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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. By cross-linking TRAIL-Receptor (TRAIL-R) 1 or TRAIL-R2, also known as death receptors 4 and 5 (DR4 and DR5), TRAIL has the capability to induce apoptosis in a wide variety of tumor cells while sparing vital normal cells. The discovery of this unique property among TNF superfamily members laid the foundation for testing the clinical potential of TRAIL-R-targeting therapies in the cancer clinic. To date, two of these therapeutic strategies have been tested clinically: (i) recombinant human TRAIL and (ii) antibodies directed against TRAIL-R1 or TRAIL-R2. Unfortunately, however, these TRAIL-R agonists have basically failed as most human tumors are resistant to apoptosis induction by them. It recently emerged that this is largely due to the poor agonistic activity of these agents. Consequently, novel TRAIL-R-targeting agents with increased bioactivity are currently being developed with the aim of rendering TRAIL-based therapies more active. This review summarizes these second-generation novel formulations of TRAIL and other TRAIL-R agonists, which exhibit enhanced cytotoxic capacity toward cancer cells, thereby providing the potential of being more effective when applied clinically than first-generation TRAIL-R agonists.

The neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) plays a pivotal role in regulating stress, fear, and anxiety responses. Genetic and molecular studies investigating PACAP demonstrate sex-dimorphic characteristics, with females exhibiting increased reactivity of PACAP signaling in neuropsychiatric disorders. Studies expand the role of PACAP to substance use disorders (SUD) by demonstrating modulation of PACAP can lead to neurobiological changes induced by nicotine, ethanol, stimulants and opioids. Given that females with SUD exhibit distinct drug use, relapse, and withdrawal sensitivity relative to males, we hypothesize that the PACAP system contributes to these sex-specific differences. Therefore, we review the role of PACAP in SUD by characterizing the role of PACAP at the molecular, brain regional, and behavioral levels relevant to the addiction cycle. We present literature linking PACAP to neuropsychiatric disorders, which demonstrate the intricate role of PACAP within neuronal signaling and pathways modulating addiction. We hypothesize that females are more particularly susceptible to PACAP-related changes during the intoxication and withdrawal phases of the addiction cycle. Altogether understanding the sex-specific differences in the PACAP system offers a foundation for future studies aimed at developing tailored interventions for addressing SUD.

Central Asia, including its freshwater basins, belongs to the Palearctic realm but exhibits significant faunal heterogeneity with localised hotspots of endemism. While several Central Asian countries have been the subject of malacological reviews, Kazakhstan, the largest country of the region, lacks a comprehensive and taxonomically updated species list. The aim of this study is to consolidate all available data on Kazakhstan’s freshwater molluscs, critically analyse their species composition, and assess the level of endemism in this group across the country. Based on the analysis of museum collections and literature sources, we estimate the species richness of freshwater molluscs in Kazakhstan at 87 species (55 Gastropoda and 32 Bivalvia), with an expected total of 93 species. Overall, species richness declines from the forest-steppe zone in the north and northeast toward the arid and mountainous regions in the south and southwest. Six potentially endemic species were identified; however, the taxonomic status of some requires further verification. The freshwater malacofauna of Kazakhstan has been affected by recent invasions, with at least seven species classified as neo-biotic, and for some, we hypothesise a recolonisation of habitats lost during the Pleistocene.

PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

Summary Apoptosis modulation is a procedure amply utilized by intracellular pathogens to favour the outcome of the infection. Nevertheless, the role of apoptosis during infection with Mycobacterium tuberculosis, the causative agent of human tuberculosis, is subject of an intense debate and still remains unclear. In this work, we describe that apoptosis induction in host cells is clearly restricted to virulent M. tuberculosis strains, and is associated with the capacity of the mycobacteria to secrete the 6 kDa early secreted antigenic target ESAT‐6 bothunder in vitro and in vivo conditions. Remarkably, only apoptosis‐inducing strains are able to propagate infection into new cells, suggesting that apoptosis is used by M. tuberculosis as a colonization mechanism. Finally, we demonstrate that in vitro modulation of apoptosis affects mycobacterial cell‐to‐cell spread capacity, establishing an unambiguous relationship between apoptosis and propagation of M. tuberculosis. Our data further indicate that BCG and MTBVAC vaccines are inefficient in inducing apoptosis and colonizing new cells, correlating with the strong attenuation profile of these strains previously observed in vitro and in vivo.

Rationale Varenicline, a smoking-cessation agent, may be useful in treating alcohol use disorders. An important consideration when studying factors that influence drinking/relapse is influence of the pharmacological effects of alcohol on these behaviors. Pre-exposure to alcohol (priming) can increase craving, drinking, and seeking behaviors. Objectives The primary goal of this work was to determine the effects of varenicline on alcohol-primed self-administration and seeking behavior in male Long-Evans rats. Methods First, we assessed whether varenicline (0, 0.3, 1, 3 mg/kg, IP) has alcohol-like discriminative stimulus effects and whether varenicline alters sensitivity to alcohol in rats trained to discriminate a moderate alcohol dose (1 g/kg, IG) vs. water. Second, animals trained to self-administer alcohol underwent assessments to test the effects of: (i) varenicline (0, 0.3, 1, 3 mg/kg, IP) on self-administration, (ii) alcohol priming (0, 0.3, 1 g/kg, IG) on self-administration and seeking behavior, and (iii) varenicline (1 mg/kg) in combination with alcohol priming (1 g/kg) on these behaviors. Results Varenicline did not substitute for alcohol but disrupted the expression of sensitivity to alcohol. Varenicline decreased self-administration but only at a motor-impairing dose (3 mg/kg). Alcohol priming decreased self-administration and seeking behavior. Varenicline (1 mg/kg) blocked this effect under self-administration conditions, but not seeking conditions, which effectively resulted in increased alcohol intake. Conclusions These findings suggest the importance of further behavioral and mechanistic studies to evaluate the use of varenicline in treating alcohol use disorders and its potential impact on drinking patterns in smokers using varenicline as a smoking-cessation aid.

Microbial engineering has made a significant breakthrough in pharmaceutical biotechnology, greatly expanding the production of biologically active compounds, therapeutic proteins, and novel drug candidates. Recent advancements in genetic engineering, synthetic biology, and adaptive evolution have contributed to the optimization of microbial strains for pharmaceutical applications, playing a crucial role in enhancing their productivity and stability. The CRISPR-Cas system is widely utilized as a precise genome modification tool, enabling the enhancement of metabolite biosynthesis and the activation of synthetic biological pathways. Additionally, synthetic biology approaches allow for the targeted design of microorganisms with improved metabolic efficiency and therapeutic potential, thereby accelerating the development of new pharmaceutical products. The integration of artificial intelligence (AI) and machine learning (ML) plays a vital role in further advancing microbial engineering by predicting metabolic network interactions, optimizing bioprocesses, and accelerating the drug discovery process. However, challenges such as the efficient optimization of metabolic pathways, ensuring sustainable industrial-scale production, and meeting international regulatory requirements remain critical barriers in the field. Furthermore, to mitigate potential risks, it is essential to develop stringent biocontainment strategies and implement appropriate regulatory oversight. This review comprehensively examines recent innovations in microbial engineering, analyzing key technological advancements, regulatory challenges, and future development perspectives.

The dwarf pond snail Galba truncatula (O.F. Müller, 1774) is a widespread freshwater species and a key intermediate host of Fasciola spp. Despite its ecological and medical significance, the evolutionary structure of its populations remains incompletely resolved. Using 78 mitochondrial COI sequences, including newly obtained material from Eastern Europe, Central Asia, and Caucasus, we reconstructed the phylogeographic pattern of Galba truncatula across Western Palearctic. Our analyses reveal the presence of three distinct phylogenetic lineages. A deeply divergent group, represented by a small number of sequences, occurs sympatrically with the main clade in Western Europe. The main clade, comprising the majority of sequences, is split into two geographically structured subclades: a western lineage (Western Europe and North Africa) and an eastern lineage (Eastern Europe, Caucasus, and Central Asia). Both major lineages are represented in South America, suggesting at least two independent colonization events. We propose that the initial divergence between the eastern and western lineages likely began in the early Pleistocene, whereas their present-day distribution may have been shaped by isolation during the Last Glacial Maximum. We reconstructed the phylogeographic structure of Galba truncatula using COI sequences from Eurasia and South America. Three distinct lineages were identified, including a deeply divergent group occurring sympatrically in Western Europe. The main lineage is split into eastern and western clades, likely diverging in the early Pleistocene. Both clades are represented in South America, indicating at least two independent colonization events. Our findings challenge the hypothesis of a South American origin and highlight the role of glacial history in shaping current diversity.

This study aims to investigate womenʼs participation in offline and online marketplaces and identify related factors, particularly the digital divide, access to the internet, and the level of information and communications technology (ICT) proficiency. It discusses the empirical methodology of its two approaches: a descriptive analysis of statistical data and a sociological survey. This study employs quantitative analyses. The respondents to this study were women who used marketplaces in Kazakhstan. The model was tested using the data for 295 respondents. The results reveal the COVID-19 pandemic affected both the number of online purchases and the structure of those purchases: women began ordering more medicines and food, and less equipment and clothing online. The main factors affecting participation in online marketplaces are income level, access to the internet, and the use of ICT. This study tries to reduce the gap in the literature on the benefits and barriers for women by providing empirical evidence about the influence of COVID-19 on online marketplaces.

Escalations in alcohol drinking associated with experiencing stressful life events and chronic life stressors may be related to altered sensitivity to the interoceptive/subjective effects of alcohol. Indeed, through the use of drug discrimination methods, rats show decreased sensitivity to the discriminative stimulus (interoceptive) effects of alcohol following exposure to the stress hormone corticosterone (CORT). This exposure produces heightened elevations in plasma CORT levels (eg, as may be experienced by an individual during stressful episodes). We hypothesized that decreased sensitivity to alcohol may be related, in part, to changes in metabotropic glutamate receptors-subtype 5 (mGluR5) in the nucleus accumbens, as these receptors in this brain region are known to regulate the discriminative stimulus effects of alcohol. In the accumbens, we found reduced mGluR5 expression (immunohistochemistry and Western blot) and decreased neural activation (as measured by c-Fos immunohistochemistry) in response to a moderate alcohol dose (1 g/kg) following CORT exposure (7 days). The functional role of these CORT-induced adaptations in relation to the discriminative stimulus effects of alcohol was confirmed, as both the systemic administration of 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) an mGluR5 positive allosteric modulator and the intra-accumbens administration of (R,S)-2-Amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt (CHPG) an mGluR5 agonist restored sensitivity to alcohol in discrimination-trained rats. These results suggest that activation of mGluR5 may alleviate the functional impact of the CORT-induced downregulation of mGluR5 in relation to sensitivity to alcohol. Understanding the contribution of such neuroadaptations to the interoceptive effects of alcohol may enrich our understanding of potential changes in subjective sensitivity to alcohol during stressful episodes.