Beyond being an excellent protective material for bioentities, zeolitic imidazolate frameworks (ZIF-8) have advanced several applications, including biomedical applications. The straightforward synthesis of ZIF-8 at mild conditions improved the biomineralization of several biomolecules, e.g., protein, peptides, carbohydrate, and biological cells, such as viruses and bacterial cells. Bioinspiration of ZIF-8 enhanced and improved the material's applications for biomedicine. This review article summarized the recent achievements of ZIF-8 for biomedical applications such as cancer therapy, antimicrobial, biosensing, and biocatalysis. ZIF8-based materials advanced cancer therapy via drug delivery of chemotherapeutic drugs, photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), gene therapy, and starvation therapy. Antibacterial agent encapsulated ZIF-8 exhibited superior biological activity compared to the free antibacterial agents. ZIF-8 based materials enhanced the selectivity and sensitivity for analytes' biosensing, ensuring their potential for electronic devices. Biocatalysis of enzyme encapsulated ZIF-8 offered high catalytic performance with robust properties for recycling. ZIF-8 acts as a protective host for enzymes, proteins, and drugs from degradation induced due to temperature, solvents, and proteolytic agents. The first part of the review discussed the structure, chemistry, and bioinspiration of ZIF-8. The second part reviewed the biomedical applications of ZIF-8. The potential risks and current challenges of using ZIF-8 for biomedical applications were also reviewed.

As a new type of nanomaterials, the gold nanoclusters (AuNCs) perform many special physical and chemical properties, such as large Stokes shift, relatively simple preparation, good water solubility, low toxicity, and good biocompatibility, which make them show infinite potential in various fields, especially in cancer treatment. In recent years, great progress has been made in the preparation, functionalization, and biomedical applications of the AuNCs. In this article, the latest research progress and synthesis methods of the AuNCs have been summarized, emphasizing the preparation using the "bottom- up" synthesis strategy. Furthermore, we introduced the in vivo pharmacokinetic performance of the AuNCs. In the last part, we exemplified the applications of the AuNCs in biomedicine, including photothermal therapy (PTT), bioimaging, drug delivery, and radiotherapy sensitization, which further confirmed the great potential of the AuNCs in tumor treatment.

Focal Adhesion Kinase (FAK) is a non-receptor tyrosine kinase involved in the process of cell proliferation, survival, migration, and invasion. It has become a promising therapeutic target for the treatment of human metastatic cancers due to its overexpression and/or activation in multiple cancer types. Since FAK is emerging as a potential cancer target because of its overexpression at both the transcriptional and translational level in cancer, different types of FAK inhibitors with diversified scaffolds have been discovered in the past few years. In this review, the progress of recently discovered small molecule FAK inhibitors was summarized. Major efforts have been focused on the rational design and synthesis of small molecule FAK inhibitors, and their structure-activity relationship (SAR) analysis wasalso discussed. Among them, while type I inhibitors remain as the major focuses, type II inhibitors and novel allosteric FAK inhibitors (type III inhibitors) have been developed to improve both potency and selectivity. Meanwhile, novel strategies, such as targeting FAK using inhibitors of protein-protein interactions, were also discovered. Lastly, some insights and perspectives on the future development of FAK inhibitors as anticancer therapeutics have been provided.

BACKGROUND: One of the main challenges in the early stages of drug discovery is the computational assessment of protein-ligand binding affinity. Machine learning techniques can contribute to predicting this type of interaction. We may apply these techniques following two approaches. Firstly, using the experimental structures for which affinity data is available. Secondly, using protein-ligand docking simulations. OBJECTIVE: In this review, we describe recently published machine learning models based on crystal structures, for which binding affinity and thermodynamic data are available. METHOD: We used experimental structures available at the protein data bank and binding affinity and thermodynamic data was accessed through BindingDB, Binding MOAD, and PDBbind databases. We reviewed machine learning models to predict binding created using open source programs, such as SAnDReS and Taba. RESULTS: Analysis of machine learning models trained against datasets, composed of crystal structure complexes indicated the high predictive performance of these models when compared with classical scoring functions. CONCLUSION: The rapid increase in the number of crystal structures of protein-ligand complexes created a favorable scenario for developing machine learning models to predict binding affinity. These models rely on experimental data from two sources, the structural and the affinity data. The combination of experimental data generates computational models that outperform the classical scoring functions.

Autism Spectrum Disorder (ASD) is a disorder with different etiologies and poor elucidation, characterized by changes in social and cognitive skills. ASD impacts a large number of people in the world. Surprisingly, in spite of its great importance, just modest progress has been achieved towards comprehending this pathology and designing new therapies. The molecular dysfunctions observed in people with autism are evidenced by the interference in the synthesis of synaptic proteins, which impairs their development and plasticity, leading to characteristics of individuals with ASD. The present work investigates the mTOR pathway and the proteins related to its regulation and neurological functioning. The path of protein synthesis and translation is promising to treat various disorders and its elucidation may, for example, result in drugs that facilitate the diagnosis and broaden the range of treatments, improving the quality of life of ASD patients.

OBJECTIVE: This review aims to study the receptor's family and functions most related to COVID-19 infection and also suggest the tissue and cell location on which the majority of COVID-19 receptors are mainly expressed. METHODS: This systematic review is according to PRISMA guidelines. PubMed, Cochrane, SciELO, Lilacs, Web of Science, and DOAJ databases were used. Clinical trials and research articles studying receptors related to COVID-19 were included in this review. R programming language was used to elaborate charts and receptors network, and SPSS(26v) software was used to perform statistical analysis (PROSPERO: CRD42020210643). RESULTS: The majority of studies on the involvement of receptors in COVID-19 included plasma receptors and G protein-coupled receptor families (p<0.05). These receptors are highly expressed in the brain (24%) and 80% of them can interact with each other in a protein network, exerting some regulatory effects on various tissues. The main influential receptor in the network of receptors involved in the COVID-19 was the EGFR and the majority of receptors were associated with pathological processes of the disease (p<0.05), including the amplification of inflammatory responses in COVID-19, which may be related to neurological disorders in some cases. Studies on receptors involved in the COVID-19 included mainly patients from the United States, Spain, and Brazil (p<0.05). CONCLUSION: Plasma receptors and G protein-coupled receptors, especially the EGFR, involved in pathological effects of the COVID-19 inflammatory process in the brain have shown significant importance in this review.

Enveloped viruses belong to a large class of pathogens responsible for multiple serious diseases. Their spread into new territories has been the cause of major epidemics throughout human history, including the Spanish flu in 1918 and the latest COVID-19 pandemic. Thanks to their outer membrane, consisting essentially of host lipids, enveloped viruses are more resistant to enzymes and are also less susceptible to host immune defenses than their naked counterparts. Therefore, the development of effective approaches to combat enveloped virus infections represents a major challenge for antiviral therapy in the current century. This review focuses on the characteristics of enveloped viruses, their importance in the entry phase, drugs targeting envelope membrane- mediated entry, and those specifically designed to target the envelope. The broad- -spectrum antiviral activity of these compounds can be attributed to their ability to affect the envelope, an essential structural feature common to several viruses. This makes this class of compounds agents of great interest when no specific drugs or vaccines are available to block viral infections.

Nucleobases represent key structural motifs in biologically active molecules, including synthetic and natural products. Molecular modifications made on nucleobases or their isolation from natural sources are being widely investigated for the development of drugs with improved potency for the treatment of different diseases, such as cancer, as well as viral and bacterial infections. This review article focuses on the nucleobase analogue drug developments of the past 20 years (2000-2020). Various pharmacological and medicinal aspects of nucleobases and their analogues are discussed. The current state and limitations are also highlighted.

Curcumin, a yellow pigment in Asian spice, is a natural polyphenol component of Curcuma longa rhizome. Curcuminoid components include curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Previous studies established curcumin as a safe agent based on preclinical and clinical evaluations and curcuminoids have been approved by the US Food and Drug Administration (FDA) as "Generally Recognized as Safe" (GRAS). The present review collects and summarizes clinical and preclinical studies of curcumin interactions, with an emphasis on the effect of curcumin and curcumin analogs on the mRNA and protein levels of microsomal CYP450 enzymes (phase I metabolism) and their interactions with toxicants, drugs and drug probes. The literature search was conducted using keywords in various scientific databases, including Web of Science, Scopus, PubMed, and Google Scholar. Studies concerning the impact of curcumin and curcumin analogs on microsomal enzyme activity are reviewed and include oral, topical, and systemic treatment in humans and experimental animals, as well as studies from in vitro research. When taken together, the data identified some inconsistent results between various studies. The findings showed significant inhibition of CYP450 enzymes by curcumin and its analogs. However, such effects are often differed when curcumin and curcumin analogs were coadministered with toxicant and other drugs and drug probes. We conclude from this review that herb-drug interactions should be considered when curcumin and curcumin analogs are consumed.

Multiple myeloma (MM) is a common malignant hematological malignancy. Recently, interest has grown in the role of non-coding regions in disease pathogenesis. MicroRNAs (miRNAs) are small non-coding RNAs containing 19-25 bases that play a crucial role in messenger RNA silencing and post-transcriptional regulation of gene expression. Several miRNAs demonstrate markedly dysregulated expression in MM, suggesting that they may act as both tumor suppressors and oncogenes. microRNAs are also reportedly involved in the regulation of other epigenetic mechanisms of gene expression. Additionally, some miRNAs have been associated with drug resistance, and therefore a further exploration of their activity may lead to its reversal. Moreover, miRNA expression patterns in either MM cells or serum exosomes have been shown to be good prognostic markers. This review describes the roles of miRNAs in MM and examines their potential to predict MM prognosis and play a role in novel therapeutic strategies.

Several clinical studies have shown that exposure of skin to solar ultraviolet (UV) radiation causes adverse effects, such as inflammation, oxidative stress and DNA damage. As a result, different skin disorders can arise, among which are skin cancer, including non-melanoma skin cancer (NMSC) and melanoma (MM). Phenolic compounds are plant-derived secondary metabolites with a well-known antioxidant activity, able to counteract the negative effects of UV radiation. In this review, we discuss the effects of some selected phenols on NMSC and MM, demonstrating that they can be useful in the prevention and in the treatment of these types of tumors. Moreover, we report the mechanisms by which these phenols carry out their antitumor action. In vitro and in vivo studies have highlighted that many phenols are capable of inducing photoprotection, apoptosis and autophagy. They can also reduce DNA methylation, tumorigenesis, tumor incidence and proliferation. Moreover, we describe some examples of plant extracts, whose anticancer activity appears to be better than that of single phenols. A great concordance of results emerged, despite the differences in experimental methods. Therefore, the knowledge compiled here could provide the basis for conducting some well-organized clinical trials to validate the chemopreventive and the therapeutic potential of some phenolic compounds in patients with NMSC and MM.

End-stage liver diseases have long been a threat to human health, and so far, the treatment of these diseases lacks effective means. Allogenic organ transplantation has become the last straw for most of the patients with end-stage liver diseases. However, this technique has been greatly limited by the serious shortage of donors and other factors, such as immune rejection, drug syndrome, and high cost. Recently, the emergence of three-dimensional (3D) bioprinting technologies, together with the magnetic resonance imaging (MRI) and computed tomography (CT) techniques, has driven the rapid growth of this field toward liver therapies. There are several basic requirements for liver 3D bioprinting. From information collection of diseased livers, to 3D printing of liver substitutes (containing the major structural, material and functional characters), and to clinical applications, suitable 'bioinks' and 'bioprinters' have played essential roles. In this review, we highlight the advanced 'bioinks' and 'bioprinters' that have been used for vascularized and innervated liver tissue 3D bioprinting. Further studies for the incorporation of biliary networks in the bioartificial livers have been emphasized. It is expected that when all the bottle-neck problems for liver 3D bioprinting are solved, batch (i.e. mass) and personalized production of bioartificial livers will make it very easy to treat end-stage liver diseases.

BACKGROUND: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. OBJECTIVE: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. RESULTS: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure- activity relationships. CONCLUSION: Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

BACKGROUND: Lipopolysaccharide (LPS), a Gram-negative bacterial cell wall component, evokes intensive inflammatory responses in the human body. Naturally, inflammation is a part of the host immune response to an infection; nonetheless, an exaggerated response can lead to a series of pathophysiological consequences, collectively known as LPS toxicity or septic shock. OBJECTIVE: This review will explore the cellular and experimental investigations that mainly focus on Curcumin's therapeutic effects on the LPS-mediated inflammatory responses. METHOD: A literature review of all relevant studies was performed. CONCLUSION: Curcumin has been reported to exert anti-inflammatory properties by interfering with LPS-induced inflammatory pathways, including binding to cell surface receptors of LPS, NF-kB activation pathway, and inflammasome activation. Further clinical studies on the effect of Curcumin in reducing the pathophysiological consequences of LPS toxicity would substantiate the use of this molecule for future therapeutic approaches.

BACKGROUND: During the past decades, an important number of anticonvulsant drugs have been incorporated into the collection of drugs to treat epilepsy. However, two main difficulties remain unsolved in therapy: the development of drug-resistant epilepsy and the occurrence of severe toxic effects caused by the medication in responsive patients. The retrospective analysis of the strategies for discovering known anticonvulsant drugs showed that screening campaigns on animal models of epilepsy have been almost the exclusive strategy for identifying the marketed compounds. However, the actual structural and functional information about the molecular targets of the anticonvulsant drugs and the increasing knowledge of the molecular alterations that generate epileptic seizures allow a more rational identification of active compounds. OBJECTIVE: This review compiles target-based strategies used for the discovery of new anticonvulsant candidates and is divided in two main topics. The first one provides an overview of the computational approaches (docking-based virtual screening and molecular dynamics) to find anticonvulsant structures that interact with the voltage-gated ion channels and the enzyme carbonic anhydrase. The second one includes the analysis of active compounds synthesized to act simultaneously on different molecular targets by the combination of pharmacophores of anticonvulsant drugs. CONCLUSION: Current knowledge of the architectures of anticonvulsant targets makes computational simulations attractive methods for the discovery and optimization of active compounds. Combining the results achieved by virtual screening of different targets could lead to multitarget compounds, as an alternative to the design of structures that merge scaffolds of known drugs.

Ferroptosis plays a critical regulatory role as a new kind of cell death, initiating and developing an array of disorders like neurological diseases, acute injury of kidney, tumors, and ischemia, etc. Although selective deposition of iron is one of the pathogenic reasons for PD, it's underlying mechanism is still unknown. In this review, the role of neuroinflammation in Parkinson's disease (PD) leading to neurodegeneration has been discussed in detail. The accumulation of brain iron has been found in many chronic neurological disorders, including PD. We have also discussed the unique features of ferroptosis , and it links in aggravating the pathology of PD. Further, the concept of targeting ferroptosis for PD pathology and inducers and inhibitors, pharmacological drugs and clinical trials for PD candidates in phase IV stage in completed status are detailed in the respective sections.

Cyclin-dependent kinases (CDKs) comprise a family of about 20 serine/threonine kinases whose catalytic activity requires a regulatory subunit known as cyclin; these enzymes play several roles in the cell cycle and transcription. PCTAIRE kinases (PCTKs) are a CDK subfamily, characterized by serine to cysteine mutation in the consensus PSTAIRE motif, involved in binding to the cyclin. One member of this class is PCTK3, which has two isoforms (a and b) and is also known as CDK18. After being activated by cyclin A2 or phosphorylation at Ser12 by PKA, PCTK3 can perform several functions. Among these functions, we may highlight the following: modulation of cargo transport in membrane traffic, p53-responsive gene, regulation of genome integrity. According to different studies, PCTK3 dysfunction is related to a wide range of diseases, such as metabolic diseases, cerebral ischemia, depression, cancer, neurological disorders, and Alzheimer's disease. Although this protein participates in different biological events, we may say that PCTK3 has received far less attention than other CDKs. There are thousands of published articles about other CDKs and less than two hundred articles related to PCTK3. The main objective of this review is to present the selected published studies about this protein. Our focus is on PCTK3 particularities compared to other CDKs. Here we give an overview of the biological functions of PCTK3 and explore its potential as a target for drug design.

Chalcones are an interesting class of compounds endowed with a plethora of biological activities beneficial to human health. These chemotypes have continued to attract increased research attention over the years; hence, numerous natural and synthetic chalcones have found with interesting anticancer activities through the inhibition of various molecular targets including ABCG2, BCRP, P-glycoprotein, 5α-reductase, Androgen Receptor (AR), Histone Deacetylases (HDAC), Sirtuin 1, proteasome, Vascular Endothelial Growth Factor (VEGF), Cathepsin-K, tubulin, CDC25B phosphatase, Topoisomerase, EBV, NF-κB, mTOR, BRAF, and Wnt/β-catenin. Moreover, the study of intrinsic mechanisms of action, particularly relating to specific cellular pathways and modes of engagement with molecular targets, may help medicinal chemists to develop more effective, selective, and cost-effective chalcone-based anticancer drugs. This review, therefore, sheds light on the effect of structural variations on the anticancer potency of chalcone hybrids reported in 2018-2019 alongside their mechanism of action, molecular targets, and potential impacts on effective cancer chemotherapy.