Exogenous Adenosine Modulates Behaviors and Stress Response in Caenorhabditis elegans.

Adenosine, a purine nucleoside with neuromodulatory actions, is part of the purinergic signaling system (PSS). Caenorhabditis elegans is a free-living nematode found in soil, used in biological research for its advantages as an alternative experimental model. Since there is a lack of evidence of adenosine's direct actions and the PSS's participation in this animal, such an investigation is necessary. In this research, we aimed to test the effects of acute and chronic adenosine at 1, 5, and 10 mM on nematode's behaviors, morphology, survival after stress conditions, and on pathways related to the response to oxidative stress (DAF-16/FOXO and SKN-1) and genes products downstream these pathways (SOD-3, HSP-16.2, and GCS-1). Acute or chronic adenosine did not alter the worms' morphology analyzed by the worms' length, width, and area, nor interfered with reproductive behavior. On the other hand, acute and chronic adenosine modulated the defecation rate, pharyngeal pumping rate, and locomotion, in addition, to interacting with stress response pathways in C. elegans. Adenosine interfered in the speed and mobility of the worms analyzed. In addition, both acute and chronic adenosine presented modulatory effects on oxidative stress response signaling. Acute adenosine prevented the heat-induced-increase of DAF-16 activation and SOD-3 levels, while chronic adenosine per se induced DAF-16 activation and prevented heat-induced-increase of HSP-16.2 and SKN-1 levels. Together, these results indicate that exogenous adenosine has physiological and biochemical effects on C. elegans and describes possible purinergic signaling in worms.

Neuroprotective effects of rutin on ASH neurons in Caenorhabditis elegans model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disease. It occurs due to a mutated huntingtin gene that contains an abnormal expansion of cytosine-adenine-guanine repeats, leading to a variable-length N-terminal polyglutamine (polyQ) chain. The mutation confers toxic functions to mutant huntingtin protein, causing neurodegeneration. Rutin is a flavonoid found in various plants, such as buckwheat, some teas, and apples. Our previous studies have indicated that rutin has protective effects in HD models, but more studies are needed to unravel its effects on protein homeostasis, and to discern the underlying mechanisms. In the present study, we investigated the effects of rutin in a Caenorhabditis elegans model of HD, focusing on ASH neurons and antioxidant defense. We tested behavioral changes (touch response, movement, and octanol response), measured neuronal polyQ aggregates, and assessed degeneration using a dye-filling assay. In addition, we analyzed expression levels of heat-shock protein-16.2 and superoxide dismutase-3. Overall, our data demonstrate that chronic rutin treatment maintains the function of ASH neurons, and decreases the degeneration of their sensory terminations. We propose that rutin does so in a mechanism that involves antioxidant activity by controlling the expression of antioxidant enzymes and other chaperones regulating proteostasis. Our findings provide new evidence of rutin's potential neuroprotective role in the C. elegans model and should inform treatment strategies for neurodegenerative diseases and other diseases caused by age-related protein aggregation.

Ilex paraguariensis extract provides increased resistance against oxidative stress and protection against Amyloid beta-induced toxicity compared to caffeine in Caenorhabditis elegans.

Ilex paraguariensis is a plant from South America, used to prepare a tea-like beverage rich in caffeine and polyphenols with antioxidant proprieties. Caffeine consumption is associated with a lower risk of age-associated neuropathologies, besides several extracts that have antioxidant proprieties are known to be neuroprotective, and oxidative stress strongly correlates with Aß-toxicity. This study aims to investigate the neuroprotective effects of the Ilex paraguariensis hydroalcoholic extract (IPHE) and to evaluate if caffeine agent present in IPHE exerts neuroprotective effects in an amyloid beta-peptide (Aß)-induced toxicity in Caenorhabditis elegans. The wild-type and CL2006 worms were treated with IPHE (2 and 4 mg/mL) or caffeine (200 and 400 µM) since larval stage 1 (L1) until they achieved the required age for each assay. IPHE and caffeine increased the lifespan and appeared to act directly by reactive oxygen species (ROS) scavenger in both wild-type and CL2006 worms, also conferred resistance against oxidative stress in wild-type animals. Furthermore, both treatments delayed Aß-induced paralysis and decreased AChE activity in CL2006. The protective effect of IPHE against Aß-induced paralysis was found to be dependent on heat shock factor hsf-1 and FOXO-family transcription factor daf-16, which are respectively involved in aging-related processes and chaperone synthesis, while that of caffeine was dependent only on daf-16. Mechanistically, IPHE and caffeine decreased the levels of Aß mRNA in the CL2006 worms; however, only IPHE induced expression of the heat shock chaperonin hsp-16.2, involved in protein homeostasis. The results were overall better when treated with IPHE than with caffeine.

The insertion of functional groups in organic selenium compounds promote changes in mitochondrial parameters and raise the antibacterial activity.

Organic selenium compounds are widely associated with numerous pharmacological properties. However, selenium compounds, such as Ebselen (Ebs) and Diphenyl Diselenide (DPDS), could interact with mitochondrial respiratory complexes, especially with thiol groups. The present study evaluated whether the insertion of functional groups, o-methoxy, and p-methyl on organic selenium compounds promotes changes in mitochondrial functioning parameters and whether this is related to antibacterial activity. Here we tested some in vitro parameters after the exposure of mitochondria to different concentrations of ß-selenoamines 1-phenyl-3-(p-tolylselanyl)propan-2-amine (C1) and 1-(2-methoxyphenylselanyl)-3-phenylpropan-2-amine (C2) and analogs of DPDS 1,2-bis(2-methoxyphenyl)diselenide (C3) and 1,2-bisp-tolyldiselenide (C4). We also evaluated the antibacterial activity of ß-selenoamines and diselenides against Methicillin-resistant Staphylococcus aureus and Escherichia coli. Our results showed that o-methoxy insertion increased the antioxidant properties, without affecting the mitochondrial membrane potential. The compounds with a p-methyl insertion affected the mitochondrial membrane potential and significantly decreased the State III respiration and RCR. Besides, the p-methyl compounds presented antibacterial activity at lower concentrations than those shown in o-methoxy, precisely by the same mechanism that promotes damage to thiol groups and better absorption in gram-positive bacteria due to their relationship with cell wall constituents. Finally, our study confirms that structural modifications in organic selenium compounds provide changes in mitochondrial functioning but also raise their antibacterial effect. This strategy can be used as a target for the development of new enough potent antibacterial to restrict the advance of resistant bacterial infections.

Guarana (Paullinia cupana Mart.) protects against amyloid-ß toxicity in Caenorhabditis elegans through heat shock protein response activation.

Alzheimer disease (AD) is a progressive neurodegenerative brain disorder that causes significant disruption in normal brain functioning, representing the most common cause of dementia in the elderly. The main hallmark of AD is the presence of amyloid plaques in the brain formed by the deposition of insoluble amyloid protein (Aß) outside of neurons. Despite intensive investigation of the mechanisms of AD pathogenesis during the past three decades, little has been achieved in terms of effective treatments or ways to prevent the disease. Paullinia cupana, known as guarana, is a plant endemic to the Amazon region in Brazil with several beneficial effects reported, including delayed aging. In this study, we investigated the effects of chronic consumption of guarana ethanolic extract (GEE) on Aß toxicity using a C. elegans model of AD. We analyzed the behavioral phenotype, oxidative damage and Aß protein expression in worms treated with GEE. In addition, we investigated the possible role of the heat shock response on the beneficial effects induced by GEE. Overall, our data demonstrate that chronic GEE treatment decreased the formation of Aß aggregates in C. elegans, preventing the behavioral deficits and the oxidative damage inducible by Aß expression, due to activation of the heat shock protein (HSP) response. This finding provides a new alternative against amyloidogenic neurodegenerative diseases and other diseases caused by protein accumulation during aging.

Combined platelet-rich plasma and cold water immersion treatment minimize the damage following a skeletal muscle stretch injury in rats.

The skeletal muscle stretch injuries are commonly observed in sports. In order to stimulate tissue healing, the platelet-rich plasma (PRP) and cold water immersion (CWI) are widely used in clinical practice. This study investigated the effects of isolated or combined PRP and/or CWI on the oxidative damage determined by a stretch injury induced in gastrocnemius muscle of rats. PRP and CWI are applied immediately after the injury, and the biochemical analysis was performed after 1, 3, 5, or 7 days. The levels of o thiobarbituric acid reactive substances and oxidized dichlorofluorescein were significantly increased, both in skeletal muscle tissue and erythrocytes preparations, and the combined PRP and CWI minimized these parameters. Moreover, combined PRP and CWI were more effective than the isolated treatments to increase catalase activity, also the ratio of reduced/oxidized glutathione, and the non-protein thiols (-SH) group levels. In conclusion, we could infer that the combination of these regular treatments used in an isolated form shows a great potential for treatments of muscular injuries.

Diclofenac attenuates inflammation through TLR4 pathway and improves exercise performance after exhaustive swimming.

BACKGROUND: The use of NSAIDs has become a common practice to counteract the pro-inflammatory acute effects of exercise, in order to improve sports performance. The liver, due to its central role in energy metabolism, may be involved primarily in the process of ROS generation and consequently inflammation after exhaustive exercise. OBJECTIVE: To analyze the influence of diclofenac on the liver TLR4 pathway and time to exhaustion in rats submitted to repeated exhaustive swimming. METHODS: An exhaustive test was performed in order to mimic athletes' routine, and inflammatory status and oxidative stress markers were evaluated in the liver. Animals were divided into sedentary and exhaustion groups, with this last performing three exhaustive swimming bouts. At the same time, diclofenac or saline was pre-administered once a day for nine days. RESULTS: Data showed significantly increased COX-2, TLR4, and MyD88 protein content in the liver after exhaustive swimming bouts. The levels of pro-inflammatory cytokines also increased after exhaustive exercise, while these effects were attenuated in the group treated with diclofenac plus exhaustive swimming bouts. The anti-inflammatory modulation provoked by diclofenac treatment was associated with an increased time to exhaustion in the exercise bouts. The exhaustive exercise increased TBARS formation, but diclofenac treatment blunted this elevation, while GSH/GSSG ratios in both exhaustion-saline and exhaustion-diclofenac-treated groups were lower than in the sedentary-saline group. CONCLUSIONS: Our findings suggest that diclofenac may improve exercise performance and represent an effective tool to ameliorate the pro-inflammatory status in liver when associated with exhaustive exercise, and the liver may be a possible therapeutic target.

Role of Astrocytes in Manganese Neurotoxicity Revisited.

Manganese (Mn) overexposure is a public health concern due to its widespread industrial usage and the risk for environmental contamination. The clinical symptoms of Mn neurotoxicity, or manganism, share several pathological features of Parkinson's disease (PD). Biologically, Mn is an essential trace element, and Mn in the brain is preferentially localized in astrocytes. This review summarizes the role of astrocytes in Mn-induced neurotoxicity, specifically on the role of neurotransmitter recycling, neuroinflammation, and genetics. Mn overexposure can dysregulate astrocytic cycling of glutamine (Gln) and glutamate (Glu), which is the basis for Mn-induced excitotoxic neuronal injury. In addition, reactive astrocytes are important mediators of Mn-induced neuronal damage by potentiating neuroinflammation. Genetic studies, including those with Caenorhabditis elegans (C. elegans) have uncovered several genes associated with Mn neurotoxicity. Though we have yet to fully understand the role of astrocytes in the pathologic changes characteristic of manganism, significant strides have been made over the last two decades in deciphering the role of astrocytes in Mn-induced neurotoxicity and neurodegeneration.

Ilex paraguariensis Attenuates Changes in Mortality, Behavioral and Biochemical Parameters Associated to Methyl Malonate or Malonate Exposure in Drosophila melanogaster.

Methylmalonic acidemia is a genetic disease characterized by accumulation of organic acids, such as methylmalonic (MMA) and malonic (MA) acids. Considering that the accumulation of MMA and MA causes several damages due to oxidative stress, antioxidants are thought to play a pivotal role in preventing deleterious effects associated with exposure to such compounds. Ilex paraguariensis (IP) was used here to test the hypothesis that supplementation with the aqueous extract of this plant could exert protective effect against MMA or MA induced mortality, behavioral and/or biochemical changes in Drosophila melanogaster (DM). Initially, a curve time- and dose-response to MMA (1-10 mM), MA (1-10 mM) and IP (63-500 µM) was performed. Thereafter, flies were concomitantly exposed to MA (5 mM), MMA (5 mM) and/or IP (250 µg/mL) during 15 days for survival assay, and for 48 hs to MA (1 or 5 mM), MMA (1 or 5 mM) and/or IP (250 µg/mL) for subsequent investigations. Both MMA and MA exposure resulted in higher incidence of mortality, a worse performance in the negative geotaxis assay and increased locomotion in open-field test as compared with control group. Furthermore, a marked increase in non-protein thiol (NPSH) and in thiobarbituric acid reactive substances (TBARS) levels, decrease in superoxide dismutase (SOD), catalase and acetylcholinesterase (AChE) activities, and decrease in MTT and resazurin reduction were noted in MMA or MA treated groups. IP treatment offered significant protection against all alterations associated to MMA or MA exposure. This study confirm the hypothesis that supplementation with IP offers protection against changes associated to MMA or MA exposure in DM, due, at least in part, to its antioxidant effect.

Molecular docking, and anti-biofilm activity of gold-complexed sulfonamides on Pseudomonas aeruginosa.

The antibacterial activity of sulfadiazine Au-PPh3, sulfadiazine Ph2P-Au-Au-PPh2, sulfamethoxazole Au-PPh3, sulfamethoxazole Ph2P-Au-Au-PPh2, sulfamethoxazole Au-PPh3 were tested against Pseudomonas aeruginosa. The antibacterial activity of sulfonamide was tested against P. aeruginosa through the MIC assay, quantitative analysis of biofilm inhibition and observation of biofilm formation with fluorescence microscopy. Besides, the compounds presented remarkable inhibition of P. aeruginosa biofilm formation. Furthermore, molecular docking was performed to identify the key structural features of these compounds with the binding site of the LasR receptor.

The antibacterial and anti-biofilm activity of gold-complexed sulfonamides against methicillin-resistant Staphylococcus aureus.

The drug-resistant strains of Staphylococcus aureus have been considered as one of the serious health threats, which are related to high patient hospitalization rates. Besides, Staphylococcus aureus biofilm formation exhibits a drug-tolerant nature and shows nonspecific resistance against a broad-spectrum of antibiotics. The emergence of drug-resistant bacteria stimulated the development of novel medicines as a strategy to control infections. In this study, we evaluated the antibacterial and anti-biofilm activity of gold-complexed sulfonamides against Staphylococcus aureus strains such as methicillin-resistant S. aureus and clinical isolates. Our data showed that the exposure of gold-complexed sulfonamides promoted a remarkable reduction in the bacterial adhesion. Also, confocal microscopy displayed the effects of the compounds on in the bacterial cell biofilm, revealed that the compounds decreased the biofilm formation. Our results also demonstrated that gold-complexed sulfonamides exhibited potent antibacterial activity against Staphylococcus aureus strains. Besides, all compounds presented a synergic antibacterial activity when were associated with classical antibiotics. Gold-complexed sulfonamide compounds did not promote toxic effects on Caenorhabditis elegans. Thus, our results showed that the coordination of sulfonamide with gold is a promising alternative in the development of safe and active compounds against methicillin-resistant and clinical isolates S. aureus.

Antioxidant protection by ß-selenoamines against thioacetamide-induced oxidative stress and hepatotoxicity in mice.

Thioacetamide (TAA) is a hepatotoxin that rapidly triggers the necrotic process and oxidative stress in the liver. Nevertheless, organic selenium compounds, such as ß-selenoamines, can be used as pharmacological agents to diminish the oxidative damage. Thus, the aim of this study was to investigate the protective effect of the antioxidant ß-selenoamines on TAA-induced oxidative stress in mice. Here, we observed that a single intraperitoneal injection of TAA (200 mg/kg) dramatically elevated some parameters of oxidative stress, such as lipid peroxidation and reactive oxygen species (ROS) production, as well as depleted cellular antioxidant defenses. In addition, TAA-induced edema and morphological changes in the liver, which correlate with high serum aspartate and alanine aminotransferase enzyme activities, and a decrease in cell viability. Conversely, a significant reduction in liver lipid peroxidation, ROS production, and edema was observed in animals that received an intraperitoneal injection of ß-selenoamines (15.6 mg/kg) 1 h after TAA administration.

Functional and biochemical adaptations of elite level futsal players from Brazil along a training season.

BACKGROUND AND OBJECTIVE: Although hard training is mandatory in elite level futsal training, few studies have proposed a biochemical follow up in futsal players during a whole season. Therefore, the aim of this study was to compare functional and biochemical markers in Brazilian elite level futsal players throughout a competition season. MATERIALS AND METHODS: Eight players aged 25.5±5.4 years were evaluated at three time points: preseason (T1), immediately before the FIFA®-Intercontinental-Futsal-Cup (T2), and at the end of the season (T3), with a tapering period of 1 week before T2. Functional parameters (weight, height, body fat, VO2max, heart rate, and distance ran) and blood sampling for cell count and lipid profile (cholesterol, HDL-C, LDL-C, triglycerides) were assessed at each time point. After, a Yo-Yo R2 test was carried out in each time point (T1, T2 and T3) and blood samples to assess skeletal muscle damage (creatine kinase [CK], lactate dehydrogenase [LDH]), inflammation (C-reactive protein [CRP]) and oxidative stress markers (ischemia modified albumin [IMA], and advanced oxidation protein products [AOPP]) were obtained before and after the tests. RESULTS: Although functional parameters did not change throughout the season, greater total number of erythrocytes (P≤0.05), and hemoglobin (P≤0.05) were found at T2 compared to T1. Similarly, lower LDH (P≤0.05) and CK (P≤0.05) levels were found at T2 compared to T1. CPR levels were also decreased at T2 in comparison to T1 both before and after Yo-Yo R2 test (P≤0.05), while IMA and AOPP levels showed only a season effect (P≤0.05). CONCLUSIONS: The tapering strategy was successful considering players presented lower levels of muscle damage, inflammation and oxidative stress makers before T2, which preceded the main championship of the year. These results are of great relevance, considering the team won the FIFA®-Intercontinental-Futsal-Cup, which happened at T2. Thus, it seems that routine-based biochemical markers may be useful as training control means in this population.

A neuronal disruption in redox homeostasis elicited by ammonia alters the glycine/glutamate (GABA) cycle and contributes to MMA-induced excitability.

Hyperammonemia is a common finding in children with methylmalonic acidemia. However, its contribution to methylmalonate-induced excitotoxicty is poorly understood. The aim of this study was to evaluate the mechanisms by which ammonia influences in the neurotoxicity induced by methylmalonate (MMA) in mice. The effects of ammonium chloride (NH4Cl 3, 6, and 12 mmol/kg; s.c.) on electroencephalographic (EEG) and behavioral convulsions induced by MMA (0.3, 0.66, and 1 µmol/2 µL, i.c.v.) were observed in mice. After, ammonia, TNF-α, IL1ß, IL-6, nitrite/nitrate (NOx) levels, mitochondrial potential (ΔΨ), reactive oxygen species (ROS) generation, Methyl-Tetrazolium (MTT) reduction, succinate dehydrogenase (SDH), and Na(+), K(+)-ATPase activity levels were measured in the cerebral cortex. The binding of [(3)H]flunitrazepam, release of glutamate-GABA; glutamate decarboxylase (GAD) and glutamine synthetase (GS) activity and neuronal damage [opening of blood brain barrier (BBB) permeability and cellular death volume] were also measured. EEG recordings showed that an intermediate dose of NH4Cl (6 mmol/kg) increased the duration of convulsive episodes induced by MMA (0.66 µmol/2 µL i.c.v). NH4Cl (6 mmol/kg) administration also induced neuronal ammonia and NOx increase, as well as mitochondrial ROS generation throughout oxidation of 2,7-dichlorofluorescein diacetate (DCFH-DA) to DCF-RS, followed by GS and GAD inhibition. The NH4Cl plus MMA administration did not alter cytokine levels, plasma fluorescein extravasation, or neuronal damage. However, it potentiated DCF-RS levels, decreased the ΔΨ potential, reduced MTT, inhibited SDH activity, and increased Na(+), K(+)-ATPase activity. NH4Cl also altered the GABA cycle characterized by GS and GAD activity inhibition, [(3)H]flunitrazepam binding, and GABA release after MMA injection. On the basis of our findings, the changes in ROS and reactive nitrogen species (RNS) levels elicited by ammonia alter the glycine/glutamate (GABA) cycle and contribute to MMA-induced excitability.

Peumus boldus (Boldo) Aqueous Extract Present Better Protective Effect than Boldine Against Manganese-Induced Toxicity in D. melanogaster.

The cellular, intracellular and molecular mechanism(s) underlying the toxicity of Mn are still incompletely understood, although several points concerning Mn neurotoxicity have been addressed. Importantly, oxidative changes have been reported to be involved in Mn-induced toxicity. As a consequence, antioxidants are expected to offer protection in Drosophila melanogaster exposed to this metal. So, in this study we evaluated the hypothesis that the aqueous extract of boldo (Peumus boldus), and its alkaloids boldine, could prevent/ameliorate behavioral and oxidative alterations induced by Mn in a D. melanogaster intoxication model. Adult wild-type flies were concomitantly exposed to Mn (3 mM) and boldo aqueous extract (5 mg/mL) or boldine (327.37 µg/mL) in the food during 9 days. Mn-fed flies had a worse performance in the negative geotaxis assay and in the open-field test, as well as a higher incidence of mortality and TBARS levels in head and body, when compared to control group. Boldo aqueous extract was found to reduce the mortality rate of the flies exposed to Mn. In turn, boldine was ineffective against Mn-induced mortality and significantly increases mortality per se. Additionally, Mn-induced locomotors dysfunction were fully ameliorated by boldo crude extract and only partially ameliorated by boldine. Likewise, boldo completely normalize head and body TBARS levels, whereas boldine only partially normalize in body. Finally, we found that flies treated with Mn presented significantly decrease in dopamine levels. Our results suggest that boldo crude extract can exert protective effect against Mn-induced toxicity in D. melanogaster, whereas boldine do not. Moreover, our data confirm the utility of this model to investigate potential therapeutic strategies on movement disorders, such as that caused by Mn.

Platelet-rich plasma reduces the oxidative damage determined by a skeletal muscle contusion in rats.

Platelet-rich plasma (PRP) has received increasing attention and is widely used in clinical practice in order to stimulate human tissue healing. Contusions are very common injuries observed in sports and affect the function of the musculoskeletal system. This study investigated the effects of PRP on the oxidative damage determined by a contusion induced in gastrocnemius muscle of rats. PRP was injected intramuscularly immediately after injury and every 48 h, and the biochemical analysis was performed 1, 3, 5, or 7 days after the contusion onset in order to evaluate the changes characteristics of the healing process. The contusion increased the levels of oxidative stress markers such as thiobarbituric acid reactive substances and oxidized dichlorofluorescein both in skeletal muscle tissue and erythrocytes preparations, and PRP treatment significantly reduced these oxidative damage markers. Furthermore, the contusion decreased the cellular viability in the site of the lesion and PRP was effective in diminishing this effect. Moreover, PRP increased the levels of enzymatic antioxidants superoxide dismutase and catalase activities in the injured muscle, and also the non-protein thiols (-SH) group levels in erythrocytes. In conclusion PRP, in the form that was used in this study, was able to modulate the oxidative damage determined by a classical skeletal muscle injury possibly by reducing the impairment of myocytes mitochondrial function and improving their endogenous antioxidant defense systems.

Extracellular dopamine and alterations on dopamine transporter are related to reserpine toxicity in Caenorhabditis elegans.

Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.

Toxicological assessment of photoactivated tetra-cationic porphyrin molecules under white light exposure in a Caenorhabditis elegans model.

Photodynamic therapy (PDT) utilizes the potential of photosensitizing substances to absorb light energy and produce reactive oxygen species. Tetra-cationic porphyrins, which have organic or coordination compounds attached to their periphery, are heterocyclic derivatives with well-described antimicrobial and antitumoral properties. This is due to their ability to produce reactive oxygen species and their photobiological properties in solution. Consequently, these molecules are promising candidates as new and more effective photosensitizers with biomedical, environmental, and other biomedical applications. Prior to human exposure, it is essential to establish the toxicological profile of these molecules using in vivo models. In this study, we used Caenorhabditis elegans, a small free-living nematode, as a model for assessing toxic effects and predicting toxicity in preclinical research. We evaluated the toxic effects of porphyrins (neutral and tetra-cationic) on nematodes under dark/light conditions. Our findings demonstrate that tetra-methylated porphyrins (3TMeP and 4TMeP) at a concentration of 3.3 µg/mL (1.36 and 0.93 µM) exhibit high toxicity (as evidenced by reduced survival, development, and locomotion) under dark conditions. Moreover, photoactivated tetra-methylated porphyrins induce higher ROS levels compared to neutral (3TPyP and 4TPyP), tetra-palladated (3PdTPyP and 4PdTPyP), and tetra-platinated (3PtTPyP and 4PtTPyP) porphyrins, which may be responsible for the observed toxic effects.

Systematic screening of synthetic organochalcogen compounds with anticancer activity using human lung adenocarcinoma spheroids.

Lung adenocarcinoma stands as a leading global cause of cancer-related fatalities, with current therapeutic approaches remaining unsatisfactory. Given the association between elevated oxidative markers and the aggressive nature of cancer cells (including multidrug resistance and metastatic potential) that can predict poor outcome of lung adenocarcinoma patients, any compounds that interfere with their aberrant redox biology should be rationally explored as innovative intervention strategies. This study was designed to screen potential anticancer activities within nine newly synthesized organochalcogen - compounds characterized by the presence of oxygen, sulfur, or selenium elements in their structure and exhibiting antioxidant activity - and systematically evaluated their performance against cisplatin, the cornerstone therapeutic agent for lung adenocarcinoma. Our methodology involved the establishment of optimal conditions for generating single tumor spheroids using A549 human lung adenocarcinoma cell line. The initiation interval for spheroid formation was determined to be four days in vitro (DIV), and these single spheroids demonstrated sustained growth over a period of 20 DIV. Toxic dose-response curves were subsequently performed for each compound after 24 and 48 h of incubation at the 12th DIV. Our findings reveal that at least two of the synthetic organochalcogen compounds exhibited noteworthy anticancer activity, surpassing cisplatin in key parameters such as lower LD (Lethal Dose) 50, larger drug activity area, and maximum amplitude of effect, and are promising drugs for futures studies in the treatment of lung adenocarcinomas. Physicochemical descriptors and prediction ADME (absorption, distribution, metabolism, and excretion) parameters of selected compounds were obtained using SwissADME computational tool; Molinspiration server was used to calculate a biological activity score, and possible molecule targets were evaluated by prediction with the SwissTargetPrediction server. This research not only sheds light on novel avenues for therapeutic exploration but also underscores the potential of synthetic organochalcogen compounds as agents with superior efficacy compared to established treatments.

4-(Phenylselanyl)-2H-chromen-2-one-Loaded Nanocapsule Suspension-A Promising Breakthrough in Pain Management: Comprehensive Molecular Docking, Formulation Design, and Toxicological and Pharmacological Assessments in Mice.

Therapies for the treatment of pain and inflammation continue to pose a global challenge, emphasizing the significant impact of pain on patients' quality of life. Therefore, this study aimed to investigate the effects of 4-(Phenylselanyl)-2H-chromen-2-one (4-PSCO) on pain-associated proteins through computational molecular docking tests. A new pharmaceutical formulation based on polymeric nanocapsules was developed and characterized. The potential toxicity of 4-PSCO was assessed using Caenorhabditis elegans and Swiss mice, and its pharmacological actions through acute nociception and inflammation tests were also assessed. Our results demonstrated that 4-PSCO, in its free form, exhibited high affinity for the selected receptors, including p38 MAP kinase, peptidyl arginine deiminase type 4, phosphoinositide 3-kinase, Janus kinase 2, toll-like receptor 4, and nuclear factor-kappa ß. Both free and nanoencapsulated 4-PSCO showed no toxicity in nematodes and mice. Parameters related to oxidative stress and plasma markers showed no significant change. Both treatments demonstrated antinociceptive and anti-edematogenic effects in the glutamate and hot plate tests. The nanoencapsulated form exhibited a more prolonged effect, reducing mechanical hypersensitivity in an inflammatory pain model. These findings underscore the promising potential of 4-PSCO as an alternative for the development of more effective and safer drugs for the treatment of pain and inflammation.