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Introduction: The online misinformation might undermine the vaccination efforts. Therefore, given the fact that no study specifically analyzed online vaccine related content written in Romanian, the main objective of the study was to detect and evaluate tweets related to vaccines and written in Romanian language., Methods: 1,400 Romanian vaccine related tweets were manually classified in true, neutral and fake information and analyzed based on wordcloud representations, a correlation analysis between the three classes and specific tweet characteristics and the validation of several predictive machine learning algorithms., Results and Discussion: The tweets annotated as misinformation showed specific word patterns and were liked and reshared more often as compared to the true and neutral ones. The validation of the machine learning algorithms yielded enhanced results in terms of Area Under the Receiver Operating Characteristic Curve Score (0.744-0.843) when evaluating the Support Vector Classifier. The predictive model estimates in a well calibrated manner the probability that a specific Twitter post is true, neutral or fake. The current study offers important insights regarding vaccine related online content written in an Eastern European language. Future studies must aim at building an online platform for rapid identification of vaccine misinformation and raising awareness for the general population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Valeanu, Mihai, Andrei, Puscasu, Ionica, Hinoveanu, Predoi, Bulancea, Chirita, Negres and Marineci.)

Resident macrophages from dorsal root ganglia are important for the development of traumatic-induced neuropathic pain. In the first 5-7 days after a traumatic sciatic nerve injury (i.e., spinal nerve ligation (SNL), spared nerve injury (SNI), sciatic nerve transection or sciatic nerve ligation and transection), Ionized binding adapter protein 1 (Iba1) (+) resident macrophages cluster around dorsal root ganglia neurons, possibly contributing to nerve injury-induced hypersensitivity. Since infiltrating macrophages gradually recruited to the lesion site peak at about 7 days, the first few days post-lesion offer a window of opportunity when the contribution of Iba1 (+) resident macrophages to neuropathic pain pathogenesis could be investigated. Iba1 is an actin cross-linking cytoskeleton protein, specifically located only in macrophages and microglia. In this study, we explored the contribution of rat Iba1 (+) macrophages in SNL-induced neuropathic pain by using intra-ganglionic injections of naked Iba1-siRNA, delivered at the time the lesion occurred. The results show that 5 days after Iba1 silencing, Iba1 (+) resident macrophages are switched from an M1 (pro-inflammatory) phenotype to an M2 (anti-inflammatory) phenotype, which was confirmed by a significant decrease of M1 markers (CD32 and CD86), a significant increase of M2 markers (CD163 and Arginase-1), a reduced secretion of pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) and an increased release of pro-regenerative factors (BDNF, NGF and NT-3) which initiated the regrowth of adult DRG neurites and reduced SNL-induced neuropathic pain. Our data show for the first time, that it is possible to induce macrophages towards an anti-inflammatory phenotype by interacting with their cytoskeleton.

Pain is one of the most common symptoms experienced by patients. The use of current analgesics is limited by low efficacy and important side effects. Transient receptor potential vanilloid-1 (TRPV1) is a non-selective cation channel, activated by capsaicin, heat, low pH or pro-inflammatory agents. Since TRPV1 is a potential target for the development of novel analgesics due to its distribution and function, we aimed to develop an in silico drug repositioning framework to predict potential TRPV1 ligands among approved drugs as candidates for treating various types of pain. Structures of known TRPV1 agonists and antagonists were retrieved from ChEMBL databases and three datasets were established: agonists, antagonists and inactive molecules (pIC50 or pEC50 < 5 M). Structures of candidates for repurposing were retrieved from the DrugBank database. The curated active/inactive datasets were used to build and validate ligand-based predictive models using Bemis−Murcko structural scaffolds, plain ring systems, flexophore similarities and molecular descriptors. Further, molecular docking studies were performed on both active and inactive conformations of the TRPV1 channel to predict the binding affinities of repurposing candidates. Variables obtained from calculated scaffold-based activity scores, molecular descriptors criteria and molecular docking were used to build a multi-class neural network as an integrated machine learning algorithm to predict TRPV1 antagonists and agonists. The proposed predictive model had a higher accuracy for classifying TRPV1 agonists than antagonists, the ROC AUC values being 0.980 for predicting agonists, 0.972 for antagonists and 0.952 for inactive molecules. After screening the approved drugs with the validated algorithm, repaglinide (antidiabetic) and agomelatine (antidepressant) emerged as potential TRPV1 antagonists, and protokylol (bronchodilator) as an agonist. Further studies are required to confirm the predicted activity on TRPV1 and to assess the candidates’ efficacy in alleviating pain.

Since the prevalence of heart failure (HF) increases with age, HF is now one of the most common reasons for the hospitalization of elderly people. Although the treatment strategies and overall outcomes of HF patients have improved over time, hospitalization and mortality rates remain elevated, especially in developed countries where populations are aging. Therefore, this paper is intended to be a valuable multidisciplinary source of information for both doctors (cardiologists and general physicians) and pharmacists in order to decrease the morbidity and mortality of heart failure patients. We address several aspects regarding pharmacological treatment (including new approaches in HF treatment strategies [sacubitril/valsartan combination and sodium glucose co-transporter-2 inhibitors]), as well as the particularities of patients (age-induced changes and sex differences) and treatment (pharmacokinetic and pharmacodynamic changes in drugs; cardiorenal syndrome). The article also highlights several drugs and food supplements that may worsen the prognosis of HF patients and discusses some potential drug-drug interactions, their consequences and recommendations for health care providers, as well as the risks of adverse drug reactions and treatment discontinuation, as an interdisciplinary approach to treatment is essential for HF patients.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

Only few applications are currently dealing with personalized adverse drug reactions (ADRs) prediction in case of polypharmacy. The study aimed to develop a patient-tailored ADR web application, considering characteristics from 734 drugs and relevant patient related factors. The application was designed in Python using a scoring and ranking system based on frequency and severity, computed for each ADR and expressed through an online platform. A neural networks algorithm was used for predicting the severity of ADRs. The application inputs are: age, gender, drugs, relevant pathologies. The outputs are: an overall severity profile (hospitalization and mortality risk), a stratified risk on specific ADR groups and a sorted list of the most important ADRs depending on frequency and severity. The Severity prediction model validation resulted in 79.7-85.1% Area Under the Receiver Operating Characteristic Curve Score, which lies in the good cut-off of 75-90%. The program offers a complex view regarding the ADR profile of a given patient and could be used by the physician and clinical pharmacist during patient safety monitoring, for a coherent therapy choice or medication adjustment, due to the good therapy coverage and the inclusion of relevant patient comorbidities.

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS) through neurodegeneration and demyelination, leading to physical/cognitive disability and neurological defects. A viable target for treating MS appears to be the Transient Receptor Potential Ankyrin 1 (TRPA1) calcium channel, whose inhibition has been shown to have beneficial effects on neuroglial cells and protect against demyelination. Using computational drug discovery and data mining methods, we performed an in silico screening study combining chemical graph mining, quantitative structure-activity relationship (QSAR) modeling, and molecular docking techniques in a global prediction model in order to identify repurposable drugs as potent TRPA1 antagonists that may serve as potential treatments for MS patients. After screening the DrugBank database with the combined generated algorithm, 903 repurposable structures were selected, with 97 displaying satisfactory inhibition probabilities and pharmacokinetics. Among the top 10 most probable inhibitors of TRPA1 with good blood brain barrier (BBB) permeability, desvenlafaxine, paliperidone, and febuxostat emerged as the most promising repurposable agents for treating MS. Molecular docking studies indicated that desvenlafaxine, paliperidone, and febuxostat are likely to induce allosteric TRPA1 channel inhibition. Future in vitro and in vivo studies are needed to confirm the biological activity of the selected hit molecules.

Background: High numbers of infection with resistant forms of Micobacterium tuberculosis (Mtb) contribute to a constant growing demand in new highly active and effective therapeutics. Current drug discovery efforts directed towards new antituberculosis agents include the development of new inhibitors of enoyl-acyl carrier protein reductase (InhA) that do not require activation by the specific enzymes. Tryptanthrin is a known inhibitor of Mtb InhA and its analogues are investigated as potential agents with antimycobacterial efficiency., Objective: The main objective of the presented research was to develop a new group of tryptanthrin analogues with good inhibition properties against Mtb., Methods: Synthesis of new derivatives of 5H-[1,3,4]thiadiazolo[2,3- b]quinazolin-5-one and evaluation of their activity against Mtb, as well as acute and chronic toxicity studies were carried out. Molecular modeling studies were performed to investigate the binding mechanisms of the synthesized ligands with InhA. Binding energies and non-covalent interactions stabilizing the ligand-receptor complexes were obtained from the results of molecular docking., Results: The most active compound in the obtained series, 2-(propylthio)-5H-[1,3,4]thiadiazolo[2,3- b]quinazolin-5-one, exhibited the superior inhibition activity (up to 100%) against mycobacterial growth at MIC 6.5 µg/mL, showed good affinity to the InhA enzyme in docking studies and demonstrated a very low per oral toxicity in animals falling under the category 5 according to GHS classification., Conclusion: 2-(propylthio)-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one can be further explored for the development of a new series of compounds active against Mtb., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pyrrolizidine alkaloids (PAs) are a widespread class of hepatotoxic heterocyclic organic compounds found in approximately 3% of world flora. Some PAs have been shown to have genotoxic and carcinogenic effects. The present study focuses on the toxicity effects of four dry extracts obtained from medicinal plants (Senecio vernalis, Symphytum officinale, Petasites hybridus and Tussilago farfara), on two aquatic organisms, Artemia salina and Daphnia magna, and the correlation with their PAs content. A new GC‑MS method, using a retention time (TR)‑5MS type capillary column was developed. PAs Kovats retention indices, for this type of column were computed for the first time. The lethal dose 50% (LC50) values for the two invertebrate models were correlated (Pearson 's coefficient, >0.9) and the toxicity was PA concentration-dependent, for three of the four extracts. All tested extracts were found to be toxic in both aquatic organism models. The results can be used to develop a GC‑MS validated method for the assay of PAs in medicinal plants with a further potential application in the risk assessment study of PAs toxicity in humans.

We have emitted the hypothesis that the double-way effect is possible not only due to the wide range of receptor substrates and receptor subtypes but it can manifest at the heterosynaptic and synaptic cotransmission level as a consequence of the informational unbalance which very low or very high doses of biological signals (in pathological disorders) or of drug signal (agonist or antagonist) can do on physiological balance between both two coupled synaptic systems. To verify this hypothesis we choosed as place of manifesting and observing of the phenomen the informational gearing between the endogenous opioid system as "modulator" and the catecholaminergic systems as "alarm". As drug signals we used naloxone (NALX) and clonidine (CLON). The function studied to reveal the double-way effect was stress analgesia monitored in the classical test of te "hot plate". The experimental stress was induced to the mouse by submitting to forced swimming using the "despair test". In the work are presented the dose-effect curves and inflexion points which mark the changing of the sense of the effect.