in MYD88 are prevalent in many B-cell malignancies, including Waldenström Macroglobulinemia (95-97%), primary CNS lymphoma (70-80%), ABC DLBCL (40%), marginal zone lymphoma (5-10%), and CLL (5-15%). Mutated MYD88 transcriptionally upregulates the SRC family member HCK, which in turn serves as a master signal for triggering multiple pro-survival cascades in mutated MYD88 lymphoma cells including BTK/NFKB, SYK, and ERK (Blood 127:3237-52; Blood Adv 4:141-153; Blood Adv 6:3332-38). In previous work, we developed and characterized a novel HCK kinase inhibitor, KIN-8194 (Blood 138:1966-79). KIN-8194 blocked both HCK and BTK and was active both in vitro and in vivo in MYD88 mutated xenograft lymphoma models, including BTK Cys481Ser ibrutinib resistant models. Proteolysis targeting chimeras (PROTACs) represent a novel approach for blocking kinase based signaling and may provide an advantage over kinase inhibitors with greater selectivity and sustained target inhibition. We therefore initiated a medicinal chemistry campaign to develop highly potent, selective, and bio-available HCK/BTK targeting PROTACS using KIN-8194 scaffold for the treatment of MYD88 driven lymphomas. Methods: We developed and characterized a large series of PROTACs using KIN-8194 as a scaffold. We rationally designed linkers to facilitate E3 ubiquitin ligase binding and improve physical properties leading to degraders with ideal oral pharmacokinetic properties and bioavailability. We characterized their kinome profiling by performing a KINOMEscan assay against a panel of 468 kinases at 1 uM ( Fig. 1). Subsequently, we conducted rigorous biological efficacy screenings using the ATP-based Cell Titer-Glo Luminescent Cell Viability Assay to identify the most potent compounds. Compounds with IC 50 scores lower than KIN-8194 were selected for further validation through flow cytometry based quantitative assays that verified apoptotic and cytotoxic effects on WM and MYD88-mutated lymphoma cell lines, as well as primary human peripheral blood mononuclear cells (PBMCs), utilizing Annexin V and Propidium iodide (PI) staining. Results: We identified and characterized several novel PROTACs from the KIN-8194 scaffold that exhibited potent dual inhibition of HCK and BTK kinase activity at 1 nM, as well as marked degradation of HCK and BTK by western blot analysis at dose levels as low as 100 nM in MYD88 mutated WM and ABC DLBCL cell lines. KINOMEscan profiling showed greater selectivity for novel PROTACs as exemplified in Fig. 1. Enhanced cell killing due to degradation of HCK and BTK versus inhibition alone was confirmed using respective PROTAC analogues with modified IMID warheads that do not bind cereblon. We observed suppression of downstream pro-survival NFKB and ERK signaling in response to the dual HCK/BTK PROTACs. Moreover, several HCK/BTK PROTACs (DFCI-004, -005, -006) demonstrated remarkable low IC 50 values (1-100 nM) in proliferation assays of MYD88 mutated BCWM.1 WM and TMD-8 ABC DLBCL cells. Importantly, the dual HCK/BTK PROTACs elicited higher levels of apoptosis in BCWM.1 WM and TMD-8 ABC DLBCL cells in comparison to the native KIN-8194 kinase inhibitor and showed sparing of healthy donor B- and T-cells akin to KIN-8194. Finally, murine PK studies showed that the HCK/BTK PROTACs DFCI-005 and -006 were highly bioavailable with F=40-42%, and C Max of 700-2700 nM at single oral dose ranges of 10-60 mg/kg. Conclusions: In these studies, we demonstrated the development and characterization of novel, dual HCK/BTK PROTACs that demonstrate potent and selective kinase inhibition and protein degradation of HCK and BTK. Importantly, the novel PROTACs showed enhanced apoptosis of MYD88 mutated WM and ABC DLBCL cells over the native kinase inhibitor KIN-8194 and sparing of healthy donor B- and T-cells. Lastly, novel HCK/BTK PROTACs exhibited high levels of bioavailability. Our studies therefore provide a framework for the advancement of dual HCK/BTK PROTACs for the treatment of MYD88 mutated lymphomas.

Biological efficacy of simulated radiolabeled Lipiodol® ultra-fluid and microspheres for various beta emitters: study based on VX2 tumors

BackgroundRadioembolization is one therapeutic option for the treatment of locally early-stage hepatocellular carcinoma. The aim of this study was to evaluate the distribution of Lipiodol® ultra-fluid and microspheres and to simulate their effectiveness with different beta emitters (90Y, 188Re, 32P, 166Ho, 131I, and 177Lu) on VX2 tumors implanted in the liver of 30 New Zealand rabbits.ResultsTwenty-three out of 30 rabbits had exploitable data: 14 in the group that received Lipiodol® ultra-fluid (group L), 6 in the group that received microspheres (group M), and 3 in the control group (group C). The histologic analysis showed that the Lipiodol® ultra-fluid distributes homogeneously in the tumor up to 12 days after injection. The X-ray μCT images showed that Lipiodol® ultra-fluid has a more distal penetration in the tumor than microspheres. The entropy (disorder of the system) in the L group was significantly higher than in the M group (4.06 vs 2.67, p = 0.01). Equivalent uniform biological effective doses (EUBED) for a tumor-absorbed dose of 100 Gy were greater in the L group but without statistical significance except for 177Lu (p = 0.03). The radionuclides ranking by EUBED (from high to low) was 90Y, 188Re, 32P, 166Ho, 131I, and 177Lu.ConclusionsThis study showed a higher ability of Lipiodol® ultra-fluid to penetrate the tumor that translated into a higher EUBED. This study confirms 90Y as a good candidate for radioembolization, although 32P, 166Ho, and 188Re can achieve similar results.

Exploring the antiviral potency of γ-FP and PA compounds: Electronic characterization, non-covalent interaction analysis and docking profiling with emphasis on QTAIM aspects

As focuses on a set of pertinent compounds that incorporate a γ-substituted halophenol linkage with pentanamide (PA). The properties of these compounds were comprehensively assessed through various analytical techniques, including density functional theory (DFT) calculations, offering insights into their geometry and electronic energy gap characteristics. Charge delocalization and stability were explored via natural bond orbital (NBO) analysis. The chemical reactivity was further scrutinized by evaluating NBO, Molecular Electrostatic Potential (MEP), Hirshfeld surface analysis and Fukui functions. The compounds were found to exhibit stability attributed to a robust hydrogen bonding network, which was corroborated by Interaction Region Indicator (IRI) and Electron Density (ED) assessments. Additionally, pharmacological properties were predicted using the PASS (Prediction of Activity Spectra for Substances) server. Molecular docking studies suggested potential antiviral and antioxidant properties, particularly concerning carbonic anhydrase. The overall results imply that these compounds possess favorable drug-like characteristics and show promise for biological efficacy. The study also includes a 2D interaction profile image of the four most interacted proteins and a Ramachandran plot to elucidate the stereochemistry of a selected protein. Furthermore, the activities of 6FDM were investigated following a comprehensive literature survey, with detailed findings presented.

Comprehensive analysis reveals the differentiated influential mechanism of degradable poly (ε-caprolactone) and polybutylene succinate microplastics on nitrogen transformation in aerobic granular sludge systems

The escalating releasing of degradable microplastics (DMPs) into wastewater may pose a potential threat to biological nitrogen removal. However, whether and how different DMPs affect nitrogen transformations in aerobic granular sludge (AGS) systems remains unclear. This work therefore aimed to fill such knowledge gaps by employing poly (ε-caprolactone) (PCL) and polybutylene succinate (PBS) as the model microplastics. Results revealed that exposure to 0.5 and 5 mg/L DMPs did not remarkably affect the nitrogen removal. However, increasing DMPs concentration to 50 mg/L suppressed the nitrogen transformation, causing a significant degree of inhibition in total nitrogen removal efficiency, particularly in the PCL-exposure group (decreased by 2.0%–25.7%). The pronounced inhibitory effects were attributed to the more readily biodegradability of PCL compared to PBS, resulting in an enhanced release of microplastics that induced excessive production of reactive oxygen species and destruction of cytomembrane integrity. Consequently, the relative abundance of denitrifiers was decreased, leading to suppressed expression of the genes (e.g. narG) involved in nitrogen transformation. This was accompanied by a decline in enzyme activity (e.g. nitrate reductase) and electron transport system activity. The correlations among genes, microbes and environmental factors were reshaped by different DMPs, underlying the intrinsic mechanism for the deteriorated nitrogen removal. Overall, this study implies that compared to PBS microplastics, the accumulation of PCL microplastics in aquatic environments poses a more significant threat to biological treatment efficacy and global nitrogen cycling, thereby warranting increased attention.

Suspension Concentrate crop protection formulation design and performance for low spray volume and UAS spray application.

Unmanned aerial systems (UAS) are providing interesting disruptive solutions for spray application of crop protection products with very-low spray volumes (VLV) down to 8 L/ha that offer improved sustainability through reduced water volumes and reduced soil compaction. However, the efficacy of products can be reduced by the significantly lower crop/plant spray coverage and formulation designs that can compensate for this are highly important here. Suspension Concentrate (SC) formulations designed for VLV use containing and delivering low dose rates (g/ha) of organosilicone alkoxylate high-spreading surfactants were found to result in leaf coverage of VLVs comparable to those observed at higher spray volumes. High spreading was observed on textured leaf surfaces containing sub-micron sized epicuticular wax crystals. Greenhouse fungal disease studies showed enhanced efficacy with these SC formulations compared to standard SC formulations without these additives and maintained the observed increase in efficacy when applied at VLV. Alternatively, SC formulations without high spreading formulants but containing uptake promoting nonionic surfactants showed enhanced cuticle penetration through isolated cuticles at VLV in comparison to higher spray volumes, with coffee-ring spray deposit microstructures present at VLVs. Similarly, greenhouse studies showed enhanced efficacy that was maintained at VLV relative to SCs without these additives. At VLVs, SC formulations applied at relatively low dose rates (g/ha) of formulants (adjuvants) enhancing spreading on the leaf surface and/or uptake of the active ingredient(s) maintained good spreading, uptake and biological efficacy in greenhouse studies overcoming the coverage limitations of SC formulations without these additives. This result is unexpected considering the low dose rate of adjuvants used. © 2023 Bayer AG. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Exploring the novel aryltellurium(IV) complexes: Synthesis, characterization, antioxidant, antimicrobial, antimalarial, theoretical and ADMET studies

The current research study is focused on biological efficacy of newly synthesized Schiff base ligand 1,1′-(ethane-1,2-diylbis(azanylylidene))bis(methanylylidene))bis(naphthalen-2-ol) (HNED) and its aryltellurium(IV) complexes. The synthesized compounds were comprehensively characterized by physical and spectral investigations such asmolar conductance, Powder-XRD, EDAX, elemental, TGA-DTG analysis, mass, FT-IR, UV–Vis, 13C NMR and 1H NMR spectroscopy. The molecular and electronic structural characteristics of the synthesized compounds were explored by theoretical chemical estimations which was based on density functional theory (DFT). The outcome of the spectroscopic and theoretical data revealed that the Schiff base HNED was coordinated with tellurium ion through oxygen and nitrogen atoms, suggesting distorted octahedral geometry of complexes. The compounds displayed mild to strong antimicrobial activity against numerous microbial species, with the growth inhibitory activities of the complexes being greater than those of the Schiff base. Complexes 6c and 6f exhibited the highest scavenging ability. Complex 6a exhibited the highest efficiency in inhibiting malarial malformation. In silico molecular docking was executed to explore the binding interaction and binding energies of compound against the active site of the various receptors (3MZF, 4DXD, 3Q70 and 2GHU). The ADMET results indicated that the synthesized compounds have favorable drug-like behavior. This study suggest that the complexes may act as promising candidates for infection ailments.

Biologic Treatment Modification Efficacy in Concurrent Inflammatory Bowel Disease and Ankylosing Spondylitis: A Retrospective Cohort Study at a Single Tertiary Center.

The link between ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) is well-established, with concurrent prevalence estimates ranging from 5-10%. However, there are still significant gaps in our understanding, and a comprehensive treatment guideline for these co-diagnosed patients has yet to be established. Our objective was to explore patterns of treatment alterations following the diagnosis of AS in patients previously diagnosed with IBD, and vice versa. Additionally, we sought to determine how these modifications influence clinical outcomes in both conditions. This retrospective data-based cohort study included patients with coexisting IBD and AS that were diagnosed between the years 2009-2022 and were followed by the gastroenterology and the rheumatology units of the Sheba Medical Center, Israel. The data were extracted from the electronic health record and included demographic information, medication history, treatment modification at the time of second diagnosis, and the characteristics and activity of both IBD and AS at the index time and at the 3-month mark. The study included a total of 68 patients, with a male predominance (40 patients, 59%). The median age was 43 years (IQR 31-55) and 78% had Crohn's disease (CD). The median duration between the diagnosis of the first disease to the second one was 4 years (IQR 1-9.5). A significant proportion of patients (85%) underwent treatment modification at their second diagnosis. Out of the total cohort, 28% initiated biological therapy, 17.6% switched their biologic regimen, and 16.2% discontinued NSAIDS. Patients who underwent biologic modifications at time of the second diagnosis (the initiation/switch/augmentation of a concurrent regimen) experienced significantly higher rates of clinical improvement in either IBD or AS at the 90-day follow-up compared to patients who did not (68% vs. 32%, p = 0.004), and biologic modification was found to be an independent predictor for clinical improvement (OR 3.69, CI 1.08-12.58, p = 0.037). Our findings suggest that biologic therapy modification at the time of the second diagnosis was associated with a higher rate of improvement in AS/IBD at the 90-day follow-up.

Abnormal activation of MAPKs pathways and inhibition of autophagy in a group of patients with Zellweger spectrum disorders and X-linked adrenoleukodystrophy

BackgroundZellweger spectrum disorders (ZSD) and X-linked adrenoleukodystrophy (X-ALD) are inherited metabolic diseases characterized by dysfunction of peroxisomes, that are essential for lipid metabolism and redox balance. Oxidative stress has been reported to have a significant role in the pathogenesis of neurodegenerative diseases such as peroxisomal disorders, but little is known on the intracellular activation of Mitogen-activated protein kinases (MAPKs). Strictly related to oxidative stress, a correct autophagic machinery is essential to eliminated oxidized proteins and damaged organelles. The aims of the current study are to investigate a possible implication of MAPK pathways and autophagy impairment as markers and putative therapeutic targets in X-ALD and ZSDs.MethodsThree patients with ZSD (2 M, 1 F; age range 8–17 years) and five patients with X-ALD (5 M; age range 5- 22 years) were enrolled. A control group included 6 healthy volunteers. To evaluate MAPKs pathway, p-p38 and p-JNK were assessed by western blot analysis on peripheral blood mononuclear cells. LC3II/LC3I ratio was evaluated ad marker of autophagy.ResultsX-ALD and ZSD patients showed elevated p-p38 values on average 2- fold (range 1.21- 2.84) and 3.30-fold (range 1.56- 4.26) higher when compared with controls, respectively. p-JNK expression was on average 12-fold (range 2.20–19.92) and 2.90-fold (range 1.43–4.24) higher in ZSD and X-ALD patients than in controls. All patients had altered autophagic flux as concluded from the reduced LC3II/I ratio.ConclusionsIn our study X-ALD and ZSD patients present an overactivation of MAPK pathways and an inhibition of autophagy. Considering the absence of successful therapies and the growing interest towards new therapies with antioxidants and autophagy inducers, the identification and validation of biomarkers to monitor optimal dosing and biological efficacy of the treatments is of prime interest.

Screening and Regulatory Mechanisms of Inter-Root Soil Nematicidal Bacteria of Pinus massoniana

Pine Wilt Disease (PWD), caused by the pathogenic nematode Bursaphelenchus xylophilus, is a systemic infectious disease commonly referred to as the “cancer” of pine trees. This devastating disease has gained this analogy due to its ability to rapidly spread within pine populations, leading to substantial losses in forest resources. The primary objective of this study is to investigate the bioprotective potential and underlying mechanisms of action exhibited by rhizosphere microorganisms associated with Masson pine (Pinus massoniana) in the context of controlling the pine wilt nematode. In this experiment, using high-throughput sequencing, significant differences were observed in the rhizosphere soil microbial communities among healthy Masson pine, standing dead trees, and diseased Masson pine. Furthermore, it was found that these microbial communities exhibited distinct community structures at different levels. This study successfully isolated and screened three strains of highly effective nematophagous bacteria from the rhizosphere soil. The identified strains were Lysinibacillus capsici, Bacillus Paramycoides, and Delftia tsuruhatensis. After applying the bacterial suspensions and fermentation extracts of these three strains to the roots of two-year-old Masson pine seedlings, followed by inoculation with pine wilt nematodes after a four-day period, distinct defense responses were observed in the Masson pine. Notably, the activities of phenylalanine ammonia-lyase (PAL) and peroxidase (POD) were significantly increased, leading to a substantial reduction in the incidence of pine wilt disease. Based on the changes in defense enzyme activities, it can be concluded that the fermentation extract of the Lysinibacillus capsici strain exhibits effective nematocidal effects and induces resistance. The significant biological control efficacy and induction of host defense activity indicate the potential application value of this strain and its metabolites as a biocontrol agent for pine wilt disease.

Changing Trends in B-Cell Non-Hodgkin Lymphoma Treatment: The Role of Novel Monoclonal Antibodies in Clinical Practice.

We are currently witnessing a dramatic shift in our approach to the treatment of B-cell non-Hodgkin lymphoma (B-NHL). In the evolving clinical landscape, novel treatments for this clinically heterogeneous disease span a wide range of interventions, encompassing targeted agents, cell therapy approaches, and novel monoclonal antibodies (NMABs). Among these, the latter are likely to exert the most profound impact due to their distinctive high efficacy and versatile applicability. NMABs represent a heterogeneous group of agents, including naked antibodies, immunotoxins, and T-cell-engaging molecules. In recent times, several NMABs have either gained regulatory approval or are on the verge of introduction into clinical practice, addressing multiple therapeutic indications and treatment regimens. Their anticipated impact is expected to be broad, initially in the context of relapsed/refractory (R/R) disease and subsequently extending to early treatment lines. The scope of this review is to provide a comprehensive overview of the biological characteristics, clinical properties, efficacy, and toxicity profiles of NMABs that have recently been introduced or are nearing integration into clinical practice.

The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model.

Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, the importance of developing multi-target drugs as a strategy to address complex diseases such as NASH has been growing; however, their manufacturing processes remain time- and cost-intensive and inefficient. To overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. We designed a tetra-specific compound, C-192, targeting glucagon-like peptide 1 (GLP-1), glucagon (GCG), fibroblast growth factor 21 (FGF21), and interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH using UniStac. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine-choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumulation, and the non-alcoholic fatty liver disease activity score. In this study, we demonstrated the feasibility of UniStac in creating multi-specific drugs and confirmed the therapeutic potential of C-192, a drug that integrates multiple mechanisms into a single molecule for the treatment of NASH.

The cross-contextual communication of biopower: From the angle of the prevalence of dietary supplements in Chinese society

Dietary Supplements (DS), rooted in Western medicine's microscopic agent, have permeated Chinese society from the late Guangxu period to the present. From domestic inception to global proliferation of the DS, conceals its commercial attributes behind the facade of a Eurocentric health concept, specifically the "add-on" theory of surplus health. Rooted in Western medicine discourse, this concept has been contextually transferred and has succeeded in infiltrating Chinese society, which represents a choice to exploit indigenous knowledge for the commercialization of medical culture. Foucault's insights in The Birth of Clinic reveal how classical medicine gave way to clinical medicine, elucidating the convergence of "science" and "power" that governs modern societies. Accordingly, DS, as well as addressing the consequences of this high-tech intervention pose critical questions about biopower. Its infusion into Chinese society, driven by social and economic factors, may lead to uncertain biological efficacy of DS when used as a public good, and the potential for intergenerational epigenetic shifts. However, all of those uncertainties, combined with the absence of research tailored to diverse ethnic groups and personalized intake programs are often going unnoticed by the general public while DS has gained popularity as both a cultural and commercial product.

Design, synthesis and biological evaluation of novel cationic liposomes loaded with melphalan for the treatment of cancer

Therapeutically active lipids in drug delivery systems offer customization for enhanced pharmaceutical and biological effects, improving safety and efficacy. Biologically active N, N-didodecyl-3,4-dimethoxy-N-methylbenzenaminium lipid (Q) was synthesized and employed to create a liposome formulation (FQ) encapsulating melphalan (M) through a thin film hydration method. Synthesized cationic lipids and their liposomal formulation underwent characterization and assessment for additive anti-cancer effects on myeloma and melanoma cancer cell lines. These effects were evaluated through various studies, including cytotoxicity assessments, cell cycle arrest analysis, apoptosis measurements, mitochondrial membrane potential depolarization, DNA fragmentation, and a significant reduction in tumorigenic potential, as evidenced by a decrease in both the number and percentage area of cancer spheroids.

Curcumin-loaded high internal phase emulsions alleviated dextran sulfate sodium-induced ulcerative colitis in mice via inhibiting inflammatory response and modulating gut microbiota

Curcumin is a polyphenol compound that presents an anti-colitis effect. However, oral curcumin exhibits limited in vivo biological efficacy, which may be solved by the use of high internal phase emulsions (HIPEs) that show remarkable abilities: bioactive compounds delivery, high chemical stability and loading capacity, as well as controlled release, etc. The objective of this study was to investigate the preventive effect of curcumin-loaded HIPEs using a dextran sulfate sodium (DSS)-induced colitis C57BL/6J mice model. After 30 mg/ml DSS treatment, all mice exhibited weight loss and shortening of colon tissues to different extents. Compared to the DSS group, the disease activity index and weight loss were considerably suppressed in the curcumin-loaded corn oil and curcumin-loaded HIPEs groups. These groups also exhibited reduced colonic crypt damage, mucosal inflammation and cellular infiltration in the histopathological sections of the colon. Dietary curcumin-loaded HIPEs inhibited the inflammatory response via reducing the contents of inflammatory factors (IL-6, TNF-α and IL-1β) and increasing the content of anti-inflammatory factor (IL-10) significantly. And the relative abundances of Firmicutes and Bacteroidetes were highly reduced and increased, respectively. These findings provide insights into expanding the utilization of curcumin and HIPEs in food systems for the treatment of colon inflammation and related diseases.

AAV6-mediated gene transfer of HCN1-ddd generates slightly faster baseline beating rates as compared to Hcn2 yet with a potential risk for pro-arrhythmia

Abstract Electronic pacing is the current treatment of choice for complete heart block (CHB) that revolutionised last century’s standard of care. Despite its success, some critical issues remain such as providing suboptimal cardiac output and a lack of direct autonomic responsiveness. To develop a more physiological and hardware-free pacemaker, we focused on developing gene therapy-based biological pacemakers by means of ion channel over-expression. Previous studies with adenoviral gene transfer indicated possible superior outcomes for the engineered mutant HCN1-ΔΔΔ as compared to wild-type Hcn2, yet a head-to-head comparison was never made. To assess the long-term biological pacemaker efficacy for AAV6-mediated gene transfer of HCN1-ΔΔΔ and Hcn2. Functional biological pacemaker studies were conducted in a porcine model of radiofrequency ablation-induced CHB. Four weeks after the ablation, animals were studied in two different groups: AAV6-cTnT-HCN1-ΔΔΔ and AAV6-cTnT-Hcn2, both immunosuppressed with prednisolone and Cyclosporine A. All animals were then followed for another four weeks to evaluate in vivo biological pacemaker performance and then organs were harvested to assess transduction efficiency. Biological pacing effectiveness was evaluated in view of maximal (max) and basal (mean) beating rates (HR), and pacemaker dependency that animals had shown throughout the study. Four weeks after the induction of CHB, on the day of the injection, all animals (n = 6) presented an average mean HR of 53,67 ± 7,64 bpm (Figure 1B) and a pacemaker dependency above 65% (Figure 1C). One week after gene transfer, these beating rates rapidly increased and pacemaker dependency declined. Hcn2 and HCN1-ΔΔΔ groups displayed a notable increase in max HR (Figure 1A), where HCN1-ΔΔΔ offered the most potent and sustained response (Hcn2 153,33 ± 47,26 bpm vs. HCN1-ΔΔΔ 220 ± 43,59 bpm; Figure 1A). In terms of mean HR, they similarly trended up in both groups (Hcn2 57,81 ± 5,49 bpm vs. HCN1-ΔΔΔ 59,22 ± 2,28 bpm; Figures 1B and E). Lastly, these faster beating rates in HCN1-ΔΔΔ resulted in modestly lower dependency in electronic back-up pacing (52 ± 7,94 % vs. 48,3 ± 22,37 % for HCN1-ΔΔΔ vs. HCN2; Figures C and F). AAV6-mediated HCN1-ΔΔΔ gene transfer produced slightly faster mean heart rates as compared to Hcn2, yet HCN1-ΔΔΔ generated persistently increased maximal heart rates (in two out of three animals) that exceeded the physiological desirable range. These findings possibly relate to the much faster channel gating kinetics of HCN1-ΔΔΔ that were previously found to be profoundly pro-arrhythmic with the chimera channel HCN212.Figure 1Abstract ESC 2023

Strike Early and Strike Strong: application of a strategy comprising first-line combination of high-intensity statins and ezetimibe for patients with acute myocardial infarction in routine practice

Abstract Aim Rapid and intense LDL-c reduction for patients with acute myocardial infarction (AMI) using a systematic combination of high intensity statins and ezetimibe, dubbed "Strike Early and Strike Strong" (SESS), has been proposed in a position paper endorsed by ESC. The applicability of this strategy in routine practice, and the tolerance and biological efficacy of such lipid lowering treatment (LLT) are poorly documented. Methods Single-center, prospective, observational study including 500 consecutive patients admitted for AMI. Unless there was known intolerance, a SESS policy was advocated at admission for AMI, irrespective of baseline LDL-c. Actual discharge LLT, LDL-c level during follow-up (3 to 8 months) and the rate of patients at ESC LDL-c target were recorded. We considered LLT to be maintained when observed LDL-c level at follow-up (FU) was not 20% higher than that expected from baseline LDL- and LLT intensity at discharge. Results Between January 2020 and July 2021, 527 patients were included, 387(75%) were male, 110(22%) had diabetes, mean age was 63±12 years. Admission LDL-c was 127±44mg/dL, 431(78%) had no previous LLT. At discharge, 456 (97%) a high intensity statin, and combined with ezetiibe in 430/456(92%). The mean capacity of the discharge LLT to decrease LDL-c was 63±10%. 12-month FU with biology was available for 273 randomly selected patients. The combination of high intensity statins and ezetimibe was maintained in 87%, although ezetimibe was stopped in 9% and the statin dose was reduced in 15% (mainly reduction from atorvastatin 80 to 40 mg/day). As a result, capacity of the LLT to decrease LDL-c was reduced to 59±11%. Mean LDL-c was 53±33 mg/dL. ESC LDL-c therapeutic goals were reached in 53%: LDL-c<55mg/dL in 62% and >50% decrease in baseline LDL-c in 74%. Regarding the need for PCSK9 inhibitors, the rate was 14% for a threshold for prescription set at a LDL-c≥ 70mg/dL, and 7% for a threshold set at ≥100mg/dL. An LDL-c level <30mg/dL was observed in 19%. Conclusion The SESS strategy before discharge after ACS is feasible in routine practice. At 12 months, LLT intensity was maintained in the majority of cases, yielding an average LDL-c level of 53±33 mg/dL, and 53% of patients at LDL-c goals.

Natural Phenolic Compounds with Neuroprotective Effects.

Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases are three of the major neurodegenerative diseases. To date, researchers have found various natural phytochemicals that could potentially be used to treat neurodegenerative diseases. Particularly, the application of natural phenolic compounds has gained significant traction in recent years, driven by their various biological activities and therapeutic efficacy in human health. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and can neutralize the effects of oxidative stress, inflammation, and apoptosis in animal models. This review focuses on the current state of knowledge on phenolic compounds, including phenolic acids, flavonoids, stilbenes, and coumarins, as well as their beneficial effects on human health. We further provide an overview of the therapeutic potential and mechanisms of action of natural dietary phenolics in curing neurodegenerative diseases in animal models.

Quantitation of polyethylene glycol by size exclusion chromatography with charged aerosol, differential refractive index, and multi-angle light scattering detectors

Polyethylene glycol (PEG) has found tremendous applications in pharmaceutical products and has played a critical role in PEGylated drug modalities to improve pharmacokinetic properties and biological efficacy. The characterization and quantitation of PEGs are essential to control manufacture process and drug product quality. However, the assay value of PEG could change dramatically depending on the structures of the PEG and the detection techniques used. In this study, we developed a size exclusion chromatographic (SEC) method for quantitative PEG analysis, and we systematically evaluated the performance of three online detectors with different operating principles: a charged aerosol detector (CAD), a differential refractive index (dRI) detector, and a multi-angle light scattering detector (MALS). Fourteen PEG compounds covering a wide range of molecular weight (MW, 1 – 40 kDa) and molecular architectures (linear, branched, Y-shaped and multi-arm geometries) were evaluated by these three detection techniques. Our study revealed that the dRI showed the most universal responses among all the PEGs regardless of their molecular weight or geometries. In the contrast, CAD and MALS detector showed MW-dependent and semi-universal geometry-dependent responses. Another key finding is that the relative response factor for each multi-arm PEG in the CAD and the MALS were inversely correlated, suggesting both can be applied to qualitatively assess polymers of different architectures, including the ones with subtle differences in their core structures. The comparison of the three detectors not only provides the fundamental and comprehensive understanding of PEG quantitation but also enables the process development and control of high-quality PEGs in producing PEGylated therapeutics in the pharmaceutical industry.