Maximum Efficacy Research Articles

Chronotropic and Inotropic Effects of Sudachitin, a Polymethoxyflavone from the Peel of Citrus sudachi on Isolated Rat Atria and Its Underlying Mechanisms.

Sudachitin, a polymethoxyflavone found in sudachi peel, has been reported to improve hyperlipidemia in humans, and is thus attracting research attention. However, its effect on cardiac function remains unclear. We investigated the mechanisms underlying the chronotropic and inotropic effects of sudachitin on rat atria. Sudachitin (0.3-30 µM) produced concentration-dependent positive chronotropic and inotropic effects. Other polymethoxyflavones, including demethoxysudachitin (0.3-30 µM) and nobiletin (0.3-30 µM), also produced positive chronotropic and inotropic effects; however, the maximum efficacy of all polymethoxyflavones, including sudachitin, was lower than that of isoproterenol. Propranolol (0.1 µM) did not affect the positive chronotropic and inotropic effects of sudachitin. The concentration-response curves for the chronotropic and inotropic effects of dibutyryl-cAMP (1-100 µM) were shifted to the left upon pretreatment with sudachitin (3, 10 µM). Phosphodiesterase inhibitors (3-isobutyl-1-methylxanthine 1 µM or milrinone 10 µM) alone, sudachitin alone (10, 30 µM), and a combination of phosphodiesterase inhibitors and sudachitin exhibited positive chronotropic and inotropic effects, whereas the lack of any interaction between each phosphodiesterase inhibitor and sudachitin indicated an additive effect of the two substances. These results suggest that sudachitin-induced positive chronotropic and inotropic effects similar to those of other polymethoxyflavones, but its maximum efficacy was lower than that of isoproterenol. Both demethoxysudachitin and nobiletin exhibited similar positive chronotropic and inotropic effects, indicating that these effects are not specific to sudachitin, but are common to polymethoxyflavones. The mechanism of action of sudachitin was associated with the enhancement of cAMP-dependent pathways, without the involvement of β-adrenoceptors.

Therapeutic mechanisms of glucocorticoids, their administration and chronotherapy

Glucocorticoids represent a cornerstone in the treatment of inflammatory and autoimmune diseases due to their potent anti-inflammatory and immunosuppressive effects. These steroid hormones, including endogenous cortisol and synthetic analogs like prednisone and dexamethasone, exert their effects through genomic and non-genomic pathways, targeting key inflammatory mediators. While genomic mechanisms regulate long-term gene expression, non-genomic pathways enable rapid modulation of immune responses, particularly at high doses. Despite their therapeutic efficacy, glucocorticoid use is often limited by significant adverse effects, including osteoporosis and metabolic disorders. Chronotherapy, which aligns medication timing with circadian rhythms, enhances therapeutic outcomes while reducing side effects, particularly in diseases like rheumatoid arthritis where inflammation peaks in the early morning. Emerging innovations, such as selective glucocorticoid receptor agonists (SEGRAs) and liposomal drug delivery systems, offer targeted anti-inflammatory effects with reduced systemic toxicity. These advancements highlight the potential for optimizing glucocorticoid therapy to achieve maximum efficacy while mitigating adverse effects. This review underscores the importance of understanding glucocorticoid mechanisms, administration methods, and novel therapeutic strategies to improve outcomes in inflammatory and autoimmune diseases.

Gas Empowered Dual‐Cascade Strategy for Augmented Single‐Atom Nanotherapies

AbstractSingle‐atom nanotherapies have received numerous attention in malignant oncotherapy. However, the insufficient enzyme substrate and the upregulation of heat shock proteins during therapeutic interventions are seldom concurrently noticed. Herein, a novel gas empowered dual‐cascade synergistic treatment strategy is demonstrated with domino effect, which can sequentially reinforce single‐atom nanozyme (SAzyme)‐based enzymatic therapeutics and mild photothermal therapy (PTT) (< 45 °C). In the proof‐of‐concept study, Fe single atom nanozyme (Fe/SAzyme) loaded with hydrogen sulfide (H2S) donor NaHS is developed for HSPs‐silencing mediated mild PTT. The generated H2S suppresses the catalase activity to achieve “intracellular H2O2 conservation”, thereby furnishing the enzyme substrate to Fe/SAzyme to produce abundant cytotoxic hydroxyl radicals (·OH) for augmented enzymatic therapeutics. Then, excess ·OH induced mitochondrial dysfunction blocks adenosine triphosphate (ATP) energy supply to realize cellular energy remodeling, which hinders overexpression of HSPs and enhances mild PTT of Fe/SAzyme both in vitro and vivo. Consequently, the gas‐triggered dual‐cascade strategy achieves domino H2S/·OH/mitochondrial dysfunction synergistic effect, endowing SAzymes with maximum antitumor efficacy via enzymatic therapeutics combined with mild PTT. This dual‐cascaded gas/enzymatic/mild PTT synergistic oncotherapy not only exhibits a new pathway for gas‐facilitated mild PTT, but also offers a valuable paradigm for the application of “1 + 1 + 1 > 3” multimodal synergistic tumor therapy.

Reprogramming the genome of M13 bacteriophage for all-in-one personalized cancer vaccine.

Peptide-based vaccines face limitations in immunogenicity and stability, and challenges in co-delivering antigens and adjuvants effectively. Virus-based nanoparticles, particularly M13 bacteriophage, present a promising solution due to their genetic modifiability, intrinsic adjuvanticity, and efficient antigen presentation capabilities. Here we developed a programmable M13 phage-based personalized cancer vaccine enabling single-step antigen-adjuvant assembly. Specifically, we designed a reprogrammed (RP) phage platform that precisely regulates Toll-like receptor 9 activation by programming its genome sequence and modulates antigen density through genetic engineering. Vaccination studies with RP phages demonstrated that the immune response could be modulated by fine-tuning the adjuvanticity and antigen density, revealing an optimal antigen dose and adjuvanticity for maximum vaccine efficacy. The RP phage induced a remarkable 24-fold increase in neoantigen-specific CD8 + T cells and eradicated established MC-38 tumors when combined with anti-PD-1 therapy. These findings highlight the RP phage's potential as a powerful nanovaccine platform for personalized cancer vaccines.

Enhancing localized chemotherapy with anti-angiogenesis and nanomedicine synergy for improved tumor penetration in well-vascularized tumors

Intratumoral delivery and localized chemotherapy have demonstrated promise in tumor treatment; however, the rapid drainage of therapeutic agents from well-vascularized tumors limits their ability to achieve maximum therapeutic efficacy. Therefore, innovative approaches are needed to enhance treatment efficacy in such tumors. This study utilizes a mathematical modeling platform to assess the efficacy of combination therapy using anti-angiogenic drugs and drug-loaded nanoparticles. Anti-angiogenic drugs are included to reduce blood microvascular density and facilitate drug retention in the extracellular space. In addition, incorporating negatively charged nanoparticles aims to enhance diffusion and distribution of therapeutic agents within well-vascularized tumors. The findings indicate that, in the case of direct injection of free drugs, using compounds with lower drainage rates and higher diffusion coefficients is beneficial for achieving broader diffusion. Otherwise, drugs tend to accumulate primarily around the injection site. For instance, the drug doxorubicin, known for its rapid drainage, requires the prior direct injection of an anti-angiogenic drug with a high diffusion rate to reduce microvascular density and facilitate broader distribution, enhancing penetration depth by 200%. Moreover, the results demonstrate that negatively charged nanoparticles effectively disperse throughout the tissue due to their high diffusion coefficient. In addition, a faster drug release rate from nanoparticles further enhance treatment efficacy, achieving the necessary concentration for complete eradication of tumor compared to slower drug release rates. This study demonstrates the potential of utilizing negatively charged nanoparticles loaded with chemotherapy drugs exhibiting high release rates for localized chemotherapy through intratumoral injection in well-vascularized tumors.

Interfacing inorganic halide perovskites with metal-organic frameworks: Color tunable emission, energy transfer, and advanced anti-counterfeiting application

This work presents an inorganic halide perovskite (CsPbBr3) is interfaced with a europium metal-organic framework (Eu-MOF). The presence of characteristic absorption edge and band edge emission of CsPbBr3 reveal a successful formation of CsPbBr3@Eu-MOF hybrid. The bi-flower morphology of Eu-MOF has tetragonal structure with space group P4322. The conical part of the bi-flower consists of many squared rods of edge length 200 nm. The CsPbBr3@Eu-MOF shows color-tunable emission under different excitation wavelengths whose CIE color coordinate covers the entire green to red region. The maximum luminous efficacy of the optical radiation achieved is 359 lm/W, and the maximum color purity is 94.4 %, which is significant for optical applications. Further for anti-counterfeiting application, a pattern “LMDD” is encrypted on four different substrates and the color change is captured under different excitation wavelengths. The results show that CsPbBr3@Eu-MOF is highly suitable for encryption and decryption of security codes particularly on plastic surface.

Reduction of pesticide dosage and off‐target drift with enhanced control efficacy in unmanned aerial vehicle‐based application using lecithin adjuvants

AbstractBACKGROUNDUnmanned aerial vehicles (UAVs) are increasingly used in precision agriculture, particularly for pesticide application in rice cultivation. One challenge is off‐target pesticide drift, which raises environmental concerns and reduces pesticide efficiency. Lecithin adjuvants have been suggested to enhance droplet stability, reduce drift, and improve control efficacy. This study aims to evaluate the efficiency of lecithin adjuvants in reducing pesticide drift and improving deposition during UAV‐based pesticide application under various paddy field conditions.RESULTSThe addition of 1% lecithin adjuvants in 75% dosage of tricyclazole and ferimzone dual active ingredient formulations reduced off‐target drift by 2.62 to 3.16 times compared to the 100% and 75% dosage of standard formulations, with deposition efficiency along the spray path increasing by up to 155%. Wind direction and speed were found to be the primary environmental factor affecting deposition efficiency and drift rate. The control efficacy against leaf blast disease was significantly improved, with a maximum efficacy of 73.7% observed in the adjuvant‐treated group. Initial pesticide residues on rice plants were the highest in treatments with adjuvants, but their harvest products, brown rice and dried straw, were still within safe limits for human consumption.CONCLUSIONLecithin adjuvants significantly reduce off‐target drift and enhance pesticide deposition during UAV‐based application. This method allowed for lower pesticide dosages without compromising control efficacy, contributing to more sustainable agricultural practices. These findings highlight the potential of adjuvants to improve UAV pesticide application and reduce the environmental impact of pesticide use. © 2024 Society of Chemical Industry.

Time-Efficacy Relationship of Semaglutide in the Treatment of Type 2 Diabetes Mellitus: A Model-Based Meta-Analysis.

Our objective was to quantify the efficacy of subcutaneous once-weekly semaglutide in treating type 2 diabetes mellitus (T2DM) over time. Based on a literature search of the PubMed, Embase, Cochrane, and Web of Science databases, a modified maximum effect (Emax) model including rebound effects was built using model-based meta-analysis with change from baseline in glycated hemoglobin as the efficacy endpoint. This was combined with the covariate model to form a final model, and then theoretical values of Emax and time to reach 50% of Emax (ET50) were obtained for each dose. Model fit and prediction were assessed using goodness-of-fit plots and visual prediction checking. Emax and ET50 were influenced by the proportion of males and the baseline values, respectively. There was no evidence of a placebo effect with semaglutide. The efficacy of other doses became more significant over time, and a rebound effect was observed after maximum efficacy, at a rate of 0.018. Simulation of the typical efficacy at the different doses yielded a maximum efficacy of -1.58% with 0.5 mg and a maximum efficacy of -1.87% with 1 mg. In addition, the six simulated doses (0, 0.1, 0.2, 0.5, 1, and 2 mg) showed a dose-dependent relationship between dose and efficacy except for 0.4 mg and 0.8 mg. A higher dose would result in greater efficacy and a faster onset of action. The efficacy of semaglutide in glucose control was investigated using the model-based meta-analysis method, which yields new insights into the treatment of T2DM with semaglutide.

Efficacy and safety of three antiseptics for neonatal skin disinfection: a cohort study.

The choice of the ideal antiseptic is not only based on its efficacy but also on safety and skin-friendliness. There are no standard recommendations regarding ideal skin preparation in neonates. This was a prospective cohort study to evaluate the efficacy of 3 antiseptics[10% Povidone Iodine(PI), 70% isopropyl alcohol(AL), 2% chlorhexidine in 70% alcohol(CHG-IPA)] in disinfecting the skin before venipuncture in term neonates as assessed by logarithmic reduction in skin bacterial colony counts post-application. Secondary objectives were to assess the changes in skin condition. Measurements were done pre-, post-antiseptic and 6-24 h (for residual effect) later. Fifty neonates were enrolled in each group. All three antiseptics caused a significant reduction in bacterial load post-application, but maximal efficacy [2.6(2.2-2.8)log reduction] and, maximal residual effect at 6-24 h was seen with CHG-IPA [2.4(2.2-2.6)log reduction]. The logarithmic reduction in colony counts from pre-intervention to 6-24 h later remained significant for all three groups [(PI, p-0.039; CHG-IPA, p-0.00; AL, p - 0.01)]. After an initial alteration in hydration, and skin condition score, there was a return to baseline after 6-24 h. 2% CHG-IPA had better efficacy than AL or PI for skin antisepsis in term neonates. There was no significant change in skin integrity in all three groups. All three antiseptics [2% chlorhexidine gluconate in 70% isopropyl alcohol(CHG + IPA), 10% Povidone Iodine(PI), and 70% isopropyl alcohol(AL)] cause significant reduction in bacterial colony counts. CHG + IPA has the maximum efficacy as assessed by log reduction of bacterial colony counts with optimal residual effect favouring its usage in term neonates. The least efficacy is seen with 70% isopropyl alcohol. All three antiseptics are skin-friendly and do not affect the skin integrity. Future studies addressing the clinical outcomes and safety in preterm populations with these commonly used antiseptics should be done.

In vitro antimicrobial and antioxidant activities of bioactive compounds extracted from Streptomyces africanus strain E2 isolated from Moroccan soil

This study aimed to isolate Streptomyces sp. from Moroccan terrestrial ecosystems and identify bioactive compounds through GC–MS analysis. Antimicrobial activity was assessed against various pathogenic microorganisms including Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922 and Candida albicans ATCC 60193, and multi-drug resistant strains comprising Listeria monocytogenes, Klebsiella pneumoniae 19K 929, Proteus sp. 19K1313, Klebsiella pneumoniae 20B1572, Proteus vulgaris 16C1737, and Klebsiella pneumoniae 20B1572. Based on the results of the gene sequencing of gene 16S rRNA and phylogenetic analysis, the E2 isolate belongs to the genus Streptomyces with the highest degree of resemblance (97.51%) to the Streptomyces africanus strain NBRC 101005 (NR_112600.1). The isolate exhibited broad-spectrum antibacterial activity, with maximum efficacy against Klebsiella pneumoniae 20B1572 indicated by an inhibition zone diameter of 22.5 ± 0.71mm and a minimum inhibitory concentration (MIC) of 0.0625 mg/mL. The in vitro antioxidant potential of E2 strain was determined through screening of its ethyl acetate extract against sets of antioxidant assays. The results were indicative of E2 strain displaying strong antioxidant activity against ABTS, DPPH free radicals, and FRAP. Furthermore, there was a high significant correlation (p < 0.0001) between the total phenolic and flavonoid content and antioxidant activities. The GC–MS analysis of the extract identified six volatile compounds, with Eugenol (96%) and Maltol (93%) being the most prominent. Additionally, the HPLC–UV/vis analysis revealed six phenolic compounds: gallic acid, chlorogenic acid, vanillic acid, trans-ferulic acid, ellagic acid, and cinnamic acid. Overall, the study highlights Streptomyces sp. strain E2 as a potential source of potent antimicrobial and antioxidant metabolites, offering promise in addressing antibiotic resistance and oxidative stress-related conditions.

Machine learning integration with response surface methodology to enhance the removal efficacy of arsenate (V) through sulfur-functionalized mxene coated QPPO/PVA AEM

Arsenic, a poisonous and carcinogenic heavy metal in drinking water, presents severe health risks to humans, including skin lesions, neurological damage, and circulatory disorders. Despite extensive research efforts have been carried out on removing arsenate (As(V)) using membrane technologies, however, there remains a critical need to further enhance membrane removal efficacy to achieve maximum reusability. Thus, to minimize this challenge, herein we explore the impact of S-functionalized Mxene coating over the surface of quaternary ammonium poly (2,6-dimethyl-1,4-phenylene oxide)/polyvinyl alcohol (QPPO/PVA) anion exchange AEM membrane against As(V) removal. To optimize and validate adsorption efficacy, response surface methodology (RSM) study was carried out using a central composite design (CCD) with R2 = 0.995. The significance of these variables was also confirmed by CCD matrix, yielding statistically significant results (p < 0.0001). Adsorption efficacy was further enhanced by employing different machine learning (ML) regression models to finely tune experimental parameters. Among ML models, Random Forest Regression (RFR) has shown highest predictive accuracy (R2 = 0.929, RMSE = 4.57 mg L-1) and identified As(V) concentration as the most influential factor affecting adsorption efficacy. ML-optimization has shown maximum adsorption efficacy at pH (3), contact time (5 min), and As(V) concentration (50 mg L−1). Freundlich isotherm model has shown adsorption capacity of 413 mg/g (R2 = 0.997), while pseudo-second-order kinetic model reflected R2 of 0.989. Thermodynamic assessments (ΔGᵒ, ΔH°, ΔS°) confirmed the process as spontaneous. To the best of our knowledge, this is the first study in which ML is employed to design highly efficient and reliable membranes, providing a novel approach to enhance membrane-based remediation strategies.

A Cross-talk between Nanomedicines and Cardiac Complications: Comprehensive View.

Cardiovascular Diseases (CVDs) are the leading cause of global morbidity and mortality, necessitating innovative approaches for both therapeutics and diagnostics. Nanoscience has emerged as a promising frontier in addressing the complexities of CVDs. This study aims to explorethe interaction of CVDs and Nanomedicine (NMs), focusing on applications in therapeutics and diagnostics. In the realm of therapeutics, nanosized drug delivery systems exhibit unique advantages, such as enhanced drug bioavailability, targeted delivery, and controlled release. NMs platform, including liposomes, nanoparticles, and carriers, allows the precise drug targeting to the affected cardiovascular tissues with minimum adverse effects and maximum therapeutic efficacy. Moreover, nanomaterial (NM) enables the integration of multifunctional components, such as therapeutic agents and target ligands, into a single system for comprehensive CVD management. Diagnostic fronts of NMs offer innovative solutions for early detection and monitoring of CVDs. Nanoparticles and nanosensors enable highly sensitive and specific detection of Cardiac biomarkers, providing valuable insights into a disease state, its progression, therapeutic outputs, etc. Further, nano-based technology via imaging modalities offers high high-resolution imaging, aiding in the vascularization of cardiovascular structures and abnormalities. Nanotechnology-based imaging modalities offer high-resolution imaging and aid in the visualization of cardiovascular structures and abnormalities. The cross-talk of CVDs and NMs holds tremendous potential for revolutionizing cardiovascular healthcare by providing targeted and efficient therapeutic interventions, as well as sensitive and early detection for the improvement of patient health if integrated with Artificial Intelligence (AI).

Design, synthesis and FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis

Farnesoid X receptor (FXR) is considered a promising therapeutic target for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Increasing evidence suggests that targeting FXR with full agonists may lead to side effects. FXR partial agonists, which moderately activate FXR signaling, are emerging as a feasible approach to mitigate side effects and address MASH. Herein, a series of novel anthranilic acid derivatives bearing aryloxy moiety were designed and synthesized using a hybrid strategy from the previously identified FXR partial agonists DM175 and AIV-25. Particularly, compound 26 exhibited potent FXR partial agonistic activity in a dual-luciferase reporter gene assay with an EC50 value of 0.09 ± 0.02 µM (75.13 % maximum efficacy relative to OCA). In the MASH mice model, compound 26 significantly ameliorated the pathological features of the liver, including steatosis, inflammation, and fibrosis. In addition, compound 26 displayed high selectivity, good oral bioavailability, high liver distribution, as well as an acceptable safety profile. Molecular simulation studies showed that compound 26 fitted well with the binding site of FXR. Collectively, these findings demonstrated that compound 26 might serve as a promising candidate targeting FXR for MASH treatment.

Chrysin alleviates salt stress in tomato by physiological, biochemical, and genetic mechanisms

Soil salinity greatly reduces agricultural productivity, especially in dry and semi-arid regions, by interfering with physiological and biochemical processes. This research aimed to determine whether Chrysin (Chr) can mitigate the negative effects of salinity on growth parameters, antioxidant enzyme activity, and gene expression in tomato (Solanum lycopersicum L.) plants. Experiments were conducted in a semi-controlled greenhouse, with plants subjected to varying concentrations of sodium chloride (NaCl) (0 and 100 mM) and Chr (0, 0.1, 0.5, and 1.0 mM). Results revealed that salinity stress significantly reduced plant height, leaf area, and chlorophyll content while increasing hydrogen peroxide (H2O2), malondialdehyde (MDA), and proline levels, indicating oxidative stress. Chr application alleviated these detrimental effects by enhancing the activity of antioxidant enzymes such as catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD), thereby reducing reactive oxygen species (ROS) accumulation. Additionally, Chr treatments improved plant water status and mineral content under salt stress. Gene expression analysis showed that Chr positively regulated the transcription of salt tolerance-related genes, including HKT1-1, HKT1-2, and PIP1-2, which are associated with sodium ion transport and water balance. These findings suggest that Chr can be an effective biostimulant for enhancing salt tolerance in tomato plants by modulating physiological, biochemical, and genetic mechanisms. This study provides insights into Chr's potential as a sustainable solution for improving crop resilience to salinity in agricultural practices. Further research is recommended to optimize Chr concentrations for maximum efficacy.

High color rendering index WLEDs enabled by multi-band tuning of InP quantum dots

Quantum dots (QDs) represent a significant class of fluorescent materials, offering the potential to reduce power consumption and enhance the color rendering index (CRI) of white light-emitting diode (WLED) devices. However, the presence of toxic elements such as Cd and Pb in traditional fluorescent QDs limits their widespread commercial application. Compared to the broad emission characteristics of environmentally friendly AgInS2 and CuInS2 QDs, the narrower linewidth of InP-based core-shell QDs is advantageous for developing WLED devices with a higher CRI. In this study, we employed a multistage heating method to synthesize a series of amino-phosphine-based InP/ZnSe core-shell QDs, which exhibited emission wavelengths ranging from 535 to 650 nm, narrow emission linewidths of 43-47 nm, and high photoluminescence quantum yields of 60%-80%. Subsequently, six different color QDs are used to fabricate a WLED device. The best WLEDs show not only bright warm light (correlated color temperature = 3323 K) with a maximum luminous efficacy of 74.1 lm W-1, but also excellent color quality (CRI Ra = 93, as well as R9 = 94.8, and R13 = 97.1). These results indicate remarkable progress in InP-based WLEDs for high-quality lighting applications.

Scaffolds functionalized with matrix metalloproteinase-responsive release of miRNA for synergistic magnetic hyperthermia and sensitizing chemotherapy of drug-tolerant breast cancer

Combining hyperthermia and chemotherapy for maximum anticancer efficacy remains a challenge because drug-tolerant cancer cells often evade this synergistic treatment due to drug resistance and asynchronous drug release. In this study, multifunctional scaffolds were designed to efficiently treat drug-tolerant breast cancer by improving the sensitization of breast cancer cells and synchronizing anticancer drug release with magnetic hyperthermia. The scaffolds contained microRNA-encapsulated matrix metalloproteinase-cleavable liposomes, doxorubicin-encapsulated thermoresponsive liposomes and Fe3O4 nanoparticles. The scaffolds could release microRNA specifically to improve the sensitization of breast cancer cells to anticancer drugs. The scaffolds also showed excellent hyperthermia effects under alternating magnetic field irradiation. Moreover, doxorubicin release was synchronized with magnetic hyperthermia. In vitro and in vivo studies demonstrated that the scaffolds effectively reduced drug resistance and eliminated doxorubicin-tolerant MDA-MB-231 cells through the synergistic effect of magnetic hyperthermia and sensitizing chemotherapy. Additionally, the scaffolds could support the proliferation and adipogenic differentiation of stem cells for adipose tissue regeneration after killing cancer cells at a late therapeutic stage. These composite scaffolds offer an innovative strategy for treating breast cancer, with synergistic anticancer effects and regenerative functions.

Fine-tuning the cytotoxicity profile of N,N,N-trimethyl chitosan through trimethylation, molecular weight, and polyelectrolyte complex nanoparticles

N,N,N-trimethyl chitosan (TMC) is a promising biopolymer for pharmaceutical applications due to its enhanced solubility and bioadhesive properties, though its cytotoxic limitations necessitate careful modification to ensure safety and efficacy. This study sought to investigate whether nanoparticle (NP) formation could reduce the anticipated cytotoxic effects of TMC, thus improving its applicability across a wider spectrum of pharmaceutical uses. TMC's capability to form NPs with anionic polyelectrolytes led to the application of chondroitin sulfate (ChS) in this study. Five TMC samples, varying in degree of trimethylation (DTM 23, 32, 46, 50 and 99 %) and molecular weight (Mw, 66–290 kDa) were synthesized, and their biocompatibility with human umbilical vein endothelial cells (HUVECs) was assessed. The results revealed a discernible impact of both DTM and Mw on cell viability, with higher DTM and lower Mw correlating with increased toxicity. Cytotoxicity studies against ovarian cancer cell lines SKOV-3 and OVISE showed a clear indication of a higher cytotoxic effect of TMC samples against cancer cells compared to healthy cells (HUVEC). The cytotoxicity against cancer cells also indicated an optimal DTM for maximum efficacy, deviating from a linear trend. The effects of Mw were cell-dependent, introducing complexity to the observed relationship. Additionally, TMC-ChS NPs were successfully prepared, demonstrating a substantial reduction in cytotoxicity compared to TMC alone in all tested cells. This promising outcome suggests the potential of NP formation to fine-tune the cytotoxicity profile of TMC, paving the way for the development of safer and more effective pharmaceutical formulations.

Building Upon “Foundationalism” to Achieve the Objectives of Contemporary Science: How this can Lead to Faster Scientific Progress and Inclusive Science

This paper is one of our most important ones in the core philosophy of science, and one that we expect to stand science in extremely good stead as well. We believe this can move the needle and push the envelope as well, and lead us to what we have always called “scientific progress at the speed of light”. We naturally commence this paper by tracing the history of the term “foundationalism” itself, right from the time of the Ancient Greeks, renaissance and enlightenment thinkers, and finally to the modern and contemporary ones. Types of foundationalism such as strong and weak foundationalism, modest foundationalism, and then finally anti-foundationalism, internalism and externalism are also discussed and dissected threadbare along with allied and related concepts such as circular logic and reasoning, regress and infinite regress, all of which form a part of epistemology. The core concepts forming a part of this paper such as forward linkages, backward linkages, and traceability matrices are also discussed. We follow this up with the core principles of this paper, and discuss the ideal and recommended direction of research, including the ideal nature of research, primary research, secondary research, basic and applied research, and cross-cultural collaboration including vertical and horizontal collaboration as well. This paper is also much more importantly linked to our papers on sociocultural change, pedagogy, scientific methods, and other papers in the social sciences for maximum impact and efficacy. It is therefore an important part and parcel of our globalization of science movement, and one that will help realize our overall goals and mission greatly.

Neuropsychiatric presentations of common dementia syndromes: A concise review for primary care team members.

Dementia is a syndrome characterized by cognitive changes which interfere with daily functioning. Neuropsychiatric symptoms (NPS) are also pervasive and may even occur prior to any noticeable cognitive decline. Still, NPS are less associated with the early stages of the disease course, despite mounting research evidence that NPS present early and often in several dementia syndromes, even in the absence of cognitive decline (i.e., mild behavioral impairment [MBI]). Primary care teams are at the forefront of dementia care, yet they frequently report insufficient training in dementia diagnosis and management. This poses a serious problem considering that timely diagnosis of dementia is critical for optimal outcomes and maximum efficacy of intervention. We provide a concise narrative review of four dementia syndromes (Alzheimer's disease, vascular dementia, dementia with Lewy bodies, and behavioral variant frontotemporal dementia) and their associated neuropsychiatric presentations, as well as at-a-glance clinical guides, to help primary care team members recognize possible prodromal neurodegenerative disease and to prompt further workup. We also review next steps in the management of dementia and symptoms of MBI for primary care team members. As evidenced by the NPS profiles of these dementia syndromes, subacute new onset of psychiatric symptoms in an older adult should prompt consideration of an emerging dementia process and possible further workup of such, even in the absence of cognitive decline.

Preparation of a nanoemulsion containing active ingredients of cannabis extract and its application for glioblastoma: in vitro and in vivo studies

Recently, the anti-tumor effects of cannabis extract on various cancers have attracted the attention of researchers. Here, we report a nanoemulsion (NE) composition designed to enhance the delivery of two active components in cannabis extracts (∆9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)) in an animal model of glioblastoma. The efficacy of the NE containing the two drugs (NED) was compared with the bulk drugs and carrier (NE without the drugs) using the C6 tumor model in rats. Hemocompatibility factors (RBC, MCV, MCH, MCHC, RDW, PPP, PT and PTT) were studied to determine the potential in vivo toxicity of NED. The optimized NED with mean ± SD diameter 29 ± 6 nm was obtained. It was shown that by administering the drugs in the form of NED, the hemocompatibility increased. Cytotoxicity studies indicated that the NE without the active components (i.e. mixture of surfactants and oil) was the most cytotoxic group, while the bulk group had no toxicity. From the in vivo MRI and survival studies, the NED group had maximum efficacy (with ~4 times smaller tumor volume on day 7 of treatment, compared with the control. Also, survival time of the control, bulk drug, NE and NED were 9, 4, 12.5 and 51 days, respectively) with no important adverse effects. In conclusion, the NE containing cannabis extract could be introduced as an effective treatment in reducing brain glioblastoma tumor progression.Graphical abstract