Toxicity, defined as the potential harm a substance can cause to living organisms, requires the implementation of stringent regulatory standards to ensure public safety. These standards involve comprehensive testing frameworks, including hazard identification, dose-response evaluation, exposure assessment, and risk characterization. In drug discovery and development, these processes are often complex, time-consuming, and also resource-intensive. Toxicity-related failures in the later stages of drug development can lead to substantial financial losses, underscoring the need for reliable toxicity prediction during the early discovery phases. The advent of computational approaches has accelerated a shift toward in silico modeling, virtual screening, and, notably, artificial intelligence (AI) to identify potential toxicities earlier in the pipeline. Ongoing advances in databases, algorithms, and computational power have further expanded AI’s role in pharmaceutical research. Today, AI models are capable of predicting wide range of toxicity endpoints, such as hepatotoxicity, cardiotoxicity, nephrotoxicity, neurotoxicity, and genotoxicity, based on diverse molecular representations ranging from traditional descriptors to graph-based methods. This review provides an in-depth examination of AI-driven toxicity prediction, emphasizing its transformative impact on drug discovery and its growing importance in improving safety assessments.

Repeated ketamine treatment to maintain a rapid antidepressant effect can lead to side effects over time, highlighting an unmet clinical need for sustaining this drug’s antidepressant action from a single administration. Ketamine-induced synaptic potentiation at CA3-CA1 synapses has been proposed to be a key synaptic substrate for antidepressant action. Here, we found that ketamine-induced CA3-CA1 synaptic potentiation could be augmented by transiently increasing extracellular signal–regulated kinase (ERK) activity through pharmacological inhibition of dual-specificity phosphatases 6 (DUSP6). The antidepressant-like behavioral effects of acute ketamine treatment were extended by DUSP6 inhibition for up to 2 months. The selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons abolished these DUSP6 inhibition–mediated synaptic and behavioral effects. These data suggest that ketamine’s rapid antidepressant effects can be sustained by selectively targeting downstream intracellular signaling.

Social support can relieve stress-induced behavioural outcomes, although its underlying molecular mechanisms are not fully understood. Here, we evaluated whether social interactions can prevent the restraint stress (RS)-induced cognitive impairments in male adolescent mice by utilizing molecular, cellular, and behavioural approaches. Acute RS in adolescent ICR mice impaired the working memory in the Y-maze test and memory consolidation and retrieval in the novel-object-recognition test (NORT). In addition, RS increased the extracellular signal-regulated kinases 1/2 phosphorylation (p-ERK1/2) in the prefrontal cortex (PFC) and corticosterone levels in the plasma. Interestingly, these outcomes were normalized by the presence of a conspecific animal (social support) during RS. RS also significantly upregulated the expression levels of known stress-relevant genes such as Egr1, Crh, and Crhr1, which were normalized by social support. Systemic injection of SL327 (an inhibitor of MEK1/2 that also blocks its downstream signal ERK1/2) prior to RS rescued the working memory impairments and the increased p-ERK1/2 while normalizing the expression of Egr1. Our results suggest that social support can alleviate the RS-induced cognitive impairments partly by modulating ERK1/2 phosphorylation and gene transcription in the PFC, and provide novel insights into the molecular mechanisms of the stress-buffering effects of social support.

Background: Autism spectrum disorder (ASD) is heterogeneous neurodevelopmental disorders that primarily display social and communication impairments and restricted/repetitive behaviors. ASD prevalence has increased in recent years, yet very limited therapeutic targets and treatments are available to counteract the incapacitating disorder. Korean Red Ginseng (KRG) is a popular herbal plant in South Korea known for its wide range of therapeutic effects and nutritional benefits and has recently been gaining great scientific attention, particularly for its positive effects in the central nervous system.Objectives: Thus, in this study, we investigated the therapeutic potential of KRG in alleviating the neurobehavioral deficits found in the valproic acid (VPA)-exposed mice models of ASD.Design: Starting at 21 days old (P21), VPA-exposed mice were given daily oral administrations of KRG solution (100 or 200 mg/kg) until the termination of all experiments. From P28, mice behaviors were assessed in terms of social interaction capacity (P28–29), locomotor activity (P30), repetitive behaviors (P32), short-term spatial working memory (P34), motor coordination (P36), and seizure susceptibility (P38).Results: VPA-exposed mice showed sociability and social novelty preference deficits, hyperactivity, increased repetitive behavior, impaired spatial working memory, slightly affected motor coordination, and high seizure susceptibility. Remarkably, long-term KRG treatment in both dosages normalized all the ASD-related behaviors in VPA-exposed mice, except motor coordination ability.Conclusion: As a food and herbal supplement with various known benefits, KRG demonstrated its therapeutic potential in rescuing abnormal behaviors related to autism caused by prenatal environmental exposure to VPA.Keywords: Panax ginseng; nutraceutical; autistic behaviors; Korean Red Ginseng; prenatal VPA exposure(Published: 1 February 2016)Citation: Food & Nutrition Research 2016, 60: 29245 - http://dx.doi.org/10.3402/fnr.v60.29245

Kim KS, et al. Korean Diabetes J. 2010 Apr;34(2):119-125. https://doi.org/10.4093/kdj.2010.34.2.119