Modulation Of Resistance Research Articles

Impact of a free normal velocity boundary on the modelling of external MHD modes

Free normal-flow (NF) conditions at the plasma boundary are shown to be essential for three-dimensional magnetohydrodynamic (MHD) simulations to agree with linear stability theory. A comparative verification study is presented between two different formulations of the boundary conditions (BCs) for velocity perturbations: (i) fully consistent free NF implementation and (ii) fixed NF formulation, neglecting flow perturbations at the numerical boundary. Numerical results are compared with consolidated figures of merit from the linear theory of external kink modes. We consider two classes of initial equilibria presenting different numerical challenges: a uniform current channel surrounded by pure vacuum and a shaped Wesson-like equilibrium, with smooth (polynomial) radial dependency. Only the fully consistent free NF formulation is invariably accurate in modelling the plasma interface at the numerical boundary, without the need of enforcing a pseudovacuum region at the edge of the simulation domain, as in most analogous past studies. This study employs the cylindrical code SPECYL (Cappello & Biskamp, Nucl. Fusion, vol. 36, no. 5, 1996, p. 571) that solves a full-MHD model without pressure gradients, whose fully consistent resistive wall module with free NF BCs was recently successfully verified against the independent code PIXIE3D (Spinicci et al., AIP Adv., vol. 13, no. 9, 2023, p. 095111).

Enhancing DOX efficacy against NSCLC through UDCA-mediated modulation of the TGF-β/MAPK autophagy pathways

Lung carcinoma, predominantly manifested as non-small cell lung cancer (NSCLC), significantly contributes to oncological mortality, underscoring an imperative for novel therapeutic paradigms. Amidst this context, the present investigation delineates the synergistic potentiation of doxorubicin (DOX)—a canonical chemotherapeutic—by Ursodeoxycholic acid (UDCA), a compound with a historical pedigree in hepatobiliary medicine, now repositioned within oncological pharmacotherapy due to its dichotomous cellular modulation—affording cytoprotection to non-malignant epithelia whilst eliciting apoptotic cascades in neoplastic counterparts. This study, through a rigorous methodological framework, elucidates UDCA’s capacity to inhibit NSCLC cellular proliferation and induce apoptosis, thereby significantly amplifying DOX’s chemotherapeutic efficacy. Notably, the co-administration of UDCA and DOX was observed to attenuate DOX-induced autophagy via the modulation of the TGF-β/MAPK signaling axis, a pathway pivotal in mediating cellular survival and autophagic mechanisms. Such findings not only underscore the therapeutic potential of UDCA as a chemosensitizer but also illuminate the molecular underpinnings of its modulatory effects, thereby contributing to the corpus of knowledge necessary to surmount chemoresistance in NSCLC. The implications of this research are twofold: firstly, it offers a compelling evidence base for the clinical reevaluation of UDCA in combinatory chemotherapeutic regimens; secondly, it posits a novel mechanistic insight into the modulation of chemotherapeutic efficacy and resistance. Collectively, these insights advocate for the expedited clinical translation of UDCA-DOX synergy, potentially heralding a paradigm shift in the management of NSCLC, thereby addressing a critical lacuna in contemporary oncological therapy.

Effect of nanoemulsion loaded with macela (Achyrocline satureioides) on the ultrastructure of Staphylococcus aureus and the modulating activity of antibiotics

Nanoformulations with herbal actives for treating bovine mastitis present an alternative for controlling bacterial infections in the emerging scenario of antimicrobial resistance. In this study, we investigated macela (Achyrocline satureioides) nanoemulsion (NE-ML), a formulation developed for the treatment of bovine mastitis (registered under Brazilian patent application BR 10 2021 008630 0), in the context of its bactericidal mechanism(s) of action and potential synergism with commercial antimicrobials. The effect of NE-ML on the integrity and cell permeability of Staphylococcus aureus was evaluated by measuring the electrical conductivity of bacterial suspensions exposed to different concentrations of NE-ML and by assessing the release of cellular constituents. Damage to bacterial ultrastructures was analyzed by transmission electron micrographs. The synergism of NE-ML with beta-lactam antibiotics and aminoglycosides was evaluated by the checkerboard test method against S. aureus (n = 6). The relative electrical conductivity of the bacterial solution gradually increased over time, reaching high values after exposure to 1xMIC (52.3%) and 2xMIC (75.34%) of NE-ML. Total proteins were detected in the bacterial suspensions exposed to NE-ML, increasing in concentration over exposure time (p < 0.05). Through bacterial micrographs, we observed that exposure to NE-ML (1xMIC) affected the integrity of the plasma membrane with invaginations in the cytosolic region and alterations in the cell wall. The increase in NE-ML concentration resulted in greater damage to the ultrastructure of S. aureus with changes in bacterial cell division patterns. When NE-ML was combined with the beta-lactam antimicrobials, the interaction was indifferent, indicating no modulation of antimicrobial resistance. In contrast, when combined with the aminoglycoside, a synergistic interaction did occur. These general findings suggest that the bactericidal action of NE-ML begins in the plasma membrane, causing alterations in its permeability and integrity, and extends to the cell wall, cytoplasm, and cell division. Although synergy was restricted to the aminoglycoside by destabilizing the bacterial cell membrane, this suggests that NE-ML can induce the entry of other actives, potentially reducing their therapeutic doses. Understanding the mechanism of action of this new nanoformulation is certain to drive pharmacological advances, broaden the perspective of its in vivo use, and improve the treatment of bovine mastitis.

Incretin-Based Therapies: A Promising Approach for Modulating Oxidative Stress and Insulin Resistance in Sarcopenia.

Recent studies have linked sarcopenia development to the hallmarks of diabetes, oxidative stress, and insulin resistance. The anti-oxidant and insulin sensitivityenhancing effects of incretin-based therapies may provide a promising option for the treatment of sarcopenia. This review aimed to unveil the role of oxidative stress and insulin resistance in the pathogenesis of sarcopenia and explore the potential benefits of incretin-based therapies in individuals with sarcopenia. PubMed, the Cochrane Library, and Google Scholar databases were searched by applying keywords relevant to the main topic, to identify articles that met our selection criteria. Incretin-based therapies manifested anti-oxidant effects by increasing the anti-oxidant defense system and decreasing free radical generation or by indirectly minimizing glucotoxicity, which was mainly achieved by improving insulin signaling and glucose homeostasis. Likewise, these drugs exhibit insulin-sensitizing activities by increasing insulin secretion, transduction, and β-cell function or by reducing inflammation and lipotoxicity. Incretin-based therapies, as modulators of oxidation and insulin resistance, may target the main pathophysiological factors of sarcopenia, thus providing a promising strategy for the treatment of this disease.

Hyaluronic acid-functionalized ruthenium photothermal nanoenzyme for enhancing osteosarcoma chemotherapy: Cascade targeting and bidirectional modulation of drug resistance

Insufficient drug delivery efficiency in vivo and robust drug resistance are two major factors to induce suboptimal efficacy in chemotherapy of osteosarcoma (OS). To address these challenges, we developed polysaccharide hyaluronic acid (HA)-functionalized ruthenium nanoaggregates (Ru NAs) to enhance the chemotherapy of doxorubicin (DOX) for OS. These NAs, comprising Ru nanoparticles (NPs) and alendronate-modified HA (HA-ALN), effectively load DOX, resulting in DOX@Ru-HA-ALN NAs. The combination of HA and ALN in NAs ensures outstanding cascade targeting towards tumor-invaded bone tissues and CD44-overexpressing tumor cells, maximizing therapeutic efficacy while minimizing off-target effects. Concurrently, the Ru NPs in NAs function as “smart” photoenzymatic agent to not only in situ relieve hypoxia of OS via the catalysis of overexpressed H2O2 to produce O2, but also generate mild photothermal effect under 808-nm laser irradiation. They can bidirectionally overcome drug resistance of DOX via downregulation of resistance-related factors including multi-drug resistant associate protein, P-glycoprotein, heat shock factor 1, etc. The integration of cascade targeting with bidirectional modulation of drug resistance positions Ru-HA-ALN NAs to substantially enhance DOX chemotherapy for OS. Therefore, the present work highlights the potential of polysaccharide-functionalized nanomaterials in advancing tumor chemotherapy by addressing challenges of both delivery efficiency and drug resistance.

Autocrine Motility Factor and Its Peptide Derivative Inhibit Triple-Negative Breast Cancer by Regulating Wound Repair, Survival, and Drug Efflux

Triple-negative breast cancer (TNBC) presents a significant challenge in oncology due to its aggressive nature and limited targeted therapeutic options. This study explores the potential of autocrine motility factor (AMF) and an AMF-derived peptide as novel treatments for TNBC. AMF, primarily secreted by neoplastic cells, plays a crucial role in cancer cell motility, metastasis, and proliferation. The research demonstrates that AMF and its derived peptide inhibit TNBC cell proliferation by modulating cellular migration, redox homeostasis, apoptotic pathways, and drug efflux mechanisms. Dose-dependent antiproliferative effects were observed across three TNBC cell lines, with higher concentrations impairing cellular migration. Mechanistic studies revealed decreased glucose-6-phosphate dehydrogenase expression and elevated reactive oxygen species production, suggesting redox imbalance as a primary mediator of apoptosis. Combination studies with conventional therapeutics showed near-complete eradication of resistant TNBC cells. The observed reduction in p53 levels and increased intranuclear doxorubicin accumulation highlight the AMF/AMF peptide’s potential as multidrug resistance modulators. This study underscores the promise of using AMF/AMF peptide as a novel therapeutic approach for TNBC, addressing current treatment limitations and warranting further investigation.

Decitabine Enhances Sorafenib Sensitivity in Renal Cell Carcinoma by Promoting BIN1 and SYNE1 Expressions.

Renal cell carcinoma (RCC), especially clear cell RCC (ccRCC), significantly impacts health, and results in particularly poor outcomes in patients at the advanced stage. Resistance to vascular endothelial growth factor (VEGF) pathway-targeting tyrosine kinase inhibitors (TKIs) is a major barrier in effective ccRCC treatment. Herein, we aim to explore how decitabine mediates bridging integrator 1 (BIN1) and spectrin repeat containing nuclear envelope protein 1 (SYNE1) to impact resistance of ccRCC to sorafenib. Employing bioinformatics on datasets GSE64052 and CancerSea, we identified genes linked to TKI resistance, ultimately focusing on SYNE1. We assessed influences of SYNE1 overexpression and BIN1 knockdown via quantitative real-time PCR (qRT-PCR) and Western blot. Assessment of cell viability and apoptosis was accomplished using cell counting kit-8 (CCK-8) assays and flow cytometry. The investigation into the potential interactions between SYNE1 and BIN1, as well as their impacts on sorafenib sensitivity was accomplished by Co-Immunoprecipitation (Co-IP) and Glutathione-S-transferase (GST) Pull-down. SYNE1 was substantially down-regulated in sorafenib-resistant ccRCC cells, and its overexpression increased sorafenib sensitivity, decreased viability and enhanced apoptosis. Interaction between BIN1 and SYNE1 was confirmed, with BIN1 level lower in resistant cells. BIN1 knockdown reduced the beneficial effects of SYNE1 overexpression on sorafenib sensitivity. Decitabine treatment elevated both SYNE1 and BIN1, while boosting apoptosis and reducing sorafenib resistance. SYNE1 contributes to the modulation of sorafenib resistance in ccRCC cells through interacting with BIN1. Decitabine treatment enhances expressions of these two proteins to improve TKI response, suggesting a potential strategy for counteracting resistance and bettering patient outcomes.

Molecular characterization of the tet (M)-carrying transposon Tn7124 and plasmids in Escherichia coli isolates recovered from swine.

Here, we report the genetic features and evolutionary mechanisms of two tet (M)-bearing plasmids (pTA2 and pTA7) recovered from swine Escherichia coli isolates. The genetic profiles of pTA2 and pTA7 and corresponding transconjugants were accessed by S1 nuclease pulsed-field gel electrophoresis and Southern hybridization, followed by whole genome sequencing and bioinformatics analysis. The biological influences of pTA2 and pTA7 were determined by stability and direct competition assays. Both pTA7 and pTA2 had the IncR backbone sequences but differed in the multidrug resistance region (MDR). The MDR of pTA2 consisted of sul3, tet (M), qnrS1, bleO, oqxAB, floR, aadA1, cmlA1, aadA2, and tet (A)-tetR (A) in addition to 22 insertion sequences. Notably, pTA2 carried the novel complex Tn7124 (IS26-ctp-lp-tet (M)-hp-IS406tnp-IntI4-IS26) harboring tet (M). The fragment carrying tet (M) (IS26-ctp-lp-tet (M)-IS406 tnp-ctp-aadA1-cmlA1-aadA2-dfrA12-IntI1), named Tn6942-like, and the two resistance modules ISVsa3-VirD2-floR-lysR and tet (A)-tetR (A) were located in the MDR of pTA7. Both pTA2 and pTA7 were highly stable in E. coli DH5α cells with no fitness cost to the host or disadvantage in growth competition. These results indicate that transposons carrying tet (M) continuously integrate via mediation with an insertion sequence, which accelerates the transmission of tet (M) in E. coli isolates through integration of other drug-resistant genes, thereby posing a potential serious threat to the efficacy of clinical treatment.

Chemical Profile, Antibacterial and Toxicological Study of Asparagus setaceus (KUNTH)

Objective: The objective of this work was to obtain the chemical profile and verify the biological activities of ethanolic extract from the leaves of Asparagus setaceus. Method: The extract was obtained with cold ethanol and the classes of secondary metabolites were identified with specific reagents. The antibacterial assays were performed using the microdilution method against the standard bacteria, Gram +: Sthaphylococcus aureus, Streptococcus mutans and Enterococcus faecalis and Gram -: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoneae and two multidrug-resistant strains: Escherichia coli 27 and Staphylococcus aureus 358 and the resistance modulation assay was performed using aminoglycoside and beta- lactam antibiotics. Toxicity was tested against the microcrustacean Artemia salina (Leach) ranging in concentrations from 10 to 500 μg/mL Results and Discussion: The ethanolic extract of Asparagus setaceus (EEAS) indicated the presence of phenols, condensed tannins, anthocyanins, anthocyanidins, flavones, flavonols, xanthones, chalcones, aurones, flavononols, catechins, leukoanthocyanidins, flavones and saponins. The EEAS presented CL50 of 90.22 μg/ mL. The microbial assay showed inhibition for standard strains of Gram + and Gram bacteria - but in the multidrug-resistant strains it showed clinically non-signific results. For the modulation of antibiotic action against bacterial strains, EEAS presented both synergistic and antagonistic action, with the synergistic action being more expressive on benzylpenicillin, amikacin and gentamicin in front of Escherichia coli 27. The aminoglycoside antibiotics showed synergistic activity on all bacteria tested. Research Implications: Given the results, it was found that the ethanolic extract of the leaves of Asparagus setaceus (Kunth) disp of chemical and biological properties that can contribute to the elaboration of therapeutic resources against inflammatory and bacterial infectious processes. Keywords: Antibacterial Assay, Secondary Metabolites, Modulation, Asparagus setaceus.

KINOME-WIDE SYNTHETIC LETHAL SCREEN IDENTIfiES PANK4 AS A MODULATOR OF TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA

Abstract AIMS Temozolomide (TMZ) represents the cornerstone of glioblastoma (GBM) therapy. However, acquisition of resistance limits its therapeutic potential. The human kinome is an undisputable source of druggable targets, still, current knowledge remains confined to a limited fraction of it, with a multitude of under-investigated proteins yet to be characterised. We aimed to uncover synthetic lethal partners of TMZ in GBM that could enhance the effect of TMZ, thus improving TMZ therapy response. METHOD A kinome-wide RNAi screen was performed in a TMZ-resistant GBM cell model. A panel of several TMZ-resistant and patient-derived GBM cell lines was implemented for in vitro validation of our findings through several phenotypic assays. In vivo TMZ-resistant GBM xenografts and immunohistochemical (IHC) analysis of IDH- wildtype GBM specimens were employed to assess the clinical relevance of our findings. Tandem Mass Tag (TMT)-based quantitative proteomic studies were undertaken to elucidate the underlying mechanisms. RESULTS Following a kinome-wide RNAi screen, pantothenate kinase 4 (PANK4) was uncovered as a modulator of TMZ resistance in GBM. Validation of PANK4 across various TMZ-resistant GBM cell models, patient-derived GBM cell lines, tissue samples, as well as in vivo studies, corroborated the potential translational significance of these findings. Moreover, PANK4 expression is induced during TMZ treatment, and its expression is associated with a worse clinical outcome. A Tandem Mass Tag (TMT)-based quantitative proteomic approach revealed that PANK4 abrogation leads to a significant downregulation of numerous proteins with central roles in cellular detoxification and cellular response to oxidative stress. Mechanistically, as cells undergo genotoxic stress during TMZ exposure, PANK4 depletion represents a crucial event that can lead to accumulation of intracellular reactive oxygen species (ROS) and subsequent cell death. CONCLUSION Our study provides novel insights into chemoresistance in GBM and unveils a previously unreported role for PANK4 in mediating therapeutic resistance to TMZ in GBM.

Bacillus subtilis and Saccharomyces cerevisiae as Potential Modulators of Hemato-Biochemical Indices, Digestive Enzymes and Disease Resistance in Labeo rohita

Bacillus subtilis and Saccharomyces cerevisiae as Potential Modulators of Hemato-Biochemical Indices, Digestive Enzymes and Disease Resistance in Labeo rohita

Identification of the drug/metabolite transporter 1 as a marker of quinine resistance in a NF54×Cam3.II P. falciparum genetic cross.

The genetic basis of Plasmodium falciparum resistance to quinine (QN), a drug used to treat severe malaria, has long been enigmatic. To gain further insight, we used FRG-NOD human liver-chimeric mice to conduct a P. falciparum genetic cross between QN-sensitive and QN-resistant parasites, which also differ in their susceptibility to chloroquine (CQ). By applying different selective conditions to progeny pools prior to cloning, we recovered 120 unique recombinant progeny. These progeny were subjected to drug profiling and QTL analyses with QN, CQ, and monodesethyl-CQ (md-CQ, the active metabolite of CQ), which revealed predominant peaks on chromosomes 7 and 12, consistent with a multifactorial mechanism of resistance. A shared chromosome 12 region mapped to resistance to all three antimalarials and was preferentially co-inherited with pfcrt. We identified an ATP-dependent zinc metalloprotease (FtsH1) as one of the top candidates and observed using CRISPR/Cas9 SNP-edited lines that ftsh1 is a potential mediator of QN resistance and a modulator of md-CQ resistance. As expected, CQ and md-CQ resistance mapped to a chromosome 7 region harboring pfcrt. However, for QN, high-grade resistance mapped to a chromosome 7 peak centered 295kb downstream of pfcrt. We identified the drug/metabolite transporter 1 (DMT1) as the top candidate due to its structural similarity to PfCRT and proximity to the peak. Deleting DMT1 in QN-resistant Cam3.II parasites significantly sensitized the parasite to QN but not to the other drugs tested, suggesting that DMT1 mediates QN response specifically. We localized DMT1 to structures associated with vesicular trafficking, as well as the parasitophorous vacuolar membrane, lipid bodies, and the digestive vacuole. We also observed that mutant DMT1 transports more QN than the wild-type isoform in vitro. Our study demonstrates that DMT1 is a novel marker of QN resistance and a new chromosome 12 locus associates with CQ and QN response, with ftsh1 is a potential candidate, suggesting these genes should be genotyped in surveillance and clinical settings.

385 (PB373): Relative levels of IQGAP1 and IQGAP2: Modulator of stemness, resistance and relapse dynamics in breast cancer

385 (PB373): Relative levels of IQGAP1 and IQGAP2: Modulator of stemness, resistance and relapse dynamics in breast cancer

Выбор сопротивления нагрузки приемной электрически малой антенны по критерию минимальной неравномерности группового времени запаздывания принятого сигнала

The accuracy of determining coordinates in terrestrial radio navigation systems (RNS) depends on the receiving antenna frequency response irregularity: received signal power and group delay time (GD). Due to the limited space on the carrier, the RNS receiving antennas are small and cannot be effectively matched with feeder over the entire operating frequency band. The paper considers two options for the RNS receiver input circuit. First is a classical matching scheme and second is direct connection of the antenna to the receiver input. It is shown that the most uniform frequency characteristics are achieved when the antenna is connected directly to reciever. In this case, the maximum received signal power occurs when the antenna input resistance module and the load resistance are equal. At the same time, high load resistance increases the frequency response irregularity. Therefore, the choice of load resistance should be made compromising manner, taking into account signal level, available input amplifier gain and the allowed frequency response irregularity.

Sign To Speech Conversion And Home Automation Control Using Smart Gloves

In today's world, there are many new technologies changing the way we do things. One interesting technology is the home automation system. It helps people control things in their homes from far away, making life more comfortable, saving money, and being easy to use. But some people find it a bit tricky to use these systems well. To make it simpler for everyone, we can use something called a flex sensor-based home automation system. This system lets you control things by moving your hands, which is really helpful for older people or those who might find it a bit hard to move. It's also great for people who haven't had much learning. And if we add voice help, it becomes even easier. This way, people who are in bed or dealing with physical problems can use it too. This makes technology not just cool but helpful for everyone in different situations. In this paper, we explore the integration of flex sensors onto hand gloves to facilitate a dynamic interaction between hand movements and technological outputs. The flex sensors, akin to miniature potentiometers, are strategically affixed to the fingers, registering changes in value corresponding to the bending action. As the finger bends, the sensor's resistance alters, influencing the output in an inversely proportional manner. This innovative system allows for nuanced control, where specific angles of finger bending lead to calibrated adjustments in output, demonstrating a responsive and intuitive interface between human gestures and technology. The implementation of flex sensor- based gloves introduces a versatile means of capturing and translating hand movements into actionable data. The project leverages the concept of resistance modulation to precisely interpret the degree of finger bending, creating a reliable framework for diverse applications such as gesturecontrolled devices or assistive technologies for individuals with limited mobility. The abstracted communication between human hand gestures and technology opens avenues for accessible and intuitive interfaces, promising potential applications across various domains.

Engineering quorum sensing-based genetic circuits enhances growth and productivity robustness of industrial E. coli at low pH

BackgroundMicrobial organisms hold significant potential for converting renewable substrates into valuable chemicals. Low pH fermentation in industrial settings offers key advantages, including reduced neutralizer usage and decreased wastewater generation, particularly in the production of amino acids and organic acids. Engineering acid-tolerant strains represents a viable strategy to enhance productivity in acidic environments. Synthetic biology provides dynamic regulatory tools, such as gene circuits, facilitating precise expression of acid resistance (AR) modules in a just-in-time and just-enough manner.ResultsIn this study, we aimed to enhance the robustness and productivity of Escherichia coli, a workhorse for amino acid and organic acid production, in industrial fermentation under mild acidic conditions. We employed an Esa-type quorum sensing circuit to dynamically regulate the expression of an AR module (DsrA-Hfq) in a just-in-time and just-enough manner. Through careful engineering of the critical promoter PesaS and stepwise evaluation, we developed an optimal Esa-PBD(L) circuit that conferred upon an industrial E. coli strain SCEcL3 comparable lysine productivity and enhanced yield at pH 5.5 compared to the parent strain at pH 6.8.ConclusionsThis study exemplifies the practical application of gene circuits in industrial environments, which present challenges far beyond those of well-controlled laboratory conditions.

Synthesis of composite coatings based on Mg and Ti oxides by PEO for modulation of Mg corrosion resistance

In this study, the application of Plasma Electrolytic Oxidation (PEO) technique was investigated for fabricating composite coatings on magnesium (Mg) substrates aimed at modulating their corrosion resistance, an important characteristic for biodegradable orthopedic implants. The coatings were manufactured using an electrolytic solution containing MgO and TiO2 oxides, varying mass ratios, at currents of 30 mA and 200 mA. X-ray diffraction patterns confirmed the presence of TiO2 and MgO phases in the coatings, demonstrating the PEO capability to modulate the chemical composition by adjusting the mass ratio of oxides in the electrolytic solution. Microstructural analysis revealed decreased surface roughness with increasing TiO2 concentration. Corrosion tests indicated a significant improvement in corrosion resistance for all coatings compared to uncoated Mg substrate. In particularly, coatings with higher TiO2 concentrations, and those applied at a current density of 30 mA exhibited, enhanced corrosion resistance.

Chemical Profile, Antioxidant and Antimicrobial Activity of Marine Sponge Species Combined with Multivariate Statistical Analyses: Desmapsamma anchorata, Dysidea etheria and Echinodictyum dendroides.

Marine sponges are sources of bioactive compounds, sparking pharmacological interest. This study aimed to evaluate the chemical profile, antioxidant, and antibacterial activities of the species Desmapsamma anchorata, Dysidea etheria, and Echinodictyum dendroides. The chemical profile was characterized by the identification and quantification of polyphenols. Antioxidant activity was assessed using different methods. Antibacterial and modulatory activities were evaluated through microdilution against pathogenic strains. The polyphenols were found in low abundance in the extracts. In the antioxidant assays, the EACDa and EMDa extracts exhibited better inhibitory results. In the antibacterial evaluation, extracts presented MIC ≥ 1024 µg mL-1. The modulation of the extracts in combination with antibiotics showed significant effects against the multiresistant bacterium Pseudomonas aeruginosa. This study contributes to the deepening of chemical and biological knowledge of sponge species, indicating that their extracts can act as good modulators of bacterial resistance to aminoglycoside antibiotics, warranting further investigation into their mechanisms of action.

Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy

Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.

Zeaxanthin and Lutein Ameliorate Alzheimer's Disease-like Pathology: Modulation of Insulin Resistance, Neuroinflammation, and Acetylcholinesterase Activity in an Amyloid-β Rat Model.

Alzheimer's disease (AD) is characterized by impaired insulin/insulin-like growth factor-1 signaling in the hippocampus. Zeaxanthin and lutein, known for their antioxidant and anti-inflammatory properties, have been reported to protect against brain damage and cognitive decline. However, their mechanisms related to insulin signaling in AD remain unclear. This study investigated the efficacy and mechanisms of zeaxanthin, lutein, and resveratrol in modulating an AD-like pathology in an amyloid-β rat model. Rats were administered hippocampal infusions of 3.6 nmol/day amyloid-β (Aβ)(25-35) for 14 days to induce AD-like memory deficits (AD-CON). Normal control rats received Aβ(35-25) (Normal-CON). All rats had a high-fat diet. Daily, AD rats consumed 200 mg/kg body weight of zeaxanthin (AD-ZXT), lutein (AD-LTN), and resveratrol (AD-RVT; positive-control) or resistant dextrin as a placebo (AD-CON) for eight weeks. The AD-CON rats exhibited a higher Aβ deposition, attenuated hippocampal insulin signaling (reduced phosphorylation of protein kinase B [pAkt] and glycogen synthase kinase-3β [pGSK-3β]), increased neuroinflammation, elevated acetylcholinesterase activity, and memory deficits compared to the Normal-CON group. They also showed systemic insulin resistance and high hepatic glucose output. Zeaxanthin and lutein prevented memory impairment more effectively than the positive-control resveratrol by suppressing acetylcholinesterase activity, lipid peroxidation, and pro-inflammatory cytokines (TNF-α, IL-1β). They also potentiated hippocampal insulin signaling and increased brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CTNF) mRNA expression to levels comparable to the Normal-CON rats. Additionally, zeaxanthin and lutein improved glucose disposal, reduced hepatic glucose output, and normalized insulin secretion patterns. In conclusion, zeaxanthin and lutein supplementation at doses equivalent to 1.5-2.0 g daily in humans may have practical implications for preventing or slowing human AD progression by reducing neuroinflammation and maintaining systemic and central glucose homeostasis, showing promise even when compared to the established neuroprotective compound resveratrol. However, further clinical trials are needed to evaluate their efficacy and safety in human populations.