A prominent research topic in contemporary advanced functional materials science is the production of smart materials based on polymers that may independently adjust their physical and/or chemical characteristics when subjected to external stimuli. Smart hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) demonstrate distinct thermoresponsive features close to a lower critical solution temperature (LCST) that enhance their capability in various biomedical applications such as drug delivery, tissue engineering, and wound dressings. Nevertheless, they have intrinsic shortcomings such as poor mechanical properties, limited loading capacity of actives, and poor biodegradability. Formulation of PNIPAM with diverse functional constituents to develop hydrogel composites is an efficient scheme to overcome these defects, which can significantly help for practicable application. This review reports on the latest developments in functional PNIPAM-based smart hydrogels for various biomedical applications. The first section describes the properties of PNIPAM-based hydrogels, followed by potential applications in diverse fields. Ultimately, this review summarizes the challenges and opportunities in this emerging area of research and development concerning this fascinating polymer-based system deep-rooted in chemistry and material science.

MicroRNAs are a class of small, single-stranded, noncoding RNAs that regulate gene expression. They can be significantly dysregulated upon exposure to any infection, serving as important biomarkers and therapeutic targets. Numerous human DNA viruses, along with several herpesviruses, have been found to encode and express functional viral microRNAs known as vmiRNAs, which can play a vital role in host–pathogen interactions by controlling the viral life cycle and altering host biological pathways. Viruses have also adopted a variety of strategies to prevent being targeted by cellular miRNAs. Cellular miRNAs can act as anti- or proviral components, and their dysregulation occurs during a wide range of infections, including herpesvirus infection. This demonstrates the significance of miRNAs in host herpesvirus infection. The current state of knowledge regarding microRNAs and their role in the different stages of herpes virus infection are discussed in this review. It also delineates the therapeutic and biomarker potential of these microRNAs in future research directions.

Herpesviral protein kinases, such as the therapy-relevant pUL97 of human cytomegalovirus (HCMV), are important for viral replication efficiency as well as pathogenesis, and represent key antiviral drug targets. HCMV pUL97 is a viral cyclin-dependent kinase (CDK) ortholog, as it shares functional and structural properties with human CDKs. Recently, the formation of vCDK/pUL97–cyclin complexes and the phosphorylation of a variety of viral and cellular substrate proteins has been demonstrated. Genetic mapping and structural modeling approaches helped to define two pUL97 interfaces, IF1 and IF2, responsible for cyclin binding. In particular, the regulatory importance of interactions between vCDK/pUL97 and host cyclins as well as CDKs has been highlighted, both as determinants of virus replication and as a novel drug-targeting option. This aspect was substantiated by the finding that virus replication was impaired upon cyclin type H knock-down, and that such host-directed interference also affected viruses resistant to existing therapies. Beyond the formation of binary interactive complexes, a ternary pUL97–cyclin H–CDK7 complex has also been described, and in light of this, an experimental trans-stimulation of CDK7 activity by pUL97 appeared crucial for virus–host coregulation. In accordance with this understanding, several novel antiviral targeting options have emerged. These include kinase inhibitors directed to pUL97, to host CDKs, and to the pUL97–cyclin H interactive complexes. Importantly, a statistically significant drug synergy has recently been reported for antiviral treatment schemes using combinations of pharmacologically relevant CDK7 and vCDK/pUL97 inhibitors, including maribavir. Combined, such findings provide increased options for anti-HCMV control. This review focuses on regulatory interactions of vCDK/pUL97 with the host cyclin–CDK apparatus, and it addresses the functional relevance of these key effector complexes for viral replication and pathogenesis. On this basis, novel strategies of antiviral drug targeting are defined.

Background. Cyclin-dependent kinase 8 (CDK8) is a multifaceted regulator and represents a catalytic component of the transcriptional Mediator complex. CDK8 activity, on the one hand, increases transcriptional elongation by the recruitment of Mediator/super elongation complexes, but, on the other hand, negatively regulates CDK7-controlled transcriptional initiation through inactivating cyclin H phosphorylation. Recently, these combined properties of CDK8 have also suggested its rate-limiting importance for herpesviral replication. Objectives. In this paper, we focused on human cytomegalovirus (HCMV) and addressed the question of whether the pharmacological inhibition or knock-down of CDK8 may affect viral replication efficiency in cell culture models. Methods. A number of human and animal herpesviruses, as well as non-herpesviruses, were used to analyze the importance of CDK8 for viral replication in cell culture models, and to assess the antiviral efficacy of CDK8 inhibitors. Results. Using clinically relevant CDK8 inhibitors (CCT-251921, MSC-2530818, and BI-1347), HCMV replication was found strongly reduced even at nanomolar drug concentrations. The EC₅₀ values were consistent for three different HCMV strains (i.e., AD169, TB40, and Merlin) analyzed in two human cell types (i.e., primary fibroblasts and astrocytoma cells), and the drugs comprised a low level of cytotoxicity. The findings highlighted the following: (i) the pronounced in vitro SI values of anti-HCMV activity obtained with CDK8 inhibitors; (ii) a confirmation of the anti-HCMV efficacy by CDK8–siRNA knock-down; (iii) a CDK8-dependent reduction in viral immediate early, early, and late protein levels; (iv) a main importance of CDK8 for viral late-stage replication; (v) several mechanistic aspects, which point to a strong impact on viral progeny production and release, but a lack of CDK8 relevance for viral entry or nuclear egress; (vi) a significant anti-HCMV drug synergy for combinations of inhibitors against host CDK8 and the viral kinase vCDK/pUL97 (maribavir); (vii) finally, a broad-spectrum antiviral activity, as seen for the comparison of selected α-, β-, γ-, and non-herpesviruses. Conclusions. In summary, these novel data provide evidence for the importance of CDK8 as a positive regulator of herpesviral replication efficiency, and moreover, suggest its exploitability as an antiviral target for novel strategies of host-directed drug development.

The rising issues of herpes simplex virus (HSV)-2 drug ramifications have encouraged the researchers to look for new and alternative approaches that pose minimum adversities in the host while efficiently reducing the HSV-2 infection. Although microRNAs (miRNAs), as unorthodox approaches, are gaining popularity due to eliciting highly reduced immunogenic reactions, their implications in HSV-2 research have been rarely explored. In this study, a pool of cellular miRNAs with significance in HSV-2-induced inflammatory and immune responses have been identified. Computationally recognizing the host targets of these miRNAs through network biology and machine learning, in vitro validation has been addressed along with the identification of their regulation in the HSV-2 infection. To signify the role of these identified miRNAs, they have been individually ectopically expressed in macrophages. The ectopic expression of the individual miRNAs was able to suppress HSV-2 viral gene expression. Taking a step forward, this study also highlights the Box–Behnken design-based combinatorial effect of ectopically expressed miRNAs on maximum suppression of HSV-2 infectivity. Therefore, the concentrations of each of the miRNAs optimized in a combination, predicted through expert systems biology tools were validated in vitro to not only recover the target expressions but also inhibit the HSV-2 infection in the macrophages. Overall, the study offers miRNAs as intriguing alternatives to commercially available medications against HSV-2. Moreover, the study illuminates the prophylactic potentiality of the miRNAs, which is significant since there are currently no vaccines available for HSV-2. Moving forward, the miRNAs are employed in an innovative strategy that incorporates intricate biological system models and in vitro confirmation methods to deliver a prospective combinatorial miRNA therapeutic against HSV-2 infection.

Autophagy, an evolutionarily conserved cellular process, influences the regulation of viral infections. While the existing understanding indicates that Herpes Simplex Virus type 2 (HSV-2) maintains a basal level of autophagy to support its viral yield, the precise pathways governing the induction of autophagy during HSV-2 infection remain unknown. Therefore, this study aims to explore the role of type I interferons (IFN-I) in modulating autophagy during HSV-2 infection and to decode the associated signaling pathways. Our findings revealed an interplay wherein IFN-I regulates the autophagic response during HSV-2 infection. Additionally, we investigated the cellular pathways modulated during this complex process. Exploring the intricate network of signaling events involved in autophagy induction during HSV-2 infection holds promising therapeutic implications. Identifying these pathways advances our understanding of host–virus interactions and holds the foundation for developing targeted therapeutic strategies against HSV-2. The insight gained from this study provides a platform for exploring potential therapeutic targets to restrict HSV-2 infections, addressing a crucial need in antiviral research.