Search Results (258)

Simultaneously inhibiting beta-amyloid protein (Aβ) aggregation and reducing metal ion overload in the brain is a promising strategy for treating Alzheimer’s disease (AD). Aloe emodin (AE) is one of the major components of the traditional Chinese medicine rhubarb. Based on its reported pharmacological effects and its structural affinity for metal ions, this study aims to explore the potential of AE in improving AD pathology. Through the injection of Aβ or copper-Aβ complex in the bilateral hippocampus of rats, we constructed two kinds of nontransgenic animal models. Behavioral tests were used to evaluate cognitive impairment, and the effects of AE on neuronal damage and Aβ deposition were measured via Nissl staining and immunohistochemistry. Furthermore, we detected copper content in the serum and brain tissues as well as some biochemical indexes of Aβ cascade pathology in the brain tissues of model rats to explore the mechanism of action. AE treatment decreased copper accumulation and regulated Aβ metabolism in the brain of model rats, thereby improving Aβ deposition, memory impairment, hippocampal nerve cell damage, and related biochemical indicators. AE ameliorated the AD pathology of the model rats by targeting copper-induced Aβ toxicity, revealing a mechanism of action by which AE may exhibit good clinical efficacy in treating AD. Full article

Chagas disease is caused by the protozoan Trypanosoma cruzi, and its current treatment is limited to the use of two nitroderivatives, benznidazole (Bz) and nifurtimox; however, their toxicity often leads to discontinuation, justifying the search for new therapeutic options. The biological activity of quinones has long shown efficacy towards pathogenic microorganisms. In our previous investigations, two naphthoquinones combining ortho- and para-quinoidal moieties exhibited remarkable trypanocidal activity and presented low toxicity to host cells. Here, these two active compounds were further assessed. On trypomastigotes and epimastigotes, brominated (NQ1) and chlorinated (NQ2) nor-beta-lapachone-derived 1,2,3-triazoles were more active than Bz, presenting IC₅₀/24 h values in the range of 0.8 to 3.1 µM. NQ1-treated epimastigotes showed a mitochondrial impairment and reactive oxygen species (ROS) production under electron microscopy and flow cytometry. The in vitro evaluation of both combinations of compounds with Bz indicated an additive interaction. In vivo, oral treatment with NQ1 reduced parasitemia in an acute model, with no evidence of toxicity. The treatment also led to a reduction in myocarditis, decreasing the PR interval in electrocardiographic analysis and reversing the sinus bradycardia caused by infection. These data suggest that T. cruzi mitochondrion are part of the NQ1 mechanism of action. In vivo, this compound presented moderate trypanocidal and promising anti-inflammatory activity. Its combination with Bz could enhance current therapeutic protocols and should be better explored in the future. Full article

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterised by Amyloid-beta 42 (Aβ42) plaque accumulation and cognitive decline, with current treatments focused on symptomatic relief. Emerging therapeutics, such as dietary interventions, can modulate cognitive decline and delay AD progression. Our previous work in Drosophila melanogaster identified cell competition as a key mechanism that eliminates unfit neurons in an AD model, improving locomotion by removing the unfit neurons expressing flower^LoseB and ahuizotl (azot). Here, we explored how diet influences azot-dependent cell competition and locomotion in the AD model. Flies were fed with either a yeast-based diet (YBD) or a synthetic (SAA) diet for up to 28 days. In contrast to YBD, SAA delayed cell competition activation until day 21, coinciding with locomotion improvement and delayed Aβ formation. The overexpression of the human Flower (hFWE) isoforms in a Drosophila neuronal context revealed functional conservation: hFWE1 acted as the sole loser isoform, and hFWE2 as a winner isoform. With the YBD, forcing cell competition by expressing hFWE2 in the AD model led to an accumulation of unfit cells and promoted worse locomotion phenotypes over time compared to with the SAA diet. Our data highlights the complex interaction between diet, cell competition, and Aβ toxicity, offering new therapeutic insights. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington’s Disease (HD), share pathologic mechanisms including oxidative stress, mitochondrial dysfunction, and protein aggregation. However, they differ in age of onset and clinical progression. Emerging evidence highlights primary cilia (PC) as a key regulator of neuronal aging and the progression of these diseases. Dysfunctional PC may impair key signaling pathways, such as Sonic Hedgehog (Shh) and Wnt, promote oxidative stress, mitochondrial damage, and epigenetic instability. PC may also influence intercellular communication by regulating the biogenesis of exosomes and modulating tunneling nanotube (TNT) formation, both of which propagate toxic proteins between neurons. Mechanistically, the regulation of ciliary length is disrupted in AD, which leads to ciliary dysfunction that interferes with signaling pathways and promotes the aggregation of amyloid-beta. This amyloid-beta is then propagated through TNTs and exosomes, spreading neuronal damage. In PD, the accumulation of alpha-synuclein (α-syn) also impairs cilia function, thereby compromising the cell’s response to oxidative stress. This results in the formation of abnormal TNTs and defective exosome-mediated clearance, ultimately contributing to neurodegeneration. Similarly, the mutant huntingtin protein aggregates within primary cilia in HD, morphologically disrupting them by obstructing intraflagellar transport. Damaged cilia are also associated with increased TNT formation and the exosomal release of toxic proteins, which leads to mitochondrial and epigenetic instability, ultimately promoting neuronal aging. Together, targeting ciliary function and its downstream regulation of TNTs and exosomes may provide a novel approach for slowing or halting disease progression across neurodegenerative diseases. Full article

Neurodegenerative diseases (NDs) have emerged as a significant global health crisis, disproportionately affecting the aging population. As longevity increases, the incidence, healthcare costs, and caregiver burden associated with NDs are escalating at an alarming rate. As of recent data, NDs such as Alzheimer’s disease (AD) are not only significant health burdens but also reflect a complex interplay between socio-economic factors and healthcare systems worldwide. Gac fruit (Momordica cochinchinensis) is a rich source of bioactive compounds that has been used as food and traditional medicine. Gac fruit ameliorates memory deficits, enhances beta amyloid (Aβ)_1–42 clearance, and induces neurite outgrowth. In this study, we examined the anti-neurodegenerative and synaptic improvement effect of fresh gac fruit parts extracts (FGPEs) produced from different solvents. Results showed that the 80% ethanol extract of peel (PE-EtOH) and ethyl acetate extract of seed (SE-EtOAc) significantly protected HT-22 cells by attenuating Aβ-induced cell death, intracellular reactive oxygen species (ROS) production, mitochondrial dysfunction, and synaptic dysfunction. PE-EtOH protected synaptic functions by significantly increasing the postsynaptic density protein-95 (PSD-95) and reducing the neurexin 2 mRNA expression. In contrast, SE-EtOAc increased the PSD-95 and neurexin 3 and reduced the neurexin 2 expressions. These findings indicate that PE-EtOH and SE-EtOAc could have great potential in ameliorating Aβ-induced toxicity in an HT-22 cell model. Full article

Alzheimer’s disease (AD) is a worldwide problem due to the lack of effective therapy and accurate methods for timely diagnosis. The complexity of AD’s pathophysiology complicates the development of effective therapeutic agents, as most drugs act on only one therapeutic target, bypassing others. The design and development of multifunctional agents capable of altering metal ion-induced abnormalities, oxidative stress, and toxic beta amyloid (Aβ) aggregates is of interest. Herein, we report the first boron dipyrromethene (BODIPY) based bifunctional copper chelator with clioquinol, BDP-CLQ, capable of both optical detection of Aβ fibrils and copper chelation, with multiple anti-AD properties. Foremost, BDP-CLQ demonstrated a 3-fold and 5-fold fluorescence increase at 650 nm and 565 nm in the presence of Aβ and effective copper chelation (pK_d = 16.6 ± 0.3). In addition, BDP-CLQ demonstrated a potent inhibition of Aβ aggregation, reduction in Aβ-induced stiffness of neuronal cells, and antioxidant activity. BDP-CLQ is the first BODIPY-based fluorescent probe with multiple anti-AD activities, as well as the first clioquinol-based probe capable of Aβ optical visualization. This study demonstrates the prospects of the development of clioquinol-based theranostic probes since this allows combining several promising anti-AD actions in a single molecule and developing multi-targeted drugs. Full article

Scorpion venom toxins are important peptides being studied for their clinical significance. These peptides act by binding to ion channels in the membrane of nerve cells, causing the symptoms associated with scorpion stings (scorpionism). They principally affect the function of voltage-gated sodium channels (Nav) and are valuable for studying ion channels. Scorpions from the Buthidae family contain toxins that affect sodium channels and have a high affinity for mammalian channels. In this study, two sodium toxins isolated from the venom of the scorpion Centruroides hirsutipalpus, a member of the Buthidae family, were identified as belonging to the beta-type subfamily. These toxins were purified from whole venom using molecular exclusion, cationic-exchange, and reverse-phase chromatography techniques. Their molecular masses were determined using mass spectrometry, while their amino acid sequences were obtained by Edman degradation. A comparative analysis revealed that the sequences are identical to ChiNaBet60 and ChiNaBet50 toxins (now named Chirp7 and Chirp9, respectively) previously identified in the venom gland transcriptomics from C. hirsutipalpus. Furthermore, toxicity studies showed that these toxins were lethal to mammals. Electrophysiological analysis revealed that these peptides act as sodium channel–modulating toxins. In addition, interaction assays with antibodies were performed to analyze the structural determinants governing the binding mechanism. Full article

Background: Inflammatory bowel diseases include Crohn’s disease (CD) and ulcerative colitis (UC). These diseases are characterized by periods of exacerbated inflammation of the gastrointestinal mucosa, interspersed with periods of remission. Current pharmacological interventions are only partially effective. There is a need for effective dietary therapies and interventions involving plant substances that can alleviate the course of this disease. Objectives: This study aimed to determine the effects of a 28-day dietary intervention involving a 3% solution of chemically pure, low-molar-mass oat beta-glucan (OBG) in patients diagnosed with de novo UC. Similar-aged men and women were compared. Methods: The OBG was isolated and prepared for consumption as a sterile aqueous suspension. This solution had previously been evaluated for in vitro toxicity using 3D intestinal co-cultures comprising Caco-2, HT29-MTX and THP-1 cells. Before and after the dietary intervention, endoscopic colon examinations were performed and blood hematological, biochemical and immunological parameters, as well as stool calprotectin concentrations, were analyzed. The Disease Activity Index (DAI), endoscopic Mayo score, the Lichtiger Colitis Activity Index (LCAI) and the neutrophil-to-lymphocyte ratio (NLR) were also determined. Following dietary intervention, the Mayo score, DAI, fecal calprotectin levels, and indices of peripheral blood white cells, CRP, and pro-inflammatory cytokine concentrations were decreased. Results/Conclusions: The obtained results demonstrated the beneficial effect of dietary intervention with OBG in accelerating the achievement of clinical remission in patients with UC. Full article

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, characterised by the build-up of amyloid beta (Aβ) plaques and neurofibrillary tangles comprising hyper-phosphorylated tau. Increasing evidence indicates that in the early stages of AD, elevated levels of oligomeric forms of Aβ and phosphorylated tau (p-tau) gives rise to impaired synaptic function which ultimately drives AD-associated cognitive abnormalities. Thus, developing drugs that can limit the synaptic impairments that occur early in AD may have therapeutic benefits. Clinical evidence increasingly supports a link between lifestyle choices and AD risk. Indeed, there is an association between the circulating levels of the metabolic hormone leptin, mid-life obesity and disease risk, which has in turn stimulated interest in targeting the leptin system to treat AD. It is well-established that leptin readily accesses the brain, with the hippocampus, a key region that degenerates in AD, identified as a prime target for this hormone. Within the hippocampus, leptin has cognitive enhancing properties as it markedly influences the cellular events underlying hippocampal-dependent learning and memory, with significant impact on synaptic plasticity and trafficking of glutamate receptors at hippocampal excitatory CA1 synapses. Moreover, studies using a range of cell-based systems and animal models of disease indicate not only that leptin has powerful pro-cognitive effects, but also that leptin protects against the unwanted synapto-toxic effects of Aβ and tau, as well as enhancing neuronal cell viability. Moreover, recent studies have demonstrated that smaller leptin-based molecules replicate the full repertoire of protective features of whole leptin. Here we review the evidence that the leptin system is a potential novel avenue for drug discovery in AD. Full article

Alzheimer’s disease is characterized by the accumulation of neurotoxic forms of amyloid-beta (Aβ) in the brain, leading to synaptic dysfunction, neuroinflammation, and neuronal death. The tetrapeptide HAEE crosses the blood–brain barrier (BBB), inhibits the formation of toxic Aβ oligomers, and reduces amyloid burden in vivo. However, the mechanisms of HAEE’s anti-amyloidogenic effect remained incompletely understood. In this study, we investigated the mechanism of HAEE-dependent Aβ clearance both in vitro and in vivo. Using ELISA, we assessed the HAEE effect on the levels of Aβ, IL-6, and TNFα in mouse brain tissue following intracerebroventricular administration. The mechanism of the anti-Aβ effect of HAEE was studied using primary brain cell cultures and a BBB transwell model through ELISA, flow cytometry, and microscopy. We showed that HAEE reduced Aβ level by 35% and IL-6 level by 40% in mouse brain tissue. HAEE enhanced Aβ clearance via LRP1- and PgP-dependent Aβ transport through the BBB and doubled the rate of Aβ degradation by microglia. In addition to inhibition of Aβ aggregation, HAEE dissolved already formed Aβ oligomers. The HAEE-induced decrease in IL-6 levels in the mouse brain was associated with reduced pro-inflammatory activation of microglia. Thus, HAEE’s effect against Aβ-related neuropathologies is realized through a decrease in the level of toxic Aβ oligomer and inhibition of neuroinflammation. Full article

Biosurfactants are environmentally friendly alternatives for chemical surfactants and have a broad spectrum of applications in different industries such as cosmetics, oleochemistry, pharmaceuticals, and detergents. It has been established that Bacillus licheniformis produces several lipopeptide-type biosurfactants, including lichenysin and iturin. However, in order to enhance the biosurfactant production by Bacillus licheniformis, it is necessary to either extend the already performed media optimization to circumvent the current limitations or defeat the product inhibition. Cyclic oligosaccharides made of glucose monomers called cyclodextrins (CD) have been shown to improve the biomass synthesis of other microorganisms, which may also increase the output of biosurfactants. The efficient fermentative production of biosurfactants is often limited by the inhibitory/toxic effect of the product on the producer cells itself. Therefore, in this work, we demonstrated that CDs may entrap biosurfactants from the broth, decreasing product inhibition. Thus, we also tested the media supplementation with three different types of cyclodextrins including alpha-, beta-, and gamma-CD and a derivative (dimethyl-beta-cyclodextrin, DIMEB); notably, DIMEB at 2.0 g/L enhanced biosurfactant production by up to 41.43% and specific product formation (g product/g cells) by 79,6% compared to the control, while mitigating the growth inhibition observed at lower concentrations. This study demonstrates, for the first time, the distinct advantage of DIMEB over native CDs in reducing product toxicity and boosting biosurfactant yields, highlighting its potential as a simple additive strategy for improving sustainable bioprocesses. Full article

In the context of multi-organ involvement in sepsis, cardiac toxicity is manifested as sepsis-induced cardiomyopathy (SICM). To date, no unified SICM definition exists, though a left ventricular ejection fraction ≤ 50% and/or an absolute drop ≥ 10% from baseline are the most widely accepted components. Several molecular pathways have been associated with SICM, including (i) pro-inflammatory mediator-induced cardiac depression; (ii) sarcolemmal membrane dysfunction; (iii) autonomic nervous system (ANS) imbalance; (iv) blunted cardiovascular response to catecholamines; (v) dysfunctional intracellular calcium handling; (vi) mitochondrial dysfunction; (vii) metabolic reprogramming; and (viii) disturbed endothelial and microcirculatory function. Atrial and ventricular arrhythmias—particularly atrial fibrillation—commonly complicate disease management and are associated with adverse outcomes. Key mechanisms outlining sepsis-induced arrhythmogenesis are (i) inflammation; (ii) electrolyte imbalances; (iii) myocardial ischemia; (iv) QT prolongation/dispersion; (v) adrenergic overactivation; (vi) calcium mishandling; and (vii) fever-induced arrhythmogenesis in Brugada. Established therapeutic approaches include prompt treatment with antibiotics, hemodynamic optimization, and/or selective use of beta-blockers. Furthermore, several molecules are currently being investigated targeting numerous pathways activated in sepsis. Vitamin C, ginsenoside Rc, Schistosoma Japonicum cystatin, and gasmerdin-D inhibitor Y2 exert anti-inflammatory actions, while melatonin and α-ketoglutarate regulate mitochondrial homeostasis. Triiodothyronine targets microcirculatory optimization and regulates protective pathways against stress-related cell death. Engineered exosomes may facilitate targeted drug delivery, inflammatory response modulation, and activation of pathways related to cell survival, while sodium octanoate exhibits anti-inflammatory actions coupled with improved energy metabolism. Finally, gene-regulating therapies aiming at inflammatory response optimization have also been proposed and are currently under development. Future research should aim to standardize the SICM definition, translate emerging therapeutics into clinical practice, identify novel molecular targets, and implement personalized treatment strategies for SICM. Full article

Sugar beet (Beta vulgaris L.) is very sensitive to fluctuations in micronutrient availability, and either an excess or a shortage of boron (B) may reduce the plant’s development and its ability to withstand stress. B is essential for photosynthesis and cell wall integrity, but the physiological requirements for an optimal supply during early development remain unclear. The photosynthetic efficiency and oxidative stress reactions of sugar beet seedlings were tested under five different B concentrations: 0, 50, 500, 1000, and 2000 µM H₃BO₃. Integrating non-invasive methods like SPAD, delayed fluorescence (DF), and maximum quantum efficiency of PSII (Fv/Fm) with red–green–blue (RGB) imaging enabled the detailed processing of both the initial and decay phases of DF. According to the results, SPAD and Fv/Fm were not sensitive indicators of early B stress; however, DF decay slopes and red–green–blue pixel distribution distinguished between optimum (500 µM), inadequate (0 µM), and hazardous (2000 µM) treatments. Moreover, lipid oxidation-related biochemical analyses were used to evaluate the ferric reducing antioxidant capacity (FRAP) and malondialdehyde (MDA) concentration. At the extremes of insufficiency and toxicity, MDA levels demonstrated enhanced lipid peroxidation, while FRAP increased with B concentration. The outcome of the research revealed optimum (500 µM) and toxicity-inducing (2000 µM) concentrations at early stages of sugar beet development. The study highlights that the combined use of DF kinetics and RGB analysis provides valuable, non-invasive markers for the early identification of B-stress, which is also confirmed by biochemical indicators, thereby promoting more efficient micronutrient management in sugar beet cultivation. Full article

Today, science and medicine are striving to develop novel techniques for treating deadly diseases, including a wide range of cancers. Efforts are being made to better understand the molecular and biochemical mechanisms of tumor cell functioning, but a particular emphasis has recently been given to investigating immune cells residing in the tumor microenvironment, which may lead to revolutionary benefits in the design of new immunotherapies. Among these cells, tumor-associated macrophages (TAMs) are highly abundant and act as critical regulators of ovarian cancer progression, metastasis, and resistance to therapy. Their dual nature—as drivers of malignancy and as potential therapeutic mediators—has positioned them at the forefront of research into next-generation immunotherapies. As therapeutic targets, approaches include blocking macrophage recruitment (e.g., CSF-1/CSF-1R inhibitors), selectively depleting subsets of TAMs (e.g., via Folate Receptor Beta), or reprogramming immunosuppressive M2-like macrophages toward an anti-tumor M1 phenotype. On the other hand, macrophages can also serve as a therapeutic tool—they may be engineered to enhance anti-tumor immunity, as exemplified by the development of Chimeric Antigen Receptor Macrophages (CAR-Ms), or leveraged as delivery vehicles for targeted drug transport into the tumor microenvironment. A particularly innovative strategy involves Macrophage–Drug Conjugates (MDCs), which employs the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular delivery of therapeutic agents, thereby enhancing drug efficacy while minimizing systemic toxicity. This review integrates current knowledge of TAM biology, highlights emerging therapeutic approaches, and underscores the promise of macrophage-based interventions in ovarian cancer. By integrating macrophage-targeting strategies with advanced immunotherapeutic platforms, novel treatment paradigms may be determined that could substantially improve outcomes for patients with ovarian cancer and other solid tumors. Our work highlights that macrophages should be a particular area of research interest in the context of cancer treatment. Full article

The Sarco Endoplasmic Reticulum Ca²⁺-ATPase (SERCA) pumps cytosolic Ca²⁺ into the endoplasmic reticulum lumen (ER) to maintain cytosolic and ER Ca²⁺ levels under physiological conditions. Previous reports suggest that cellular Ca²⁺ homeostasis is compromised in Alzheimer’s Disease (AD) and that SERCA activity can modulate the phenotype of AD mouse models. Here, we used a C. elegans strain that overexpresses the most toxic human ß-amyloid peptide (Aß_(1-42)) in body-wall muscle cells to study the effects of SERCA (sca-1) silencing on Aß_(1-42)-induced body-wall muscle dysfunction. sca-1 knockdown reduced the percentage of paralyzed worms, improved locomotion in free-mobility assays, and restored pharynx pumping in Aß_(1-42)-overexpressing worms. At the cellular level, sca-1 silencing partially prevented Aß_(1-42)-induced exacerbated mitochondrial respiration and mitochondrial ROS production and restored mitochondrial organization around sarcomeres. sca-1 knockdown reduced the number and size of Aß_(1-42) aggregates in body–wall muscle cells and prevented the formation of Aß_(1-42) oligomers. Aß_(1-42) expression induced a slower kinetics of spontaneous cytosolic Ca²⁺ transients in muscle cells and sca-1 partially restored these changes. We propose that partial sca-1 loss of function prevents the toxicity associated with beta-amyloid accumulation by reducing the formation of Aß_(1-42) oligomers and improving mitochondrial function, in a mechanism that requires remodeling of cytosolic Ca²⁺ dynamics and partial ER Ca²⁺ depletion. Full article