Search Results (30)

Background/Objectives: Dopamine is well known for its role in reward learning, where phasic activity encodes prediction errors and supports the formation of cue–outcome associations. More recently, dopamine has been implicated in encoding salience, novelty, and aversive events, suggesting a broader function in shaping learning and memory across motivational contexts. However, how accumbal dopamine contributes to the recovery of extinguished fear, a process central to relapse in anxiety and trauma-related disorders, remains unclear. Methods: Here, we examined NAc core dopamine dynamics during shock-induced reinstatement of an extinguished fear memory. Using dLight fiber photometry, we found that a sustained decrease in baseline dopamine marked extinction recall. In contrast, an unexpected reminder footshock prevented this reduction, maintaining dopamine levels near baseline as freezing behavior re-emerged. Results: The reminder shock also evoked a transient dopamine peak, and optogenetic manipulations demonstrated that dopamine signaling during this period bidirectionally modulated reinstatement, with enhancement of dopamine release increasing reinstatement and inhibition of dopamine terminals markedly attenuating it. Together, these results demonstrate that unexpected aversive events reset NAc core dopamine levels and gate the return of extinguished fear. Conclusions: By revealing that accumbal dopamine contributes to fear recovery, this work broadens current models of dopamine function and identifies a neural mechanism through which surprising events may promote relapse of aversive memories in anxiety- and stress-related disorders. Full article

Background: Cocaine use disorder (CUD) remains a major global health concern, with no FDA-approved pharmacological treatments currently available. Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa L., has shown promising preclinical effects in disrupting the consolidation and retrieval of drug-associated memories, thereby attenuating relapse-like behaviors. Objectives: The present study evaluated the effects of a low-THC CBD-rich cannabis extract (NPCE) on the reinstatement and reconsolidation of cocaine-induced conditioned place preference (CPP) in male CD1 (ICR) mice, an approach not previously investigated. Methods: The extract was administered at a dose equivalent to 20 mg/kg of CBD. Treatment significantly attenuated both priming- and stress-induced reinstatement of cocaine-induced CPP. Reinstatement was triggered either by a cocaine priming injection or by acute stress exposure, whereas reconsolidation-like processes were assessed by administering the extract following memory reactivation sessions and subsequently evaluating the persistence of cocaine-associated preference over time. Results: NPCE showed a consistent result with disruption of reconsolidation-like processes of cocaine-associated memory, with effects persisting for at least two weeks. The extract alone did not induce conditioned preference or aversion. Conclusions: These findings suggest that NPCE modulates drug-associated memory processes involved in relapse-like behavior. However, the underlying mechanisms were not directly evaluated and remain to be elucidated. Further studies are warranted to include both sexes, evaluate effects across multiple behavioral paradigms, directly compare full-spectrum extracts with isolated cannabinoids, and incorporate receptor-specific approaches to clarify the mechanisms of action. Full article

Oxidative stress is believed to deteriorate production performance and cause substantial economic losses in commercial poultry farming. Resveratrol (RES) is a polyphenolic antioxidant that can improve intestinal barrier function and regulate gut microbiota composition. This study aimed to evaluate whether short-term (14 days) dietary resveratrol (1000–3000 mg/kg) mitigates dexamethasone (DEX)-induced oxidative stress and performance loss in yellow-feathered broilers. Two hundred and forty 52-day-old birds were assigned to five treatments (n = 8 pens × 6). Control (CON) and DEX groups received the basal diet; DR1, DR2 and DR3 were provided with the basal diet plus 1000, 2000 or 3000 mg/kg RES. During days 1–5, the DEX and RES (DR1, DR2 and DR3) groups were intraperitoneally injected with 5 mg/kg BW DEX; CON birds received saline. DEX significantly reduced average daily gain (ADG) and raised feed conversion ratio (FCR) (p < 0.05) without altering feed intake. RES at 1000–2000 mg/kg improved ADG, reduced FCR and lowered serum corticosterone and blood urea nitrogen while increasing albumin (p < 0.05). DEX elevated malondialdehyde (MDA) in liver and thigh muscle, suppressed liver catalase (CAT) activity, and suppressed thigh muscle superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and CAT activities. In serum, only SOD activity decreased. RES partially alleviated the abnormal changes in these antioxidant indices. Intestinally, DEX increased MDA, shortened villi and reduced the villus-to-crypt ratio, whereas RES partially reinstated ileal morphology, decreased MDA dose-dependently and linearly enhanced duodenal SOD activity (p < 0.05). DEX downregulated Occludin mRNA; RES upregulated Occludin and elevated ileal GPX2, SOD, CAT and PPAR-γ transcripts with a quadratic response to RES dose, while lowering duodenal CAT mRNA. Overall, short-term RES supplementation—particularly at 1000–2000 mg/kg—improves growth performance, meat quality and intestinal health of yellow-feathered broilers under DEX-induced oxidative stress by enhancing systemic and intestinal antioxidant capacity and reinforcing epithelial barrier integrity. Full article

Background: Skeletal muscle aging is characterized by impaired myogenic differentiation, disrupted circadian rhythms, elevated oxidative stress, and mitochondrial dysfunction. Rutin, a natural flavonoid with antioxidant properties, has been suggested to mitigate aging processes; however, its effects on circadian regulation and muscle homeostasis remain unclear. Methods: In vitro, differentiated C2C12 myotubes were treated with D-galactose (D-gal, 20 g/L) with or without rutin (20 μM). In vivo, C57BL/6 mice were supplemented with rutin (100 mg/kg b.w.) via oral gavage in a D-gal-induced aging mouse model (150 mg/kg b.w., i.p.). Results: D-gal induced cellular senescence, impaired myogenic differentiation, disrupted circadian oscillations, increased oxidative stress, and compromised mitochondrial function. Rutin treatment restored myotube formation, enhanced circadian rhythmicity of differentiation-related genes, and corrected the antiphase patterns of Per2 and Rorc. It also reduced reactive oxygen species and malondialdehyde levels; increased superoxide dismutase, catalase, and glutathione peroxidase activity; improved ATP production and membrane potential; and decreased mitochondrial oxidative aging, as confirmed by pMitoTimer imaging. Furthermore, rutin reinstated the rhythmic expression of oxidative phosphorylation proteins and Pgc1α. In vivo, rutin supplementation enhanced muscle performance (prolonged hanging time) and oxidative capacity, particularly at night (ZT14–ZT16), without altering muscle fiber-type distribution, and normalized circadian rhythmicity of core clock genes. Conclusions: Rutin attenuates D-gal-induced cellular senescence by modulating circadian rhythms, reducing oxidative stress, and improving mitochondrial function. Importantly, its in vivo effects on muscle performance and circadian regulation suggest that rutin is a promising therapeutic strategy to counteract skeletal muscle aging and sarcopenia. Full article

Kappa opioid receptor (KOR) antagonists may have therapeutic potential to prevent stress-induced relapse in abstinent individuals with cocaine use disorder (CUD). The macrocyclic peptide [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) is an orally bioavailable, brain–penetrant selective KOR antagonist that prevents stress-induced reinstatement of cocaine-seeking behavior in a mouse model of CUD. We synthesized and evaluated analogs of this lead compound with substitutions for the D-Trp residue to identify analogs that exhibit more potent central KOR antagonism following oral administration. The peptides were synthesized by a combination of solid phase and solution peptide synthetic methodologies, and their pharmacological activity was evaluated both in vitro (for KOR affinity, selectivity and antagonism) and in vivo (for antinociception and KOR antagonism), with promising analogs evaluated for their ability to prevent stress-induced reinstatement of cocaine-seeking behavior in the mouse conditioned place preference (CPP) assay. A variety of substituted D-Phe or modified D-Trp derivatives were tolerated by KOR with retention of significant KOR antagonism in vivo after oral administration. Macrocyclic peptide pretreatment, per os, significantly prevented stress-induced reinstatement of cocaine CPP at doses of 10 and 30 mg/kg of [D-Phe⁴]CJ-15,208, 4, and 30 mg/kg of [D-Trp(formamide)]CJ-15,208, 3, which are 6-fold and 2-fold lower, respectively, than that needed for {D-Trp]CJ-15,208. Full article

The purpose of this study was to examine the role of traditional fire management practices in the general mitigation of wildfire risk in Greece. Major emphasis was placed on assessing people’s opinions about the perceived effectiveness of traditional fire management strategies that were historically and culturally employed by local communities—such as weather condition monitoring, prescribed burning, proper land use planning, and mosaic burning—in the general mitigation of wildfire risks. An online questionnaire was used to collect data from 397 environmental experts in Greece. The study shows that traditional fire control methods reduce wildfire risk. First, weather monitoring was found to be crucial to wildfire forecasting and prevention. The results showed that early warning, successful firefighting, and fire prevention depend on meteorological data. Additionally, prescribed burning was revealed to have reduced wildfire risk. Respondents accepted that they could reduce unprescribed fires, protect natural ecosystems, remove wildfire-prone areas, and regulate flame intensity. This suggests that scheduled burning in Greece may reduce wildfire damage. The study underlines the importance of including conventional fire management in the wildfire mitigation strategy of Greece. The aforementioned activities may help the environment and civilization progress by safeguarding ecosystems and reducing wildfire damage. These techniques, combined with community engagement and improved early warning systems, may help manage climate change-induced wildfires. Overall, the study contributes to wildfire management in Greece and other Mediterranean countries. The study emphasizes the need to incorporate traditional fire practices into Greece’s wildfire risk reduction strategies. Taking into account the success rates of these practices in other areas, as well as Greece’s old tradition of conducting fire, this paper stresses that further studies and policy developments be made in order to reinstate these practices in today’s wildfire management. Full article

Inflammatory bowel disease (IBD) is a chronic disease influenced by a complex interplay of factors, including genetics, environmental, and gut microbiota. This study aimed to explore the therapeutic potential of the natural polyphenolic compound hydroxytyrosol (HT) in modulating dextran sodium sulfate (DSS)-induced colitis in mice. The findings demonstrate that oral administration of HT significantly alleviated colitis symptoms, as evidenced by a reduction in the disease activity index and improvements in colonic pathology. HT was found to inhibit the release of pro-inflammatory cytokines, enhance antioxidant status, and mitigate oxidative stress. Furthermore, HT contributed to the restoration of the gut barrier by reinstating tight junction proteins, reducing the inflammatory marker lipopolysaccharide (LPS), and suppressing inflammation-related genes. This compound also modulated the NLRP3-Cas-1-GSDMD-IL-1β inflammatory pathway and inhibited the NF-κB (nuclear factor kappa B) pathway, thereby alleviating colitis. Gut microbial analysis revealed that HT enriched the abundance of Bacteroidota and altered the balance between Bacteroidota and Firmicutes in mice. Correlation analysis between bacterial microbiota and inflammatory factors suggested that HT may alleviate colitis by modulating the relative abundance of Alistipes, Bacteroides, and unclassified_f__Muribaculaceae. These findings underscore the potential of HT as a therapeutic agent in the treatment of colitis. Full article

The tomato is among the crops with the most extensive cultivated area and greatest consumption in our nation; nonetheless, secondary salinization of facility soil significantly hinders the sustainable growth of facility agriculture. Melatonin (MT), as an innovative plant growth regulator, is essential in stress responses. This research used a hydroponic setup to replicate saline stress conditions. Different endogenous levels of melatonin (MT) were established by foliar spraying of 100 μmol·L⁻¹ MT, the MT synthesis inhibitor p-CPA (100 μmol·L⁻¹), and a combination of p-CPA and MT, to investigate the mechanism by which MT mitigates the effects of salt stress on the photosynthetic efficiency of tomato seedlings. Results indicated that after six days of salt stress, the endogenous MT content in tomato seedlings drastically decreased, with declines in the net photosynthetic rate and photosystem performance indices (PI_total and PI_abs). The OJIP fluorescence curve exhibited distortion, characterized by anomalous K-band and L-band manifestations. Exogenous MT dramatically enhanced the gene (TrpDC, T5H, SNAcT, and AcSNMT) expression of critical enzymes in MT synthesis, therefore boosting the level of endogenous MT. The application of MT enhanced the photosynthetic parameters. MT treatment decreased the fluorescence intensities of the J-phase and I-phase in the OJIP curve under salt stress, attenuated the irregularities in the K-band and L-band performance, and concurrently enhanced quantum yield and energy partitioning ratios. It specifically elevated φP_o, φE_o, and ψ_o, while decreasing φD_o. The therapy enhanced parameters of both the membrane model (ABS/RC, DI_o/RC, ET_o/RC, and TR_o/RC) and leaf model (ABS/CS_m, TR_o/CS_m, ET_o/CS_m, and DI_o/CS_m). Conversely, the injection of exogenous p-CPA exacerbated salt stress-related damage to the photosystem of tomato seedlings and diminished the beneficial effects of MT. The findings suggest that exogenous MT mitigates salt stress-induced photoinhibition by (1) modulating endogenous MT concentrations, (2) augmenting PSII reaction center functionality, (3) safeguarding the oxygen-evolving complex (OEC), (4) reinstating PSI redox potential, (5) facilitating photosynthetic electron transport, and (6) optimizing energy absorption and dissipation. As a result, MT markedly enhanced photochemical performance and facilitated development and salt stress resilience in tomato seedlings. Full article

Botryocladia leptopoda is a red macroalga known for its bioactive compounds with antioxidant, anti-inflammatory, and skin-regenerative properties. The study aimed to examine their effects on UV protection, collagen synthesis, fibroblast proliferation, and pigmentation modulation. Bioactive compounds were extracted using two solvents, producing ethanol extract (FE) and alkaline extracts (AE). Methods involved characterizing extracts using mass spectrometry and assessing their effects on human fibroblasts under UVB-induced damage. UV absorbance, ROS production, and collagen synthesis were evaluated. The FE extract, which comprised 4-hydroxyquinoline, phytosphingosine, and docosapentaenoic acid, reinstated procollagen type I synthesis to 113% of baseline levels and reduced TGF-β1-mediated fibroblast proliferation to 87.78%. FE also suppressed Smad2 and α-SMA by 71% and 68%, respectively, indicating modulation of fibrosis-associated pathways. AE, containing 4-hydroxyquinoline and phenylalanine betaine, demonstrated dose-responsive cellular repair, reducing fibroblast proliferation to 97.86% and collagen Type I expression by 73% at 1000 μg/mL. Both extracts decreased ROS production, with FE and AE reducing levels by 21.4% and 19.7%, respectively, under UVB-induced oxidative stress. FE showed superior scar inhibition, while AE excelled in skin regeneration and pigmentation management. Full article

Pancreatic cancer (PC) is currently recognized as the seventh most prevalent cause of cancer-related mortality among individuals of both genders. It is projected that a significant number of individuals will succumb to this disease in the forthcoming years. Extensive research and validation have been conducted on both gemcitabine and 5-fluorouracil as viable therapeutic options for PC. Nevertheless, despite concerted attempts to enhance treatment outcomes, PC continues to pose significant challenges in terms of achieving effective treatment alone through chemotherapy. Gallic acid, an endogenous chemical present in various botanical preparations, has attracted considerable attention due to its potential as an anticancer agent. The results of the study demonstrated that gallic acid exerted a decline in cell viability that was dependent on its concentration. Furthermore, it efficiently suppressed cell proliferation in PC cells. This study observed a positive correlation between gallic acid and the production of reactive oxygen species (ROS). Additionally, it confirmed the upregulation of proteins associated with the protein kinase-like endoplasmic reticulum kinase (PERK) pathway, which is one of the pathways involved in endoplasmic reticulum (ER) stress. Moreover, the administration of gallic acid resulted in verified alterations in the transmission of mitogen-activated protein kinase (MAPK) signals. Notably, an elevation in the levels of p-p38, which represents the phosphorylated state of p38 MAPK was detected. The scavenger of reactive oxygen species (ROS), N-Acetyl-L-cysteine (NAC), has shown inhibitory effects on phosphorylated p38 (p-p38), whereas the p38 inhibitor SB203580 inhibited C/EBP homologous protein (CHOP). In both instances, the levels of PARP have been successfully reinstated. In other words, the study discovered a correlation between endoplasmic reticulum stress and the p38 signaling pathway. Consequently, gallic acid induces the activation of both the p38 pathway and the ER stress pathway through the generation of ROS, ultimately resulting in apoptosis. The outcomes of this study provide compelling evidence to support the notion that gallic acid possesses considerable promise as a viable therapeutic intervention for pancreatic cancer. Full article

Ultraviolet B (UVB) radiation induces oxidative stress in skin cells, generating reactive oxygen species (ROS) and perturbing enzyme-mediated metabolism. This disruption is evidenced with elevated concentrations of metabolites that play important roles in the modulation of redox homeostasis and inflammatory responses. Thus, this research sought to determine the impacts of the lipid extract derived from the Nannochloropsis oceanica microalgae on phospholipid metabolic processes in keratinocytes subjected to UVB exposure. UVB-irradiated keratinocytes were treated with the microalgae extract. Subsequently, analyses were performed on cell lysates to ascertain the levels of phospholipid/free fatty acids (GC-FID), lipid peroxidation byproducts (GC-MS), and endocannabinoids/eicosanoids (LC-MS), as well as to measure the enzymatic activities linked with phospholipid metabolism, receptor expression, and total antioxidant status (spectrophotometric methods). The extract from N. oceanica microalgae, by diminishing the activities of enzymes involved in the synthesis of endocannabinoids and eicosanoids (PLA2/COX1/2/LOX), augmented the concentrations of anti-inflammatory and antioxidant polyunsaturated fatty acids (PUFAs), namely DHA and EPA. These concentrations are typically diminished due to UVB irradiation. As a consequence, there was a marked reduction in the levels of pro-inflammatory arachidonic acid (AA) and associated pro-inflammatory eicosanoids and endocannabinoids, as well as the expression of CB1/TRPV1 receptors. The microalgal extract also mitigated the increase in lipid peroxidation byproducts, specifically MDA in non-irradiated samples and 10-F4t-NeuroP in both control and post-UVB exposure. These findings indicate that the lipid extract derived from N. oceanica, by mitigating the deleterious impacts of UVB radiation on keratinocyte phospholipids, assumed a pivotal role in reinstating intracellular metabolic equilibrium. Full article

The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides’ opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [³⁵S]GTPγS assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2′-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP. Full article

Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK_1/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK_1/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK_1/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK_1/2 /ERK_1/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist’s efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK_1/2 pathways in memory-processing nuclei. Full article

Alcohol use disorder is a significant public health concern, further exacerbated by an increased risk of relapse due to stress. In addition, factors such as biological sex may contribute to the progression of addiction, as females are especially susceptible to stress-induced relapse. While there have been many studies surrounding potential pharmacological interventions for male stress-induced ethanol reinstatement, research regarding females is scarce. Recently, the neuropeptide oxytocin has gained interest as a possible pharmacological intervention for relapse. The present study examines how oxytocin affects yohimbine-induced reinstatement of ethanol-seeking in female rats using a self-administration paradigm. Adult female rats were trained to press a lever to access ethanol in daily self-administration sessions. Rats then underwent extinction training before a yohimbine-induced reinstatement test. Rats administered with yohimbine demonstrated significantly higher lever response indicating a reinstatement of ethanol-seeking behavior. Oxytocin administration, both systemically and directly into the central amygdala, attenuated the effect of yohimbine-induced reinstatement of ethanol-seeking behavior. The findings from this study establish that oxytocin is effective at attenuating alcohol-relapse behavior mediated by the pharmacological stressor yohimbine and that this effect is modulated by the central amygdala in females. This provides valuable insight regarding oxytocin’s potential therapeutic effect in female stress-induced alcohol relapse. Full article

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund’s adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked. Full article