Search Results (2,210)

Pathogen manipulation of host behavior is a widespread evolutionary strategy to enhance its transmission, yet whether different pathogens elicit distinct behavioral and molecular responses in the same host remains poorly understood. We performed parallel behavioral assays and comparative transcriptomic analyses on third-instar Lymantria dispar larvae infected with Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV, virus), Staphylococcus aureus (bacterium) and Metarhizium anisopliae (fungus). Climbing height was recorded over 72 h post-infection, and gene expression pattern was profiled using RNA-seq at 72 h. Only LdMNPV infection induced significant, sustained upward climbing behavior among the three pathogen infection groups. All three pathogens activated Toll and IMD immune pathways, but LdMNPV triggered substantially broader transcriptomic reprogramming. Notably, the virus specifically upregulated multiple energy metabolism pathways (nicotinate/nicotinamide metabolism, pyruvate metabolism, TCA cycle and oxidative phosphorylation) and the neuroactive ligand-receptor interaction pathway—a pattern absent in bacterial and fungal infections. LdMNPV drove tree-top disease through a virus-specific, multi-system manipulation strategy that couples metabolic activation with neural signaling modulation. This comparative study reveals fundamental differences in behavioral manipulation across pathogen kingdoms and provides candidate pathways for functional validation. Full article

Cytisine is a plant-derived quinolizidine alkaloid found, among other sources, in the seeds of the common laburnum (Laburnum anagyroides). It has properties that enable it to act as a partial agonist of brain nicotinic α4β2 receptors, which play a key role in the development and maintenance of nicotine addiction. Clinical studies have shown that cytisine is a more effective smoking cessation aid than nicotine replacement therapy and at least as effective as varenicline in treating tobacco cigarette addiction. It may also be an effective agent in treating addiction to electronic cigarettes. Cytisine is also significantly cheaper than other anti-nicotine medications. This is of great importance for the population of smokers in developing countries, who cannot afford anti-nicotine treatment. In recent years, the role of cytisine in the pharmacotherapy of nicotine addiction worldwide has increased significantly. This drug is becoming available in an increasing number of countries, and in 2025 the World Health Organization (WHO) added cytisine to the list of essential medicines. The need for further development of the drug poses additional challenges for scientists, including the creation of new pharmaceutical forms, optimization of dosing regimens, and expansion of indications to include the treatment of nicotine addiction supplied into the body in forms other than traditional tobacco products. This review describes the use of cytisine in the treatment of nicotine addiction, the drug’s mechanism of action, pharmacokinetics, efficacy, safety of use, and the available pharmaceutical preparations. It also presents research directions on cytisine related to the development of innovative pharmaceutical products, new dosing regimens, and new indications associated with the treatment of addiction to various nicotine-containing products. Conclusions indicate that cytisine has a difficult dosing regimen, which is why patients do not adhere to it, limiting the effectiveness of the therapy. This necessitates optimizing the dosage of existing capsules and tablets or introducing, for example, new extended-release forms of the drug containing cytisine. Full article

Background/Objectives: The American Heart Association Life’s Essential 8 (LE8) is a tool proposed to categorize overall cardiovascular health (CVH), ranging from 0 to 100 and classifies CVH as low (<50), moderate (50–79) or high (≥80), based on the following health behaviors (diet, physical activity, nicotine exposure and sleep) and health factors (body mass index—BMI, lipid levels, glycemic profile and blood pressure). Although used in the general population, it is not part of the health assessment routine in the workplace. We assessed CVH of healthcare workers using an LE8-based score through a mobile application. Methods: Cross-sectional pilot study with adults working at a tertiary hospital in Brazil. We used an app for self-reporting LE8 metrics. Additionally, data on age, sex, and mental health (10-item Perceived Stress Scale, PSS-10) were collected. Results: Sixty-five adults (58.5% female; mean age 36 ± 9.01 years) were included. The mean LE8 overall score was 69.39 ± 12.63. The proportion of participants in the low, moderate and high cardiovascular health categories were 6.2%, 69.2% and 24.6%, respectively. Diet quality (34.76 ± 24.3) and physical activity (45.38 ± 40.58) were in the “low cardiovascular health” category. “Health behaviors” had a significantly lower mean score than “health factors” (58.90 ± 20.53 vs. 79.88 ± 15.55, p < 0.001). The mean PSS-10 score was 19.01 ± 7.49, indicating moderate perceived stress. Overall LE8 and PSS-10 scores were not significantly correlated (r_s = −0,0.17; p = 0.161). There was no significant difference in the mean overall LE8 score in the linear regression model adjusting for age, sex and perceived stress. Conclusions: Among employees of a Brazilian tertiary hospital, the adapted LE8 score indicated overall moderate CVH. Health behaviors—particularly diet quality and physical activity—were the main vulnerable areas. Implementation of an LE8-based assessment in the workplace may be useful for targeted prevention strategies in Brazil. Future larger and longitudinal studies are warranted to confirm these findings. Full article

Hearing loss is detrimental to human health, and currently, more than 1.5 billion people are affected by hearing loss. Active military personnel and construction workers are examples of individuals in the workplace who are exposed to loud noise and are at serious risk of hearing loss. While there is currently no therapy for hearing loss, evidence supports investigating the enhancement of the Medial Olivocochlear (MOC) system, an efferent pathway for hearing that serves as a gain-control for hearing loss protection. Selectively modulating the α9α10 nicotinic acetylcholine receptor (nAChRs) found within this pathway is promising for the development of a new drug class. In this review article, we present the most current findings related to the therapeutic targeting of α9α10 nAChRs for hearing loss. We discuss the loss- or gain-of-function of the receptor, evaluate the known modulators of the receptor, examine their clinical relevance, and discuss their chemical and physical properties. Investigation of this novel pathway may aid in the development of a therapeutic for hearing loss. Full article

Kynurenic acid (KYNA), a metabolite of the L-kynurenine pathway of L-tryptophan degradation, is an endogenous blocker of glutamate ionotropic excitatory amino acid (EAA) receptors and nicotinic acetylcholine receptors (nAChRs). KYNA plays a significant role in various neuropsychiatric disorders and the aging process. Some researchers have suggested that KYNA may contribute to memory impairment. In this study, we examined the impact of L-kynurenine (a KYNA substrate) and the anti-dementia drugs D-cycloserine and Cerebrolysin on kynurenine aminotransferase (KAT) activity, an enzyme forming KYNA, in liver homogenates of Helix pomatia snails. Furthermore, a memory model was established using these snails, wherein tentacle shortening served as an indicator of learning activity. In vitro experiments on Helix pomatia demonstrated the significant impact of L-kynurenine and anti-dementia drugs on KYNA synthesis. KYNA levels increased significantly in the presence of L-kynurenine in liver homogenate. However, KYNA formation decreased when anti-dementia drugs, including Cerebrolysin or D-cycloserine, were administered to the snails’ liver homogenate. L-kynurenine has been shown to impair the learning process in vivo in snails, but an anti-dementia drug has been demonstrated to reverse this effect. Significant inhibition of tentacle lowering was observed in response to L-kynurenine treatment, which corresponded with elevated KYNA levels in the central nervous system. Administering D-cycloserine or Cerebrolysin alongside L-kynurenine reversed its effects. The Helix pomatia memory model is a valuable tool for studying learning and memory formation in various conditions and in the presence of different pharmacological agents. A drug or natural extract that blocks KYNA synthesis has the ability to increase tentacle lowering and could be considered an anti-dementia agent. Furthermore, this metabolite may also protect against aging and delay damage to the central nervous system related to memory. Full article

Chronic oxidative stress and lipid imbalance drive metabolic disorders such as obesity and non-alcoholic fatty liver disease, yet few therapies target the upstream redox imbalance in key tissues. Human carbonic anhydrase III (hCA III), a redox-associated enzyme enriched in liver and adipose tissue, has long remained pharmacologically elusive due to its low catalytic activity and lack of modulators. Here, we identify fragment-like nicotinic acid derivatives as non-sulfonamide hCA III modulators and evaluate their associated cellular effects. Using an esterase activity assay, we screened 25 analogues and identified two fragment-like hits, compound 17 (2-thioethyl) and compound 22 (6-morpholino), with IC₅₀ values of 487 and 361 µM, respectively. Orthogonal thermal shift analysis supported compound-protein interaction, and selected hits were subsequently evaluated in HepG2 cells. Both compounds were associated with reduced CA3 mRNA expression after treatment at 1 µM, while their cellular phenotypes diverged, with compound 22 increasing ROS under oxidative stress conditions and compound 17 affecting mitochondrial membrane potential. Taken together, these findings identify tractable nicotinic acid-derived fragment hits and associated cellular phenotypes that warrant further mechanistic investigation. These fragment-like hits provide a practical starting point for studying the redox-linked biology of hCA III. Full article

Background/Objectives: Recently, a randomized clinical trial evaluated whether a six-month probiotic administration could reduce symptom severity in preschool children with Autism Spectrum Disorders (ASD), with (GI) or without (NGI) gastrointestinal symptoms. Significant positive changes were observed only in NGI children. A second explorative study on children prior to intervention identified a fecal metabolome fingerprint associated with ASD severity. Building on these findings, the present study aimed to assess whether metabolomics could monitor changes in ASD severity following probiotic administration using a subset of samples from the same trial. Second, this study aimed to identify fecal metabolites to be monitored in children to predict whether their autism severity may decrease after probiotic or placebo treatment. Methods: Evaluations of the fecal metabolome and microbiota could be completed on 57 children before and after a double-blind administration of a probiotic mixture or a placebo. Results: In NGI children the probiotic was found to influence the concentration of the amino acids aspartate, leucine, tryptophan, and valine, together with nicotinate and the short chain fatty acids acetate, butyrate, isobutyrate, and propionate. Lactobacilli and Sutterella showed significant changes in response to probiotic administration (p < 0.05). Acetate, 4-hydroxyphenyl, galactose, proline, and tyramine were identified as key fecal metabolites for prediction purposes. Conclusions: The present exploratory analysis, despite the small sample size, suggests that fecal metabolomics may provide a useful approach for monitoring and potentially for predicting changes in ASD severity following probiotics administration. Full article

Neuroinflammation is determinant in the progression of neurodegenerative diseases. One of the main mechanisms underlying this process involves the persistent activation of glial cells. Persistent activation of glial cells induces proinflammatory transcription factors and the release of cytokines, chemokines, and reactive oxygen species that exacerbate cellular dysfunction. This neurotoxic environment promotes neuronal death, while the products of cellular damage feed back into glial activation, establishing a self-sustaining pathogenic cycle that drives neurodegeneration. Alkaloids present in Amaryllidaceae plants support the use of this resource in folk medicine, displaying potent effects as acetylcholinesterase inhibitors and allosteric modulators of nicotinic receptors (nAChR). In this study, a murine microglial cell (IMG) model of LPS-induced inflammation was used to evaluate the involvement of α7 and α4β2 nAChRs in glioprotection and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine (OHDA). GC-MS analysis revealed differences in the alkaloid profile between in vitro cultures with fructose and wild-type Rhodophiala pratensis. Homolycorine-type, norbelladine-type and crinine-type alkaloids produced in vitro reduced LPS-induced inflammation (5 µg/mL), possibly via α7 and α4β2 nAChRs, and showed a protective effect against OHDA-induced oxidative stress (1–3 µg/mL) and inhibited AChE and BuChE (24–78 µg/mL). Full article

Background: Obstructive sleep apnoea (OSA) is a highly prevalent yet underdiagnosed disorder in patients with cardiovascular disease. Growing evidence suggests a pathophysiological link between OSA and coronary artery disease (CAD); however, the relationship between OSA severity and anatomical complexity of coronary lesions remains incompletely understood. Aim: The aim of this study is to assess the prevalence of OSA in patients undergoing coronary angiography and to evaluate the association between sleep-disordered breathing parameters and the severity of CAD expressed by the SYNTAX score. Methods: This prospective study enrolled 103 consecutive patients referred for invasive coronary angiography. All participants underwent overnight type III cardiorespiratory polygraphy. OSA severity was classified according to the Apnea–Hypopnea Index (AHI). The anatomical complexity of CAD was assessed using the SYNTAX score. Linear regression analyses were performed to determine associations between polysomnographic parameters and SYNTAX score. Results: Significant CAD was diagnosed in 74.8% of patients. OSA was highly prevalent, with severe OSA observed in 36.4% of patients with significant CAD compared to 3.8% in those without significant stenoses (p = 0.003). Patients with significant CAD had higher AHI (18.8 vs. 13.5 events/h; p = 0.003), higher oxygen desaturation index (ODI) (19.3 vs. 12.9 events/h; p = 0.003), and greater mean oxygen desaturation (4.1% vs. 3.8%; p = 0.008). In multivariable regression analysis, AHI (B = 0.329; 95% CI [0.083, 0.576]; p = 0.009) and nicotinism (B = 8.693; 95% CI [2.573, 14.814]; p = 0.006) independently predicted higher SYNTAX scores. Interestingly, each 1% increase in snoring percentage was associated with a 0.203-point reduction in SYNTAX score (95% CI [−0.339, −0.068]; p = 0.004). Conclusions: OSA is highly prevalent in patients undergoing coronary angiography and is independently associated with greater anatomical complexity of CAD. Sleep-disordered breathing, particularly AHI and nocturnal hypoxemia, may represent important non-traditional risk markers of advanced coronary atherosclerosis. Systematic screening for OSA should be considered in patients with suspected or confirmed CAD. Full article

Background/Objectives: The renin–angiotensin–aldosterone (RAA) system is a key regulator of cardiovascular homeostasis. Recent evidence suggests that Angiotensin II (Ang II) can trigger ferroptosis, an iron-dependent form of cell death. We previously demonstrated that periodontitis induces neurovascular dysfunction, and our preliminary observations indicate that this oral inflammatory model is associated with elevated blood pressure. However, the mechanism by which Ang II impaired nitrergic vasodilation and triggered ferroptosis in cerebral arteries remains unclear. This study investigates the functional effects of electrical and chemical nerve stimulation in adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Methods: Endothelium-denuded basilar arterial (BA) rings from SHRs and WKYs were used to assess the impact of Ang II on neurogenic relaxation via wire myography. Results: Vascular relaxation responses to nicotine and transmural nerve stimulation (TNS) were significantly diminished in SHRs compared to WKYs. This impairment was reversed by both acute preincubation and chronic treatment with losartan (an AT1 receptor antagonist). In WKY BAs, exogenous Ang II pretreatment inhibited relaxation responses to nicotine, TNS, and isoproterenol. Importantly, this inhibition was effectively reversed by marimastat (MMP inhibitor), catalase (antioxidant), and ferrostatin-1 (ferroptosis inhibitor). Conclusions: Our findings indicate that Ang II induces functional alterations in neurovascular signaling patterns by triggering ferroptosis within nerve terminals. This process leads to a functional imbalance between sympathetic and parasympathetic influences, ultimately impairing neurogenic nitrergic dilation in the BAs of SHRs. These results suggest that targeting Ang II-induced ferroptosis may alleviate the neuroinflammation and cognitive decline associated with hypertension-related cerebrovascular dysfunction. Full article

Substance use disorder (SUD) is a chronic neuropsychiatric condition characterized by persistent drug seeking and impaired behavioral control. Dopaminergic signaling has long been recognized as a central regulator of reinforcement learning, motivation, and habit formation. Addictive substances profoundly alter dopamine transmission through multiple mechanisms. These drug-induced changes contribute to the initiation, escalation, and persistence of addictive behaviors. In addition to dopamine, the cholinergic system has emerged as an important modulator of striatal circuit function. Acetylcholine and its receptors interact extensively with dopaminergic pathways, shaping striatal signaling dynamics and influencing learning and action selection, with particularly strong relevance for nicotine dependence. In this review, we discuss how striatal dopamine and acetylcholine contribute to learning, habit formation, and addiction-related behaviors, as well as how these systems interact at the circuit level. By integrating these findings, we propose a framework for understanding how dopamine–acetylcholine interactions may influence behavioral regulation relevant to substance use disorders. Full article

Antimicrobial resistance (AMR) poses a significant global health threat, with multidrug-resistant pathogens undermining the effectiveness of conventional antibiotics. Natural alkaloids, a diverse group of nitrogen-containing compounds mainly derived from plants, are gaining attention as potential antimicrobial agents due to their broad-spectrum activity, structural variety, and unique mechanisms of action. This review examines the antimicrobial properties of natural alkaloids, classifying them by chemical structure (e.g., quinoline, isoquinoline, pyridine, indole, and imidazole alkaloids). Their antibacterial, antifungal, and antiviral activities are discussed, along with the mechanisms by which they target pathogenic microorganisms, including disruption of cell walls and membranes, inhibition of protein synthesis, interference with DNA replication, and viral assembly. The review also explores the synergistic effects of alkaloids when combined with conventional antimicrobial agents. Alkaloids demonstrate potent antimicrobial activity against various pathogens. Quinoline alkaloids, such as quinine, inhibit DNA replication and damage cell membranes. Isoquinoline alkaloids like berberine and sanguinarine exhibit broad-spectrum antibacterial effects. Pyridine alkaloids, including nicotine, disrupt bacterial membranes. In fungi, alkaloids such as sanguinarine and indole derivatives prevent cell wall synthesis and spore germination. Antiviral alkaloids like lycorine target viral RNA polymerases. Additionally, alkaloids enhance the activity of traditional antibiotics by overcoming resistance. Natural alkaloids represent a promising source of antimicrobial agents with diverse mechanisms to combat AMR. Future research should focus on optimizing alkaloid structures, ensuring safety and efficacy, and exploring combination therapies to address the escalating AMR challenge. Full article

Cigarette smoke contains a high concentration of carcinogenic substances to which smokers are regularly exposed. Passive smoking is seriously harmful to the health of non-smoking humans and animals. Domestic cats are particularly vulnerable because of their constant grooming activity, which can promote oral ingestion of smoke-derived residues. Cotinine, a nicotine metabolite, is a reliable biomarker for tobacco exposure. Considering these observations, our study aimed to (1) characterize cytological alterations in oral mucosal epithelial cells by conventional morphology and automated digital cytomorphometry; (2) quantify urinary cotinine concentration and investigate its possible correlation with oral epithelial cytological alterations. To this aim, oral smears were collected from 30 cats divided into two groups (20 exposed; 10 non-exposed). Smears were stained with May–Grünwald–Giemsa and Papanicolaou to assess inflammation and dysplasia; digital cytomorphometric analysis was used to quantify the nucleus-to-cytoplasm (N/C) ratio. Urinary cotinine was measured by ELISA. Our results showed that exposed cats had significantly higher urinary cotinine levels and higher N/C ratios (p < 0.01) than non-exposed controls, along with mild-to-severe inflammation and dysplastic-like epithelial alterations. These findings support urinary cotinine as a valid biomarker of household tobacco smoke exposure in domestic cats and suggest that such exposure may be correlated with early cytological and cytomorphometric changes in the oral mucosa. Further studies are needed to better investigate the relationship between exposure duration and cytological, cytomorphometric, and molecular alterations. Full article

Background/Objectives: Tobacco use is a leading cause of preventable death worldwide and is linked to major health and economic burden. Many smokers attempt to quit, yet long-term success rates with current medicines and counseling are still modest. Long-term nicotine exposure distorts brain systems involved in reward, craving, and self-control. These changes weaken inhibitory control and strengthen responses to smoking cues, which increases the risk of relapse. Transcranial magnetic stimulation (TMS) is a non-invasive technique that delivers magnetic pulses to specific cortical regions, most commonly the dorsolateral prefrontal cortex, to influence neural activity. This narrative review explored how transcranial magnetic stimulation may aid smoking cessation by acting on neural circuits linked to nicotine dependence. Methods: Five major databases were searched for studies published between 2015 and 2026. After removal of duplicates and screening, a total of 34 studies were included in this narrative synthesis. Randomized controlled trials, clinical studies, and neuroimaging investigations involving adults with nicotine dependence were included. A thematic narrative method was employed to synthesize findings due to the differences in study designs, protocols, and outcome measures. Results: TMS has been shown to attenuate cravings, decrease daily cigarette consumption, and decrease nicotine dependence in various studies. Several trials reported higher abstinence rates with active stimulation compared with sham treatment. Meta-analytic findings indicate stronger effects with 10 Hz stimulation and treatment courses of 20 sessions or more. Neuroimaging studies report changes in functional connectivity within reward, executive control, and salience networks, suggesting partial restoration of disrupted circuits. Treatment response varies according to age, educational level, baseline dependence, and stimulation parameters. Conclusions: These findings support transcranial magnetic stimulation as a promising brain-based approach for smoking cessation, while further well-designed trials with longer follow-up are still needed. Full article

The fruit of Aronia melanocarpa (Michx.) Elliott is a berry with multiple properties and was included as a new raw food material by the National Health Commission of China (NHC) in September 2018. This study focused on the immune regulatory properties and underlying mechanism of polysaccharides extracted from Aronia melanocarpa fruit (AMFP) by undertaking an integrated analysis of multiple endogenous metabolic pathways. An improvement in AMFP in immunosuppressed model mice at three levels of immune organs, immune cells, and immune factors was determined. The immunomodulatory role of AMFP was assessed through measurement of metabolomic and lipidomic profilings by UPLC-Q-TOF/MS. A total of 53 differential endogenous metabolites in the urinary, serum, and lipid metabolomics were identified, followed by KEGG pathway enrichment. Furthermore, the underlying mechanisms were elucidated by an integrated analysis of multiple metabolomics and lipidomics. Primarily, we found regulation of immune-related metabolic pathways, including nicotinate and nicotinamide metabolism, sphingolipid metabolism, glycerophospholipid metabolism, purine metabolism, steroid hormone biosynthesis, and arachidonic acid metabolism. The results also demonstrated the mutual validation of key pathways and mechanisms. AMFP potentiated both humoral and cellular immunity responses and protected the immune system from oxidative damage. This research provides a reference and a basis for the development and application of AMFP in the field of health foods that regulate immunity. Full article