Search Results (1,067)

Background: Bipolar disorder (BD) is a chronic and disabling psychiatric condition characterized by recurring episodes of mania, hypomania, and depression. Despite the availability of mood stabilizers, antipsychotics, and antidepressants, long-term management remains challenging due to incomplete symptom control, adverse effects, and high relapse rates. Methods: This paper is a narrative review aimed at synthesizing emerging trends and future directions in the pharmacological treatment of BD. Results: Future pharmacotherapy for BD is likely to shift toward precision medicine, leveraging advances in genetics, biomarkers, and neuroimaging to guide personalized treatment strategies. Novel drug development will also target previously underexplored mechanisms, such as inflammation, mitochondrial dysfunction, circadian rhythm disturbances, and glutamatergic dysregulation. Physiological endophenotypes, such as immune-metabolic profiles, circadian rhythms, and stress reactivity, are emerging as promising translational tools for tailoring treatment and reducing associated somatic comorbidity and mortality. Recognition of the heterogeneous longitudinal trajectories of BD, including chronic mixed states, long depressive episodes, or intermittent manic phases, has underscored the value of clinical staging models to inform both pharmacological strategies and biomarker research. Disrupted circadian rhythms and associated chronotypes further support the development of individualized chronotherapeutic interventions. Emerging chronotherapeutic approaches based on individual biological rhythms, along with innovative monitoring strategies such as saliva-based lithium sensors, are reshaping the future landscape. Anti-inflammatory agents, neurosteroids, and compounds modulating oxidative stress are emerging as promising candidates. Additionally, medications targeting specific biological pathways implicated in bipolar pathophysiology, such as N-methyl-D-aspartate (NMDA) receptor modulators, phosphodiesterase inhibitors, and neuropeptides, are under investigation. Conclusions: Advances in pharmacogenomics will enable clinicians to predict individual responses and tolerability, minimizing trial-and-error prescribing. The future landscape may also incorporate digital therapeutics, combining pharmacotherapy with remote monitoring and data-driven adjustments. Ultimately, integrating innovative drug therapies with personalized approaches has the potential to enhance efficacy, reduce adverse effects, and improve long-term outcomes for individuals with bipolar disorder, ushering in a new era of precision psychiatry. Full article

Background/objectives: Polycystic ovary syndrome (PCOS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are common co-morbidities in women of reproductive age. PCOS is highly heterogeneous and is, therefore, divided into four phenotypes. MASLD leads to numerous systemic complications. Studies to date have shown an association between PCOS and MASLD. This study was designed to compare the FIB-4 score (based on age, alanine aminotransferase, aspartate aminotransferase and platelet count) and the results of shear wave elastography in assessing the risk of developing MASLD by patients with PCOS divided by phenotypes. Methods: The study enrolled 242 women age 18–35 years with PCOS diagnosed according to Rotterdam criteria, hospitalized at the Department of Gynaecological Endocrinology of the University Clinical Centre in Katowice. The study subjects were assigned to phenotypes A to D. Clinical and biochemical assessments were performed (including androgens and metabolic parameters), and the FIB-4 index was calculated. Liver fibrosis was evaluated by shear wave elastography. To balance the group sizes of phenotypes, oversampling with replacement was applied (PROC SURVEYSELECT, SAS), increasing the number of observations for phenotypes B, C, and D fivefold. Statistical analyses were performed based on data distribution (Shapiro–Wilk test), using ANOVA or the Kruskal–Wallis test with Dunn’s correction. Statistical significance was set at p < 0.05. Results: The FIB-4 score was the highest in phenotype B patients (0.50 ± 0.15), and the lowest in phenotypes A and C (0.42 ± 0.14). The highest rate of positive elastography findings was recorded in phenotype A patients (34.7%) and the lowest in phenotype C group (13.5%). Significant differences between the phenotypes were also found in terms of androgen levels, insulin, HOMA-IR, and the lipid profile. Among patients with positive elastography, the highest FIB-4 scores were recorded in phenotype C group (0.44 ± 0.06), but the differences between the phenotypes were not statistically significant. Conclusions: The FIB-4 score was the highest in phenotype B patients and differed significantly from phenotypes A, C and D. In the elastography exam, the fibrosis index was statistically significantly higher in phenotype A compared to other phenotypes. No correlation was detected between the FIB-4 index and positive elastography. The findings suggest that the FIB-4 index may be used for MASLD screening, but its usefulness as a predictor of eligibility for elastography requires more research. Full article

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy. Full article

Dietary tannin supplementation represents a potential strategy to modulate rumen fermentation and enhance lactation performance in dairy cows, though responses remain inconsistent. A 21-day feeding trial was conducted to evaluate the effect of chestnut tannin (CNT) extract on the enteric methane emissions (EME), blood metabolites, and milk production traits in mid-lactation dairy cows. Thirty-six Holstein cows were allocated to three homogeneous treatment groups: control (CNT₀, 0 g/d CNT), CNT₄₀ (40 g/d CNT), and CNT₈₀ (80 g/d CNT). Measurements of EME, dry matter intake (DMI), milk yield (MY), and blood and milk parameters were carried out pre- and post-21-day supplementation period. Compared with the no-additive group, the CNT extract reduced methane production, methane yield, and methane intensity in CNT₄₀ and CNT₈₀ (p < 0.001). CNT₄₀ and CNT₈₀ cows exhibited lower blood urea nitrogen (p = 0.019 and p = 0.002) and elevated serum insulin (p = 0.003 and p < 0.001) and growth hormone concentrations (p = 0.046 and p = 0.034), coinciding with reduced aspartate aminotransferase (p = 0.016 and p = 0.045), and lactate dehydrogenase (p = 0.011 and p = 0.008) activities compared to control. However, CNT₈₀ had higher circulating NEFA and BHBA than CNT₀ (p = 0.003 and p = 0.004) and CNT₄₀ (p = 0.035 and p = 0.019). The blood glucose, albumin, and total bilirubin concentrations were not affected. MY and fat- and protein-corrected milk (FPCM), MY/DMI, and FPCM/DMI were higher in both CNT₄₀ (p = 0.004, p = 0.003, p = 0.014, p = 0.010) and CNT₈₀ (p = 0.002, p = 0.003, p = 0.008, p = 0.013) cows compared with controls. Feeding CNT₈₀ resulted in higher protein content (p = 0.015) but lower fat percentage in milk (p = 0.004) compared to CNT₀. Milk urea nitrogen and somatic cell counts were significantly lower in both CNT₄₀ (p < 0.001, p = 0.009) and CNT₈₀ (p < 0.001 for both) compared to CNT₀, while milk lactose did not differ between treatments. These findings demonstrate that chestnut tannin extract effectively mitigates EME while enhancing lactation performance in mid-lactation dairy cows. Full article

Nonspecific toxicity to normal and malignant cells restricts the clinical utility of many anticancer drugs. In particular, anemia in cancer patients develops due to drug-induced toxicity to red blood cells (RBCs). The anticancer alkaloid, cepharanthine (CEP), elicits distinct forms of cell death including apoptosis and autophagy, but its cytotoxicity to RBCs has not been investigated. Colorimetric and fluorometric techniques were used to assess eryptosis and hemolysis in control and CEP-treated RBCs. Cells were labeled with Fluo4/AM and annexin-V-FITC to measure Ca²⁺ and phosphatidylserine (PS) exposure, respectively. Forward scatter (FSC) was detected to estimate cell size, and extracellular hemoglobin along with lactate dehydrogenase and aspartate transaminase activities were assayed to quantify hemolysis. Physiological manipulation of the extracellular milieu and various signaling inhibitors were tested to dissect the underlying mechanisms of CEP-induced RBC death. CEP increased PS exposure and hemolysis indices and decreased FSC in a concentration-dependent manner with prominent membrane blebbing. Although no Ca²⁺ elevation was detected, chelation of intracellular Ca²⁺ by BAPTA-AM reduced hemolysis. Whereas SB203580, D4476, acetylsalicylic acid, necrosulfonamide, and melatonin inhibited both PS exposure and hemolysis, staurosporin, L-NAME, ascorbate, caffeine, adenine, and guanosine only prevented hemolysis. Interestingly, sucrose had a unique dual effect by exacerbating PS exposure and reversing hemolysis. Of note, blocking KCl efflux augmented PS exposure while aggravating hemolysis only under Ca²⁺-depleted conditions. CEP activates Ca²⁺-independent pathways to promote eryptosis and hemolysis. The complex cytotoxic profile of CEP can be mitigated by targeting the identified modulatory pathways to potentiate its anticancer efficacy. Full article

Experimental and theoretical studies were applied to investigate the adsorption properties of testagen (KEDG) peptide on copper surfaces in sodium chloride solution and, implicitly, its inhibition efficiency (IE) on metal corrosion. The tetrapeptide synthesized from the amino acids lysine (Lys), glutamic acid (Glu), aspartic acid (Asp), and glycine (Gly), named as H-Lys-Glu-Asp-Gly-OH, achieved an inhibition efficiency of around 86% calculated from electrochemical measurements, making KEDG a promising new copper corrosion inhibitor. The experimental data were best fitted to the Freundlich adsorption isotherm. The standard free energy of adsorption ($\mathsf{\Delta }{\mathrm{G}}_{\mathrm{a}\mathrm{d}\mathrm{s}}^{\mathrm{o}}$) reached the value of −30.86 kJ mol⁻¹, which revealed a mixed action mechanism of tetrapeptide, namely, chemical and physical spontaneous adsorption. The copper surface characterization was performed using optical microscopy and SEM/EDS analysis. In the KEDG presence, post-corrosion, SEM images showed a network surface morphology including microdeposits with an acicular appearance, and EDS analysis highlighted an upper surface layer consisting of KEDG, sodium chloride, and copper corrosion compounds. The computational study based on DFT and Monte Carlo simulation confirmed the experimental results and concluded that the spontaneous adsorption equilibrium establishment was the consequence of the contribution of noncovalent (electrostatic, van der Waals) interactions and covalent bonds. Full article

Objectives: (R)-ketamine hydrochloride injection is a novel, rapid-acting antidepressant for the treatment of treatment-resistant depression. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of (R)-ketamine hydrochloride injection in healthy Chinese subjects following ascending single intravenous doses ranging from 10.0 mg to 180 mg. Methods: This randomized, double-blind, placebo-controlled study was conducted in 50 healthy male and female Chinese subjects after single ascending doses of (R)-ketamine hydrochloride injection (10.0, 30.0, 60.0, 120, and 180 mg). Ten subjects (including two subjects treated with a placebo) were included in each dose cohort. Pharmacokinetic characteristics, safety, and tolerability profiles of the study drug were evaluated. Results: After the intravenous doses administered from 10.0 mg to 180 mg of (R)-ketamine hydrochloride injection to the subjects, the C_max and AUC values for both (R)-ketamine and its metabolite (R)-norketamine in the subjects increased approximately proportionally to the doses. The average peak plasma concentration levels at the five dose cohorts ranged from 56.0 to 1424 ng/mL and 27.7 to 491 ng/mL for (R)-ketamine and (R)-norketamine, respectively. The adverse events of (R)-ketamine hydrochloride injection were temporary and recovered spontaneously without treatment. Conclusions: In summary, (R)-ketamine hydrochloride injection was safe and well tolerated in healthy Chinese subjects. The clinical study results laid a foundation for the further clinical studies of (R)-ketamine hydrochloride injection in patients. Full article

Background: The amylin receptor is a receptor for the peptide hormone amylin, and its activation is known to reduce body weight. The amylin receptor functions as a heterodimer complex that consists of the calcitonin receptor for peptide hormone calcitonin and an accessary protein. Although the structural information of amylin receptors is currently available, receptor–ligand binding studies that support the peptide binding mode for amylin receptors remain incomplete. Methods: Here, we introduced mutagenesis to the amylin receptor 1 extracellular domain and examined mutational effects on peptide binding affinity. We focused on several residues mainly from the peptide-binding pocket (D97, D101, E123, N124, and N135 of the calcitonin receptor). Two well-known peptide ligands for amylin receptors were used for this study: a salmon calcitonin fragment and an antagonist amylin analog AC413 fragment with Y25P mutation. Results: Among the introduced mutations, D101A and N135A mutations abolished peptide ligand binding, suggesting that these residues are critical for peptide interaction. The N124A mutation also significantly decreased the peptide binding affinity by more than 8-fold. Intriguingly, the N124D mutation restored the decreased affinity of the salmon calcitonin fragment, while it failed to restore the decreased affinity of the AC413 fragment. Structural analyses suggested that there was a potential role of salmon calcitonin serine 29 in the interaction with aspartate of the N124D mutation. Conclusions: This study validates the critical residues of the amylin receptor 1 extracellular domain for the interaction with C-terminal fragments of peptide ligands. This study also suggests that modulating receptor–ligand interaction is feasible by the modification of receptor amino acids near an interacting peptide ligand. Full article

Optimizing the metabolizable protein level in ruminant diets represents a promising strategy to increase nitrogen use efficiency and mitigate environmental pollution. This study explored the impacts of varying metabolizable protein (MP) levels on amino acid (AA) balance, nitrogen (N) utilization, and the ruminal microbiota in Hu lambs. Fifty-four female Hu lambs of 60 d old, with an average body weight (BW) of 18.7 ± 2.37 kg, were randomly allocated to three dietary MP groups: (1) low MP (LMP, 7.38% of DM), (2) moderate MP (MMP, 8.66% of DM), and (3) high MP (HMP, 9.93% of DM). Three lambs with similar BW within each group were housed together in a single pen, serving as one experimental replicate (n = 6). The feeding trial lasted for 60 days with 10 days for adaptation. The final BW of lambs in the MMP and HMP groups increased (p < 0.05) by 5.64% and 5.26%, respectively, compared to the LMP group. Additionally, lambs fed the MMP diet exhibited an 11.6% higher (p < 0.05) average daily gain than those in the LMP group. Increasing dietary MP levels enhanced (p < 0.05) N intake, urinary N, retained N, and percent N retained, but decreased apparent N digestibility (p < 0.05). Urinary uric acid, total purine derivatives, intestinally absorbable dietary protein, microbial crude protein, intestinally absorbable microbial crude protein, and actual MP supply all increased (p < 0.05) with higher MP values in the diet. The plasma concentrations of arginine, lysine, methionine, phenylalanine, threonine, aspartic acid, proline, total essential AAs, and total nonessential AAs were the lowest (p < 0.05) in the LMP group. In the rumen, elevated MP levels led to a significant increase (p < 0.05) in the ammonia N content. The relative abundances of Candidatus_Saccharimonas, Ruminococcus, and Oscillospira were the lowest (p < 0.05), whereas the relative abundances of Terrisporobacter and the Christensenellaceae_R-7_group were the highest (p < 0.05) in the MMP group. In conclusion, the moderate dietary metabolizable protein level could enhance growth performance, balance the plasma amino acid profiles, and increase nitrogen utilization efficiency in Hu lambs, while also altering the rumen bacterial community by increasing beneficial probiotics like the Christensenellaceae_R-7_group. Full article

Aminopeptidase A (APA) cleaves a single aspartate residue from the amino terminus of peptides within the renin angiotensin system (RAS). Since several RAS peptides contain an N-terminal aspartate, we developed an assay to evaluate the effect of recombinant APA on the cleavage of Ang I, Ang II, Ang-(1-7), Ang-(1-9), and Ang-(1-12). The latter peptide has been proposed to be a functional Ang II-forming substrate with a hypertensive action attributable to the formed Ang II acting on AT1 receptors. Here we investigated the following: (a) the hydrolytic action of APA on Ang-(1-12), Ang I (1-10), Ang-(1-9), Ang II and Ang-(1-7) and (b) whether Ang-(1-12) pressor activity is altered by recombinant APA (r-APA) or genetic APA deficiency. We found that (a) r-APA cleaves the N-terminal aspartate of not only Ang II but also [Ang-(1-12), Ang I (1-10), Ang-(1-9)] and [Ang-(1-7)]; (b) the pressor activity of Ang-(1-12) was abolished in the presence of Lisinopril or Telmisartan; (c) r-APA significantly attenuated the pressor activities of infused Ang I and Ang II but not Ang-(1-12); and (d) r-ACE2 also did not attenuate the pressor effect of infused Ang-(1-12). Thus, in addition to increasing blood pressure indirectly via the formation of Ang II, Ang-(1-12) increases blood pressure by an Ang II-independent mechanism. We conclude that APA has an antihypertensive effect attributable to rapid degradation of Ang II, and this action may have a therapeutic potential in forms of hypertension that are Ang II-dependent. In addition, APA metabolizes Ang-(1-12), a peptide that has a prohypertensive action, in part, as a source of Ang II formation but also by a yet to be determined action independent of Ang II. Full article

Colorectal cancer is one of the most commonly diagnosed types of cancer and constitutes the second most frequent cancer in women (W) and the third most frequent cancer in men (M). The aim of the study was to determine if environmental exposure to zearalenone (ZEN) (a mycoestrogen) affects the metabolic profile of patients diagnosed with sigmoid colorectal cancer (SCC) and colorectal cancer (CRC) (division based on their location) at hospital admission. Male and female patients who were diagnosed with SCC or CRC and whose blood samples tested positive or negative for ZEN participated in a year-long study. Seventeen patients with symptoms of SCC and CRC, in whom ZEN and its metabolites were not detected in peripheral blood, constituted the patients without ZEN (PWZ) group. The experimental groups comprised a total of 16 patients who were diagnosed with SCC or CRC and tested positive for ZEN but negative for ZEN metabolites. Patients exposed to ZEN were characterized by increased levels of liver enzymes (alanine aminotransferase (ALT) from 5.8 to 18.1 IU/L; aspartate aminotransferase (AST) from 2.8 to 10.7 IU/L) and decrease in the value of the De Ritis ratio (below 1.0), different gamma glutamyl transpeptidase and AST activity, lower albumin (from 0.24 g/dL in M to 0.67 g/dL in W) and total protein levels (from 0.75 to 1.76 g/dL), a decrease in total cholesterol (from 21.6 to 40.3 mg/dL) and triglyceride levels (from 7.8 to 37.2 mg/dL), and lower activity of lipase C (from 28.72 to 64.75 IU/L). The metabolic profile of M and W patients diagnosed with SCC and CRC and exposed to ZEN revealed intensified biotransformation processes in the liver, liver damage, and a predominance of catabolic processes. Full article

Cordycepin, a bioactive adenosine analog, holds promise in pharmaceutical and health product development. However, large-scale production remains constrained by the limitations of natural producers, Cordyceps spp. Herein, we report the reconstruction of the first genome-scale metabolic model (GSMM) for a cordycepin-producing strain of recombinant Aspergillus oryzae. The model, iNR1684, incorporated 1684 genes and 1947 reactions with 93% gene-protein-reaction coverage, which was validated by the experimental biomass composition and growth rate. In silico analyses identified key gene amplification targets in the pentose phosphate and one-carbon metabolism pathways, indicating that folate metabolism is crucial for enhancing cordycepin production. Nutrient optimization simulations revealed that chitosan, D-glucosamine, and L-aspartate preferentially supported cordycepin biosynthesis. Additionally, a carbon-to-nitrogen ratio of 11.6:1 was identified and experimentally validated to maximize production, higher than that reported for Cordyceps militaris. These findings correspond to a faster growth rate, enhanced carbon assimilation, and broader substrate utilization by A. oryzae. This study demonstrates the significant role of GSMM in uncovering rational engineering strategies and provides a quantitative framework for precision fermentation, offering scalable and sustainable solutions for industrial cordycepin production. Full article

In this study, we identify cortical molecular biomarkers potentially associated with learning in mice using artificial intelligence (AI), inclusive of established and novel feature selection combined with supervised learning technologies. We applied multiple machine learning (ML) algorithms, using public domain ML software, to a public domain dataset, in order to support reproducible findings. We developed technologies tasked with predicting whether a given mouse was shocked to learn, based on protein expression levels extracted from their cortices. Results indicate that it is possible to predict whether a mouse has been shocked to learn or not based only on the following cortical molecular biomarkers: brain-derived neurotrophic factor (BDNF), NR2A subunit of N-methyl-D-aspartate receptor, B-cell lymphoma 2 (BCL2), histone H3 acetylation at lysine 18 (H3AcK18), protein kinase R-like endoplasmic reticulum kinase (pERK), and superoxide dismutase 1 (SOD1). These results were obtained with a novel redundancy-aware feature selection method. Five out of six protein expression biomarkers (BDNF, NR2A, H3AcK18, pERK, SOD1) identified have previously been associated with aspects of learning in the literature. Three of the proteins (BDNF, NR2A, and BCL2) have previously been associated with pruning, and one has previously been associated with apoptosis (BCL2), implying a potential connection between learning and both cortical pruning and apoptosis. The results imply that these six protein expression profiles (BDNF, NR2A, BCL2, H3AcK18, pERK, SOD1) are highly predictive of whether or not a mouse has been shocked to learn. Full article

To date, serum biochemical analytes reference intervals (RIs) in Lusitano horses have not been studied. This study aimed to establish the RIs for biochemical analytes following the American Society of Veterinary Clinical Pathology guidelines and to compare them with the general equine population’s RIs. Blood samples were collected from 76 clinically healthy adult Lusitano horses, and RIs of 22 biochemical variables were determined using Reference Value Advisor software. Lusitano horse-specific RIs are proposed for the following variables: total protein (3.9–7.0 g/dL), albumin (2.5–3.8 g/dL), globulin (1.1–3.7 g/dL), total bilirubin (1.0–5.6 mg/dL), direct bilirubin (0.09–0.68 mg/dL), indirect bilirubin (0.7–5.2 mg/dL), urea (21.0–38.9 mg/dL), creatinine (0.9–2.0 mg/dL), aspartate aminotransferase (150.7–345.1 IU/L), alkaline phosphatase (60.7–227.4 IU/L), lactate dehydrogenase (247.6–959.0 IU/L), glucose (75.5–131.5 mg/dL), cholesterol (58.6–125.2 mg/dL), sodium (129.0–154.9 mmol/L), phosphorus (1.8–4.5 mmol/L), chloride (90.3–107.0 mmol/L), and calcium (8.9–12.6 mg/dL). Different RIs were identified for healthy adult Lusitano horses for 17/22 serum biochemical analytes tested, emphasizing the need for breed-specific RIs to prevent misinterpretation of laboratory results. Full article

Ketamine infusion therapy has gained recognition as an innovative treatment for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects. Its therapeutic promise is increasingly understood to involve molecular and neurobiological processes that promote neural plasticity and cognitive flexibility. These changes may create a unique window for psychotherapeutic interventions to take deeper effect. This retrospective chart review examined the clinical outcomes of individuals with TRD who received either single or repeated ketamine infusion(s), with or without weekly psychotherapy. Depression severity, measured by Beck Depression Inventory scores, was assessed pre-treatment and 30 days post-infusion(s). The results showed significant symptom reduction across all groups, with the most pronounced effects observed in those who received concurrent psychotherapy. While infusion number did not significantly alter outcomes, the integration of ketamine with psychotherapy appeared to enhance treatment response. Full article